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HIF
HIF
HIF(5)

In response to decreased oxygen levels, cells activate the transcription factors HIFs, which lead to metabolic adaptation to hypoxia, as well as to generate new vasculature to increase oxygen supply. Emerging evidence indicates that ROS generated by mitochondrial complex III are required for hypoxic activation of HIF. Although the PHDs are the proximal regulators of HIF-a protein stabilization, much evidence has emerged to suggest that the mitochondrial electron transport chain is involved in oxygen sensing and would therefore need to respond to changes in oxygen levels.(1) The reduction in the normal level of tissue oxygen tension or hypoxia is a characteristic of solid tumors that triggers the activation of signaling pathways promoting neovascularization, metastasis, increased tumor growth, and resistance to treatments. The activation of HIF-1A is the master mechanism of adaptation to hypoxia.(2) HIF-1 can activate more than 60 known genes, related to cell proliferation, survival, apoptosis, cell mortality, adhesion, erythropoiesis, cytoskeletal structure, pH regulation, epithelial homeostasis, drug resistance, iron, nucleotide, glucose, energy, amino acid, and extracellular-matrix metabolisms, vascular tone, and angiogenesis.(3, 4)
HIF-1 is heterodimeric, composed of a constitutively expressed nuclear h subunit and an oxygen sensitive a subunit.(6) HIF-1 regulates VEGF expression by binding to the hypoxia responsive element (HRE) of VEGF promoter.(7, 8) The SphK1/S1P pathway elicits various cellular processes including cell proliferation, cell survival, or angiogenesis, as a new modulator of HIF-1A activity under hypoxic conditions.(2)
The hydroxylation of HIF-1A is required for its recognition by the von Hippel-Lindau tumor suppressor gene product (pVHL) of the E3 ubiquitin ligase complex, followed by its ubiquination and proteasomal degradation. Under low oxygen conditions or in cells lacking functional pVHL, HIF-1a remains unhydroxylated, and therefore accumulates, and then translocates to the nucleus where it heterodimerizes with its partner HIF-1H. HIF-1a is overexpressed in the majority of human cancers.(2) The VHL tumor suppressor gene is inactivated in the majority of RCC cases. The VHL protein (pVHL) acts as an E3 ligase that targets HIF-1 for degradation by the ubiquitin proteasome system.(5)

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References

1. Klimova T CN. Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ. 2008;15(4):660-6. PMCID: 18219320.

2. Ader I MB, Cuvillier O. When the sphingosine kinase 1/sphingosine 1-phosphate pathway meets hypoxia signaling: new targets for cancer therapy. Cancer Res. 2009;69(9):3723-6. PMCID: 19383898.

3. Jiang BH LL. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res. 2009;102:19-65. PMCID: 19595306.

4. GL S. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721-32. PMCID: 13130303.

5. PG C. Role of the ubiquitin proteasome system in renal cell carcinoma. BMC Biochem. 2007;8(Suppl 1:S4). PMCID: 18047741.

6. Wang GL SG. Purification and characteriza-tion of hypoxia-inducible factor 1. J Biol Chem. 1995;270:1230-7. PMCID: 10.1074/jbc.270.3.1230.

7. Levy AP LN, Wegner S, Goldberg MA. Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem. 1995;270:13333-40. PMCID: 7768934.

8. Wang GL JB, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 1995;92:5510-4. PMCID: 7539918.

9. Ma WW AA. Novel agents on the horizon for cancer therapy. CA Cancer J Clin. 2009;59(2):111-37. PMCID: 19278961.

10. H N. Pathophysiological response to hypoxia - from the molecular mechanisms of malady to drug discovery: drug discovery for targeting the tumor microenvironment. J Pharmacol Sci. 20111;115(4):446-52. PMCID: 21422725.



