Generic placeholder image

Current Pharmaceutical Biotechnology


ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Review Article

The Role of Hypoxia in Endometrial Cancer

Author(s): Yarely M. Salinas-Vera, Dolores Gallardo-Rincón, Erika Ruíz-García, Macrina B. Silva-Cázares, Carmen Sol de la Peña-Cruz and César López-Camarillo*

Volume 23, Issue 2, 2022

Published on: 24 February, 2021

Page: [221 - 234] Pages: 14

DOI: 10.2174/1389201022666210224130022

Price: $65


Endometrial cancer represents the most frequent neoplasia from the corpus uteri and comprises the 14th leading cause of death in women worldwide. Risk factors that contribute to the disease include early menarche, late menopause, nulliparity, and menopausal hormone use, as well as hypertension and obesity comorbidities. The clinical effectiveness of chemotherapy is variable, suggesting that novel molecular targeted therapies against specific cellular processes associated with the maintenance of cancer cell survival and therapy resistance ameliorate the rates of success in endometrial cancer treatment. In the course of tumor growth, cancer cells must adapt to decreased oxygen availability in the microenvironment by upregulation of hypoxia-inducible factors, which orchestrate the activation of a transcriptional program leading to cell survival. During this adaptative process, the hypoxic cancer cells may acquire invasive and metastatic properties as well as increased cell proliferation and resistance to chemotherapy, enhanced angiogenesis, vasculogenic mimicry, and maintenance of cancer cell stemness, which contribute to more aggressive cancer phenotypes. Several studies have shown that hypoxia-inducible factor 1 alpha (HIF-1α) protein is aberrantly overexpressed in many solid tumors of the breast, prostate, ovarian, bladder, colon, brain, and pancreas. Thus, it has been considered an important therapeutic target. Here, we reviewed the current knowledge of the relevant roles of cellular hypoxia mechanisms and HIF-1α functions in diverse processes associated with endometrial cancer progression. In addition, we also summarize the role of microRNAs in the posttranscriptional regulation of protein-encoding genes involved in the hypoxia response in endometrial cancer. Finally, we pointed out the need for urgent targeted therapies to impair the cellular processes activated by hypoxia in the tumor microenvironment.

Keywords: Endometrial cancer, hypoxia, HIF-1α, microRNAs, therapy, chemotherapy.

Graphical Abstract
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[] [PMID: 30207593]
Lortet-Tieulent, J.; Ferlay, J.; Bray, F.; Jemal, A. International patterns and trends in endometrial cancer incidence, 1978-2013. J. Natl. Cancer Inst., 2018, 110(4), 354-361.
[] [PMID: 29045681]
Moore, K.; Brewer, M.A. Endometrial Cancer: Is This a New Disease? Am. Soc. Clin. Oncol. Educ. Book, 2017, 37, 435-442.
[] [PMID: 28561715]
Hopkins, B.D.; Goncalves, M.D.; Cantley, L.C. Obesity and Cancer Mechanisms: Cancer Metabolism. J. Clin. Oncol., 2016, 34(35), 4277-4283.
[] [PMID: 27903152]
Stewart, B.W.; Wild, C. International Agency for Research on Cancer, World Health Organization, editors.World cancer report 2014. 3rd ed; International Agency for Research on Cancer: Lyon, France, 2014, p. 630;
Finucane, M.M.; Stevens, G.A.; Cowan, M.J.; Danaei, G.; Lin, J.K.; Paciorek, C.J.; Singh, G.M.; Gutierrez, H.R.; Lu, Y.; Bahalim, A.N.; Farzadfar, F.; Riley, L.M.; Ezzati, M. Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index). National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9•1 million participants. Lancet, 2011, 377(9765), 557-567.
[] [PMID: 21295846]
Arnold, M.; Pandeya, N.; Byrnes, G.; Renehan, P.A.G.; Stevens, G.A.; Ezzati, P.M.; Ferlay, J.; Miranda, J.J.; Romieu, I.; Dikshit, R.; Forman, D.; Soerjomataram, I. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol., 2015, 16(1), 36-46.
