Mild chronic hypoxia-induced HIF-2α interacts with c-MYC through competition with HIF-1α to induce hepatocellular carcinoma cell proliferation.

Publisher: Springer Country of Publication: Netherlands NLM ID: 101552938 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-3436 (Electronic) Linking ISSN: 22113428 NLM ISO Abbreviation: Cell Oncol (Dordr) Subsets: MEDLINE

Original Publication: Dordrecht : Springer

Basic Helix-Loop-Helix Transcription Factors/*genetics ; Carcinoma, Hepatocellular/*genetics ; Cell Proliferation/*genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/*genetics ; Liver Neoplasms/*genetics ; Proto-Oncogene Proteins c-myc/*genetics; Aged ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Binding, Competitive ; Blotting, Western ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic ; Hep G2 Cells ; Humans ; Hypoxia/genetics ; Hypoxia/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Male ; Middle Aged ; Protein Binding ; Proto-Oncogene Proteins c-myc/metabolism ; Reverse Transcriptase Polymerase Chain Reaction

Purpose: Hepatocellular carcinoma (HCC) has emerged as a leading cause of cancer-related deaths globally, in which hypoxia and activated hypoxia-inducible factors (HIFs) play important roles. The sibling rivalry between HIF-1α and HIF-2α in hypoxic tumor growth and progression still remains to be resolved, including in HCC. In this study, we aimed to analyze the mechanism by which HIF-1α and HIF-2α balance the proliferative response of HCC cells to hypoxia.
Methods: The expression of HIF-1α, HIF-2α, c-MYC, Rictor and Raptor in corresponding tumor and non-tumor tissues from twenty-six patients with HCC was analyzed. The relationships between HIF-1α and HIF-2α and their respective effects were evaluated further in vitro in hypoxic HCC cells using co-immunoprecipitation, chromatin immunoprecipitation, in situ proximity ligation, annexin V-FITC/PI staining apoptosis and MTT assay. In addition, short hairpin RNA (shRNA) transfections targeting HIF-1α/2α and Rictor and Western blotting were applied in HCC cells to study the underlying mechanism.
Results: We found that HIF-2α expression showed a positive correlation with c-MYC expression in tumor tissues, whereas HIF-1α did not. In vitro, increased HCC cell proliferation and an increased interaction between HIF-2α and c-MYC were observed under mild chronic hypoxic conditions. Although mild hypoxia led to HIF-1α, HIF-2α and c-MYC up-regulation, we found that mTORC2-regulated HIF-2α competed with HIF-1α to bind to c-MYC. Moreover, we found that HIF-2α knockdown decreased the expression of downstream c-MYC, suppressed hypoxic cell proliferation, and induced HCC cell apoptosis, whereas HIF-1α knockdown did not. Additionally, we found that the PI3K inhibitor apitolisib counteracted the effect of HIF-2α, thereby inducing HCC cell apoptosis.
Conclusions: Our data highlight a role of HIF-2α in activating and binding c-MYC, thereby inducing HCC cell proliferation during mild chronic hypoxia. The PI3K/mTORC2/HIF-2α/c-MYC axis may play a key role in this process. The PI3K inhibitor apitolisib may serve as a potential treatment option for patients suffering from HCC, especially in cases with rapidly growing tumors under mild chronic hypoxic conditions.
(© 2021. Springer Nature Switzerland AG.)

