Stanniocalcin‑1 promotes cell proliferation, chemoresistance and metastasis in hypoxic gastric cancer cells via Bcl‑2

Wang,Yan; Qi,Zihao; Zhou,Menglong; Yang,Wang; Hu,Ran; Li,Guichao; Ma,Xuejun; Zhang,Zhen

doi:10.3892/or.2019.6980

Stanniocalcin‑1 promotes cell proliferation, chemoresistance and metastasis in hypoxic gastric cancer cells via Bcl‑2

Authors:
- Yan Wang
- Zihao Qi
- Menglong Zhou
- Wang Yang
- Ran Hu
- Guichao Li
- Xuejun Ma
- Zhen Zhang
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Affiliations: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China, Department of Surgery, Huadong Hospital affiliated to Fudan University, Shanghai 200040, P.R. China
Published online on: January 23, 2019 https://doi.org/10.3892/or.2019.6980
Pages: 1998-2008

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Abstract

Gastric cancer (GC) is one of the most lethal diseases worldwide, but the mechanism of GC development remains elusive. In the present study, the roles of stanniocalcin‑1 (STC1) in GC were investigated. It was demonstrated that overexpression of STC1 mRNA and protein were associated with poor survival of patients with GC. The expression of STC1 was enhanced in hypoxic GC cells and overexpression of STC1 facilitated cell proliferation in hypoxia but not in normoxia. Furthermore, STC1 promoted chemoresistance, migration and invasion in hypoxia. Upregulating the expression of STC1 enhanced the expression of B cell lymphoma (Bcl)‑2, neural‑cadherin and matrix metalloproteinase‑2, whereas it reduced the levels of cytochrome c, cleaved‑caspase‑9, cleaved‑caspase‑3 and epithelial‑cadherin. However, downregulation of STC1 altered the expression of these proteins in the opposite direction. Furthermore, disturbing the expression of Bcl‑2 partly reversed the changes to these proteins and also the pro‑proliferation, anti‑apoptosis and pro‑invasion potential of STC1. In vivo experiments indicated that enhanced expression of STC1 promoted tumor growth and metastasis in mice. Collectively, the results indicated that STC1 may serve an oncogenic role in hypoxic GC via dysregulating Bcl‑2, indicating that STC1 may be a potential therapeutic target in the treatment of GC.