[] [PMID: 25467404]
Setiawan, V.W.; Yang, H.P.; Pike, M.C.; McCann, S.E.; Yu, H.; Xiang, Y-B.; Wolk, A.; Wentzensen, N.; Weiss, N.S.; Webb, P.M.; van den Brandt, P.A.; van de Vijver, K.; Thompson, P.J.; Strom, B.L.; Spurdle, A.B.; Soslow, R.A.; Shu, X.O.; Schairer, C.; Sacerdote, C.; Rohan, T.E.; Robien, K.; Risch, H.A.; Ricceri, F.; Rebbeck, T.R.; Rastogi, R.; Prescott, J.; Polidoro, S.; Park, Y.; Olson, S.H.; Moysich, K.B.; Miller, A.B.; McCullough, M.L.; Matsuno, R.K.; Magliocco, A.M.; Lurie, G.; Lu, L.; Lissowska, J.; Liang, X.; Lacey, J.V., Jr; Kolonel, L.N.; Henderson, B.E.; Hankinson, S.E.; Håkansson, N.; Goodman, M.T.; Gaudet, M.M.; Garcia-Closas, M.; Friedenreich, C.M.; Freudenheim, J.L.; Doherty, J.; De Vivo, I.; Courneya, K.S.; Cook, L.S.; Chen, C.; Cerhan, J.R.; Cai, H.; Brinton, L.A.; Bernstein, L.; Anderson, K.E.; Anton-Culver, H.; Schouten, L.J.; Horn-Ross, P.L. Australian National Endometrial Cancer Study Group. Type I and II endometrial cancers: have they different risk factors? J. Clin. Oncol., 2013, 31(20), 2607-2618.
[] [PMID: 23733771]
National Cancer Institute. Cancer of the Endometrium - Cancer Stat Facts SEER.,,[cited 2020 Oct 13]. Available from:
Lynch, H.T.; Snyder, C.L.; Shaw, T.G.; Heinen, C.D.; Hitchins, M.P. Milestones of Lynch syndrome: 1895-2015. Nat. Rev. Cancer, 2015, 15(3), 181-194.
[] [PMID: 25673086]
Briggs, S.; Tomlinson, I. Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers. J. Pathol., 2013, 230(2), 148-153.
[] [PMID: 23447401]
Ngeow, J.; Stanuch, K.; Mester, J.L.; Barnholtz-Sloan, J.S.; Eng, C. Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations. J. Clin. Oncol., 2014, 32(17), 1818-1824.
[] [PMID: 24778394]
Bestvina, C.M.; Fleming, G.F. Chemotherapy for endometrial cancer in adjuvant and advanced disease settings. Oncologist, 2016, 21(10), 1250-1259.
[] [PMID: 27412393]
Sousa, G. F de.; Wlodarczyk, S.R.; Monteiro, G. Carboplatin: molecular mechanisms of action associated with chemoresistance. Braz. J. Pharm. Sci., 2014, 50(4), 693-701.
Urick, M.E.; Bell, D.W. Clinical actionability of molecular targets in endometrial cancer. Nat. Rev. Cancer, 2019, 19(9), 510-521.
[] [PMID: 31388127]
Wang, G.L.; Jiang, B.H.; Rue, E.A.; Semenza, G.L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA, 1995, 92(12), 5510-5514.
[] [PMID: 7539918]
Harris, A.L. Hypoxia--a key regulatory factor in tumour growth. Nat. Rev. Cancer, 2002, 2(1), 38-47.
[] [PMID: 11902584]
Semenza, G.L. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol. Sci., 2012, 33(4), 207-214.
[] [PMID: 22398146]
Blancher, C.; Moore, J.W.; Talks, K.L.; Houlbrook, S.; Harris, A.L. Relationship of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines. Cancer Res., 2000, 60(24), 7106-7113.
[PMID: 11156418]
Semenza, G.L. Hypoxia-inducible factors in physiology and medicine. Cell, 2012, 148(3), 399-408.
[] [PMID: 22304911]
Xiang, L.; Semenza, G.L. Hypoxia-inducible factors promote breast cancer stem cell specification and maintenance in response to hypoxia or cytotoxic chemotherapy. Advances in Cancer Research; Elsevier, 2019, pp. 175-212.
Bruick, R.K.; McKnight, S.L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science, 2001, 294(5545), 1337-1340.
[] [PMID: 11598268]
Kaelin, W.G., Jr; Ratcliffe, P.J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell, 2008, 30(4), 393-402.
[] [PMID: 18498744]
Ivan, M.; Kondo, K.; Yang, H.; Kim, W.; Valiando, J.; Ohh, M.; Salic, A.; Asara, J.M.; Lane, W.S.; Kaelin, W.G. Jr HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science, 2001, 292(5516), 464-468.
[] [PMID: 11292862]
Tanimoto, K.; Makino, Y.; Pereira, T.; Poellinger, L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J., 2000, 19(16), 4298-4309.
