Expression analysis of HIF-3α as a potent prognostic biomarker in various types of human cancers: a case of meta-analysis
Abstract
Background and purpose: Hypoxia-inducible factors (HIFs) are transcription factors that get activated and stabilized in the heterodimerized form under hypoxic conditions. many studies have reported the importance of the HIF-1α and HIF-2α activity in biological pathways of hypoxic cancer cells. However, the importance of HIF-3α in a variety of cancers remains unknown.
Experimental approach: The expression profile of 13 different types of cancer samples from the Cancer Genome Atlas (TCGA) database were subjected to normalization, and differential gene expression analysis was performed using computational algorithms by R programming. Receiver operating characteristic tests and survival analyses were carried out for HIF-α subunits in different cancers.
Findings / Results: The expression status of HIF-3α was notably less in all cancer samples in contrast to their adjacent normal tissues. The expression degree of HIF-1α varied among distinct types of cancer and the expression degree of HIF-2α was lower in nearly all types of cancers. HIF-3α had very weak diagnostic potential, while HIF-2α had better diagnostic potential in most types of cancers compared to HIF-1α. Patients who had a higher level of HIF-3α had better survival, while the higher expression level of HIF-1α and HIF-2α were associated with worse survival in many types of cancers.
Keywords
Full Text:
PDFReferences
Brahimi-Horn MC, Chiche J, Pouysségur J. Hypoxia and cancer. J Mol Med (Berl). 2007;85(12): 1301-1307. DOI: 10.1007/s00109-007-0281-3.
Moeller BJ, Richardson RA, Dewhirst MW. Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment. Cancer Metastasis Rev. 2007;26(2):241-248. DOI: 10.1007/s10555-007-9056-0.
Sørensen BS, Horsman MR. Tumor hypoxia: impact on radiation therapy and molecular pathways. Front Oncol. 2020;10:562.
DOI: 10.3389/fronc.2020.00562.
Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4(6):437-447. DOI: 10.1038/nrc1367.5. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40(2):294-309. DOI: 10.1016/j.molcel.2010.09.022.
Keith B, Simon MC. Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007;129(3):465-472. DOI: 10.1016/j.cell.2007.04.019.
Rankin E, Giaccia AJ. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 2008;15(4):678-685. DOI: 10.1038/cdd.2008.21.
Maynard MA, Ohh M. The role of hypoxia-inducible factors in cancer. Cell Mol Life Sci. 2007;64(16):2170-2180. DOI: 10.1007/s00018-007-7082-2.
Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW. Hypoxia-inducible factor (HIF-1) α: its protein stability and biological functions. Exp Mol Med. 2004;36(1):1-12. DOI: 10.1038/emm.2004.1.10. Webb JD, Coleman ML, Pugh CW. Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing. Cell Mol Life Sci. 2009;66(22):3539-3554. DOI: 10.1007/s00018-009-0147-7.
Chun YS, Kim MS, Park JW. Oxygen-dependent and-independent regulation of HIF-1alpha. J Korean Med Sci. 2002;17(5):581-588. DOI: 10.3346/jkms.2002.17.5.581.
Weidemann A, Johnson R. Biology of HIF-1alpha. Cell Death Differ. 2008;15(4):621-627. DOI: 10.1038/cdd.2008.12.
Maxwell PH, Pugh CW, Ratcliffe PJ. The pVHL-HIF-1 System. In: Crusio WE, Dong H, Radeke HH, Rezaei N, Steinlein O, Xiao J, editors. Advances in Experimental Medicine and Biology Hypoxia: Springer; 2001. pp. 365-376. DOI: 10.1007/978-1-4757-3401-0_24.
Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001;13(2):167-171. DOI: 10.1016/S0955-0674(00)00194-0.
Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5(5):343-354. DOI: 10.1038/nrm1366.
Chan DA, Sutphin PD, Yen SE, Giaccia AJ. Coordinate regulation of the oxygen-dependent degradation domains of hypoxia-inducible factor 1α. Mol Cell Biol. 2005;25(15):6415-6426. DOI: 10.1128/MCB.25.15.6415-6426.2005.
Wu D, Potluri N, Lu J, Kim Y, Rastinejad F. Structural integration in hypoxia-inducible factors. Nature. 2015;524(7565):303-308. DOI: 10.1038/nature14883.
Robey IF, Lien AD, Welsh SJ, Baggett BK, Gillies RJ. Hypoxia-inducible factor-1α and the glycolytic phenotype in tumors. Neoplasia. 2005;7(4):324-330. DOI: 10.1593/neo.04430.
Semenza GL. HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010;20(1):51-56. DOI: 10.1016/j.gde.2009.10.009.
Mucaj V, Shay JE, Simon MC. Effects of hypoxia and HIFs on cancer metabolism. Int J Hematol. 2012;95(5):464-470. DOI: 10.1007/s12185-012-1070-5
Duan C. Hypoxia-inducible factor 3 biology: complexities and emerging themes. Am J Physiol Cell Physiol. 2016;310(4):C260-C269. DOI: 10.1152/ajpcell.00315.2015.
Dengler VL, Galbraith MD, Espinosa JM. Transcriptional regulation by hypoxia inducible factors. Crit Rev Biochem Mol Biol. 2014;49(1):1-15. DOI: 10.3109/10409238.2013.838205
Heikkilä M, Pasanen A, Kivirikko KI, Myllyharju J. Roles of the human hypoxia-inducible factor (HIF)-3α variants in the hypoxia response. Cell Mol Life Sci. 2011;68(23):3885-3901. DOI: 10.1007/s00018-011-0679-5.
