4.1N suppresses hypoxia-induced epithelial-mesenchymal transition in epithelial ovarian cancer cells

Zhang,Letian; Hu,Ajin; Li,Mengrui; Zhang,Hongquan; Ren,Caixia; An,Xiuli; Liu,Congrong

doi:10.3892/mmr.2015.4634

4.1N suppresses hypoxia-induced epithelial-mesenchymal transition in epithelial ovarian cancer cells

Authors:
- Letian Zhang
- Ajin Hu
- Mengrui Li
- Hongquan Zhang
- Caixia Ren
- Xiuli An
- Congrong Liu
View Affiliations

Affiliations: Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China, Department of Histology and Embryology, Peking University Health Science Center, Beijing 100191, P.R. China, College of Life Science, Zhengzhou University, Zhengzhou, Henan 450051, P.R. China, Department of Pathology, School of Basic Medical Sciences, Third Hospital, Peking University Health Science Center, Beijing 100191, P.R. China
Published online on: December 1, 2015 https://doi.org/10.3892/mmr.2015.4634
Pages: 837-844

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Protein 4.1N (4.1N) is a member of the protein 4.1 family and is essential for the regulation of cell adhesion, motility and signaling. Previous studies have suggested that 4.1N may serve a tumor suppressor role. However, the molecular mechanisms remain unclear. In the current study, the role of 4.1N in the downregulation of hypoxia‑induced factor 1α (HIF‑1α) under hypoxic conditions and therefore the suppression of hypoxia induced epithelial‑mesenchymal transition (EMT) was investigated. The data were obtained from overexpressed and knockdown 4.1N epithelial ovarian cancer (EOC) cell lines. It was identified that 4.1N was capable of regulating the sub‑cellular localization and expression levels of HIF‑1α, by which 4.1N served a dominant role in the suppression of hypoxia‑induced EMT and associated genes. Collectively, the data of the current study identified 4.1N as an inhibitor of hypoxia‑induced tumor progression in EOC cells and highlighted its potential role in EOC therapy.