[] [PMID: 10944113]
Jaakkola, P.; Mole, D.R.; Tian, Y-M.; Wilson, M.I.; Gielbert, J.; Gaskell, S.J.; von Kriegsheim, A.; Hebestreit, H.F.; Mukherji, M.; Schofield, C.J.; Maxwell, P.H.; Pugh, C.W.; Ratcliffe, P.J. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 2001, 292(5516), 468-472.
[] [PMID: 11292861]
Schofield, C.J.; Ratcliffe, P.J. Oxygen sensing by HIF hydroxylases. Nat. Rev. Mol. Cell Biol., 2004, 5(5), 343-354.
[] [PMID: 15122348]
Maxwell, P.H.; Wiesener, M.S.; Chang, G-W.; Clifford, S.C.; Vaux, E.C.; Cockman, M.E.; Wykoff, C.C.; Pugh, C.W.; Maher, E.R.; Ratcliffe, P.J. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 1999, 399(6733), 271-275.
[] [PMID: 10353251]
Creighton, C.J.; Chang, J.C.; Rosen, J.M. Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. J. Mammary Gland Biol. Neoplasia, 2010, 15(2), 253-260.
[] [PMID: 20354771]
Salinas-Vera, Y.M.; Marchat, L.A.; García-Vázquez, R.; González de la Rosa, C.H.; Castañeda-Saucedo, E.; Tito, N.N.; Flores, C.P.; Pérez-Plasencia, C.; Cruz-Colin, J.L.; Carlos-Reyes, Á.; López-González, J.S.; Álvarez-Sánchez, M.E.; López-Camarillo, C. Cooperative multi-targeting of signaling networks by angiomiR-204 inhibits vasculogenic mimicry in breast cancer cells. Cancer Lett., 2018, 432, 17-27.
[] [PMID: 29885516]
Maniotis, A.J.; Folberg, R.; Hess, A.; Seftor, E.A.; Gardner, L.M.G.; Pe’er, J.; Trent, J.M.; Meltzer, P.S.; Hendrix, M.J. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am. J. Pathol., 1999, 155(3), 739-752.
[] [PMID: 10487832]
Salinas-Vera, Y.M.; Gallardo-Rincón, D.; García-Vázquez, R.; Hernández-de la Cruz, O.N.; Marchat, L.A.; González-Barrios, J.A.; Ruíz-García, E.; Vázquez-Calzada, C.; Contreras-Sanzón, E.; Resendiz-Hernández, M.; Astudillo-de la Vega, H.; Cruz-Colin, J.L.; Campos-Parra, A.D.; López-Camarillo, C. HypoxamiRs profiling identify miR-765 as a regulator of the early stages of vasculogenic mimicry in SKOV3 ovarian cancer cells. Front. Oncol., 2019, 9, 381.
[] [PMID: 31157166]
Hess, A.R.; Seftor, E.A.; Gardner, L.M.; Carles-Kinch, K.; Schneider, G.B.; Seftor, R.E.; Kinch, M.S.; Hendrix, M.J. Molecular regulation of tumor cell vasculogenic mimicry by tyrosine phosphorylation: role of epithelial cell kinase (Eck/EphA2). Cancer Res., 2001, 61(8), 3250-3255.
[PMID: 11309274]
Basu, G.D.; Liang, W.S.; Stephan, D.A.; Wegener, L.T.; Conley, C.R.; Pockaj, B.A.; Mukherjee, P. A novel role for cyclooxygenase-2 in regulating vascular channel formation by human breast cancer cells. Breast Cancer Res., 2006, 8(6), R69.
[] [PMID: 17156488]
Liao, Y.; Lu, W.; Che, Q.; Yang, T.; Qiu, H.; Zhang, H.; He, X.; Wang, J.; Qiu, M.; Zou, Y.; Gu, W.; Wan, X. SHARP1 suppresses angiogenesis of endometrial cancer by decreasing hypoxia-inducible factor-1α level. PLoS One, 2014, 9(6)e99907
[] [PMID: 24918449]
Zhang, C.; Samanta, D.; Lu, H.; Bullen, J.W.; Zhang, H.; Chen, I.; He, X.; Semenza, G.L. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. Proc. Natl. Acad. Sci. USA, 2016, 113(14), E2047-E2056.
[] [PMID: 27001847]
Li, Z.; Rich, J.N. Hypoxia and hypoxia inducible factors in cancer stem cell maintenance. in current topics in microbiology and immunology; Springer Berlin Heidelberg: Berlin, Heidelberg, 2010, pp. 21-30.
