Oncology Intelligence

Liver Cancer
Thursday, September 22, 2016 6:00 PM|Frank Dombrowski|International Journal of Molecular Sciences|Labels: EGFR, liver cancer
Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions to HCC. In short- and long-term experiments, administration of N-Nitrosomorpholine (NNM) or intrahepatic transplantation of pancreatic islets in diabetic (PTx), thyroid follicles in thyroidectomized (TTx) and ovarian fragments in ovariectomized (OTx) rats was conducted for the induction of foci of altered hepatocytes (FAH). Gefitinib was administered for two weeks (20 mg/kg) or three and nine months (10 mg/kg). In NNM-treated rats, Gefitinib administration decreased the amount of FAH when compared to controls. The amount of HCA and HCC was decreased, but development was not prevented. Upon all transplantation models, proliferative activity of FAH was lower after administration of Gefitinib in short-term experiments. Nevertheless, the burden of HCA and HCC was not changed in later stages. Thus, EGFR inhibition by Gefitinib diminishes chemical and hormonal also induced hepatocarcinogenesis in the initiation stage in the non-cirrhotic liver. However, progression to malignant hepatocellular tumors was not prevented, indicating only a limited relevance of the EGFR signaling cascade in later stages of hepatocarcinogenesis.
Thursday, September 22, 2016 6:00 PM|Ling Qi|International Journal of Molecular Sciences|Labels: liver cancer
Hepatocellular carcinoma (HCC) is the most common subtype of liver malignancy, and it is characterized by poor prognosis because of cancer stem cell (CSC)-mediated high postsurgical recurrence rates. Thus, targeting CSCs, or HCC cells with CSC-like properties, is an effective strategy for HCC therapy. Here, using long noncoding RNA (lncRNA) microarray analysis, we identified a novel lncRNA termed lncCAMTA1 that is increased in both liver CSCs and HCC. High lncCAMTA1 expression in HCC indicates poor clinical outcome. In vitro and in vivo functional experiments showed that overexpression of lncCAMTA1 promotes HCC cell proliferation, CSC-like properties, and tumorigenesis. Conversely, depletion of lncCAMTA1 inhibits HCC cell proliferation, CSC-like properties, and tumorigenesis. Mechanistically, we demonstrated that lncCAMTA1 physically associates with the calmodulin binding transcription activator 1 (CAMTA1) promoter, induces a repressive chromatin structure, and inhibits CAMTA1 transcription. Furthermore, CAMTA1 is required for the effects of lncCAMTA1 on HCC cell proliferation and CSC-like properties, and the expression of lncCAMTA1 and CAMTA1 is significantly negatively correlated in HCC tissues. Collectively, our study revealed the important roles and underlying molecular mechanisms of lncCAMTA1 on HCC, and suggested that lncCAMTA1 could be an effective prognostic factor and a potential therapeutic target for HCC.
Wednesday, September 21, 2016 8:09 AM|Elsevier|JournalTOCs API - Biochemical and Biophysical Research Communications (50 articles)|Labels: P53, liver cancer

Rapamycin regulates the proliferation of Huh7, a hepatocellular carcinoma cell line, by up-regulating p53 expression

Biochemical and Biophysical Research Communications, Vol. , No. (2016) pp. -
Publication date: 7 October 2016 Source:Biochemical and Biophysical Research Communications, Volume 479, Issue 1 Author(s): Sora Kwon, Ji-Sook Jeon, Curie Ahn, Jung-Suk Sung, Inho Choi Rapamycin, a specific inhibitor of mTOR used extensively as an immunosuppressant, has been expanded recently to cancer therapy, because the mTOR signal is known to be up-regulated in various cancer cells including hepatocellular carcinoma (HCC) cells. In spite of extensive efforts to employ mTOR inhibitors as anti-HCC therapy, they have not yet been approved by the FDA. Because of the heterogeneity and complexity of molecular signaling in HCC, suitable biomarkers should be identified or discovered to improve clinical efficacy of mTOR-specific inhibitors to HCC cells. In this study, the effect of rapamycin was investigated on two different HCC cell lines, Huh7 cells and HepG2 cells. Rapamycin was found to inhibit the proliferation of Huh7 cells but not of HepG2 cells. Moreover, it was found that rapamycin can up-regulate p53 at the protein level, but not affect its transcript. To understand the critical role of p53 in the rapamycin effect, knock-down experiments were performed using small-interfering RNAs (siRNAs). The anti-proliferative effect of rapamycin on Huh7 cells clearly disappeared after blocking p53 production with siRNA, which indicates that p53 is a critical factor in the anti-proliferative effect of rapamycin in HCC cells. The over-expression system of p53 was also employed to mimic the effect of rapamycin and found that cell proliferation was clearly down-regulated by p53 over-expression. Finally, we found that the extracellular signal-regulated kinase 1/2 (ERK1/2) signal was regulated by p53 whose expression was induced by rapamycin. Overall, this study demonstrates that rapamycin inhibited the proliferation of Huh7 cells by up-regulating the expression of p53 and down-regulating the ERK1/2 signal, indicating that p53 is a useful biomarker for anti-cancer therapy using the specific inhibitor of mTOR signal, rapamycin, against hepatocellular carcinoma cells.

Monday, September 19, 2016 10:00 PM|New GEO Series|Labels: liver cancer
Contributors : Edoardo Abeni ; Alessandro Salvi ; Michele Traversa ; Bruna Arici ; Giuseppina D Petro
Series Type : Methylation profiling by genome tiling array
Organism : Homo sapiens

Sorafenib is currently the standard treatment for advanced hepatocellular carcinoma (HCC). Epigenetic alterations such as DNA methylation, play a decisive role in the development and progression of HCC. To our knowledge, there are no studies that have analyzed the global DNA methylation changes in HCC cells treated with sorafenib. Using MeDip-chip technologies we analyzed sorafenib effects on the methylome of human HCC cells. We found 1230 differentially methylated genes in HA22T/VGH cells treated with sorafenib compared to untreated cells. Gene ontology and pathway analysis found enriched several GO terms related to transcription factors and different pathways involved in tumorigenesis and cancer progression. Among the genes differentially methylated we found genes related to apoptosis (FOXO3, SMAD2, p21), angiogenesis (EPAS1) and invasion (MMP3, MMP7, RAC1, RHOC), genes belonged to pathways deregulated in HCC such as RAF/MEK/ERK (MAPK3, MAP2K2), JNK (MAPK8, MAP2K7), JAK-STAT (JAK1, STAT3, STAT5, CCND3), PI3K/AKT/mTOR (TSC2, PRKCZ) and NF-κB (IKBKG, MALT1, MAP3K14) and cancer-associated non-coding genes such as MALAT1, miR-149 and miR-675. We found a general trend where oncogenes were hypermethylated and tumor suppressor genes were hypomethylated after sorafenib treatment. Finally, we validated MeDip-chip results on several differentially methylated genes using COBRA and direct bisulfite sequencing and for these genes we evaluated the relationship between methylation level and mRNA expression.Our results suggest that in HCC cells sorafenib could affect the methylation level of genes associated to cancer-related processes and pathways related to sorafenib mechanism of action. These results identified novel sorafenib targets genes which could be targets in a new design of multi-target and combined therapies, and to better understand the emergence of resistance in HCC.

Friday, September 16, 2016 10:23 AM|Valerie Fako, Zhipeng Yu, Curtis J. Henrich, Tanya Ransom, Anuradha S. Budhu, Xin W. Wang|International Journal of Biological Sciences|Labels: WNT, liver cancer

Hepatocellular carcinoma (HCC) is one of the most common forms of malignant cancers in the world, yet very few effective systemic treatments for HCC patients exist. Thus, the development of new treatment modalities presents a great need. The wnt/β-catenin signaling pathway is highly activated in stem cell-like aggressive HCC, which is associated with chemoresistance and poor survival in HCC patients. In a previous study, we found that an FDA-approved psychiatric drug, pimozide (PMZ), has anti-cancer properties in HCC cell lines that express epithelial cell adhesion molecule (EpCAM), a hepatic stem cell marker that is a functional down-stream target of the wnt/β-catenin pathway. In this study, we demonstrate that PMZ effectively inhibits cell growth of HCC cells by disrupting the wnt/β-catenin signaling pathway and reducing EpCAM expression. Thus, PMZ may be a useful molecular entity that could be repurposed as an anti-cancer therapy for treatment of HCC.