View Figures

View References

1	Hess LM and Stehman FB: State of the science in ovarian cancer quality of life research: A systematic review. Int J Gynecol Cancer. 22:1273–1280. 2012. View Article : Google Scholar : PubMed/NCBI
2	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
3	Rooth C: Ovarian cancer: Risk factors, treatment and management. Br J Nurs. 22(Suppl): S23–S30. 2013. View Article : Google Scholar : PubMed/NCBI
4	Hua KT, Wang MY, Chen MW, Wei LH, Chen CK, Ko CH, Jeng YM, Sung PL, Jan YH, Hsiao M, et al: The H3K9 meth-yltransferase G9a is a marker of aggressive ovarian cancer that promotes peritoneal metastasis. Mol Cancer. 13:1892014. View Article : Google Scholar
5	Naora H and Montell DJ: Ovarian cancer metastasis: Integrating insights from disparate model organisms. Nat Rev Cancer. 5:355–366. 2005. View Article : Google Scholar : PubMed/NCBI
6	Auersperg N, Wong AS, Choi KC, Kang SK and Leung PC: Ovarian surface epithelium: Biology, endocrinology and pathology. Endocr Rev. 22:255–288. 2001.PubMed/NCBI
7	Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T and Konishi I: Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol. 163:1437–1447. 2003. View Article : Google Scholar : PubMed/NCBI
8	Peters LL, Weier HU, Walensky LD, Snyder SH, Parra M, Mohandas N and Conboy JG: Four paralogous protein 4.1 genes map to distinct chromosomes in mouse and human. Genomics. 54:348–350. 1998. View Article : Google Scholar : PubMed/NCBI
9	Conboy J, Kan YW, Shohet SB and Mohandas N: Molecular cloning of protein 4.1, a major structural element of the human erythrocyte membrane skeleton. Proc Natl Acad Sci USA. 83:9512–9516. 1986. View Article : Google Scholar : PubMed/NCBI
10	Parra M, Gascard P, Walensky LD, Gimm JA, Blackshaw S, Chan N, Takakuwa Y, Berger T, Lee G, Chasis JA, et al: Molecular and functional characterization of protein 4.1B, a novel member of the protein 4.1 family with high level, focal expression in brain. J Biol Chem. 275:3247–3255. 2000. View Article : Google Scholar : PubMed/NCBI
11	Walensky LD, Blackshaw S, Liao D, Watkins CC, Weier HU, Parra M, Huganir RL, Conboy JG, Mohandas N and Snyder SH: A novel neuron-enriched homolog of the erythrocyte membrane cytoskeletal protein 4.1. J Neurosci. 19:6457–6467. 1999.PubMed/NCBI
12	Wang H, Liu C, Debnath G, Baines AJ, Conboy JG, Mohandas N and An X: Comprehensive characterization of expression patterns of protein 4.1 family members in mouse adrenal gland: Implications for functions. Histochem Cell Biol. 134:411–420. 2010. View Article : Google Scholar : PubMed/NCBI
13	Sun CX, Robb VA and Gutmann DH: Protein 4.1 tumor suppressors: Getting a FERM grip on growth regulation. J Cell Sci. 115:3991–4000. 2002. View Article : Google Scholar : PubMed/NCBI
14	Dafou D, Grun B, Sinclair J, Lawrenson K, Benjamin EC, Hogdall E, Kruger-Kjaer S, Christensen L, Sowter HM, Al-Attar A, et al: Microcell-mediated chromosome transfer identifies EPB41L3 as a functional suppressor of epithelial ovarian cancers. Neoplasia. 12:579–589. 2010. View Article : Google Scholar : PubMed/NCBI
15	Wong SY, Haack H, Kissil JL, Barry M, Bronson RT, Shen SS, Whittaker CA, Crowley D and Hynes RO: Protein 4.1B suppresses prostate cancer progression and metastasis. Proc Natl Acad Sci U S A. 104:12784–12789. 2007. View Article : Google Scholar : PubMed/NCBI
16	Robb VA, Li W, Gascard P, Perry A, Mohandas N and Gutmann DH: Identification of a third protein 4.1 tumor suppressor, protein 4.1R, in meningioma pathogenesis. Neurobiol Dis. 13:191–202. 2003. View Article : Google Scholar : PubMed/NCBI
17	Xi C, Ren C, Hu A, Lin J, Yao Q, Wang Y, Gao Z, An X and Liu C: Defective expression of protein 4.1N is correlated to tumor progression, aggressive behaviors and chemotherapy resistance in epithelial ovarian cancer. Gynecol Oncol. 131:764–771. 2013. View Article : Google Scholar : PubMed/NCBI
18	Pouysségur J, Dayan F and Mazure NM: Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 441:437–443. 2006. View Article : Google Scholar : PubMed/NCBI
19	Nakayama K, Kanzaki A, Hata K, Katabuchi H, Okamura H, Miyazaki K, Fukumoto M and Takebayashi Y: Hypoxia-inducible factor 1 alpha (HIF-1 alpha) gene expression in human ovarian carcinoma. Cancer Lett. 176:215–223. 2002. View Article : Google Scholar : PubMed/NCBI
20	Semenza GL: Oxygen sensing, homeostasis and disease. N Engl J Med. 365:537–547. 2011. View Article : Google Scholar : PubMed/NCBI
21	Liao D and Johnson RS: Hypoxia: A key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 26:281–290. 2007. View Article : Google Scholar : PubMed/NCBI
22	Lee K, Zhang H, Qian DZ, Rey S, Liu JO and Semenza GL: Acriflavine inhibits HIF-1 dimerization, tumor growth and vascularization. Proc Natl Acad Sci U S A. 106:17910–17915. 2009. View Article : Google Scholar : PubMed/NCBI
23	Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A and Semenza GL: Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 145:732–744. 2011. View Article : Google Scholar : PubMed/NCBI
24	Moeller BJ, Richardson RA and Dewhirst MW: Hypoxia and radiotherapy: Opportunities for improved outcomes in cancer treatment. Cancer Metastasis Rev. 26:241–248. 2007. View Article : Google Scholar : PubMed/NCBI
25	Rohwer N and Cramer T: Hypoxia-mediated drug resistance: Novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat. 14:191–201. 2011. View Article : Google Scholar : PubMed/NCBI
26	Esteban MA, Tran MG, Harten SK, Hill P, Castellanos MC, Chandra A, Raval R, O'brien TS and Maxwell PH: Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res. 66:3567–3575. 2006. View Article : Google Scholar : PubMed/NCBI
27	Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH and Semenza GL: Hypoxia-inducible factor-1-dependent repression of E-cadherin in von hippel-lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A and ZFHX1B. Cancer Res. 66:2725–2731. 2006. View Article : Google Scholar : PubMed/NCBI