A. Forner, M. Reig, J. Bruix, Hepatocellular carcinoma. Lancet 391, 1301–1314 (2018). (PMID: 2930746710.1016/S0140-6736(18)30010-2)
A. Villanueva, Hepatocellular carcinoma. N. Engl. J. Med. 380, 1450–1462 (2019). (PMID: 3097019010.1056/NEJMra1713263)
J.M. Llovet, R. Montal, D. Sia, R.S. Finn, Molecular therapies and precision medicine for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 15, 599–616 (2018). (PMID: 3006173910.1038/s41571-018-0073-4)
R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020). (PMID: 10.3322/caac.2159031912902)
S.R. McKeown, Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response. Br. J. Radiol. 87, 20130676 (2014). (PMID: 24588669406460110.1259/bjr.20130676)
G.K. Wilson, D.A. Tennant, J.A. McKeating, Hypoxia inducible factors in liver disease and hepatocellular carcinoma: current understanding and future directions. J. Hepatol. 61, 1397–1406 (2014). (PMID: 2515798310.1016/j.jhep.2014.08.025)
C. Chen, T. Lou, Hypoxia inducible factors in hepatocellular carcinoma. Oncotarget 8, 46691–46703 (2017). (PMID: 28493839554230310.18632/oncotarget.17358)
C. Mendez-Blanco, F. Fondevila, A. Garcia-Palomo, J. Gonzalez-Gallego, J.L. Mauriz, Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors. Exp. Mol. Med. 50, 1–9 (2018). (PMID: 3031518210.1038/s12276-018-0159-1)
L. Tang, J. Zeng, P. Geng, C. Fang, Y. Wang, M. Sun, C. Wang, J. Wang, P. Yin, C. Hu, L. Guo, J. Yu, P. Gao, E. Li, Z. Zhuang, G. Xu, Y. Liu, Global metabolic profiling identifies a pivotal role of proline and hydroxyproline metabolism in supporting hypoxic response in hepatocellular carcinoma. Clin. Cancer Res. 24, 474–485 (2018). (PMID: 2908491910.1158/1078-0432.CCR-17-1707)
G.L. Semenza, Hypoxia-inducible factors in physiology and medicine. Cell 148, 399–408 (2012). (PMID: 22304911343754310.1016/j.cell.2012.01.021)
K. Helczynska, A.M. Larsson, L. Holmquist Mengelbier, E. Bridges, E. Fredlund, S. Borgquist, G. Landberg, S. Pahlman, K. Jirstrom, Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer. Cancer Res. 68, 9212–9220 (2008). (PMID: 1901089310.1158/0008-5472.CAN-08-1135)
R. Noguera, E. Fredlund, M. Piqueras, A. Pietras, S. Beckman, S. Navarro, S. Pahlman, HIF-1alpha and HIF-2alpha are differentially regulated in vivo in neuroblastoma: high HIF-1alpha correlates negatively to advanced clinical stage and tumor vascularization. Clin. Cancer Res. 15, 7130–7136 (2009). (PMID: 1990379210.1158/1078-0432.CCR-09-0223)
W.Y. Kim, S. Perera, B. Zhou, J. Carretero, J.J. Yeh, S.A. Heathcote, A.L. Jackson, P. Nikolinakos, B. Ospina, G. Naumov, K.A. Brandstetter, V.J. Weigman, S. Zaghlul, D.N. Hayes, R.F. Padera, J.V. Heymach, A.L. Kung, N.E. Sharpless, W.G. Kaelin Jr., K.K. Wong, HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice. J. Clin. Invest. 119, 2160–2170 (2009). (PMID: 19662677271995010.1172/JCI38443)
N. Qin, A.A. de Cubas, R. Garcia-Martin, S. Richter, M. Peitzsch, M. Menschikowski, J.W. Lenders, H.J. Timmers, M. Mannelli, G. Opocher, M. Economopoulou, G. Siegert, T. Chavakis, K. Pacak, M. Robledo, G. Eisenhofer, Opposing effects of HIF1alpha and HIF2alpha on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC-associated factor X. Int. J. Cancer 135, 2054–2064 (2014). (PMID: 2467684010.1002/ijc.28868)