Friday, September 16, 2016 10:23 AM|Alip Ghosh, Suchandrima Ghosh, Debanjali Dasgupta, Amit Ghosh, Somenath Datta, Nilabja Sikdar, Simanti Datta, Abhijit Chowdhury, Soma Banerjee|International Journal of Biological Sciences|Labels: liver cancer

The precise mechanism by which HBx protein of hepatitis B virus (HBV) impacts on hepato-carcinogenesis remain largely elusive despite strong evidences for its' involvement in the process. Here, we have investigated the role of HBx on expression of a novel gene hELG1/ATAD5, which is required for genome maintenance and its' importance in hepatocarcinogenesis. This study has for the first time showed that the expression of this gene was significantly higher in human cancer such as HBV-associated hepatocellular carcinoma (HCC) and in different HCC cell lines compared to normal liver. In addition, a significant elevation in ATAD5 expression was also found in HBx transfected HCC cell lines implicating HBx mediated transcriptional regulation on ATAD5. Using different deletion mutant constructs of putative promoter, the active promoter region was first identified here and subsequently the regulatory region of HBx was mapped by promoter-luciferase assay. But ChIP assay with anti-HBx antibody revealed that HBx was not physically present in ATAD5 transcription machinery whereas anti-E2F1 antibody showed the presence of E2F1 in the complex. Luciferase assay with E2F1 binding site mutant had further confirmed it. Moreover, both loss-and gain-of-function studies of ATAD5 showed that ATAD5 could enhance HBV production in transfected cells whereas knock down of ATAD5 increased the sensitivity of HCC cell line to chemotherapeutics 5-fluorouracil. Overall, this data suggests that a positive feedback loop regulation between ATAD5 and HBV contributed to both viral replication and chemo-resistance of HCC cells.

Thursday, September 15, 2016 7:51 PM|Ze-Wei Lin, Li-Xuan Wu, Yong Xie, Xi Ou, Pei-Kai Tian, Xiao-Ping Liu, Jun Min, Jie Wang, Ru-Fu Chen, Ya-Jing Chen, Chao Liu, Hua Ye, Qing-Jia Ou|International Journal of Medical Sciences|Labels: liver cancer

Objectives: To investigate the expression of transcriptional factors (TFs) T-bet, GATA-3, RORγt and FOXP in peripheral blood mononuclear cells (PBMC) of patients with hepatocellular carcinoma (HCC) and to evaluate the correlation between the imbalances of Th1/Th2, Th17/Treg at the expression levels and liver cancer

Methods: The peripheral venous blood was drawn from 20 HCC-patients (HCC-group) and 20 health participants (C-group). The expression levels of Th1, Th2 and Th17 and the major Treg-specific TFs T-bet, GATA-3, RORγt and FOXP3 in the PBMC were measured with quantitative real-time PCR(RT-qPCR).

Results: The mRNA level of Th1-specific TF T-bet in HCC-group was significantly lower than that of C-group (52.34±34.07 VS 104.01±56.00, P<0.01); the mRNA level of Th2-specifc TF, GATA-3, in HCC group was significantly higher than that in C-group (1.38±1.15 VS 0.58±0.65, P<0.05) and T-bet mRNA/GATA-3 mRNA ratio was significantly lower in HCC-group than in C-group (86.01±116.71 VS 461.88±708.81, P<0.05). The mRNA level of Th17-specific TF RORγt in HCC-group was significantly higher than that of C-group (72.32±32.82 VS 33.07±22.86, P<0.01). Treg-specific TF FOXP3 mRNA level was significant higher in HCC-group than in C-group (3.17±1.59 VS 1.39±1.13, P<0.01)

Conclusion: T-bet mRNA level was reduced whereas GATA-3 mRNA level was increased and T-bet/GATA-3 ratio was significantly reduced in PBMC, indicating that Th1/Th2 ratio was of imbalance at TF levels in PBMC of HCC, displaying Th2 thrift phenomena. The mRNA levels of RORγt and FOXP3 in PBMC of HCC were significantly increased, indicating the existence of a predominant phenomenon of Th17- and Treg-expressing PBMC in HCC.

Thursday, September 15, 2016 6:45 AM|Wolf, B., Krieg, K., Falk, C., Breuhahn, K., Keppeler, H., Biedermann, T., Schmid, E., Warmann, S., Fuchs, J., Vetter, S., Thiele, D., Nieser, M., Avci–Adali, M., Skokowa, Y., Schols, L., Hauser, S., Ringelhan, M., Yevsa, T., Heikenwalder, M., Kossatz–Boehlert, U.|Cancer Research recent issues|Labels: liver cancer
Hepatocellular carcinoma (HCC) represents the second leading cause of cancer-related deaths and is reported to be resistant to chemotherapy caused by tumor-initiating cells. These tumor-initiating cells express stem cell markers. An accumulation of tumor-initiating cells can be found in 2% to 50% of all HCC and is correlated with a poor prognosis. Mechanisms that mediate chemoresistance include drug export, increased metabolism, and quiescence. Importantly, the mechanisms that regulate quiescence in tumor-initiating cells have not been analyzed in detail so far. In this research we have developed a single cell tracking method to follow up the fate of tumor-initiating cells during chemotherapy. Thereby, we were able to demonstrate that mCXCL1 exerts cellular state-specific effects regulating the resistance to chemotherapeutics. mCXCL1 is the mouse homolog of the human IL8, a chemokine that correlates with poor prognosis in HCC patients. We found that mCXCL1 blocks differentiation of premalignant cells and activates quiescence in tumor-initiating cells. This process depends on the activation of the mTORC1 kinase. Blocking of the mTORC1 kinase induces differentiation of tumor-initiating cells and allows their subsequent depletion using the chemotherapeutic drug doxorubicin. Our work deciphers the mCXCL1–mTORC1 pathway as crucial in liver cancer stem cell maintenance and highlights it as a novel target in combination with conventional chemotherapy. Cancer Res; 76(18); 5550–61. ©2016 AACR.
Wednesday, September 14, 2016 10:47 PM|Bin Wang, Chao-Bin Yeh, Ming-Yu Lein, Chen-Ming Su, Shun-Fa Yang, Yu-Fan Liu, Chih-Hsin Tang|International Journal of Medical Sciences|Labels: liver cancer

Hepatocellular carcinoma (HCC) is a malignancy of liver and a leading cause of cancer mortality worldwide. Its management is compounded by biological and clinical heterogeneity. These interindividual genetic variations can modulate the effects of HCC treatment. High-mobility group box protein 1 (HMGB1) is a well investigated, ubiquitous nuclear protein found in eukaryotic cells that plays a multiple biological roles such as DNA stability, program cell death, immune response, and furthermore in cancer progression. In this report, we examined HMGB1 single nucleotide polymorphisms (SNPs) with multiple risk factors related to HCC susceptibility and clinicopathological characteristics. Four HMGB1 SNPs (rs1412125, rs2249825, rs1045411, and rs1360485) were assessed by using a TaqMan SNPs Genotyping in 324 patients with HCC and in 695 cancer-free controls. The results showed that HMGB1 SNP rs1045411 with CT or at least one T alleles has lower risk of HCC than wild-type (CC) carriers. Moreover, HMGB1 SNP rs1412125 with TT allele has a higher risk of distant metastasis compared with patients carrying at least one C allele. The present study is the first report to discuss the risk factors associated with HMGB1 SNPs in HCC progression in Taiwan.

Wednesday, September 14, 2016 5:53 PM|Changsong Zhang, Yang Ling, Chenghui Zhang, Yun Xu, Lu Gao, Rong Li, Jing Zhu, Lieying Fan, Lixin Wei|International Journal of Biological Sciences|Labels: liver cancer

Background: To evaluate the promoter methylation status of RECK gene and mRNA expression in patients with hepatocellular carcinoma (HCC).

Methods: We analyzed RECK methylation by MSP, and RECK mRNA by real-time PCR in 74 HCC. The liver cell lines (7721, Chang and Hep-G2) were treated with 5-Aza-CdR and TSA.

Results: RECK mRNA were lower in HCC tissues (Mean -∆Ct = -3.29) than that in Non-Hcc tissues (Mean -∆Ct = -2.42). Expression of RECK was elevated in only 24 (32.43%) of the 74 HCC patients but decreased (-∆∆Ct<0) in 50 (67.57%) of the patients. RECK promoter was hypermethylated in 55.4% (41/74) of HCCs, and in only 17.6% (13/74) of Non-Hcc samples. RECK mRNA were lower in HCC patients with hypermethylation (∆MI>=0.5) (Mean -∆∆Ct = -1.75) than those with demethylation (∆MI<0.5) (Mean -∆∆Ct = 0.05), and there is a decreased tendency for RECK mRNA in HCC patients with promoter hypermethylation (p = 0.002). There was a significantly correlation found between RECK mRNA and poor survival after surgery. After treated by 5-Aza-CdR and TSA, we found that RECK mRNA induced different changes in 7721, Chang and Hep-G2 cells. And RECK demethylation also induced by epigenetic inhibitors.

Conclusion: The results suggested that the hypermethylation may lead to promoter silencing of RECK mRNA and associated with poor survival in HCC.