28	Mak P, Leav I, Pursell B, Bae D, Yang X, Taglienti CA, Gouvin LM, Sharma VM and Mercurio AM: ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: Implications for gleason grading. Cancer Cell. 17:319–332. 2010. View Article : Google Scholar : PubMed/NCBI
29	Nieto MA: The ins and outs of the epithelial to mesenchymal transition in health and disease. Ann Rev Cell Dev Biol. 27:347–376. 2011. View Article : Google Scholar
30	Yang J and Weinberg RA: Epithelial-mesenchymal transition: At the crossroads of development and tumor metastasis. Dev Cell. 14:818–829. 2008. View Article : Google Scholar : PubMed/NCBI
31	Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI
32	Evans AJ, Russell RC, Roche O, Burry TN, Fish JE, Chow VW, Kim WY, Saravanan A, Maynard MA, Gervais ML, et al: VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol Cell Biol. 27:157–169. 2007. View Article : Google Scholar :
33	Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC and Wu KJ: Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol. 10:295–305. 2008. View Article : Google Scholar : PubMed/NCBI
34	Pouyssegur J, Dayan F and Mazure NM: Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 441:437–443. 2006. View Article : Google Scholar : PubMed/NCBI
35	Bernkopf DB and Williams ED: Potential role of EPB41L3 (protein 4.1B/Dal-1) as a target for treatment of advanced prostate cancer. Expert Opin Ther Targets. 12:845–853. 2008. View Article : Google Scholar : PubMed/NCBI
36	Joshi HP, Subramanian IV, Schnettler EK, Ghosh G, Rupaimoole R, Evans C, Saluja M, Jing Y, Cristina I, Roy S, Zeng Y, Shah VH, Sood AK and Ramakrishnan S: Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis. Proc Natl Acad Sci USA. 111:5331–5336. 2014. View Article : Google Scholar : PubMed/NCBI
37	Milosevic M, Warde P, Ménard C, Chung P, Toi A, Ishkanian A, McLean M, Pintilie M, Sykes J, Gospodarowicz M, et al: Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin Cancer Res. 18:2108–2114. 2012. View Article : Google Scholar : PubMed/NCBI
38	Cangul H, Salnikow K, Yee H, Zagzag D, Commes T and Costa M: Enhanced overexpression of an HIF-1/hypoxia-related protein in cancer cells. Environ Health Perspect. 110(Suppl 5): S783–S788. 2002. View Article : Google Scholar
39	Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL and Simons JW: Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 59:5830–5835. 1999.PubMed/NCBI
40	Ji F, Wang Y, Qiu L, Li S, Zhu J, Liang Z, Wan Y and Di W: Hypoxia inducible factor 1α-mediated LOX expression correlates with migration and invasion in epithelial ovarian cancer. Int J Oncol. 42:1578–1588. 2013.PubMed/NCBI
41	Wong C, Wellman TL and Lounsbury KM: VEGF and HIF-1alpha expression are increased in advanced stages of epithelial ovarian cancer. Gynecol Oncol. 91:513–517. 2003. View Article : Google Scholar : PubMed/NCBI
42	Osada R, Horiuchi A, Kikuchi N, Yoshida J, Hayashi A, Ota M, Katsuyama Y, Melillo G and Konishi I: Expression of hypoxia-inducible factor 1alpha, hypoxia-inducible factor 2alpha and von hippel-lindau protein in epithelial ovarian neoplasms and allelic loss of von hippel-lindau gene: Nuclear expression of hypoxia-inducible factor 1alpha is an independent prognostic factor in ovarian carcinoma. Hum Pathol. 38:1310–1320. 2007. View Article : Google Scholar : PubMed/NCBI
43	Beavon IR: Regulation of E-cadherin: Does hypoxia initiate the metastatic cascade? Mol Pathol. 52:179–188. 1999. View Article : Google Scholar
44	Tomita K, van Bokhoven A, van Leenders GJ, Ruijter ET, Jansen CF, Bussemakers MJ and Schalken JA: Cadherin switching in human prostate cancer progression. Cancer Res. 60:3650–3654. 2000.PubMed/NCBI
45	Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F and Nieto MA: The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2:76–83. 2000. View Article : Google Scholar : PubMed/NCBI
46	Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A and Weinberg RA: Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 117:927–939. 2004. View Article : Google Scholar : PubMed/NCBI
47	Polyak K and Weinberg RA: Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nat Rev Cancer. 9:265–273. 2009. View Article : Google Scholar : PubMed/NCBI
48	De Craene B and Berx G: Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 13:97–110. 2013. View Article : Google Scholar : PubMed/NCBI
49	Thomassin L, Werneck CC, Broekelmann TJ, Gleyzal C, Hornstra IK, Mecham RP and Sommer P: The pro-regions of lysyl oxidase and lysyl oxidase-like 1 are required for deposition onto elastic fibers. J Biol Chem. 280:42848–42855. 2005. View Article : Google Scholar : PubMed/NCBI
50	Peinado H, Del Carmen Iglesias-de la Cruz M, Olmeda D, Csiszar K, Fong KS, Vega S, Nieto MA, Cano A and Portillo F: A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J. 24:3446–3458. 2005. View Article : Google Scholar : PubMed/NCBI
51	Pez F, Dayan F, Durivault J, Kaniewski B, Aimond G, Le Provost GS, Deux B, Clézardin P, Sommer P, Pouysségur J and Reynaud C: The HIF-1-inducible lysyl oxidase activates HIF-1 via the Akt pathway in a positive regulation loop and synergizes with HIF-1 in promoting tumor cell growth. Cancer Res. 71:1647–1657. 2011. View Article : Google Scholar : PubMed/NCBI
52	Ye K, Hurt KJ, Wu FY, Fang M, Luo HR, Hong JJ, Blackshaw S, Ferris CD and Snyder SH: Pike. A nuclear gtpase that enhances PI3kinase activity and is regulated by protein 41N. Cell. 103:919–930. 2000. View Article : Google Scholar
53	Kisseleva MV, Cao L and Majerus PW: Phosphoinositide-specific inositol polyphosphate 5-phosphatase IV inhibits Akt/protein kinase B phosphorylation and leads to apoptotic cell death. J Biol Chem. 277:6266–6272. 2002. View Article : Google Scholar