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5:17 AM|KODA, K., MIYAUCHI, H., KOSUGI, C., KAIHO, T., TAKIGUCHI, N., KOBAYASHI, S., MARUYAMA, T., MATSUBARA, H., (Boso Clinical Oncology Group)|Anticancer Research current issue|Labels: HIF, CRC

Background: It has not been elucidated whether the clinical efficacy of oral fluoropyrimidines for adjuvant chemotherapy of colorectal cancer varies with tumor biological characteristics. Patients and Methods: A multicenter randomized trial was performed comparing oral tegafur/gimeracil/oteracil (S-1) and uracil-tegafur/ leucovorin (UFT/LV) as adjuvant therapy for stage III colorectal cancer. Postoperative survival was compared based on the 5-FU-related mRNA levels in cancer tissues. Results: Among patients with tumor expressing dihydropyrimidine dehydrogenase (DPD) mRNA within the 66.7th percentile (lower 2/3) of all cases, overall survival (OS) was significantly better in the S-1 than in the UFT/LV group. In the S-1 group, patients with low DPD-expressing tumors had significantly better OS than those with highly expressing tumors. Patients with low thymidine synthase (TS)-expressing tumors had significantly better OS than those with highly expressing tumors. Conclusion: The efficacy of oral fluoropyrimidines as adjuvant chemotherapy for colorectal cancer may be influenced by the level of 5-FU-related mRNA in cancer tissues.

Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide. OSCC falls into a larger category known as head and neck squamous cell carcinomas (HNSCCs). This collection constitutes all squamous cell carcinomas of the oral cavity, larynx, pharynx and oesophagus of which OSCC is the most common. Cancer cells involve morphological cellular transformation, dysregulation of apoptosis, uncontrolled cellular proliferation, invasion, angiogenesis, and metastasis. Also, one of the hallmarks of cancer is the elevated uptake of glucose even under normal oxygen conditions, known as aerobic glycolysis or the “Warburg effect”. The Warburg effect is the cellular phenomenon in which the tumor cells primarily use glycolysis for energy production instead of mitochondrial oxidative phosphorylation like normal cells. These cellular responses have been shown to cause distinct transformations like the upregulation of proteins such as hypoxia-inducible factor 1-α that help the tumor survive adverse conditions in which normal cells cannot persist. HIF-1α stimulates transcriptional induction of a series of genes that participate in iron metabolism, glucose metabolism, cell proliferation / survival and angiogenesis.
Friday, September 16, 2016 4:27 PM|Alessia Lo Dico, Viviana Costa, Cristina Martelli, Cecilia Diceglie, Francesca Rajata, Aroldo Rizzo, Carmine Mancone, Marco Tripodi, Luisa Ottobrini, Riccardo Alessandro, Alice Conigliaro|Theranostics|Labels: HIF, brain cancer

Hypoxia is a common feature in solid tumours. In glioma, it is considered the major driving force for tumour angiogenesis and correlates with enhanced resistance to conventional therapies, increased invasiveness and a poor prognosis for patients. Here we describe, for the first time, that miR675-5p, embedded in hypoxia-induced long non-coding RNA H19, plays a mandatory role in establishing a hypoxic response and in promoting hypoxia-mediated angiogenesis. We demonstrated, in vitro and in vivo, that miR675-5p over expression in normoxia is sufficient to induce a hypoxic moreover, miR675-5p depletion in low oxygen conditions, drastically abolishes hypoxic responses including angiogenesis. In addition, our data indicate an interaction of miR675-5p, HIF-1α mRNA and the RNA Binding Protein HuR in hypoxia-induced responses. We suggest the modulation of miR675-5p as a new therapeutic option to promote or abolish hypoxia induced angiogenesis.

Thursday, September 15, 2016 7:51 PM|Lilia Dimitrov, Christopher S. Hong, Chunzhang Yang, Zhengping Zhuang, John D. Heiss|International Journal of Medical Sciences|Labels: HIF, brain cancer, clinical trial

In the last five years, IDH1 mutations in human malignancies have significantly shaped the diagnosis and management of cancer patients. Ongoing intense research efforts continue to alter our understanding of the role of the IDH1 mutation in tumor formation. Currently, evidence suggests the IDH1 mutation to be an early event in tumorigenesis with multiple downstream oncogenic consequences including maintenance of a hypermethylator phenotype, alterations in HIF signalling, and disruption of collagen maturation contributing to a cancer-promoting extracellular matrix. The most recent reports elucidating these mechanisms is described in this review with an emphasis on the pathogenesis of the IDH1 mutation in glioma. Conflicting findings from various studies are discussed, in order to highlight areas warranting further research. Finally, the latest progress in developing novel therapies against the IDH1 mutation is presented, including recent findings from ongoing phase 1 clinical trials and the exciting prospect of vaccine immunotherapy targeting the IDH1 mutant protein.