Wednesday, September 14, 2016 5:53 PM|Yi Chen, Dongke Yu, Hao Zhang, Hongwei He, Caixia Zhang, Wuli Zhao, Rong-guang Shao|International Journal of Biological Sciences|Labels: liver cancer

Background: EpCAM or CD133 has been used as the tumor initiating cells (TICs) marker in hepatocellular carcinoma (HCC). We investigated whether cells expressing with both EpCAM and CD133 surface marker were more representative for TICs in hepatocellular carcinoma Huh7 cells.

Methods: Four different phenotypes of CD133+EpCAM+, CD133+EpCAM-, CD133-EpCAM+ and CD133-EpCAM- in Huh7 cells were sorted by flow cytometry. Then cell differentiation, self-renewal, drug-resistance, spheroid formation and the levels of stem cell-related genes were detected to compare the characteristics of TICs. The ability of tumorigenicity was measured in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice to verify TICs.

Results: CD133+EpCAM+ cells have many characteristics of TICs in Huh7 cells compared with CD133+EpCAM-, CD133-EpCAM+, CD133-EpCAM- cells, including enrichment in side population cells, higher differentiation capacity, increased colony-formation ability, preferential expression of stem cell-related genes, appearance of drug-resistant to some chemotherapeutics, more spheroid formation of culture cells and stronger tumorigenicity in NOD/SCID mice.

Conclusion: CD133+EpCAM+ phenotype is precisely represented TICs in Huh7 cells. It might be useful for studying biology mechanism of TICs in hepatocellular carcinoma and screening new targets for cancer therapy.

Wednesday, September 14, 2016 5:53 PM|Julia WACHTER, Daniel NEUREITER, Beate ALINGER, Martin PICHLER, Julia FUEREDER, Christian OBERDANNER, Pietro Di FAZIO, Matthias OCKER, Frieder BERR, Tobias KIESSLICH|International Journal of Biological Sciences|Labels: WNT, liver cancer

Background: The role of Wnt signalling in carcinogenesis suggests compounds targeting this pathway as potential anti-cancer drugs. Several studies report activation of Wnt signalling in biliary tract cancer (BTC) thus rendering Wnt inhibitory drugs as potential candidates for targeted therapy of this highly chemoresistant disease.

Methods: In this study we analysed five compounds with suggested inhibitory effects on Wnt signalling (DMAT, FH535, myricetin, quercetin, and TBB) for their cytotoxic efficiency, mode of cell death, time- and cell line-dependent characteristics as well as their effects on Wnt pathway activity in nine different BTC cell lines.

Results: Exposure of cancer cells to different concentrations of the compounds results in a clear dose-dependent reduction of viability for all drugs in the order FH535 > DMAT > TBB > myricetin > quercetin. The first three substances show high cytotoxicity in all tested cell lines, cause a direct cytotoxic effect by induction of apoptosis and inhibit pathway-specific signal transduction in a Wnt transcription factor reporter activity assay. Selected target genes such as growth-promoting cyclin D1 and the cell cycle progression inhibitor p27 are down- and up-regulated after treatment, respectively.

Conclusions: Taken together, these data demonstrate that the small molecular weight inhibitors DMAT, F535 and TBB have a considerable cytotoxic and possibly Wnt-specific effect on BTC cell lines in vitro. Further in vivo investigation of these drugs as well as of new Wnt inhibitors may provide a promising approach for targeted therapy of this difficult-to-treat tumour.

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MET, VEGF, liver cancer, clinical trial
The purpose of this study is to evaluate the effect of Cabozantinib (XL184) compared with placebo on overall survival in subjects with advanced hepatocellular carcinoma who have received prior sorafenib.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: kidney cancer, liver cancer, melanoma, clinical trial
To assess the safety and tolerability at increasing dose levels of PF-04518600 in patients with advanced or metastatic hepatocellular carcinoma (HCC), melanoma, clear cell renal cell carcinoma (RCC) or squamous cell head and neck cancer (SCCHN) in order to determine the maximum tolerated dose and select the recommended Phase 2 dose.
Wednesday, September 14, 2016 7:55 AM|INOKAWA, Y., SONOHARA, F., KANDA, M., HAYASHI, M., NISHIKAWA, Y., SUGIMOTO, H., KODERA, Y., NOMOTO, S.|Anticancer Research recent issues|Labels: liver cancer

Background/Aim: Post-resection recurrence of hepatocellular carcinoma (HCC) tends to derive from multicentric origins, which indicates that the background liver microenvironment affects carcinogenesis. Materials and Methods: We obtained control liver samples [super normal (SN)] from 11 patients with secondary metastatic liver malignancies and used expression and methylation arrays to compare them with non-cancerous liver tissue from a patient with typical HCC with chronic hepatitis C (corresponding normal (CN)]. Results: The expression array showed that gene expression of tubulin polymerization-promoting protein (TPPP) was lower in CN compared with SN. The methylation array showed a greater TPPP methylation index for CN than for SN. Transcripts of TPPP differed significantly among SN (n=11), CN (n=179), and tumor tissue of HCC (n=179) (median of 116, 4.60, and 2.63, respectively, p<0.001). Multivariate analysis showed lower TPPP expression in tumor than in normal tissue (ratio <0.3, n=57) to independently predict poor overall survival (p=0.031). Conclusion: Significantly lower TPPP expression was found in HCC and CN tissue compared to SN and indicated poor prognosis.

Tuesday, September 13, 2016 11:38 PM|Tiejun Li, Yuwen Xue, Guilan Wang, Tingting Gu, Yunlong Li, York Yuanyuan Zhu, Li Chen|Journal of Cancer|Labels: VEGF, liver cancer

Multiple targets RNAi strategy is a preferred way to treat multigenic diseases, especially cancers. In the study, multi-target siRNAs were designed to inhibit NET-1, EMS1 and VEGF genes in hepatocellular carcinoma (HCC) cells. And multi-target siRNAs showed better silencing effects on NET-1, EMS1 and VEGF, compared with single target siRNA. Moreover, multi-target siRNA showed greater suppression effects on proliferation, migration, invasion, angiogenesis and induced apoptosis in HCC cells. The results suggested that multi-target siRNA might be a preferred strategy for cancer therapy and NET-1, EMS1 and VEGF could be effective targets for HCC treatments.

Tuesday, September 13, 2016 11:38 PM|Dongyan Zhang, Chuanhui Cao, Li Liu, Dehua Wu|Journal of Cancer|Labels: liver cancer

Recent studies indicated that long noncoding RNAs (lncRNAs) played important regulatory roles in carcinogenesis and cancer progression. However, the contribution of small nucleolar RNA host gene 20 (SNHG20) to cancer development remains largely unknown. The aim of the study is to investigate the expression of SNHG20 and its clinical significance in hepatocellular carcinoma (HCC). Our results showed that the expression of SNHG20 was remarkably up-regulated in HCC tissues compared with adjacent non-tumor liver tissues from 49 fresh HCC samples (cohort 1) detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR, P = 0.004). The results were confirmed in 144 formalin-fixed, paraffin-embedded HCC tissues (cohort 2) by in situ hybridization (ISH). Meanwhile, the expression of SNHG20 was associated with tumor size (P = 0.027 for cohort 1 and P = 0.046 for cohort 2) and clinical stage (P = 0.027 for cohort 1 and P = 0.028 for cohort 2). Importantly, patients with high expression of SNHG20 had a shorter overall survival (OS, P < 0.001) and disease-free survival (DFS, P < 0.001) than those with low expression of SNHG20. Univatiate and multivariate analysis showed that SNHG20 was a significant and independent prognostic predictor for OS of HCC patients (hazard ratio = 3.985, 95% CI = 1.981-8.017, P < 0.001). In addition, a total of 331 HCC patients' data from the Caner Genome Atlas project (TCGA) were used to validate our findings. Consistently, the results from TCGA HCC cohort demonstrated that SNHG20 were overexpressed in HCC tissues compared with non-tumor liver tissues (P < 0.001). Patients with higher expression levels of SNHG20 had poorer OS (P = 0.021) and DFS (P < 0.001). Functionally, knockdown of SNHG20 in SK-Hep-1 cells significantly inhibited cellular proliferation, migration, and invasion. In conclusion, SNHG20, up-regulated in patients with HCC, may serve as an independent prognostic predictor for HCC patients.

Tuesday, September 13, 2016 11:38 PM|Cheng Zhang, Yunfei Peng, Fan Yang, Ruixi Qin, Wenjun Liu, Cuijuan Zhang|Journal of Cancer|Labels: liver cancer

AIM: Protocadherin-8 (PCDH8) plays an important role in signaling pathways of cell adhesin, proliferation, and migration. It has been reported that PCDH8 is mutated or methylated in several human cancers. However, little is known about PCDH8 in liver cancer. The aim of this study was to investigate the protein expression and promoter methylation status of PCDH8 in liver cancer and evaluate the association between PCDH8 methylation and the clinicopathological features.

