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Sohlh2 alleviates malignancy of EOC cells under hypoxia via inhibiting the HIF1α/CA9 signaling pathway

  • Xiaoli Zhang , Xinyu Liu , Weiwei Cui , Ruihong Zhang , Yang Liu , Yongkun Li and Jing Hao EMAIL logo
Published/Copyright: August 5, 2019

Abstract

Epithelial ovarian cancer (EOC) is the most common and deadly ovarian cancer. Most of the patients have abdominal/pelvic invasion and metastasis at the time of diagnosis, but the underlying mechanism remains unclear. Insufficiency of blood perfusion and diffusion within most solid tumors can lead to a hypoxic tumor microenvironment and promotes tumor malignancy. In the present study, we detected the role of the spermatogenesis- and oogenesis-specific basic helix-loop-helix (bHLH) transcription factor 2 (sohlh2) on migration, invasion and epithelial-mesenchymal transition (EMT) of EOC cell lines under hypoxia in vitro. We also investigated the possible mechanism underlying it. The results showed that sohlh2 inhibited the migration, invasion and EMT of EOC cells and might function through suppression of the hypoxia-inducible factor 1α (HIF1α)/carbonic anhydrase 9 (CA9) signaling pathway. Our results may open a new avenue for the further development of diagnostic tools and novel therapeutics that will benefit EOC patients.

Award Identifier / Grant number: 81672861

Award Identifier / Grant number: 81874118

Award Identifier / Grant number: 2019GSF107013

Award Identifier / Grant number: 2017GSF218029

Award Identifier / Grant number: ZR2014HM017

Award Identifier / Grant number: ZR2016HM79

Award Identifier / Grant number: ZR201702180317

Award Identifier / Grant number: ZR2014HM035

Funding statement: This work was supported by the National Natural Science Foundation of China under Grant numbers 81672861 and 81874118, The Shandong Department of Science and Technology Plan Project under Grant numbers 2019GSF107013 and 2017GSF218029, and the Natural Science Foundation of Shandong Province under Grant numbers ZR2014HM017, ZR2016HM79, ZR201702180317 and ZR2014HM035.

  1. Conflict of interest statement: The authors declare no conflict of interest.

References

Ahmed, N. and Stenvers, K.L. (2013). Getting to know ovarian cancer ascites: opportunities for targeted therapy-based translational research. Front. Oncol. 3, 256.10.3389/fonc.2013.00256Search in Google Scholar PubMed PubMed Central

Ballow, D.J., Xin, Y., Choi, Y., Pangas, S.A., and Rajkovic, A. (2006). Sohlh2 is a germ cell-specific bHLH transcription factor. Gene Expr. Patterns 6, 1014–1018.10.1016/j.modgep.2006.04.007Search in Google Scholar PubMed

Chafe, S.C., McDonald, P.C., Saberi, S., Nemirovsky, O., Venkateswaran, G., Burugu, S., Gao, D., Delaidelli, A., Kyle, A.H., Baker, J.H.E., et al. (2019). Targeting hypoxia-induced carbonic anhydrase IX enhances immune-checkpoint blockade locally and systemically. Cancer Immunol. Res. 7, 1064–1078.10.1158/2326-6066.CIR-18-0657Search in Google Scholar PubMed

Chia, S.K., Wykoff, C.C., Watson, P.H., Han, C., Leek, R.D., Pastorek, J., Gatter, K.C., Ratcliffe, P., and Harris, A.L. (2001). Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J. Clin. Oncol. 19, 3660–3668.10.1200/JCO.2001.19.16.3660Search in Google Scholar PubMed

Eastham, A.M., Spencer, H., Soncin, F., Ritson, S., Merry, C.L.R., Stern, P.L., and Ward, C.M. (2007). Epithelial-mesenchymal transition events during human embryonic stem cell differentiation. Cancer Res. 67, 11254–11262.10.1158/0008-5472.CAN-07-2253Search in Google Scholar PubMed

Gao, D., Vahdat, L.T., Wong, S., Chang, J.C., and Mittal, V. (2012). Microenvironmental regulation of epithelial-mesenchymal transitions in cancer. Cancer Res. 72, 4883–4889.10.1158/0008-5472.CAN-12-1223Search in Google Scholar PubMed PubMed Central

Gao, T., Li, J.Z., Lu, Y., Zhang, C.Y., Li, Q., Mao, J., and Li, L.H. (2016). The mechanism between epithelial mesenchymal transition in breast cancer and hypoxia microenvironment. Biomed. Pharmacother. 80, 393–405.10.1016/j.biopha.2016.02.044Search in Google Scholar PubMed

Giatromanolaki, A., Koukourakis, M.I., Sivridis, E., Pastorek, J., Wykoff, C.C., Gatter, K.C., and Harris, A.L. (2001). Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res. 61, 7992–7998.Search in Google Scholar