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1	Khazaei S, Rezaeian S, Soheylizad M, Khazaei S and Biderafsh A: Global incidence and mortality rates of stomach cancer and the human development index: An ecological study. Asian Pac J Cancer Prev. 17:1701–1704. 2016. View Article : Google Scholar : PubMed/NCBI
2	Sullivan R and Graham CH: Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev. 26:319–331. 2007. View Article : Google Scholar : PubMed/NCBI
3	Vaupel P and Mayer A: Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev. 26:225–239. 2007. View Article : Google Scholar : PubMed/NCBI
4	Liu G, Yang G, Chang B, Mercado-Uribe I, Huang M, Zheng J, Bast RC, Lin SH and Liu J: Stanniocalcin 1 and ovarian tumorigenesis. J Natl Cancer Inst. 102:812–827. 2010. View Article : Google Scholar : PubMed/NCBI
5	Tamura S, Oshima T, Yoshihara K, Kanazawa A, Yamada T, Inagaki D, Sato T, Yamamoto N, Shiozawa M, Morinaga S, et al: Clinical significance of STC1 gene expression in patients with colorectal cancer. Anticancer Res. 31:325–329. 2011.PubMed/NCBI
6	Chang AC, Doherty J, Huschtscha LI, Redvers R, Restall C, Reddel RR and Anderson RL: STC1 expression is associated with tumor growth and metastasis in breast cancer. Clin Exp Metastasis. 32:15–27. 2015. View Article : Google Scholar : PubMed/NCBI
7	Fang Z, Tian Z, Luo K, Song H and Yi J: Clinical significance of stanniocalcin expression in tissue and serum of gastric cancer patients. Chinese J Cancer Res. 26:602–610. 2014.
8	Zhang K, Lindsberg PJ, Tatlisumak T, Kaste M, Olsen HS and Andersson LC: Stanniocalcin: A molecular guard of neurons during cerebral ischemia. Proc Natl Acad Sci USA. 97:3637–3642. 2000. View Article : Google Scholar : PubMed/NCBI
9	Yeung HY, Lai KP, Chan HY, Mak NK, Wagner GF and Wong CK: Hypoxia-inducible factor-1-mediated activation of stanniocalcin-1 in human cancer cells. Endocrinology. 146:4951–4960. 2005. View Article : Google Scholar : PubMed/NCBI
10	Shroff EH, Snyder C and Chandel NS: Bcl-2 family members regulate anoxia-induced cell death. Antioxid Redox Signal. 9:1405–1409. 2007. View Article : Google Scholar : PubMed/NCBI
11	Liu L, Ning X, Sun L, Zhang H, Shi Y, Guo C, Han S, Liu J, Sun S, Han Z, et al: Hypoxia-inducible factor-1 alpha contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci. 99:121–128. 2008.PubMed/NCBI
12	Capes-Davis A, Theodosopoulos G, Atkin I, Drexler HG, Kohara A, MacLeod RA, Masters JR, Nakamura Y, Reid YA, Reddel RR, et al: Check your cultures! A list of cross-contaminated or misidentified cell lines. Int J Cancer. 127:1–8. 2010. View Article : Google Scholar : PubMed/NCBI
13	Sun T, Sun BC, Zhao XL, Zhao N, Dong XY, Che N, Yao Z, Ma YM, Gu Q, Zong WK, et al: Promotion of tumor cell metastasis and vasculogenic mimicry by way of transcription coactivation by Bcl-2 and Twist1: a study of hepatocellular carcinoma. Hepatology. 54:1690–1706. 2011. View Article : Google Scholar : PubMed/NCBI
14	Wang Y, Wang Z, Qi Z, Yin S, Zhang N, Liu Y, Liu M, Meng J, Zang R, Zhang Z, et al: The negative interplay between Aurora A/B and BRCA1/2 controls cancer cell growth and tumorigenesis via distinct regulation of cell cycle progression, cytokinesis, and tetraploidy. Mol Cancer. 13:942014. View Article : Google Scholar : PubMed/NCBI
15	Sun H, Wang Y, Wang Z, Meng J, Qi Z and Yang G: Aurora-A controls cancer cell radio- and chemoresistance via ATM/Chk2-mediated DNA repair networks. Biochim Biophys Acta 1843. 934–944. 2014.
16	Hou J, Wang Z, Xu H, Yang L, Yu X, Yang Z, Deng Y, Meng J, Feng Y, Guo X, et al: Stanniocalicin 2 suppresses breast cancer cell migration and invasion via the PKC/claudin-1-mediated signaling. PloS One. 10:e01221792015. View Article : Google Scholar : PubMed/NCBI
17	Szasz AM, Lanczky A, Nagy A, Förster S, Hark K, Green JE, Boussioutas A, Busuttil R, Szabó A and Győrffy B: Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget. 7:49322–49333. 2016. View Article : Google Scholar : PubMed/NCBI
18	Wang W, Sun XW, Li CF, Lv L, Li YF, Chen YB, Xu DZ, Kesari R, Huang CY, Li W, et al: Comparison of the 6th and 7th editions of the UICC TNM staging system for gastric cancer: Results of a Chinese single-institution study of 1,503 patients. Ann Surg Oncol. 18:1060–1067. 2011. View Article : Google Scholar : PubMed/NCBI
19	Salnikow K, Donald SP, Bruick RK, Zhitkovich A, Phang JM and Kasprzak KS: Depletion of intracellular ascorbate by the carcinogenic metals nickel and cobalt results in the induction of hypoxic stress. J Biol Chem. 279:40337–40344. 2004. View Article : Google Scholar : PubMed/NCBI
20	Rath S, Anand A, Ghosh N, Das L, Kokate SB, Dixit P, Majhi S, Rout N, Singh SP and Bhattacharyya A: Cobalt chloride-mediated protein kinase Calpha (PKCalpha) phosphorylation induces hypoxia-inducible factor 1alpha (HIF1alpha) in the nucleus of gastric cancer cell. Biochem Biophys Res Commun. 471:205–212. 2016. View Article : Google Scholar : PubMed/NCBI