METHODS: The methylation status of PCDH8 in 42 hepatocellular carcinoma (HCC), 8 Cholangiocarcinoma (CC) and 50 normal liver tissues were examined using methylation-specific PCR (MSP) and the protein expression of PCDH8 was detected by immunohistochemistry. The relationships between PCDH8 methylation and clinicopathological features as well as overall survival of patients were evaluated.

RESULTS: The PCDH8 methylation was more frequent in liver cancer tissues than that in the normal liver tissues (88% vs. 32%, P < 0.001), and is significantly associated with loss of its protein expression (P = 0.004). Moreover, there is a significant correlation between PCDH8 methylation and the alpha-fetoprotein (AFP) level (P = 0.008). Kaplan-Meier survival analysis revealed that patients with PCDH8 methylation have shorter OS and PFS than those without PCDH8 methylation (P = 0.041 and P = 0.028, respectively).

CONCLUSION: PCDH8 is often inactivated by promoter methylation in liver cancer. PCDH8 methylation can serve as a valuable diagnostic biomarker for early detection of liver cancer and might be useful to predict an unfavorable clinical feature.

Tuesday, September 13, 2016 11:38 PM|Jing Zhao, Jing Wu, Hao Cai, Dan Wang, Long Yu, Wen-Hong Zhang|Journal of Cancer|Labels: liver cancer

Hepatocellular carcinoma (HCC) is a common worldwide malignancy with high morbidity and mortality. Hepatitis B viral (HBV)-encoded X protein (HBx) and natural HBx variants play important roles in HBV-associated HCC development. HBx is an unstable protein that can be degraded in vivo. Our previous study found that the E3 ubiquitin ligase Siah-1 could target HBx for poly-ubiquitylation and proteasomal degradation and attenuate the transcriptional activity of HBx. However, in HCC patients, high expression levels of HBx and HBx variants are frequently observed and are associated with HCC progression. The mechanism underlying their up-regulation is largely unknown. In this study, we screened for Siah-1 mutations in 270 HCC samples and 9 HCC cell lines, and examined Siah-1 mRNA and protein expression in a subset of paired HCC specimens. Our results demonstrate that Siah-1 is highly conserved, as no somatic mutation was identified, with the exception of one synonymous transition from G to A at codon 67. Both the mRNA and protein levels of Siah-1 were significantly down-regulated in HCC tissues compared with their adjacent normal counterparts. We constructed three natural HBx truncates that were identified in our HCC cases. We found that Siah-1 failed to decrease the stability of these HBx variants and was unable to inhibit the transcriptional activity of these HBx truncates at heat shock elements (HSEs). Moreover, Siah-1 had weaker association with three HBx mutants than full length HBx. Therefore, our findings suggest that down-regulation of Siah-1, but not its mutations, and natural HBx variants resistant to Siah-1-induced degradation may be a novel mechanism for HCC development.

Tuesday, September 13, 2016 8:19 PM|Haiyan Chen, Tingguo Zhang, Yan Sheng, Cheng Zhang, Yunfei Peng, Xiao Wang, Cuijuan Zhang|Journal of Cancer (RSS 2.0)|Labels: liver cancer

DNA methylation is considered as a significant mechanism that silences tumor suppressor genes (TSGs) and could be used in the early diagnosis of cancer. Histone modifications often work together with DNA methylation; however, how these epigenetic alterations regulate TSGs remains unclear. Here, we determined the methylation status of ten TSGs (3OST2, ppENK, CHFR, LKB1, THBS1, HIC1, SLIT2, EDNRB, COX2, and CLDN7) in hepatocellular carcinoma (HCC) and corresponding noncancerous tissues. Methylation profiling revealed that four genes had very high frequencies of methylation in HCCs, but interestingly, similar high frequencies were also detected in corresponding noncancerous tissues (97.9% vs 95.8% for SLIT2, 93.8% vs 81.3% for EDNRB, 66.7% vs 85.4% for HIC1, and 56.3% vs 56.3% for ppENK, P > 0.05). Only the 3OST2 gene was frequently methylated in HCCs and there was significant difference between HCCs and corresponding noncancerous tissues (68.8% vs 37.5%, P < 0.05). 5-aza-2'-deoxycytidine (5-Aza-CdR) or trichostatin A (TSA) alone could partially reverse 3OST2 methylation, and their combination resulted in complete reversal. UHRF1 and histone H3R8me2s were both enriched on the hypermethylated 3OST2 promoter, but H3R8me2a was not. After 5-Aza-CdR or TSA treatment, the UHRF1 and H3R8me2s enrichment was decreased, while H3R8me2a enrichment increased. We demonstrated that 3OST2 methylation may play a critical role in the earliest steps of hepatocarcinogenesis and is directly regulated by UHRF1. Furthermore, H3R8me2s acted as a repressive mark, while H3R8me2a was correlated with 3OST2 transcriptional activity.

Tuesday, September 13, 2016 8:19 PM|Jing Yan, Yuan Zhou, DaiXing Chen, LiLi Li, Xin Yang, Yang You, Xianlong Ling|Journal of Cancer (RSS 2.0)|Labels: telomerase, liver cancer

Hepatocellular carcinoma (HCC) cells exhibit multidrug resistance (MDR), but the underlying mechanisms remain unclear. Cancer cells that overexpress telomerase are resistant to chemotherapeutic drugs. This study aimed to determine the effects of mitochondrial translocation of telomerase on MDR in HCC cells. HepG2 cells were transfected with negative plasmid and PTPN11 (Shp-2) short hairpin RNA (ShRNA) plasmid to establish HepG2-negative (HepG2 transfected with negative plasmid) and HepG2-ShShp-2 (HepG2 transfected with Shp-2 ShRNA plasmid) cells. Sensitivity to chemotherapeutic drugs was assessed by Cell Counting Kit-8 (CCK-8) assays. Distribution of human telomerase reverse transcriptase (hTERT) within mitochondria was detected by western blotting and immunofluorescence combined with laser scanning confocal microscopy. Mitochondrial reactive oxygen species (ROS) generation was demonstrated by flow cytometry with the mitochondrial superoxide (Mito-Sox) indicator. The frequency of damaged mitochondrial DNA (mtDNA) was illustrated by quantitative real-time polymerase chain reaction (Q-PCR). Expression of mitochondrial respiratory chain complex subunits ND1 and COXII were also demonstrated by western blotting. Knockdown of Shp-2 in HepG2 cells resulted in upregulation of mitochondrial TERT expression and increased resistance to cisplatin (CDDP) and 5-fluorouracil (5-FU) (resistance indices, 2.094 and 1.863, respectively). In addition, both the mitochondrial ROS and the frequency of mtDNA damage were decreased, and COXII expression was upregulated. Our results suggest that Mitochondrial translocation of hTERT may lead to chemotherapeutic resistance in HCC cells. Mitochondrial hTERT contributes to the drug resistance of tumor cells by reducing ROS production and mtDNA damage, and exerting a protective effect on the mitochondrial respiratory chain.

Tuesday, September 13, 2016 2:05 PM|Kazuaki Ozaki, Nobuyuki Toshikuni, Joseph George, Takahiro Minato, Yasuhiro Matsue, Tomiyasu Arisawa, Mikihiro Tsutsumi|Journal of Cancer|Labels: liver cancer, biomarker diagnostic

Endocan is a vascular endothelium-derived factor regulated by angiogenic factors. The aim of this study was to determine whether serum endocan levels are prognostic for survival in patients with hepatocellular carcinoma (HCC). Serum endocan levels were measured in 64 HCC patients who were naïve to treatment, eight apparently healthy subjects, and 68 patients with liver cirrhosis; the latter two groups served as controls. Prognostic factors for the survival of HCC patients were examined using a Cox proportional hazards model. The median serum endocan levels were 1.145 ng/mL (range, 0.93-1.68 ng/mL) in healthy subjects, 1.93 ng/mL (range, 0.45-8.47 ng/mL) in liver cirrhosis patients, and 3.73 ng/mL (range, 0.74-10.95 ng/mL) in HCC patients (P = 0.0001). In HCC patients, elevated serum endocan levels were significantly associated with poor hepatic function (P = 0.015), a greater number of tumors (P = 0.034), and vascular invasion (P = 0.043). The median follow-up period was 23.0 months, and 33 HCC patients died during follow up. Multivariate analysis showed that serum endocan levels ≥ 2.20 ng/mL (hazard ratio 2.36, 95% confidence interval 1.22-5.36, P = 0.008) as well as elevated serum α-fetoprotein and des-γ-carboxy prothrombin levels were independent prognostic biomarkers for poor survival. The combination of serum endocan and these two additional markers was significantly predictive of worse survival (P < 0.0001). Thus, serum endocan may be a prognostic biomarker for survival in HCC patients, and the combination of serum endocan, α-fetoprotein, and des-γ-carboxy prothrombin levels can result in better prognostic stratification of these patients.