Wednesday, September 14, 2016 4:23 PM|A. Slominski|JournalTOCs API - Journal of Investigative Dermatology (875 articles)|Labels: HIF, RXR, melanoma

476 Expression of retinoic acid receptor-related orphan receptors (ROR) α and γ correlates with hypoxia in cutaneous melanomas
A.A. Brozyna W. Jozwicki, M. Pawlikowska, E. Wedrowska, A. Slominski
Journal of Investigative Dermatology, Vol. 136, No. 9 (2016) pp. S241 -
Hypoxia is one of the hallmarks of the tumor microenvironment and up-regulation of hypoxia-inducible factor 1 alpha (HIF-1α) is considered as a negative prognostic marker. Recently the role of retinoic acid–related orphan receptor (ROR) α and γ in hypoxia signaling pathway have been identified. RORα and RORγ are involved in many physiological functions in several organs. Previously we showed that RORs are expressed in human normal skin and melanocytic tumors including nevi and melanomas. Furthermore, we reported that HIF-1α expression and HIF-1α dependent pathways can be regulated by melanogenesis and are related to poorer prognosis of melanoma.

Tuesday, September 13, 2016 11:38 PM|Yasushi Kimura, Atsushi Kasamatsu, Dai Nakashima, Masanobu Yamatoji, Yasuyuki Minakawa, Kazuyuki Koike, Kazuaki Fushimi, Morihiro Higo, Yosuke Endo-Sakamoto, Masashi Shiiba, Hideki Tanzawa, Katsuhiro Uzawa|Journal of Cancer|Labels: HIF

Aryl hydrocarbon receptor nuclear translocator (ARNT) 2 is a transcriptional factor related to adaptive responses against cellular stress from a xenobiotic substance. Recent evidence indicates ARNT is involved in carcinogenesis and cancer progression; however, little is known about the relevance of ARNT2 in the behavior of oral squamous cell carcinoma (OSCC). In the current study, we evaluated the ARNT2 mRNA and protein expression levels in OSCC in vitro and in vivo and the clinical relationship between ARNT2 expression levels in primary OSCCs and their clinicopathologic status by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemistry. Using ARNT2 overexpression models, we performed functional analyses to investigate the critical roles of ARNT2 in OSCC. ARNT2 mRNA and protein were down-regulated significantly (P < 0.05 for both comparisons) in nine OSCC-derived cells and primary OSCC (n=100 patients) compared with normal counterparts. In addition to the data from exogenous experiments that ARNT2-overexpressed cells showed decreased cellular proliferation, ARNT2-positive OSCC cases were correlated significantly (P < 0.05) with tumoral size. Since von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase, a negative regulator of hypoxia-inducible factor (HIF1)-α, is a downstream molecule of ARNT2, we speculated that HIF1-α and its downstream molecules would have key functions in cellular growth. Consistent with our hypothesis, overexpressed ARNT2 cells showed down-regulation of HIF1-α, which causes hypofunctioning of glucose transporter 1, leading to decreased cellular growth. Our results proposed for the first time that the ARNT2 level is an indicator of cellular proliferation in OSCCs. Therefore, ARNT2 may be a potential therapeutic target against progression of OSCCs.

Tuesday, September 13, 2016 8:19 PM|Eun Jung Sohn, Gunho Won, Jihyun Lee, Sangyoon Lee, Sung-hoon Kim|Journal of Cancer (RSS 2.0)|Labels: HIF, VEGF, prostate cancer

Recently microRNAs (miRNAs) have been attractive targets with their key roles in biological regulation through post-transcription to control mRNA stability and protein translation. Though melatonin was known as an anti-angiogenic agent, the underlying mechanism of melatonin in PC-3 prostate cancer cells under hypoxia still remains unclear. Thus, in the current study, we elucidated the important roles of miRNAs in melatonin-induced anti-angiogenic activity in hypoxic PC-3 cells. miRNA array revealed that 33 miRNAs (>2 folds) including miRNA3195 and miRNA 374b were significantly upregulated and 16 miRNAs were downregulated in melatonin-treated PC-3 cells under hypoxia compared to untreated control. Melatonin significantly attenuated the expression of hypoxia-inducible factor (HIF)-1 alpha, HIF-2 alpha and vascular endothelial growth factor (VEGF) at mRNA level in hypoxic PC-3 cells. Consistently, melatonin enhanced the expression of miRNA3195 and miRNA 374b in hypoxic PC-3 cells by qRT-PCR analysis. Of note, overexpression of miRNA3195 and miRNA374b mimics attenuated the mRNA levels of angiogenesis related genes such as HIF-1alpha, HIF-2 alpha and VEGF in PC-3 cells under hypoxia. Furthermore, overexpression of miRNA3195 and miRNA374b suppressed typical angiogenic protein VEGF at the protein level and VEGF production induced by melatonin, while antisense oligonucleotides against miRNA 3195 or miRNA 374b did not affect VEGF production induced by melatonin. Also, overexpression of miR3195 or miR374b reduced HIF-1 alpha immunofluorescent expression in hypoxic PC-3 compared to untreated control. Overall, our findings suggest that upregulation of miRNA3195 and miRNA374b mediates anti-angiogenic property induced by melatonin in hypoxic PC-3 cells.