B. Keith, R.S. Johnson, M.C. Simon, HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 12, 9–22 (2011). (PMID: 22169972340191210.1038/nrc3183)
L.E. Huang, Carrot and stick: HIF-alpha engages c-Myc in hypoxic adaptation. Cell Death Differ. 15, 672–677 (2008). (PMID: 1818816610.1038/sj.cdd.4402302)
C.V. Dang, c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol. Cell. Biol. 19, 1–11 (1999). (PMID: 98585268386010.1128/MCB.19.1.1)
J.W. Kim, P. Gao, Y.C. Liu, G.L. Semenza, C.V. Dang, Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol. Cell. Biol. 27, 7381–7393 (2007). (PMID: 17785433216905610.1128/MCB.00440-07)
J. Zhang, M. Sattler, G. Tonon, C. Grabher, S. Lababidi, A. Zimmerhackl, M.S. Raab, S. Vallet, Y. Zhou, M.A. Cartron, T. Hideshima, Y.T. Tai, D. Chauhan, K.C. Anderson, K. Podar, Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma. Cancer Res. 69, 5082–5090 (2009). (PMID: 1950923110.1158/0008-5472.CAN-08-4603)
M.R. Doe, J.M. Ascano, M. Kaur, M.D. Cole, Myc posttranscriptionally induces HIF1 protein and target gene expression in normal and cancer cells. Cancer Res. 72, 949–957 (2012). (PMID: 2218613910.1158/0008-5472.CAN-11-2371)
C. Chen, S. Cai, G. Wang, X. Cao, X. Yang, X. Luo, Y. Feng, J. Hu, c-Myc enhances colon cancer cell-mediated angiogenesis through the regulation of HIF-1α. Biochem. Biophys. Res. Commun. 430, 505–511 (2013). (PMID: 2323780710.1016/j.bbrc.2012.12.006)
L. Ma, G. Li, H. Zhu, X. Dong, D. Zhao, X. Jiang, J. Li, H. Qiao, S. Ni, X. Sun, Sun, 2-Methoxyestradiol synergizes with sorafenib to suppress hepatocellular carcinoma by simultaneously dysregulating hypoxia-inducible factor-1 and – 2. Cancer Lett. 355, 96–105 (2014). (PMID: 2521835010.1016/j.canlet.2014.09.011)
M.S. Wiesener, J.S. Jurgensen, C. Rosenberger, C.K. Scholze, J.H. Horstrup, C. Warnecke, S. Mandriota, I. Bechmann, U.A. Frei, C.W. Pugh, P.J. Ratcliffe, S. Bachmann, P.H. Maxwell, K.U. Eckardt, Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. FASEB J. 17, 271–273 (2003). (PMID: 1249053910.1096/fj.02-0445fje)
D.M. Sabatini, Twenty-five years of mTOR: Uncovering the link from nutrients to growth. Proc. Natl. Acad. Sci. U. S. A. 114, 11818–11825 (2017). (PMID: 29078414569260710.1073/pnas.1716173114)
M. Laplante, D.M. Sabatini, mTOR signaling at a glance. J. Cell Sci. 122, 3589–3594 (2009). (PMID: 19812304275879710.1242/jcs.051011)
P. Liu, H. Cheng, T.M. Roberts, J.J. Zhao, Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 8, 627–644 (2009). (PMID: 19644473314256410.1038/nrd2926)
K.M. Dodd, J. Yang, M.H. Shen, J.R. Sampson, A.R. Tee, mTORC1 drives HIF-1alpha and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene 34, 2239–2250 (2015). (PMID: 2493116310.1038/onc.2014.164)
F. Melendez-Rodriguez, O. Roche, R. Sanchez-Prieto, J. Aragones, Hypoxia-inducible factor 2-dependent pathways driving Von Hippel-Lindau-deficient renal cancer. Front. Oncol. 8, 214 (2018). (PMID: 29938199600253110.3389/fonc.2018.00214)