Sunday, September 11, 2016 11:00 PM|Wu, Lili; Guo, Haifei; Sun, Hongyu; Zhang, Wu; Sun, Changzheng; Wang, Jianhua|Anti-Cancer Drugs - Published Ahead-of-Print|Labels: liver cancer
UNC119 (uncoordinated 119 or retinal protein 4), specifically expressed in the photoreceptors in the retina, has recently been found to be upregulated in hepatocellular carcinoma (HCC) tissues, predicting a poor prognosis. However, the biological role of UNC119 in cancer treatment is still poorly understood. Gambogic acid (GA), a major component of gambogic resin, has been shown to possess anticancer activity against multiple human cancer cell lines. In the present study, we discovered that GA was more effective in inhibiting cell proliferation in HCC cells with a higher level of UNC119. In addition, GA inhibited UNC119 expression and induced Hep3B cells G0/G1 arrest. Cell-cycle-related proteins, such as cyclin A, E, D1, and p-cyclin-dependent kinase 2, 4, 6 were downregulated in GA-treated cells. Glycogen synthase kinase 3[beta] (Gsk3[beta])/[beta]-catenin signaling, the downstream of UNC119, was also found to be suppressed after GA treatment. UNC119 knockdown or over expression experiment further proved that UNC119 mediated the effect of GA on the HCC cell cycle and Gsk3[beta]/[beta]-catenin signaling. In BALB/c mice bearing xenotransplanted tumors, the growth of the Hep3B tumor was inhibited by GA treatment. Immunohistochemistry results of tumor tissues suggested that GA might also exert its anticancer effect by inhibiting UNC119 and regulating cell cycle in vivo. Thus, GA could be a potential therapeutic agent in the treatment of human HCC. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
Thursday, September 8, 2016 12:34 PM|Sanoff, H. K., Chang, Y., Lund, J. L., ONeil, B. H., Dusetzina, S. B.|The Oncologist current issue|Labels: liver cancer, clinical trial

Phase III trials show sorafenib improves survival in advanced hepatocellular carcinoma (HCC). Because of narrow trial eligibility, results may not be generalizable to a broader HCC population. We sought to evaluate the effectiveness of initial sorafenib versus no treatment among Medicare beneficiaries with advanced HCC.

Materials and Methods.

Patients with advanced HCC diagnosed from 2008 to 2011 were identified from the Surveillance, Epidemiology, and End Results–Medicare database. Eligible patients received initial sorafenib or no therapy and were covered by Medicare parts A, B, and D. Sorafenib use and outcomes were described in this population. Using a propensity score (PS)-matched sample, we compared the effectiveness of sorafenib versus no treatment by Cox proportional hazards and binomial regression, using a landmark requiring all patients to survive ≥60 days after diagnosis.


Of 1,532 patients, 27% received initial sorafenib. Median duration of sorafenib use was 60 days (interquartile range [IQR], 30–107 days), and median survival from first prescription was 3 months (IQR, 1–8 months). In the PS-matched cohort, median survival was 3 months from the 60-day landmark in sorafenib-treated (n = 223) and 2 months in untreated (n = 223) patients (adjusted hazard ratio, 0.95 [95% confidence interval (CI), 0.78–1.16]). Sorafenib was associated with a nonsignificant reduction in mortality at 3 months (44% versus 51%; adjusted risk ratio, 0.88 [95% CI, 0.72–1.07]), but no reduction thereafter.


Survival after sorafenib initiation in newly diagnosed Medicare beneficiaries with HCC is exceptionally short, suggesting trial results are not generalizable to all HCC patients. The downsides of sorafenib use—high drug-related symptom burden and high drug cost—must be considered in light of this minimal benefit.

Implications for Practice:

The findings of a median survival of only 3 months in Medicare beneficiaries with HCC prescribed sorafenib as first-line therapy highlight the questionable value of sorafenib in this population. Patients should be cautioned that outside of the narrow confines of randomized trials, their life expectancy may be very short, and any benefit of sorafenib is likely to be quite small. Given that sorafenib causes considerable adverse effects and offers no symptom palliation, supportive care should be discussed as a reasonable alternative to sorafenib, particularly for patients who have a poor performance status or advanced cirrhosis.

Friday, September 2, 2016 1:30 AM|Junya Azumi, Toshiaki Tsubota, Tomohiko Sakabe, Goshi Shiota|Cancer Science|Labels: MapK, liver cancer
Sorafenib, a multi-kinase inhibitor, is the only standard clinical drug for patients with advanced hepatocellular carcinoma (HCC); however, development of sorafenib resistance in HCC often prevents its long-term efficacy. Therefore, novel targets and strategies are urgently needed to improve the antitumor effect of sorafenib. In the present study, we examined the novel mechanisms of sorafenib resistance of HCC cells by investigating the difference in sorafenib sensitivity between two HCC cell lines. Sorafenib induced more apoptosis of HepG2 cells compared to Hep3B cells. Sorafenib exposure to HepG2 cells but not Hep3B cells increased the expression of proapoptotic factor PUMA, and activated PARP and caspase-3. Notably, microRNA-181a (miR-181a) expression levels were lower in HepG2 cells than in Hep3B cells. Exogenous miR-181a expression in HepG2 cells reduced apoptosis, whereas inhibition of miR-181a in Hpe3B cells increased apoptosis. In addition, we demonstrated that miR-181a directly targets RASSF1, a MAPK signaling factor, and knockdown of RASSF1 increased sorafenib resistance. Taken together, these results suggest that miR-181a provokes sorafenib resistance through suppression of RASSF1. Our data provide important insight into the novel therapeutic strategy against sorafenib resistance of HCC cells by targeting of miR-181a pathway. Sorafenib, a multi-kinase inhibitor, is the first systemic drug against patients with advanced hepatocellular carcinoma (HCC), however, development of sorafenib resistance in HCC often prevents its long-term efficacy. We demonstrate that miR-181a, an onco-microRNA, provokes sorafenib resistance by suppression of tumor suppressor gene RASSF1.
Wednesday, August 24, 2016 6:00 PM|Qing-Hai Ye, Wen-Wei Zhu, Ju-Bo Zhang, Yi Qin, Ming Lu, Guo-Ling Lin, Lei Guo, Bo Zhang, Zhen-Hai Lin, Stephanie Roessler, Marshonna Forgues, Hu-Liang Jia, Lu Lu, Xiao-Fei Zhang, Bao-Feng Lian, Lu Xie, Qiong-Zhu Dong, Zhao-You Tang, Xin Wei Wang, Lun-Xiu Qin|Cancer Cell|Labels: EGFR, liver cancer
Ye et al. identify GOLM1 as a key promoter of hepatocellular carcinoma (HCC) metastasis and determine its critical roles in the recycling, spatial redistribution, and signaling kinetics of EGFR/RTKs. In human HCC, GOLM1 expression is correlated with early recurrence, metastasis, and poor patient survival.
Saturday, August 20, 2016 6:00 PM|Amal Ahmed Mohamed, Naglaa El-Toukhy, Ayman Abdel-Hady Alkhalegy, Sherif Boraii|Journal of Gastroenterology and Hepatology Research|Labels: liver cancer, biomarker diagnostic

Aim: Hepatocellular carcinoma (HCC) is a global health problem because of its increasing prevalence worldwide and its poor prognosis. In Egypt HCC incidence has increased sharply and nearly doubled over the last decade. The outcome of HCC depends mainly on its early diagnosis; therefore, new and specific markers for HCC are critically needed. Osteopontin(OPN) is a glycoprotein that overexpressed in HCC, and known to be an independent predictor of poor prognosis.  The aim was to assess the value of OPN in Egyptian patients with HCC.

Methods: This study was included 40 patients with HCC, 20 patients with liver cirrhosis and 20 healthy controls. For all groups, clinical data and image findings were studied, serum alpha-fetoprotein & OPN levels were detected by enzyme immunoassay (EIA) kit. Tumour characteristics were assessed including size, number and site. Tumor staging was done using Okuda, CLIP, VISUM and Tokyo staging systems.

Results: Serum OPN was significantly higher in HCC patients compared to cirrhotic and controls. The sensitivity and specificity in diagnosis of HCC were 92.5% and 85% respectively at cutoff of 239 ng/ml with accuracy 91.1%.OPN has a positive significant correlation with tumour number (p=0.036),CLIP (p=0.02),Tokyo (P=0.03), and VISUM (P=0.01) staging systems.