Tolonen J-P, Heikkilä M, Malinen M, Lee H-M, Palvimo JJ, Wei G-H, et al. A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin. Cell Mol Life Sci. 2020;77(18):3627-3642. DOI: 10.1007/s00018-019-03387-9.
Torii S, Goto Y, Ishizawa T, Hoshi H, Goryo K, Yasumoto K, et al. Pro-apoptotic activity of inhibitory PAS domain protein (IPAS), a negative regulator of HIF-1, through binding to pro-survival Bcl-2 family proteins. Cell Death Differ. 2011;18(11):1711-1725. DOI: 10.1038/cdd.2011.47.
Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl). 2015;3:83-92. DOI: 10.2147/HP.S93413.
Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D. Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev. 2003;29(4):297-307. DOI: 10.1016/S0305-7372(03)00003-3.
Semenza GL. Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer Cell. 2004;5(5):405-406. DOI: 10.1016/S1535-6108(04)00118-7.
Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 2002;62(12):3387-3394. PMID: 12067980.
Ruan K, Song G, Ouyang G. Role of hypoxia in the hallmarks of human cancer. J Cell Biochem. 2009;107(6):1053-1062. DOI: 10.1002/jcb.22214.
Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Turley H, Talks K, et al. Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2002;53(5):1192-1202. DOI: 10.1016/S0360-3016(02)02848-1.
Baba Y, Nosho K, Shima K, Irahara N, Chan AT, Meyerhardt JA, et al. HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am J Pathol. 2010;176(5): 2292-2301. DOI: 10.2353/ajpath.2010.090972.
Ebright RY, Zachariah MA, Micalizzi DS, Wittner BS, Niederhoffer KL, Nieman LT, et al. HIF1A signaling selectively supports proliferation of breast cancer in the brain. Nat Commun. 2020;11(1): 6311,1-13. DOI: 10.1038/s41467-020-20144-w.
de Heer EC, Jalving M, Harris AL. HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. J Clin Invest. 2020;130(10):5074-5087. DOI: 10.1172/JCI137552.
Giatromanolaki A, Koukourakis M, Sivridis E, Turley H, Talks K, Pezzella F, et al. Relation of hypoxia inducible factor 1 α and 2 α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer. 2001;85(6):881-890. DOI: 10.1054/bjoc.2001.2018.
Zhang C, Liu J, Zhang Y, Luo C, Zhu T, Zhang R, et al. LINC01342 promotes the progression of ovarian cancer by absorbing microRNA‐30c‐2‐3p to upregulate HIF3A. J Cell Physiol. 2020;235(4):3939-3949. DOI: 10.1002/jcp.29289.
Bjerre MT, Strand SH, Nørgaard M, Kristensen H, Rasmussen AK, Mortensen MM, et al. Aberrant DOCK2, GRASP, HIF3A and PKFP hypermethylation has potential as a prognostic biomarker for prostate cancer. Int J Mol Sci. 2019;20(5):1173. DOI: 10.3390/ijms20051173.
Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, et al. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature. 2001;414(6863):550-554. DOI: 10.1038/35107085.
Zhou X, Guo X, Chen M, Xie C, Jiang J. HIF-3a promotes metastatic phenotypes in pancreatic cancer by transcriptional regulation of the RhoC-ROCK1 signaling pathway. Mol Cancer Res. 2018;16(1):124-134. DOI: 10.1158/1541-7786.MCR-17-0256.
Xue X, Jungles K, Onder G, Samhoun J, Győrffy B, Hardiman KM. HIF-3α1 promotes colorectal tumor cell growth by activation of JAK-STAT3 signaling. Oncotarget. 2016;7(10):11567-11579. DOI: 10.18632/oncotarget.7272.
Liu P, Fang X, Song Y, Jiang JX, He QJ, Liu XJ. Expression of hypoxia‑inducible factor 3α in hepatocellular carcinoma and its association with other hypoxia‑inducible factors. Exp Ther Med. 2016;11(6):2470-2476. DOI: 10.3892/etm.2016.3193.
Goryo K, Torii S, Yasumoto K-i, Sogawa K. Tumour necrosis factor-α suppresses the hypoxic response by NF-κB-dependent induction of inhibitory PAS domain protein in PC12 cells. J Biochem. 2011;150(3):311-318. DOI: 10.1093/jb/mvr061.
Tanaka T, Wiesener M, Bernhardt W, Eckardt K-U, Warnecke C. The human HIF (hypoxia-inducible factor)-3 α gene is a HIF-1 target gene and may modulate hypoxic gene induction. Biochem J. 2009;424(1):143-151. DOI: 10.1042/BJ20090120.
Li QF, Wang XR, Yang YW, Lin H. Hypoxia upregulates hypoxia-inducible factor (HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α. Cell Res. 2006;16(6):548-558. DOI: 10.1038/sj.cr.7310072.
Maynard MA, Evans AJ, Shi W, Kim WY, Liu F-F, Ohh M. Dominant-negative HIF-3α4 suppresses VHL-null renal cell carcinoma progression. Cell Cycle. 2007;6(22):2810-2816. DOI: 10.4161/cc.6.22.4947.
Refbacks
- There are currently no refbacks.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.