Semenza, G.L. The hypoxic tumor microenvironment: A driving force for breast cancer progression. Biochim. Biophys. Acta, 2016, 1863(3), 382-391.
[] [PMID: 26079100]
Higgins, D.F.; Kimura, K.; Bernhardt, W.M.; Shrimanker, N.; Akai, Y.; Hohenstein, B.; Saito, Y.; Johnson, R.S.; Kretzler, M.; Cohen, C.D.; Eckardt, K.U.; Iwano, M.; Haase, V.H. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Invest., 2007, 117(12), 3810-3820.
[] [PMID: 18037992]
Chen, X.; Zhang, S.; Wang, Z.; Wang, F.; Cao, X.; Wu, Q.; Zhao, C.; Ma, H.; Ye, F.; Wang, H.; Fang, Z. Supervillin promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma in hypoxia via activation of the RhoA/ROCK-ERK/p38 pathway. J. Exp. Clin. Cancer Res., 2018, 37(1), 128.
[] [PMID: 29954442]
Pansare, V.; Munkarah, A.R.; Schimp, V.; Haitham Arabi, M.; Saed, G.M.; Morris, R.T.; Ali-Fehmi, R. Increased expression of hypoxia-inducible factor 1α in type I and type II endometrial carcinomas. Mod. Pathol., 2007, 20(1), 35-43.
[] [PMID: 17099695]
Min, J-H.; Yang, H.; Ivan, M.; Gertler, F.; Kaelin, W.G., Jr; Pavletich, N.P. Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling. Science, 2002, 296(5574), 1886-1889.
[] [PMID: 12004076]
Zhu, C.; Ding, H.; Yang, J.; Zhou, Y.; Luo, Y.; Shi, S.; Zhang, Y.; Wei, Y.; Ni, G. Downregulation of Proline Hydroxylase 2 and Upregulation of Hypoxia-Inducible Factor 1α are Associated with Endometrial Cancer Aggressiveness. Cancer Manag. Res., 2019, 11, 9907-9912.
[] [PMID: 31819628]
Fujimoto, J.; Sato, E.; Alam, S.M.; Jahan, I.; Toyoki, H.; Hong, B.L.; Sakaguchi, H.; Tamaya, T. Plausible linkage of hypoxia-inducible factor (HIF) in uterine endometrial cancers. Oncology, 2006, 71(1-2), 95-101.
[] [PMID: 17341889]
Yunokawa, M.; Tanimoto, K.; Nakamura, H.; Nagai, N.; Kudo, Y.; Kawamoto, T.; Kato, Y.; Hiyama, E.; Hiyama, K.; Nishiyama, M. Differential regulation of DEC2 among hypoxia-inducible genes in endometrial carcinomas. Oncol. Rep., 2007, 17(4), 871-878.
[] [PMID: 17342330]
Giatromanolaki, A.; Koukourakis, M.I.; Gatter, K.C.; Harris, A.L.; Sivridis, E. BNIP3 expression in endometrial cancer relates to active hypoxia inducible factor 1alpha pathway and prognosis. J. Clin. Pathol., 2008, 61(2), 217-220.
[] [PMID: 17513511]
Meng, X.; Huang, Z.; Teng, F.; Xing, L.; Yu, J. Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy. Cancer Treat. Rev., 2015, 41(10), 868-876.
[] [PMID: 26589760]
Tawadros, A.I.F.; Khalafalla, M.M.M. Expression of programmed death-ligand 1 and hypoxia-inducible factor-1α proteins in endometrial carcinoma. J. Cancer Res. Ther., 2018, 14(7)(Suppl.), S1063-S1069.
[] [PMID: 30539847]
Green, S.L.; Giaccia, A.J. Tumor hypoxia and the cell cycle: implications for malignant progression and response to therapy. Cancer J. Sci. Am., 1998, 4(4), 218-223.
[PMID: 9689978]
Massagué, J. G1 cell-cycle control and cancer. Nature, 2004, 432(7015), 298-306.
[] [PMID: 15549091]
Schmitz, M.J.; Hendricks, D.T.; Farley, J.; Taylor, R.R.; Geradts, J.; Rose, G.S.; Birrer, M.J. p27 and cyclin D1 abnormalities in uterine papillary serous carcinoma. Gynecol. Oncol., 2000, 77(3), 439-445.