Conclusion: OPN could be a useful diagnostic & prognostic marker for detection of HCC.
Friday, August 19, 2016 6:00 PM|Alfred Cheng|Cancers|Labels: WNT, liver cancer
Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein) or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.
Wednesday, August 17, 2016 1:13 PM|Liu, H., Xu, Y., Xiang, J., Long, L., Green, S., Yang, Z., Zimdahl, B., Lu, J., Cheng, N., Horan, L. H., Liu, B., Yan, S., Wang, P., Diaz, J., Jin, L., Nakano, Y., Morales, J. F., Zhang, P., Liu, L.-x., Staley, B. K., Priceman, S. J., Brown, C. E., Forman, S. J., Chan, V. W., Liu, C.|Clinical Cancer Research Online First Articles|Labels: liver cancer

Purpose: The majority of tumor-specific antigens are intracellular and/or secreted and therefore previously inaccessible by conventional chimeric antigen receptor (CAR) T cell therapy. Given that all intracellular/secreted proteins are processed into peptides and presented by class I major histocompatibility complexes (MHC) on the surface of tumor cells, we used alpha-fetoprotein (AFP), a specific liver cancer marker, as an example to determine whether peptide-MHC complexes can be targets for CAR T cell therapy against solid tumors. Experimental Design: We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP158-166 peptide complexed with human leukocyte antigen (HLA)-A*02:01. Results: We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01+/AFP+ while sparing cells from multiple tissue types that were negative for either expressed proteins. In vivo, intratumoral injection of AFP-CAR T cells significantly regressed both Hep G2 and AFP-expressing SK-HEP-1 tumors in SCID-Beige mice (n=8 for each). Moreover, intravenous administration of AFP-CAR T cells in Hep G2 tumor-bearing NSG mice lead to rapid and profound tumor growth inhibition (n=6). Finally, in an established intraperitoneal liver cancer xenograft model, AFP-CAR T cells showed robust anti-tumor activity (n=6). Conclusions: This study demonstrates that CAR T cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent anti-tumor response. Our approach expands the spectrum of antigens available for redirected T cell therapy against solid malignancies and offers a promising new avenue for liver cancer immunotherapy.

Sunday, August 14, 2016 10:05 PM|Chen, M.-H., Weng, J.-J., Cheng, C.-T., Wu, R.-C., Huang, S.-C., Wu, C.-E., Chung, Y.-H., Liu, C.-Y., Chang, M.-H., Chen, M.-H., Chiang, K.-C., Yeh, T.-S., Su, Y., Yeh, C.-N.|Clinical Cancer Research recent issues|Labels: childhood cancer, liver cancer

Purpose: Intrahepatic cholangiocarcinoma is a fatal primary liver cancer resulting from diagnosis at an advanced stage. Understanding the mechanisms of drug resistance and metastasis of cholangiocarcinoma may improve the disease prognosis. Enhanced aldehyde dehydrogenase (ALDH) activity is suggested to be associated with increased drug resistance and the metastasis. This study aims to investigate the roles of the ALDH isoforms in cholangiocarcinoma.

Experimental Design: Aldefluor assays, RT-PCR, and Western blot analysis were used to identify the major ALDH isoforms contributing to Aldefluor activity in human cholangiocarcinoma cell lines. We manipulated isoform expression in HuCCT1 cells to elucidate the role of ALDH1A3 in the malignant progression of these cells. Finally, we used immunohistochemical staining to evaluate the clinical significance of ALDH1A3 in 77 hepatectomized cholangiocarcinoma patients and an additional 31 patients with advanced cholangiocarcinoma who received gemcitabine-based therapy.

Results: ALDHhigh cholangiocarcinoma cells not only migrated faster but were more resistant to gemcitabine. Among the 19 ALDH isoforms studied, ALDH1A3 was found to be the main contributor to Aldefluor activity. In addition, we also found that knockdown of ALDH1A3 expression in HuCCT1 cells markedly reduced not only their sensitivity to gemcitabine, which might be attributed to a decreased expression of ribonucleotide reductase M1, but also their migration. Most importantly, this enzyme was also identified as an independent poor prognostic factor for patients with intrahepatic cholangiocarcinoma, as well as a prognostic biomarker of gemcitabine-treated patients.

Conclusions: ALDH1A3 plays an important role in enhancing malignant behavior of cholangiocarcinoma and serves as a new therapeutic target. Clin Cancer Res; 22(16); 4225–35. ©2016 AACR.

Sunday, July 31, 2016 10:05 PM|Eso, Y., Takai, A., Matsumoto, T., Inuzuka, T., Horie, T., Ono, K., Uemoto, S., Lee, K., Edelmann, W., Chiba, T., Marusawa, H.|Cancer Research recent issues|Labels: NFKb, liver cancer
Inflammation predisposes to tumorigenesis in various organs by potentiating a susceptibility to genetic aberrations. The mechanism underlying the enhanced genetic instability through chronic inflammation, however, is not clear. Here, we demonstrated that TNFα stimulation induced transcriptional downregulation of MSH2, a member of the mismatch repair family, via NF-κB–dependent miR-21 expression in hepatocytes. Liver cancers developed in ALB-MSH2−/−AID+, ALB-MSH2−/−, and ALB-AID+ mice, in which MSH2 is deficient and/or activation-induced cytidine deaminase (AICDA) is expressed in cells with albumin-producing hepatocytes. The mutation signatures in the tumors developed in these models, especially ALB-MSH2−/−AID+ mice, closely resembled those of human hepatocellular carcinoma. Our findings demonstrated that inflammation-mediated dysregulation of MSH2 may be a mechanism of genetic alterations during hepatocarcinogenesis. Cancer Res; 76(15); 4383–93. ©2016 AACR.
Thursday, July 28, 2016 10:01 AM| Nachrichten zu ONXEO SA|Labels: liver cancer, clinical trial, financial
Expansion of orphan oncology pipeline through acquisition of DNA Therapeutics and lead compound AsiDNATM Important development milestones on existing assets: Livatag® Phase III trial in HCC: 80% o...
Thursday, July 28, 2016 7:56 AM|Hyemi, K., Gyu, L. H., Myun, L. J., Han, P. J.|Cancer Research recent issues|Labels: liver cancer
The clinical usefulness of 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET), based on aerobic glycolysis, has been recently challenged in hepatocellular carcinoma (HCC) due to the heterogeneity of 18F-FDG uptake. Although inconsistent 18F-FDG uptake in HCCs is explained by the heterogeneous expression of hexokinase 2 (HK2), the underlying molecular mechanism remains elusive. Here, we examined the methylation status of the HK2 promoter and its influence on hypoxia-inducible factor-1α (HIF-1α) binding. We first confirmed inconsistent 18F-FDG uptake and correlative HK2 expression. Utilizing the HumanMethylation450 array, we discovered hypermethylation of the HK2 promoter CpG island (CGI) region in HK2negative HCCs. Studies using HK2 promoter luciferase constructs showed that a newly defined hypoxia responsive element (HRE) regulates HK2 expression. We also found that differential glucose uptake is caused by the differential HK2 expression due to differential methylation of the HK2 promoter CGI region in HCC cell lines. Finally, treatment with 5-Aza-2-deoxycytidine and hypoxic stimuli significantly increased HK2 expression due to increased HIF-1α binding to the HRE, resulting in increased glucose uptake in HK2negative SNU449 cells. Conclusion: These data indicate that methylation changes in the HK2 promoter CGI region in HCCs influence HK2 expression by regulating HIF-1α binding to the HRE in the CGI region. Hypermethylation of the HK2 promoter CGI region in HK2negative tissues inhibits the binding of HIF-1α to the HK2 promoter, resulting in the suppression of HK2 expression, which contributes to the heterogeneity of 18F-FDG uptake.Citation Format: Kim Hyemi, Lee Hyun Gyu, Lee Jae Myun, Park Jeon Han. Epigenetic repression of hexokinase 2 is responsible for the heterogeneity of 18F-FDG uptake in hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C35.
Wednesday, July 27, 2016 11:11 AM|NANASHIMA, A., IZUMINO, H., SUMIDA, Y., TOMINAGA, T., WAKATA, K., HIDAKA, S., TSUCHIYA, T., NAGAYASU, T.|Anticancer Research recent issues|Labels: liver cancer

Background/Aim: Oxidative stress is defined as an imbalance between the pro-oxidant and antioxidant potential of cells leading to intracellular DNA damage. To clarify the oxidative stress response as a tumor marker, we investigated measurement of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels in hepatobiliary diseases. Materials and Methods: Relationships between urinary 8-OHdG levels and clinicopathological factors were analyzed in 101 patients, including 84 with hepatobiliary malignancies, and 18 healthy volunteers. Co-existing biliary inflammation was detected in 8 patients. Results: Urinary 8-OHdG levels did not correlate with any clinical or liver functional parameters. The existence of inflammation and any tumor-related factor did not correlate with urinary 8-OHdG levels either. Urinary 8-OHdG levels were significantly higher in patients with benign and malignant diseases than in healthy volunteers (p<0.05), but not significantly different between benign and malignant diseases. Among patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma, urinary 8-OHdG levels tended to be higher in patients with lymph node metastasis-positive than in those with lymph node-negative disease (p=0.057). Conclusion: The clinical significance of oxidative DNA damage and increases in its urinary metabolites in patients with hepatobiliary malignancies or inflammatory diseases remain unknown. Further studies are necessary to clarify the relationship between node metastasis and oxidative stress as a prognostic marker.