Tuesday, September 13, 2016 2:05 PM|Yi Lu, Chikezie Madu, Jordan Masters, Andrew Lu, Liyuan Li|Journal of Cancer|Labels: HIF, VEGF

Breast cancer (BCa) is the most diagnosed cancer and the second leading cause of cancer death in the American women. Adaptation to the hypoxic environment seen in solid tumors is critical for tumor cell survival and growth. The activation of hypoxia inducible factor-1 alpha (HIF-1α), an important master transcriptional factor that is induced and stabilized by intratumoral hypoxia, stimulates a group of HIF-1α-regulated genes including vascular endothelial growth factor (VEGF), leading tumor cells towards malignant progression. Therefore, a promising therapeutic approach to cancer treatment is to target HIF-1α. The goal of this project was to develop and validate a screening system coupled with secondary screen/validation process that has the capability to screen large numbers of potential anti-cancer small-molecule compounds based on their anti-HIF-1α activities. Breast cancer MDA-231 cells were used as the model to select potent anti-HIF-1α compounds by their abilities to inhibit transactivation of a VEGF promoter fused to a luciferase reporter gene under hypoxia. Positive compounds were then validated by a series of assays that confirm compounds' anti-HIF-1α activities including measurement of HIF-1α downstream VEGF gene expression and angiogenic ability of BCa cells. Results of our pilot screening demonstrate that this prototype screening coupled with validation system can effectively select highly potent anti-HIF-1α agents from the compound library, suggesting that this prototype screen system has the potential to be developed into a high-throughput screen (HTS) coupled with automated validation process for the screening and identification of novel and effective anti-cancer drugs based on anti-HIF-1α mechanism.

Tuesday, September 13, 2016 1:08 PM| Daniel Triner, Yatrik M. Shah |The Journal of Clinical Investigation -- Current Issue|Labels: HIF
The tumor immune response is in a dynamic balance between antitumor mechanisms, which serve to decrease cancer growth, and the protumor inflammatory response, which increases immune tolerance, cell survival, and proliferation. Hypoxia and expression of HIF-1α and HIF-2α are characteristic features of all solid tumors. HIF signaling serves as a major adaptive mechanism in tumor growth in a hypoxic microenvironment. HIFs represent a critical signaling node in the switch to protumorigenic inflammatory responses through recruitment of protumor immune cells and altered immune cell effector functions to suppress antitumor immune responses and promote tumor growth through direct growth-promoting cytokine production, angiogenesis, and ROS production. Modulating HIF function will be an important mechanism to dampen the tumor-promoting inflammatory response and inhibit cancer growth.
Tuesday, September 13, 2016 11:40 AM|Top Health News -- ScienceDaily|Labels: HIF, kidney cancer
New insights into the potential for new classes of HIF inhibitors to restore control of the hypoxia response -- representing the potential foundation of a new cancer-fighting strategy -- are the focus of recently published research.
Monday, September 5, 2016 10:23 PM|News-Medical.Net VEGF News Feed|Comments|Labels: HIF, kidney cancer
A new class of drugs called HIF-2 inhibitors is more effective and better tolerated than the standard of care drug sunitinib in treating kidney cancer, researchers with the Kidney Cancer Program at Harold C. Simmons Comprehensive Cancer Center have found.
Wednesday, August 17, 2016 10:10 AM|Budda, S. A., Girton, A., Henderson, J. G., Zenewicz, L. A.|Next in The JI|Labels: HIF, CRC, IL