21	Bai Y, Xiao Y, Dai Y, Chen X, Li D, Tan X and Zhang X: Stanniocalcin 1 promotes cell proliferation via cyclin E1/cyclin-dependent kinase 2 in human prostate carcinoma. Oncol Rep. 37:2465–2471. 2017. View Article : Google Scholar : PubMed/NCBI
22	Zuo J, Ishikawa T, Boutros S, Xiao Z, Humtsoe JO and Kramer RH: Bcl-2 overexpression induces a partial epithelial to mesenchymal transition and promotes squamous carcinoma cell invasion and metastasis. Mol Cancer Res. 8:170–182. 2010. View Article : Google Scholar : PubMed/NCBI
23	Choi J, Choi K, Benveniste EN, Rho SB, Hong YS, Lee JH, Kim J and Park K: Bcl-2 promotes invasion and lung metastasis by inducing matrix metalloproteinase-2. Cancer Res. 65:5554–5560. 2005. View Article : Google Scholar : PubMed/NCBI
24	Sumiyoshi Y, Kakeji Y, Egashira A, Mizokami K, Orita H and Maehara Y: Overexpression of hypoxia-inducible factor 1alpha and p53 is a marker for an unfavorable prognosis in gastric cancer. Clin Cancer Res. 12:5112–5117. 2006. View Article : Google Scholar : PubMed/NCBI
25	Lu X and Kang Y: Hypoxia and hypoxia-inducible factors: Master regulators of metastasis. Clin Cancer Res. 16:5928–5935. 2010. View Article : Google Scholar : PubMed/NCBI
26	Lal A, Peters H, St Croix B, Haroon ZA, Dewhirst MW, Strausberg RL, Kaanders JH, van der Kogel AJ and Riggins GJ: Transcriptional response to hypoxia in human tumors. J Natl Cancer Inst. 93:1337–1343. 2001. View Article : Google Scholar : PubMed/NCBI
27	Ma X, Gu L, Li H, Gao Y, Li X, Shen D, Gong H, Li S, Niu S, Zhang Y, et al: Hypoxia-induced overexpression of stanniocalcin-1 is associated with the metastasis of early stage clear cell renal cell carcinoma. J Transl Med. 13:562015. View Article : Google Scholar : PubMed/NCBI
28	Law AY, Ching LY, Lai KP and Wong CK: Identification and characterization of the hypoxia-responsive element in human stanniocalcin-1 gene. Mol Cell Endocrinol. 314:118–127. 2010. View Article : Google Scholar : PubMed/NCBI
29	Cornmark L, Lonne GK, Jogi A and Larsson C: Protein kinase Calpha suppresses the expression of STC1 in MDA-MB-231 breast cancer cells. Tumour Biol. 32:1023–1030. 2011. View Article : Google Scholar : PubMed/NCBI
30	Nguyen A, Chang AC and Reddel RR: Stanniocalcin-1 acts in a negative feedback loop in the prosurvival ERK1/2 signaling pathway during oxidative stress. Oncogene. 28:1982–1992. 2009. View Article : Google Scholar : PubMed/NCBI
31	Shi X, Wang J and Qin Y: Recombinant adeno-associated virus-delivered hypoxia-inducible stanniocalcin-1 expression effectively inhibits hypoxia-induced cell apoptosis in cardiomyocytes. J Cardiovasc Pharmacol. 64:522–529. 2014. View Article : Google Scholar : PubMed/NCBI
32	Westberg JA, Serlachius M, Lankila P, Penkowa M, Hidalgo J and Andersson LC: Hypoxic preconditioning induces neuroprotective stanniocalcin-1 in brain via IL-6 signaling. Stroke. 38:1025–1030. 2007. View Article : Google Scholar : PubMed/NCBI
33	Liu D, Shang H and Liu Y: Stanniocalcin-1 protects a mouse model from renal ischemia-reperfusion injury by affecting ROS-mediated multiple signaling pathways. Int J Mol Sci. 17:E10512016. View Article : Google Scholar : PubMed/NCBI
34	Arigami T, Uenosono Y, Ishigami S, Hagihara T, Haraguchi N, Matsushita D, Yanagita S, Nakajo A, Okumura H, Hokita S, et al: Expression of stanniocalcin 1 as a potential biomarker of gastric cancer. Oncology. 83:158–164. 2012. View Article : Google Scholar : PubMed/NCBI
35	He LF, Wang TT, Gao QY, Zhao GF, Huang YH, Yu LK and Hou YY: Stanniocalcin-1 promotes tumor angiogenesis through up-regulation of VEGF in gastric cancer cells. J Biomed Sci. 18:392011. View Article : Google Scholar : PubMed/NCBI
36	Yoon JH, Kim J, Kim KL, Kim DH, Jung SJ, Lee H, Ghim J, Kim D, Park JB, Ryu SH, et al: Proteomic analysis of hypoxia-induced U373MG glioma secretome reveals novel hypoxia-dependent migration factors. Proteomics. 14:1494–1502. 2014. View Article : Google Scholar : PubMed/NCBI
37	An J, Lv J, Li A, Qiao J, Fang L, Li Z, Li B, Zhao W, Chen H and Wang L: Constitutive expression of Bcl-2 induces epithelial-Mesenchymal transition in mammary epithelial cells. BMC Cancer. 15:4762015. View Article : Google Scholar : PubMed/NCBI
38	Leng J, Song Q, Zhao Y and Wang Z: miR15a represses cancer cell migration and invasion under conditions of hypoxia by targeting and downregulating Bcl2 expression in human osteosarcoma cells. Int J Oncol. 52:1095–1104. 2018.PubMed/NCBI
39	Duan Y, He Q, Yue K, Si H, Wang J, Zhou X and Wang X: Hypoxia induced Bcl-2/Twist1 complex promotes tumor cell invasion in oral squamous cell carcinoma. Oncotarget. 8:7729–7739. 2017. View Article : Google Scholar : PubMed/NCBI