Tuesday, July 26, 2016 2:20 AM|oslocancer|investoropportunities – Oslo Cancer Cluster|Labels: liver cancer, regulatory

Oslo Cancer Cluster member PCI Biotech has received positive opinion from the European Medicine Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) for its lead product candidate, fimaporfin. Firmaprofin is intended to be used in the treatment of bile duct cancer,  cholangiocarcinoma.

Fimaporfin (AmphinexTM) is in clinical phase I/II development for inoperable bile duct cancer, a disease without approved medicinal treatment and a high need of better local treatment alternatives.


About bile duct cancer (cholangiocarcinoma)  
The bile duct drains bile from the liver into the small intestine. Biliary tract sepsis, liver failure and/or malnutrition and cachexia due to locoregional effects of the disease are the most important causes of death. Currently, surgery is the only curative option for these patients; yet the majority of the tumors are inoperable at presentation. Inoperable patients are treated with stenting to keep the bile duct open and with chemotherapy. The combination of gemcitabine and cisplatin has shown promising results and has become standard treatment in some regions, but there is still a need for better treatments to increase overall survival and quality of life.


About PCI Biotech         
PCI Biotech is a cancer focused biopharmaceutical company headquartered in Norway and listed on the Oslo Stock Exchange (Axess). The company is developing therapeutic products based on its proprietary photochemical internalisation (PCI) technology. The PCI technology works by inducing triggered endosomal release and may be used to unlock the true potential of a wide array of therapeutic modalities, such as small molecules, vaccines and nucleic acids.  The company has a clinical Phase I/II program in bile duct cancer.

The company is also developing PCI as a vaccination technology. When applied in the emerging field of cancer immunotherapy, PCI can be used to enhance the important cytotoxic effect of therapeutic cancer vaccines. The PCI technology is also very well suited for intracellular delivery of nucleic acids, such as RNA therapeutics. By releasing nucleic acid compounds from endosomes where they are trapped following administration, PCI addresses one of the major bottlenecks facing this emerging and exciting field.  PCI Biotech follows a strategy to create value by improving the effect of existing cancer drugs and by realising the large potential in new therapeutics.


Thursday, June 30, 2016 10:05 PM|Ran, L.-K., Chen, Y., Zhang, Z.-Z., Tao, N.-N., Ren, J.-H., Zhou, L., Tang, H., Chen, X., Chen, K., Li, W.-Y., Huang, A.-L., Chen, J.|Clinical Cancer Research recent issues|Labels: Bcl-2, liver cancer

Purpose: To characterize the functional role of SIRT6 in hepatocellular carcinoma (HCC).

Experimental Design: The expression of SIRT6 in 60 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry. The expression of SIRT6 in 101 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by Western blotting analysis and qPCR. The biologic consequences of overexpression and knockdown of SIRT6 in HCC cell lines were studied in vitro and in vivo.

Results: SIRT6 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with tumor grade (P = 0.02), tumor size (P = 0.02), vascular invasion (P = 0.004), and shorter survival (P = 0.024). Depletion of SIRT6 from multiple liver cancer cell lines inhibited their growth and induced apoptosis in vitro. At the molecular level, we observed that the activation of the BCL2-associated X protein (Bax) signaling pathway, a major pathway that determines cancer cell apoptosis, is regulated by SIRT6 via its deacetylase activity. SIRT6 was recruited to the promoter of Bax, where it deacetylated histone 3 lysine 9 and suppressed its promoter activity. Binding of transcription factors (p53 and E2F-1) to Bax promoter was also generally increased in SIRT6-depleted cells. In mouse xenografts, SIRT6 suppression inhibited tumor growth and induced apoptosis. Finally, there is a negative correlation between SIRT6 and Bax mRNA expressions in human HCC samples.

Conclusions: SIRT6 is an important protumorigenic factor in liver carcinogenesis. Thus, the therapeutic targeting of SIRT6 may offer options for HCC treatment. Clin Cancer Res; 22(13); 3372–82. ©2016 AACR.

Thursday, June 30, 2016 10:05 PM|Kamiya, T., Chang, Y.-H., Campana, D.|Cancer Immunology Research recent issues|Labels: liver cancer

Viral infection of the liver is a major risk factor for hepatocellular carcinoma (HCC). Natural killer (NK) cells recognize virally infected and oncogenically transformed cells, suggesting a therapeutic role for NK-cell infusions in HCC. Using the K562-mb15-41BBL cell line as a stimulus, we obtained large numbers of activated NK cells from the peripheral blood of healthy donors. Expanded NK cells exerted remarkably high cytotoxicity against HCC cell lines, which was generally much higher than that of unstimulated or IL2-activated NK cells. In immunodeficient NOD/scid IL2RGnull mice engrafted with Hep3B, treatment with expanded NK cells markedly reduced tumor growth and improved overall survival. HCC cells exposed for 48 hours to 5 μmol/L of sorafenib, a kinase inhibitor currently used for HCC treatment, remained highly sensitive to expanded NK cells. HCC cell reductions of 39.2% to 53.8% caused by sorafenib in three cell lines further increased to 80.5% to 87.6% after 4 hours of culture with NK cells at a 1:1 effector-to-target ratio. NK-cell cytotoxicity persisted even in the presence of sorafenib. We found that NKG2D, an NK-cell–activating receptor, was an important mediator of anti-HCC activity. We therefore enhanced its signaling capacity with a chimeric NKG2D-CD3-DAP10 receptor. This considerably increased the anti-HCC cytotoxicity of expanded NK cells in vitro and in immunodeficient mice. The NK expansion and activation method applied in this study has been adapted to clinical-grade conditions. Hence, these results warrant clinical testing of expanded NK-cell infusions in patients with HCC, possibly after genetic modification with NKG2D-CD3-DAP10. Cancer Immunol Res; 4(7); 574–81. ©2016 AACR.

Thursday, June 30, 2016 10:40 AM|News-Medical.Net Gastrointestinal Cancer News Feed|Comments|Labels: liver cancer, clinical trial
Oral multikinase inhibitor regorafenib achieves significantly improved survival rates compared to placebo in patients with hepatocellular carcinoma, according to data from the phase III RESORCE trial, presented at the ESMO 18th World Congress of Gastrointestinal Cancer in Barcelona, Spain.
Monday, June 27, 2016 10:52 AM|SAKAMOTO, T., ISHII, Y., SHIBA, H., FURUKAWA, K., FUJIWARA, Y., HARUKI, K., IWASE, R., SHIRAI, Y., YANAGA, K.|Anticancer Research recent issues|Labels: liver cancer

Background/Aim: Angiogenesis is a known factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to assess the property of iguratimod, that is an anti-inflammatory drug for rheumatoid arthritis, on anti-angiogenesis and anti-carcinogensis for HCC. Materials and Methods: In vitro, human umbilical vein endothelial cells were cultured under interleukin-8 (IL-8) with or without iguratimod. In vivo, a rat model with HCC received iguratimod or distilled water for 6 weeks. Diameter of the largest tumor, number of tumors and serum interleukin-8 concentration were compared between iguratimod and control groups. Results: By an in vitro angiogenesis assay, it was found angiogenesis in iguratimod group was significantly lower than that in control group (p=0.013). In vivo, largest tumor diameter (p=0.036), number of the tumor (p=0.011) and serum interleukin-8 concentration (p=0.036) in the iguratimod group were significantly smaller and lower than those in the control group. Conclusion: Iguratimod may inhibit hepatocellular carcinogensis by inhibition of interleukin-8 production in a rat model.