IL-22 is expressed by activated lymphocytes and is important in modulation of tissue responses during inflammation. The cytokine induces proliferative and antiapoptotic pathways in epithelial cells allowing enhanced cell survival. This can have positive effects, such as in the maintenance of epithelial barriers in the gastrointestinal tract, but also negative effects, such as contributing to colorectal tumorigenesis. Because IL-22 can be dual-natured, we hypothesized that its biological activity should be tightly regulated to limit IL-22 expression to the sites of inflammation. One such environmental cue could be low oxygen, which often accompanies inflammation. We show that in CD4 T cells IL-22 expression is upregulated in hypoxia. The Il22 promoter contains a putative conserved hypoxic response element suggesting that the transcription factor HIF-1α may influence IL-22 expression. Differentiation in the presence of dimethyloxallyl glycine, a stabilizer of HIF-1α at normoxia, increased IL-22 expression. Using HIF-1α–deficient CD4 T cells, we show that hypoxic IL-22 upregulation is dependent on HIF-1α. These findings have implications on the regulation of Il22 gene expression and the presence of the cytokine in different inflammatory environments.

Sunday, August 14, 2016 10:05 PM|Lobo, N., Gedye, C., Brown, K. R., Paterson, J., Stickle, N., Moffat, J., Jewett, M. A. S., Ailles, L. E.|Clinical Cancer Research recent issues|Labels: HIF, kidney cancer

Patients with clear cell renal cell carcinoma (ccRCC) have few therapeutic options, as ccRCC is unresponsive to chemotherapy and is highly resistant to radiation. Recently targeted therapies have extended progression-free survival, but responses are variable and no significant overall survival benefit has been achieved. Commercial ccRCC cell lines are often used as model systems to develop novel therapeutic approaches, but these do not accurately recapitulate primary ccRCC tumors at the genomic and transcriptional levels. Furthermore, ccRCC exhibits significant intertumor genetic heterogeneity, and the limited cell lines available fail to represent this aspect of ccRCC. Our objective was to generate accurate preclinical in vitro models of ccRCC using tumor tissues from ccRCC patients.

ccRCC primary single cell suspensions were cultured in fetal bovine serum (FBS)-containing media or defined serum-free media (DFSM). The apparent efficiency of primary cell culture establishment was high in both culture conditions, but genotyping by single nucleotide polymorphism (SNP) arrays revealed that the majority of cultures in FBS (6 of 8), and all of the cultures in DFSM (8 of 8), contained normal, not cancer cells. To distinguish cancer vs. normal cells in subsequent experiments, we sequenced the von Hippel Lindau (VHL) gene, which is mutated in a large percentage of patients, in a cohort of samples for which cryopreserved viable single cell suspensions were available. Once patients with sequence-detectable mutations were identified, the cells were thawed and cultured as before. Established cultures were then sequenced for the patient-specific VHL mutations. Once again, the majority of cultures in FBS (1 of 7), and all of the cultures in DSFM (7 of 7) contained VHL-wild type cells. The loss of VHL leads to accumulation of hypoxia-inducible factor (HIF) and expression of HIF target genes. Therefore, in an attempt to select for VHL-mutant cancer cells, we used fluorescence activated cell sorting (FACS) to isolate cells expressing Carbonic Anhydrase IX (CA9), a cell surface HIF target. Isolated CA9+ cells were cultured in FBS-containing media, and upon genotyping, we found that VHL-mutant ccRCC cell cultures were established with an efficiency of ~85%. Parallel cultures of bulk single cell suspensions in serum-free conditions again selected for growth of normal (VHL-wild type) cells. The normal cells were verified to be renal proximal tubule epithelial cells based on their expression of renal proximal tubule markers Aquaporin-1 and Alkaline Phosphatase. Transcriptional profiling of ccRCC and matched normal cell cultures identified up- and down-regulated networks in ccRCC and comparison to The Cancer Genome Atlas confirmed the clinical validity of our cell cultures. The ability to establish patient-derived cultures of ccRCC cells and matched normal kidney epithelial cells from almost every patient provides a resource for future development of novel therapies and personalized medicine for ccRCC patients.

Citation Format: Nazleen Lobo, Craig Gedye, Kevin R. Brown, Joshua Paterson, Natalie Stickle, Jason Moffat, Michael A.S. Jewett, Laurie E. Ailles. Efficient generation of patient-matched malignant and normal primary cell cultures from clear cell renal cell carcinoma patients: clinically relevant models for research and personalized medicine. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B09.