Gupta, G.P. and Massagué, J. (2006). Cancer metastasis: building a framework. Cell 127, 679–695.10.1016/j.cell.2006.11.001Search in Google Scholar PubMed

Hao, J., Yamamoto, M., Richardson, T.E., Chapman, K.M., Denard, B.S., Hammer, R.E., Zhao, G.Q., and Hamra, F.K. (2008). Sohlh2 knockout mice are male-sterile because of degeneration of differentiating type a spermatogonia. Stem Cells 26, 1587–1597.10.1634/stemcells.2007-0502Search in Google Scholar PubMed

Harris, A.L. (2002). Hypoxia-a key regulatory factor in tumor growth. Nat. Rev. Cancer 2, 38–47.10.1038/nrc704Search in Google Scholar PubMed

Hoskin, P.J., Sibtain, A., Daley, F.M., and Wilson, G.D. (2003). GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of arcon. Br. J. Cancer 89, 1290–1297.10.1038/sj.bjc.6601260Search in Google Scholar PubMed PubMed Central

Hyuga, S., Wada, H., Eguchi, H., Otsuru, T., Iwgami, Y., Yamada, D., Noda, T., Asaoka, T., Kawamoto, K., Gotoh, K., et al. (2017). Expression of carbonic anhydrase ix is associated with poor prognosis through regulation of the epithelial-mesenchymal transition in hepatocellular carcinoma. Int. J. Oncol. 51, 1179–1190.10.3892/ijo.2017.4098Search in Google Scholar PubMed

Kaluz, S., Kaluzová, M., Chrastina, A., Olive, P.L., Pastoreková, S., Pastorek, J., Lerman, M.I., and Stanbridge, E.J. (2002). Lowered oxygen tension induces expression of the hypoxia marker MN/carbonic anhydrase IX in the absence of hypoxia-inducible factor 1 alpha stabilization: a role for phosphatidylinositol 3′-kinase. Cancer Res. 62, 4469–4477.Search in Google Scholar

Kim, H.L., Seligson, D., Liu, X., Janzen, N., Bui, M.H., Yu, H., Shi, T., Figlin, R.A., Horvath, S., and Belldegrun, A.S. (2004). Using protein expressions to predict survival in clear cell renal carcinoma. Clin. Cancer Res. 10, 5464–5471.10.1158/1078-0432.CCR-04-0488Search in Google Scholar PubMed

Krishnamachary, B., Berg-Dixon, S., Kelly, B., Agani, F., Feldser, D., Ferreira, G., Iyer, N., LaRusch, J., Pak, B., Taghavi, P., et al. (2003). Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 63, 1138–1143.Search in Google Scholar

Lengyel, E. (2010). Ovarian cancer development and metastasis. Am. J. Pathol. 177, 1053–1064.10.2353/ajpath.2010.100105Search in Google Scholar PubMed PubMed Central

Li, L. and Li, W. (2015). Epithelial-mesenchymal transition in human cancer: comprehensive reprogramming of metabolism, epigenetics, and differentiation. Pharmacol. Ther. 150, 33–46.10.1016/j.pharmthera.2015.01.004Search in Google Scholar PubMed

Li, M., Wang, Y.X., Luo, Y., Zhao, J., Li, Q., Zhang, J., and Jiang, Y. (2016). Hypoxia-inducible factor-1α-dependent epithelial to mesenchymal transition under hypoxic conditions in prostate cancer cells. Oncol. Rep. 36, 521–527.10.3892/or.2016.4766Search in Google Scholar PubMed

Myszczyszyn, A., Czarnecka, A.M., Matak, D., Szymanski, L., Lian, F., Kornakiewicz, A., Bartnik, E., Kukwa, W., Kieda, C., and Szczylik, C. (2015). The role of hypoxia and cancer stem cells in renal cell carcinoma pathogenesis. Stem Cell Rev. 11, 919–943.10.1007/s12015-015-9611-ySearch in Google Scholar PubMed PubMed Central

Pastorek, J. and Pastorekova, S. (2015). Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: from biology to clinical use. Semin. Cancer Biol. 31, 52–64.10.1016/j.semcancer.2014.08.002Search in Google Scholar PubMed

Peinado, H., Olmeda, D., and Cano, A. (2007). Snail, Zeb and bHLH factors in tumor progression: an alliance against the epithelial phenotype? Nat. Rev. Cancer 7, 415–428.10.1038/nrc2131Search in Google Scholar PubMed

Sedlakova, O., Svastova, E., Takacova, M., Kopacek, J., Pastorek, J., and Pastorekova, S. (2014). Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH regulating machinery in tumors. Front. Physiol. 4, 400.10.3389/fphys.2013.00400Search in Google Scholar PubMed PubMed Central