Monday, June 6, 2016 4:58 AM|KOMATSU, H., IGUCHI, T., MASUDA, T., UEDA, M., KIDOGAMI, S., OGAWA, Y., NAMBARA, S., SATO, K., HU, Q., SAITO, T., HIRATA, H., SAKIMURA, S., UCHI, R., HAYASHI, N., ITO, S., EGUCHI, H., SUGIMACHI, K., EGUCHI, H., DOKI, Y., MORI, M., MIMORI, K.|Anticancer Research recent issues|Labels: liver cancer, biomarker diagnostic

Background/Aim: Homeobox B7 (HOXB7) gene is involved in various cellular functions. We investigated the clinical significance of HOXB7 expression in hepatocellular carcinoma (HCC). Materials and Methods: HOXB7 mRNA expression in 103 HCC samples and 58 matched non-cancerous liver tissues were examined by quantitative real-time polymerase chain reaction (qRT-PCR). HOXB7 protein expression was also examined by immunohistochemistry. Gene set enrichment analysis (GSEA) was performed using a public dataset. Results: HOXB7 expression was significantly higher in HCC tissues than in liver parenchyma. Ten-year overall survival (OS) and 5-year recurrence-free survival (RFS) of cases with higher HOXB7 expression were significantly poorer than those with lower HOXB7 expression. HOXB7 expression was significantly associated with larger tumor size and higher rate of biliary invasion and constituted an independent prognostic factor for OS by multivariate analysis. These results were supported by GSEA. Conclusion: HOXB7 expression in HCC could be a novel biomarker for long-term prognosis after tumor resection.

Thursday, April 28, 2016 9:59 AM|IGUCHI, T., KOMATSU, H., MASUDA, T., NAMBARA, S., KIDOGAMI, S., OGAWA, Y., HU, Q., SAITO, T., HIRATA, H., SAKIMURA, S., UCHI, R., HAYASHI, N., ITO, S., EGUCHI, H., SUGIMACHI, K., MAEHARA, Y., MIMORI, K.|Anticancer Research recent issues|Labels: liver cancer

Background/Aim: Defects in alternative splicing contribute to carcinogenesis, cancer progression and chemoresistance. The spliceosome pathway, including SF3B4, a component of spliceosomal complex is suggested to play a role in progression of hepatocellular carcinoma (HCC); however, the clinical relevance of SF3B4 in HCC remains unknown. Patients and Methods: SF3B4 expression was evaluated by real-time reverse transcription polymerase chain reaction in 72 HCC samples and non-cancerous liver samples. The relationship between the DNA copy number and SF3B4 expression levels was investigated using TCGA datasets. Results: SF3B4 expression was significantly higher in cancerous than in non-cancerous tissues and positively correlated with SF3B4 DNA copy number. High SF3B4 expression is significantly associated with intrahepatic metastasis and poor prognosis. These results were consistent with data from the public datasets. Conclusion: Overexpression of SF3B4, that is due to DNA copy number increase, is suggested to play a role in progression of HCC.

Authors: Zhang N, Bi C, Liu L, Dou Y, Tang S, Pang W, Deng H, Song D Abstract Sophoridinic acid derivatives have received considerable attentions for their potencies in cancer therapy. IMB-6G is a novel N-substituted sophoridinic acid derivative with potent cytotoxicity against tumor cells. In the present study, we explored the antitumor abilities of IMB-6G in human hepatocellular carcinoma (HCC) cells and investigated the underlying mechanisms. We found that IMB-6G inhibited cell growth and induced mitochondrial-dependent apoptosis in HepG2 and SMMC7721 cells. Analyses of the molecular mechanism of IMB-6G-induced apoptosis indicated IMB-6G induced endoplasmic reticulum (ER) stress activation. Incubation of HCC cells with IMB-6G induced increase in Bip and CHOP levels, which preced...
In this study, we identified the “stem-like” characteristics of SP cells in the MHCC97 and Hepa 1-6 HCC cell lines. We found that SP cells express high levels of tumor-associated antigens and MHC class I molecules. Although loading with cell lysates did not change the characteristics of DCs, SP cell lysate-pulsed DCs induced antigen-specific T cell responses, including T cell proliferation and increased IFN-γ production by stimulated CD8+ T cells. We investigated the cytotoxicity of T cells stimulated by SP cell lysate-pulsed DCs in nude mice co-injected with MHCC97 cells. To mimic the in vivo environment, we also confirmed the result in mouse HCC cell line Hepa 1-6 induced tumor-bearing C57/BL6 immune competent mice, and we demonstrated that vaccination with DCs loaded with Hepa 1-6 ...
Tuesday, March 1, 2016 4:00 PM|Current Pharmaceutical Design|Current Pharmaceutical Design via|Comments|Labels: liver cancer, biomarker diagnostic
Authors: Mirzaei HR, Sahebkar A, Yazdi F, Salehi H, Jafari MH, Namdar A, Khabazian E, Jaafri MR, Mirzaei H Abstract Hepatocellular carcinoma (HCC) is one of the most common types of malignancies worldwide. There is little information on the mechanisms involved in the pathogenesis of this disease. Diagnosis of HCC at early stages would be crucial for increasing the survival of patients. Circulating miRNAs have emerged as one of the most attractive tools for an early diagnosis of cancers. Various studies have shown that there is an aberrant expression of miRNAs such as miR-25, miR-375, miR-206, miR-223, miR- 92a, miR-222, miR-1, let-7f and miR-21 in HCC. Circulating and tissue miRNAs have also key roles in the pathogenesis of HCC by affecting several biologically important pathways s...
Sunday, February 21, 2016 4:00 PM|Cancer Letters|MedWorm: Cancer Therapy|Comments|Labels: liver cancer
• Several large projects have provided insight into genomic alterations that are prevalent in gastrointestinal and liver cancers• Recent developments in next generation sequencing technologies have allowed investigators to identify hereditary mutations and markers of response or resistance to cancer therapy.• Challenges that limit the clinical utility of next generation sequencing in clinical practice include the long turnaround time, rapid decline of patients' condition as testing is being performed, lack of actionable mutations, lack of available clinical trials or patient refusal to enroll in clinical trials (Source: Cancer Letters)
Friday, February 19, 2016 5:16 AM|Oncotarget|MedWorm: Cancer Therapy|Comments|Labels: STAT, CRC, liver cancer
Authors: Chongqiang Z, Wenlong W, Wenying Y, David J, Yina W, Haiyan M, Hui X, Hua Q, Z, Jiagao L, Sheng L, Chenglong L, Jiayuh L, Li L Abstract Signal Transducer and Activator of Transcription 3 (STAT3) is persistently activated in human liver and colon cancer cells and is required for cancer cell viability, survival and migration. Therefore, inhibition of STAT3 signaling may be a viable therapeutic approach for these two cancers. We recently designed a non-peptide small molecule STAT3 inhibitor, LY5, using in silico site-directed Fragment-based drug design (FBDD). The inhibitory effect on STAT3 phosphorylation, cell viability, migration and colony forming ability by LY5 were examined in human liver and colon cancer cells. We demonstrated that LY5 inhibited constitutive Inter...
Thursday, February 11, 2016 8:42 PM|Oncotarget|MedWorm: Cancer Therapy|Comments|Labels: liver cancer
In conclusion, our findings suggest the oncogenic potential of H2A.Z.1 in liver tumorigenesis and that it plays established role in accelerating cell cycle transition and EMT during hepatocarcinogenesis. This makes H2A.Z.1 a promising target in liver cancer therapy. PMID: 26863632 [PubMed - as supplied by publisher] (Source: Oncotarget)
Wednesday, January 20, 2016 5:32 PM|Molecular Biology Reports|MedWorm: Cancer Therapy|Comments|Labels: liver cancer
Authors: Mehdizadeh A, Somi MH, Darabi M, Jabbarpour-Bonyadi M Abstract Extracellular signal-regulated kinases (ERK) pathway plays a crucial role in cancer cell survival and proliferation. This signaling pathway has been related to epithelial to mesenchymal transition and drug resistance in hepatocellular carcinoma (HCC) cells, which is a common challenge in chemotherapy. Consequently, mediators of this pathway have recently been considered as novel therapeutic targets in HCC. In this review the impact of ERK1 and ERK2 as major components of ERK signaling pathway, in HCC biology and drug resistance will be highlighted and discussed. PMID: 26767647 [PubMed - in process] (Source: Molecular Biology Reports)
Wednesday, January 13, 2016 4:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: liver cancer
Frequent Arid1a loss-of-function mutations suggest tumor suppressive roles, but the functional impact of Arid1a and SWI/SNF chromatin-remodeling aberrations in human cancer are not clear. Liver-specific Arid1a knockout mice do not develop cancer after 15 months and surprisingly, homozygous mice are potently protected from diethylnitrosamine (DEN) + carbon tetrachloride induced hepatocellular carcinoma (HCC). This is likely due to the fact that Arid1a deficient livers are resistant to chemical damage in a Cytochrome P450 dependent fashion. To determine if genetic drivers of cancer might reveal additional roles for Arid1a, we showed that Arid1a loss results in increased survival in a MYC driven liver cancer model. Given the physical interactions between MYC and Arid1a and a global reduction ...

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