[] [PMID: 10831356]
Horrée, N.; Gort, E.H.; van der Groep, P.; Heintz, A.P.; Vooijs, M.; van Diest, P.J. Hypoxia-inducible factor 1 α is essential for hypoxic p27 induction in endometrioid endometrial carcinoma. J. Pathol., 2008, 214(1), 38-45.
[] [PMID: 17985331]
Seeber, L.M.; Horrée, N.; van der Groep, P.; van der Wall, E.; Verheijen, R.H.; van Diest, P.J. Necrosis related HIF-1α expression predicts prognosis in patients with endometrioid endometrial carcinoma. BMC Cancer, 2010, 10(1), 307.
[] [PMID: 20565904]
Potter, C.; Harris, A.L. Hypoxia inducible carbonic anhydrase IX, marker of tumour hypoxia, survival pathway and therapy target. Cell Cycle, 2004, 3(2), 164-167.
[] [PMID: 14712082]
Hayashi, M.; Sakata, M.; Takeda, T.; Yamamoto, T.; Okamoto, Y.; Sawada, K.; Kimura, A.; Minekawa, R.; Tahara, M.; Tasaka, K.; Murata, Y. Induction of glucose transporter 1 expression through hypoxia-inducible factor 1α under hypoxic conditions in trophoblast-derived cells. J. Endocrinol., 2004, 183(1), 145-154.
[] [PMID: 15525582]
Liberti, M.V.; Locasale, J.W. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem. Sci., 2016, 41(3), 211-218.
[] [PMID: 26778478]
Sadlecki, P.; Bodnar, M.; Grabiec, M.; Marszalek, A.; Walentowicz, P.; Sokup, A.; Zegarska, J.; Walentowicz-Sadlecka, M. The role of Hypoxia-inducible factor-1 α, glucose transporter-1, (GLUT-1) and carbon anhydrase IX in endometrial cancer patients. BioMed Res. Int., 2014.2014616850
[] [PMID: 24745019]
Singh, H.; Li, Y.; Fuller, P.J.; Harrison, C.; Rao, J.; Stephens, A.N.; Nie, G. HtrA3 is downregulated in cancer cell lines and significantly reduced in primary serous and granulosa cell ovarian tumors. J. Cancer, 2013, 4(2), 152-164.
[] [PMID: 23412729]
Lv, Q.; Yang, B.; Ning, C.; Xie, B.; Nie, G.; Chen, X.; Chen, Q. Hypoxia is involved in the reduction of HtrA3 in patients with endometrial hyperplasia and cancer. Biochem. Biophys. Res. Commun., 2018, 503(4), 2918-2923.
[] [PMID: 30139517]
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell, 2000, 100(1), 57-70.
[] [PMID: 10647931]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell, 2011, 144(5), 646-674.
[] [PMID: 21376230]
Nakazawa, M.S.; Keith, B.; Simon, M.C. Oxygen availability and metabolic adaptations. Nat. Rev. Cancer, 2016, 16(10), 663-673.
[] [PMID: 27658636]
Pavlova, N.N.; Thompson, C.B. The Emerging Hallmarks of Cancer Metabolism. Cell Metab., 2016, 23(1), 27-47.
[] [PMID: 26771115]
Pastorekova, S.; Gillies, R.J. The role of carbonic anhydrase IX in cancer development: links to hypoxia, acidosis, and beyond. Cancer Metastasis Rev., 2019, 38(1-2), 65-77.
[] [PMID: 31076951]
Hong, X-Y.; Wang, J.; Li, Z. AGR2 expression is regulated by HIF-1 and contributes to growth and angiogenesis of glioblastoma. Cell Biochem. Biophys., 2013, 67(3), 1487-1495.
[] [PMID: 23712868]
Kamal, A.; Valentijn, A.; Barraclough, R.; Rudland, P.; Rahmatalla, N.; Martin-Hirsch, P.; Stringfellow, H.; Decruze, S.B.; Hapangama, D.K. High AGR2 protein is a feature of low grade endometrial cancer cells. Oncotarget, 2018, 9(59), 31459-31472.
[] [PMID: 30140383]
Gong, W.; Ekmu, B.; Wang, X.; Lu, Y.; Wan, L. AGR2-induced glucose metabolism facilitated the progression of endometrial carcinoma via enhancing the MUC1/HIF-1α pathway. Hum. Cell, 2020, 33(3), 790-800.
[] [PMID: 32304027]
Lee, T.Y.; Martinez-Outschoorn, U.E.; Schilder, R.J.; Kim, C.H.; Richard, S.D.; Rosenblum, N.G.; Johnson, J.M. Metformin as a therapeutic target in endometrial cancers. Front. Oncol., 2018, 8, 341.