Semenza, G.L. (2010). Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625–634.10.1038/onc.2009.441Search in Google Scholar PubMed PubMed Central

Sun, H., Ghaffari, S., and Taneja, R. (2007). bHLH-orange transcription factors in development and cancer. Transl. Oncogenomics 2, 107–120.10.4137/TOG.S436Search in Google Scholar PubMed PubMed Central

Svastova, E., Witarski, W., Csaderova, L., Kosik, I., Skvarkova, L., Hulikova, A., Zatovicova, M., Barathova, M., Kopacek, J., Pastorek, J., et al. (2012). Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J. Biol. Chem. 287, 3392–3402.10.1074/jbc.M111.286062Search in Google Scholar PubMed PubMed Central

Swietach, P., Patiar, S., Supuran, C.T., Harris, A.L., and Vaughan-Jones, R.D. (2009). The role of carbonic anhydrase 9 in regulating extracellular and intracellular pH in three-dimensional tumor cell growths. J. Biol. Chem. 284, 20299–20310.10.1074/jbc.M109.006478Search in Google Scholar PubMed PubMed Central

Swinson, D.E., Jones, J.L., Richardson, D., Wykoff, C., Turley, H., Pastorek, J., Taub, N., Harris, A.L., and O’Byrne, K.J. (2003). Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer. J. Clin. Oncol. 21, 473–482.10.1200/JCO.2003.11.132Search in Google Scholar PubMed

Tan, E.Y., Yan, M., Campo, L., Han, C., Takano, E., Turley, H., Candiloro, I., Pezzella, F., Gatter, K.C., Millar, E.K., et al. (2009). The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy. Br. J. Cancer 100, 405–411.10.1038/sj.bjc.6604844Search in Google Scholar PubMed PubMed Central

Torre, L.A., Trabert, B., DeSantis, C.E., Miller, K.D., Samimi, G., Runowicz, C.D., Gaudet, M.M., Jemal, A., and Siegel, R.L. (2018). Ovarian cancer statistics. CA Cancer J. Clin. 68, 284–296.10.3322/caac.21456Search in Google Scholar PubMed PubMed Central

Vaupel, P., Hockel, M., and Mayer, A. (2007). Detection and characterization of tumor hypoxia using pO2 histography. Antioxid. Redox Signal. 9, 1221–1235.10.1089/ars.2007.1628Search in Google Scholar PubMed

Wang, Y., Ma, J., Shen, H., Wang, C., Sun, Y., Howell, S.B., and Lin, X. (2014). Reactive oxygen species promote ovarian cancer progression via the HIF-1α/LOX/E-cadherin pathway. Oncol. Rep. 32, 2150–2158.10.3892/or.2014.3448Search in Google Scholar PubMed PubMed Central

Wykoff, C.C., Beasley, N.J., Watson, P.H., Turner, K.J., Pastorek, J., Sibtain, A., Wilson, G.D., Turley, H., Talks, K.L., Maxwell, P.H., et al. (2000). Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 60, 7075–7083.Search in Google Scholar

Xing, F., Okuda, H., Watabe, M., Kobayashi, A., Pai, S.K., Liu, W., Pandey, P.R., Fukuda, K., Hirota, S., Sugai, T., et al. (2011). Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells. Oncogene 30, 4075–4086.10.1038/onc.2011.122Search in Google Scholar PubMed PubMed Central

Ye, L.Y., Chen, W., Bai, X.L., Xu, X.Y., Zhang, Q., Xia, X.F., Sun, X., Li, G.G., Hu, Q.D., Fu, Q.H., et al. (2016). Hypoxia-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma induces an immunosuppressive tumor microenvironment to promote metastasis. Cancer Res. 76, 818–830.10.1158/0008-5472.CAN-15-0977Search in Google Scholar PubMed

Zhang, H., Zhang, X., Ji, S., Zhang, X., Zhang, W., Zhao, Q., Sun, J., and Hao, J. (2014). Sohlh2 inhibits ovarian cancer cell proliferation by upregulation of p21 and downregulation of cyclin D1. Carcinogenesis 35, 1863–1871.10.1093/carcin/bgu113Search in Google Scholar PubMed

Zhang, H., Hao, C., Wang, Y., Ji, S., Zhang, X., Zhang, W., Zhao, Q., Sun, J., and Hao, J. (2016). Sohlh2 inhibits human ovarian cancer cell invasion and metastasis by transcriptional inactivation of MMP9. Mol. Carcinog. 55, 1127–1137.10.1002/mc.22355Search in Google Scholar PubMed

Received: 2019-01-18
Accepted: 2019-07-08
Published Online: 2019-08-05
Published in Print: 2020-02-25

©2020 Walter de Gruyter GmbH, Berlin/Boston

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