H. Cam, J.B. Easton, A. High, P.J. Houghton, mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1alpha. Mol. Cell 40, 509–520 (2010). (PMID: 21095582300476810.1016/j.molcel.2010.10.030)
Z. Xu, M. Xu, P. Liu, S. Zhang, R. Shang, Y. Qiao, L. Che, S. Ribback, A. Cigliano, K. Evert, R.M. Pascale, F. Dombrowski, M. Evert, X. Chen, D.F. Calvisi, X. Chen, The mTORC2-Akt1 cascade Is crucial for c-Myc to promote hepatocarcinogenesis in mice and humans. Hepatology 70, 1600–1613 (2019). (PMID: 3106236810.1002/hep.30697)
P. Liu, M. Ge, J. Hu, X. Li, L. Che, K. Sun, L. Cheng, Y. Huang, M.G. Pilo, A. Cigliano, G.M. Pes, R.M. Pascale, S. Brozzetti, G. Vidili, A. Porcu, A. Cossu, G. Palmieri, M.C. Sini, S. Ribback, F. Dombrowski, J. Tao, D.F. Calvisi, L. Chen, X. Chen, A functional mammalian target of rapamycin complex 1 signaling is indispensable for c-Myc-driven hepatocarcinogenesis. Hepatology 66, 167–181 (2017). (PMID: 2837028710.1002/hep.29183)
X. Yang, Y. Xu, D. Gao, L. Yang, S.Y. Qian, Dihomo-gamma-linolenic acid inhibits growth of xenograft tumors in mice bearing human pancreatic cancer cells (BxPC-3) transfected with delta-5-desaturase shRNA. Redox Biol. 20, 236–246 (2019). (PMID: 3038425810.1016/j.redox.2018.10.001)
J.D. Gordan, J.A. Bertout, C.J. Hu, J.A. Diehl, M.C. Simon, HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11, 335–347 (2007). (PMID: 17418410314540610.1016/j.ccr.2007.02.006)
S. Mohlin, A. Hamidian, K. von Stedingk, E. Bridges, C. Wigerup, D. Bexell, S. Pahlman, PI3K-mTORC2 but not PI3K-mTORC1 regulates transcription of HIF2A/EPAS1 and vascularization in neuroblastoma. Cancer Res. 75, 4617–4628 (2015). (PMID: 2643240510.1158/0008-5472.CAN-15-0708)
T. Powles, M.R. Lackner, S. Oudard, B. Escudier, C. Ralph, J.E. Brown, R.E. Hawkins, D. Castellano, B.I. Rini, M.D. Staehler, A. Ravaud, W. Lin, B. O’Keeffe, Y. Wang, S. Lu, J.M. Spoerke, L.Y. Huw, M. Byrtek, R. Zhu, J.A. Ware, R.J. Motzer, Randomized open-label Phase II trial of apitolisib (GDC-0980), a novel Inhibitor of the PI3K/mammalian target of rapamycin pathway, versus everolimus in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 34, 1660–1668 (2016). (PMID: 26951309556969110.1200/JCO.2015.64.8808)
S.O. Dolly, A.J. Wagner, J.C. Bendell, H.L. Kindler, L.M. Krug, T.Y. Seiwert, M.G. Zauderer, M.P. Lolkema, D. Apt, R.F. Yeh, J.O. Fredrickson, J.M. Spoerke, H. Koeppen, J.A. Ware, J.O. Lauchle, H.A. Burris III., J.S. de Bono, Phase I study of apitolisib (GDC-0980), dual phosphatidylinositol-3-kinase and mammalian target of rapamycin kinase inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 22, 2874–2884 (2016). (PMID: 26787751487692810.1158/1078-0432.CCR-15-2225)
V. Makker, F.O. Recio, L. Ma, U.A. Matulonis, J.O. Lauchle, H. Parmar, H.N. Gilbert, J.A. Ware, R. Zhu, S. Lu, L.Y. Huw, Y. Wang, H. Koeppen, J.M. Spoerke, M.R. Lackner, C.A. Aghajanian, A multicenter, single-arm, open-label, phase 2 study of apitolisib (GDC-0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study). Cancer 122, 3519–3528 (2016). (PMID: 2760300510.1002/cncr.30286)