[] [PMID: 30211120]
Sivalingam, V.N.; Latif, A.; Kitson, S.; McVey, R.; Finegan, K.G.; Marshall, K.; Lisanti, M.P.; Sotgia, F.; Stratford, I.J.; Crosbie, E.J. Hypoxia and hyperglycaemia determine why some endometrial tumours fail to respond to metformin. Br. J. Cancer, 2020, 122(1), 62-71.
[] [PMID: 31819173]
Meireles, C.G.; Pereira, S.A.; Valadares, L.P.; Rêgo, D.F.; Simeoni, L.A.; Guerra, E.N.S.; Lofrano-Porto, A. Effects of metformin on endometrial cancer: Systematic review and meta-analysis. Gynecol. Oncol., 2017, 147(1), 167-180.
[] [PMID: 28760367]
Perez-Lopez, F.R.; Pasupuleti, V.; Gianuzzi, X.; Palma-Ardiles, G.; Hernandez-Fernandez, W.; Hernandez, A.V. Systematic review and meta-analysis of the effect of metformin treatment on overall mortality rates in women with endometrial cancer and type 2 diabetes mellitus. Maturitas, 2017, 101, 6-11.
[] [PMID: 28539171]
Calgani, A.; Delle Monache, S.; Cesare, P.; Vicentini, C.; Bologna, M.; Angelucci, A. Leptin contributes to long-term stabilization of HIF-1α in cancer cells subjected to oxygen limiting conditions. Cancer Lett., 2016, 376(1), 1-9.
[] [PMID: 26996298]
Koda, M.; Sulkowska, M.; Wincewicz, A.; Kanczuga-Koda, L.; Musiatowicz, B.; Szymanska, M.; Sulkowski, S. Expression of leptin, leptin receptor, and hypoxia-inducible factor 1 alpha in human endometrial cancer. Ann. N. Y. Acad. Sci., 2007, 1095(1), 90-98.
[] [PMID: 17404022]
Sceneay, J.; Liu, M.C.P.; Chen, A.; Wong, C.S.F.; Bowtell, D.D.L.; Möller, A. The antioxidant N-acetylcysteine prevents HIF-1 stabilization under hypoxia in vitro but does not affect tumorigenesis in multiple breast cancer models in vivo. PLoS One, 2013, 8(6)e66388
[] [PMID: 23840457]
Tomczyk, M.; Tumanov, A.; Zaniewska, A.; Surazynski, A. The potential mechanism of tiliroside-dependent inhibition of t-butylhydroperoxide-induced oxidative stress in endometrial carcinoma cells. Planta Med., 2010, 76(10), 963-968.
[] [PMID: 20186656]
Ozer, A.; Bruick, R.K. Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one? Nat. Chem. Biol., 2007, 3(3), 144-153.
[] [PMID: 17301803]
Chen, Q.; Espey, M.G.; Krishna, M.C.; Mitchell, J.B.; Corpe, C.P.; Buettner, G.R.; Shacter, E.; Levine, M. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc. Natl. Acad. Sci. USA, 2005, 102(38), 13604-13609.
[] [PMID: 16157892]
Chen, C.; Sun, J.; Liu, G.; Chen, J. Effect of small interference RNA targeting HIF-1α mediated by rAAV combined L: -ascorbate on pancreatic tumors in athymic mice. Pathol. Oncol. Res., 2009, 15(1), 109-114.
[] [PMID: 18509748]
Chen, Q.; Espey, M.G.; Sun, A.Y.; Pooput, C.; Kirk, K.L.; Krishna, M.C.; Khosh, D.B.; Drisko, J.; Levine, M. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. USA, 2008, 105(32), 11105-11109.
[] [PMID: 18678913]
Kuiper, C.; Molenaar, I.G.M.; Dachs, G.U.; Currie, M.J.; Sykes, P.H.; Vissers, M.C.M. Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. Cancer Res., 2010, 70(14), 5749-5758.
[] [PMID: 20570889]
Feng, W.; Ye, F.; Xue, W.; Zhou, Z.; Kang, Y.J. Copper regulation of hypoxia-inducible factor-1 activity. Mol. Pharmacol., 2009, 75(1), 174-182.
[] [PMID: 18842833]
Kim, K.K.; Abelman, S.; Yano, N.; Ribeiro, J.R.; Singh, R.K.; Tipping, M.; Moore, R.G. Tetrathiomolybdate inhibits mitochondrial complex IV and mediates degradation of hypoxia-inducible factor-1α in cancer cells. Sci. Rep., 2015, 5(1), 14296.