Thursday, July 28, 2016 7:56 AM|Tiram, G., Ofek, P., Udagawa, T., Shomron, N., Roniger, M., Kerem, B., Shaked, Y., Aviel-Ronen, S., Barshack, I., Calderon, M., Haag, R., Satchi-Fainaro, R.|Cancer Research recent issues|Labels: HIF, MET
The presence of dormant, microscopic cancerous lesions possesses a major obstacle for the treatment of metastatic and recurrent cancers. While it is well-established that microRNAs play a major role in tumorigenesis, their involvement in tumor dormancy has yet to be fully elucidated. We established and comprehensively characterized a human osteosarcoma dormancy model of a pair of cells originating from the same parental tissue; one that remains avascular and non-palpable a year following inoculation into mice and another that generates vascularized palpable tumors one month following inoculation. Using this model of cell lines generating dormant or fast-growing osteosarcomas, we identified three novel regulators of osteosarcoma dormancy: miR-34a, miR-93 and miR-200c. This is the first report showing that loss of these three microRNAs occurs during the switch from dormant avascular into fast-growing angiogenic phenotype. Furthermore, we validated their downregulation in patients' tumor samples compared to normal bone, making them attractive candidates for osteosarcoma therapy. Reconstitution of these microRNAs into Soas-2 and MG-63 cells, which generate fast-growing osteosarcomas, reduced the levels of their target genes, MET proto-oncogene, hypoxia-inducible factor 1α, and moesin, critical to cancer angiogenesis and cancer cells' migration. We further demonstrate that these miRNAs attenuate the angiogenic capabilities of fast-growing osteosarcoma in vitro and in vivo. Moreover, treatment with each of these microRNAs using our novel polyglycerol dendritic nanocarrier significantly prolonged their dormancy period. Taken together, these findings suggest that miR-34a, miR-93 and miR-200c have a key role in osteosarcoma progression, and provide the rationale for the development of novel diagnostic and therapeutic tools for osteosarcoma and other malignancies.Citation Format: Galia Tiram, Paula Ofek, Taturo Udagawa, Noam Shomron, Maayan Roniger, Batsheva Kerem, Yuval Shaked, Sarit Aviel-Ronen, Iris Barshack, Marcelo Calderon, Rainer Haag, Ronit Satchi-Fainaro. Dysregulation of key microRNAs controlling tumor-host interactions triggers escape from osteosarcoma dormancy. [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 B42.
Thursday, April 28, 2016 9:59 AM|SADAHIRO, S., SUZUKI, T., TANAKA, A., OKADA, K., SAITO, G., KAMIJO, A., NAGASE, H.|Anticancer Research recent issues|Labels: HIF, CRC

Aim: The aim of the study was to identify biomarkers capable of predicting response to preoperative chemoradiotherapy (CRT) including S-1 or UFT for rectal cancer using biopsy specimens obtained before CRT (Pre-samples) and 7 days after the start of CRT (Day-7 samples). Materials and Methods: Preoperative CRT including S-1 or UFT was performed in 82 patients with locally advanced rectal cancer. The expression levels of 18 genes related to 5-fluorouracil, folate, and radiation in the Pre-samples and the Day-7 samples were evaluated using reverse transcription polymerase chain reaction (RT-PCR) assay. Results: The gene expression levels of hypoxia inducible factor 1 alpha subunit (HIF1A), dihydropyrimidine dehydrogenase (DPYD) and thymidine phosphorylase (TYMP) were found significantly increased in Day-7 samples compared to Pre-samples in responders, but not in non-responders. Conclusion: Increases in gene expression levels of TYMP, DPYD, and HIF1A in tumor tissues at 7 days after the start of CRT may be useful for predicting the efficacy of CRT including S-1 or UFT.

Friday, March 25, 2016 10:58 AM|International Journal of Radiation Biology|MedWorm: Transitional Cell Carcinoma|Comments|Labels: HIF, bladder cancer
CONCLUSIONS: HIF1α and LDH5 are markers of poor outcome in patients with bladder cancer treated with radiotherapy. Blockage of anaerobic metabolism may prove of importance in clinical radiotherapy. PMID: 27010533 [PubMed - as supplied by publisher] (Source: International Journal of Radiation Biology)