M.R. Morris, D.J. Hughes, Y.M. Tian, C.J. Ricketts, K.W. Lau, D. Gentle, S. Shuib, P. Serrano-Fernandez, J. Lubinski, M.S. Wiesener, C.W. Pugh, F. Latif, P.J. Ratcliffe, E.R. Maher, Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma. Anticancer Res. 29, 4337–4343 (2009). (PMID: 20032376)
G. Bangoura, Z.S. Liu, Q. Qian, C.Q. Jiang, G.F. Yang, S. Jing, Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma. World J. Gastroenterol. 13, 3176–3182 (2007). (PMID: 17589895443660210.3748/wjg.v13.i23.3176)
K. Wei, S.M. Piecewicz, L.M. McGinnis, C.M. Taniguchi, S.J. Wiegand, K. Anderson, C.W. Chan, K.X. Mulligan, D. Kuo, J. Yuan, M. Vallon, L. Morton, E. Lefai, M.C. Simon, J.J. Maher, G. Mithieux, F. Rajas, J. Annes, O.P. McGuinness, G. Thurston, A.J. Giaccia, C.J. Kuo, A liver Hif-2alpha-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition. Nat. Med. 19, 1331–1337 (2013). (PMID: 24037094379583810.1038/nm.3295)
S. Anavi, M. Hahn-Obercyger, Z. Madar, O. Tirosh, Mechanism for HIF-1 activation by cholesterol under normoxia: a redox signaling pathway for liver damage. Free Radic. Biol. Med. 71, 61–69 (2014). (PMID: 2463219610.1016/j.freeradbiomed.2014.03.007)
Y. Asai, T. Yamada, S. Tsukita, K. Takahashi, M. Maekawa, M. Honma, M. Ikeda, K. Murakami, Y. Munakata, Y. Shirai, S. Kodama, T. Sugisawa, Y. Chiba, Y. Kondo, K. Kaneko, K. Uno, S. Sawada, J. Imai, Y. Nakamura, H. Yamaguchi, K. Tanaka, H. Sasano, N. Mano, Y. Ueno, T. Shimosegawa, H. Katagiri, Activation of the hypoxia inducible factor 1α subunit pathway in steatotic liver contributes to formation of cholesterol gallstones. Gastroenterology 152(6), 1521–1535.e8 (2017).
W. Hu, S. Zheng, H. Guo, B. Dai, J. Ni, Y. Shi, H. Bian, L. Li, Y. Shen, M. Wu, Z. Tian, G. Liu, M.A. Hossain, H. Yang, D. Wang, Q. Zhang, J. Yu, L. Birnbaumer, J. Feng, D. Yu, Y. Yang, PLAGL2-EGFR-HIF-1/2α signaling loop promotes HCC progression and Erlotinib insensitivity. Hepatology 73, 674-691 (2021).
A. Qu, M. Taylor, X. Xue, T. Matsubara, D. Metzger, P. Chambon, F.J. Gonzalez, Y.M. Shah, Hypoxia-inducible transcription factor 2alpha promotes steatohepatitis through augmenting lipid accumulation, inflammation, and fibrosis. Hepatology 54, 472–483 (2011). (PMID: 2153844310.1002/hep.24400)
X. Wang, J. Dong, L. Jia, T. Zhao, M. Lang, Z. Li, C. Lan, X. Li, J. Hao, H. Wang, T. Qin, C. Huang, S. Yang, M. Yu, H. Ren, HIF-2-dependent expression of stem cell factor promotes metastasis in hepatocellular carcinoma. Cancer Lett. 393, 113–124 (2017). (PMID: 2815379010.1016/j.canlet.2017.01.032)
C. He, X.P. Sun, H. Qiao, X. Jiang, D. Wang, X. Jin, X. Dong, J. Wang, H. Jiang, X. Sun, Downregulating hypoxia-inducible factor-2alpha improves the efficacy of doxorubicin in the treatment of hepatocellular carcinoma. Cancer Sci. 103, 528–534 (2012). (PMID: 22145922771241710.1111/j.1349-7006.2011.02177.x)
H.Z. Imtiyaz, E.P. Williams, M.M. Hickey, S.A. Patel, A.C. Durham, L.J. Yuan, R. Hammond, P.A. Gimotty, B. Keith, M.C. Simon, Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Invest. 120, 2699–2714 (2010). (PMID: 20644254291217910.1172/JCI39506)