[] [PMID: 26469226]
Veiseh, O.; Kievit, F.M.; Ellenbogen, R.G.; Zhang, M. Cancer cell invasion: treatment and monitoring opportunities in nanomedicine. Adv. Drug Deliv. Rev., 2011, 63(8), 582-596.
[] [PMID: 21295093]
Friedl, P.; Wolf, K. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol., 2010, 188(1), 11-19.
[] [PMID: 19951899]
Pennacchietti, S.; Michieli, P.; Galluzzo, M.; Mazzone, M.; Giordano, S.; Comoglio, P.M. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell, 2003, 3(4), 347-361.
[] [PMID: 12726861]
Abouhashem, N.S.; Ibrahim, D.A.; Mohamed, A.M. Prognostic implications of epithelial to mesenchymal transition related proteins (E-cadherin, Snail) and hypoxia inducible factor 1α in endometrioid endometrial carcinoma. Ann. Diagn. Pathol., 2016, 22, 1-11.
[] [PMID: 27180053]
Tanaka, Y.; Terai, Y.; Kawaguchi, H.; Fujiwara, S.; Yoo, S.; Tsunetoh, S.; Takai, M.; Kanemura, M.; Tanabe, A.; Ohmichi, M. Prognostic impact of EMT (epithelial-mesenchymal-transition)-related protein expression in endometrial cancer. Cancer Biol. Ther., 2013, 14(1), 13-19.
[] [PMID: 23114646]
Feng, Z.; Gan, H.; Cai, Z.; Li, N.; Yang, Z.; Lu, G.; Chen, J. Aberrant expression of hypoxia-inducible factor 1α, TWIST and E-cadherin is associated with aggressive tumor phenotypes in endometrioid endometrial carcinoma. Jpn. J. Clin. Oncol., 2013, 43(4), 396-403.
[] [PMID: 23372184]
Wan, J.; Qin, J.; Cao, Q.; Hu, P.; Zhong, C.; Tu, C. Hypoxia-induced PLOD2 regulates invasion and epithelial-mesenchymal transition in endometrial carcinoma cells. Genes Genomics, 2020, 42(3), 317-324.
[] [PMID: 31872384]
Yang, X.; Zhang, X.; Wu, R.; Huang, Q.; Jiang, Y.; Qin, J.; Yao, F.; Jin, G.; Zhang, Y. DPPIV promotes endometrial carcinoma cell proliferation, invasion and tumorigenesis. Oncotarget, 2017, 8(5), 8679-8692.
[] [PMID: 28060721]
Pugh, C.W.; Ratcliffe, P.J. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat. Med., 2003, 9(6), 677-684.
[] [PMID: 12778166]
Horrée, N.; van Diest, P.J.; van der Groep, P.; Sie-Go, D.M.; Heintz, A.P. Hypoxia and angiogenesis in endometrioid endometrial carcinogenesis. Cell. Oncol., 2007, 29(3), 219-227.
[PMID: 17452774]
Koukourakis, M.I. Tumour angiogenesis and response to radiotherapy. Anticancer Res., 2001, 21(6B), 4285-4300.
[PMID: 11908683]
Sivridis, E.; Giatromanolaki, A.; Gatter, K.C.; Harris, A.L.; Koukourakis, M.I. Tumor and Angiogenesis Research Group. Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma. Cancer, 2002, 95(5), 1055-1063.
[] [PMID: 12209691]
Aybatlı, A.; Sayın, C.; Kaplan, P.B.; Varol, F.; Altaner, S.; Süt, N. The investigation of tumoral angiogenesis with HIF-1 alpha and microvessel density in women with endometrium cancer. J. Turk. Ger. Gynecol. Assoc., 2012, 13(1), 37-44.
[] [PMID: 24627673]
Bredholt, G.; Mannelqvist, M.; Stefansson, I.M.; Birkeland, E.; Bø, T.H.; Øyan, A.M.; Trovik, J.; Kalland, K.H.; Jonassen, I.; Salvesen, H.B.; Wik, E.; Akslen, L.A. Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses. Oncotarget, 2015, 6(37), 39676-39691.
[] [PMID: 26485755]
Karna, E.; Szoka, L.; Palka, J.A. Betulinic acid inhibits the expression of hypoxia-inducible factor 1α and vascular endothelial growth factor in human endometrial adenocarcinoma cells. Mol. Cell. Biochem., 2010, 340(1-2), 15-20.