H. Menrad, C. Werno, T. Schmid, E. Copanaki, T. Deller, N. Dehne, B. Brune, Roles of hypoxia-inducible factor-1alpha (HIF-1alpha) versus HIF-2alpha in the survival of hepatocellular tumor spheroids. Hepatology 51, 2183–2192 (2010). (PMID: 2051300310.1002/hep.23597)
M. Koshiji, K.K. To, S. Hammer, K. Kumamoto, A.L. Harris, P. Modrich, L.E. Huang, HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Mol. Cell 17, 793–803 (2005). (PMID: 1578093610.1016/j.molcel.2005.02.015)
M. Koshiji, Y. Kageyama, E.A. Pete, I. Horikawa, J.C. Barrett, L.E. Huang, HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J. 23, 1949–1956 (2004). (PMID: 1507150340431710.1038/sj.emboj.7600196)
T. Lofstedt, E. Fredlund, L. Holmquist-Mengelbier, A. Pietras, M. Ovenberger, L. Poellinger, S. Pahlman, Hypoxia inducible factor-2alpha in cancer. Cell Cycle 6, 919–926 (2007). (PMID: 1740450910.4161/cc.6.8.4133)
L. Holmquist-Mengelbier, E. Fredlund, T. Lofstedt, R. Noguera, S. Navarro, H. Nilsson, A. Pietras, J. Vallon-Christersson, A. Borg, K. Gradin, L. Poellinger, S. Pahlman, Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell 10, 413–423 (2006). (PMID: 1709756310.1016/j.ccr.2006.08.026)
P. Vaupel, M. Hockel, A. Mayer, Detection and characterization of tumor hypoxia using pO2 histography. Antioxid. Redox Signal. 9, 1221–1235 (2007). (PMID: 1753695810.1089/ars.2007.1628)
M.W. Dewhirst, Y. Cao, B. Moeller, Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat. Rev. Cancer 8, 425–437 (2008). (PMID: 18500244394320510.1038/nrc2397)
Q. Lin, X. Cong, Z. Yun, Differential hypoxic regulation of hypoxia-inducible factors 1alpha and 2alpha. Mol. Cancer Res. 9, 757–765 (2011). (PMID: 21571835311796910.1158/1541-7786.MCR-11-0053)
A.T. Henze, J. Riedel, T. Diem, J. Wenner, I. Flamme, J. Pouyseggur, K.H. Plate, T. Acker, Prolyl hydroxylases 2 and 3 act in gliomas as protective negative feedback regulators of hypoxia-inducible factors. Cancer Res. 70, 357–366 (2010). (PMID: 2002886310.1158/0008-5472.CAN-09-1876)
M.Y. Koh, R. Lemos Jr., X. Liu, G. Powis, The hypoxia-associated factor switches cells from HIF-1alpha- to HIF-2alpha-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res. 71, 4015–4027 (2011). (PMID: 21512133326865110.1158/0008-5472.CAN-10-4142)
A. Toschi, E. Lee, N. Gadir, M. Ohh, D.A. Foster, Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. J. Biol. Chem. 283, 34495–34499 (2008). (PMID: 18945681259640010.1074/jbc.C800170200)
P.M. LoRusso, Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors. J. Clin. Oncol. 34, 3803–3815 (2016). (PMID: 27621407636630410.1200/JCO.2014.59.0018)

NO. TJ20170110 The funding from Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

Keywords: HIF-1α; HIF-2α; Hepatocellular carcinoma; apitolisib; c-MYC; mild chronic hypoxia

0 (Basic Helix-Loop-Helix Transcription Factors)
0 (HIF1A protein, human)
0 (Hypoxia-Inducible Factor 1, alpha Subunit)
0 (MYC protein, human)
0 (Proto-Oncogene Proteins c-myc)
1B37H0967P (endothelial PAS domain-containing protein 1)

Date Created: 20210802 Date Completed: 20220207 Latest Revision: 20220829

20231215

10.1007/s13402-021-00625-w

34339013