[] [PMID: 20174965]
Clarke, M.F.; Dick, J.E.; Dirks, P.B.; Eaves, C.J.; Jamieson, C.H.M.; Jones, D.L.; Visvader, J.; Weissman, I.L.; Wahl, G.M. Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res., 2006, 66(19), 9339-9344.
[] [PMID: 16990346]
Yuan, L.; Jiang, Z.M.; Chen, X.H.; Bian, X.Y.; Li, Y.X.; Ma, X.F.; Liu, X.Z. Hypoxia inducible factor-1α deSUMOylation reduces the stemness maintenance ability of endometrial cancer stem cell and increases its chemosensitivity Zhonghua Yi Xue Za Zhi, 2017, 97(45), 3579-3582.
[PMID: 29275599]
Shukla, G.C.; Singh, J.; Barik, S. MicroRNAs: Processing, Maturation, Target Recognition and Regulatory Functions. Mol. Cell. Pharmacol., 2011, 3(3), 83-92.
[PMID: 22468167]
Zhang, B.; Pan, X.; Cobb, G.P.; Anderson, T.A. microRNAs as oncogenes and tumor suppressors. Dev. Biol., 2007, 302(1), 1-12.
[] [PMID: 16989803]
Chan, S.Y.; Loscalzo, J. MicroRNA-210: a unique and pleiotropic hypoxamir. Cell Cycle, 2010, 9(6), 1072-1083.
[] [PMID: 20237418]
Pocock, R. Invited review: decoding the microRNA response to hypoxia. Pflugers Arch., 2011, 461(3), 307-315.
[] [PMID: 21207057]
Xu, T-X.; Zhao, S-Z.; Dong, M.; Yu, X-R. Hypoxia responsive miR-210 promotes cell survival and autophagy of endometriotic cells in hypoxia. Eur. Rev. Med. Pharmacol. Sci., 2016, 20(3), 399-406.[Internet].
[PMID: 26914112]
Eismann, J.; Hirschfeld, M.; Erbes, T.; Rücker, G.; Jäger, M.; Ritter, A.; Weiss, D.; Gitsch, G.; Mayer, S. Hypoxia- and acidosis-driven aberrations of secreted microRNAs in endometrial cancer in vitro. Oncol. Rep., 2017, 38(2), 993-1004.
[] [PMID: 28627686]
Hsiao, K-Y.; Wu, M-H.; Chang, N.; Yang, S-H.; Wu, C-W.; Sun, H-S.; Tsai, S.J. Coordination of AUF1 and miR-148a destabilizes DNA methyltransferase 1 mRNA under hypoxia in endometriosis. Mol. Hum. Reprod., 2015, 21(12), 894-904.
[] [PMID: 26433194]
Penolazzi, L.; Bonaccorsi, G.; Gafà, R.; Ravaioli, N.; Gabriele, D.; Bosi, C.; Lanza, G.; Greco, P.; Piva, R. SLUG/HIF1-α/miR-221 regulatory circuit in endometrial cancer. Gene, 2019.711143938
[] [PMID: 31220580]
Shen, J.; Chen, L.; Cheng, J.; Jin, X.; Mu, Y.; Li, Q.; Xia, L.; Gao, Y.; Xia, Y. Circular RNA sequencing reveals the molecular mechanism of the effects of acupuncture and moxibustion on endometrial receptivity in patients undergoing infertility treatment. Mol. Med. Rep., 2019, 20(2), 1959-1965.
[] [PMID: 31257480]
Qu, J.; Zhang, L.; Li, L.; Su, Y. miR-148b functions as a tumor suppressor by targeting endoplasmic reticulum metallo protease 1 in human endometrial cancer cells. Oncol. Res., 2018, 27(1), 81-88.
[] [PMID: 29523216]
Dai, L.; Lou, W.; Zhu, J.; Zhou, X.; Di, W. MiR-199a inhibits the angiogenic potential of endometrial stromal cells under hypoxia by targeting HIF-1α/VEGF pathway. Int. J. Clin. Exp. Pathol., 2015, 8(5), 4735-4744.
[PMID: 26191163]
Lin, S-C.; Wang, C-C.; Wu, M-H.; Yang, S-H.; Li, Y-H.; Tsai, S.J. Hypoxia-induced microRNA-20a expression increases ERK phosphorylation and angiogenic gene expression in endometriotic stromal cells. J. Clin. Endocrinol. Metab., 2012, 97(8), E1515-E1523.
[] [PMID: 22648654]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy