RNA interference targeting inhibition of S100A4 suppresses cell growth and promotes apoptosis in human laryngeal carcinoma Hep‑2 cells

Liu,Jia; Fu,Shuang; Xu,Yingqi; Zheng,Zhihong

doi:10.3892/mmr.2014.2345

RNA interference targeting inhibition of S100A4 suppresses cell growth and promotes apoptosis in human laryngeal carcinoma Hep‑2 cells

Authors:
- Jia Liu
- Shuang Fu
- Yingqi Xu
- Zhihong Zheng
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Affiliations: Laboratory Animal Center, China Medical University, Shenyang, Liaoning 110001, P.R. China, Department of Hematology Laboratory, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, P.R. China
Published online on: June 19, 2014 https://doi.org/10.3892/mmr.2014.2345
Pages: 1389-1394

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Abstract

S100A4 is a small Ca2+ binding protein that belongs to the S100 family and is involved in a number of cellular functions, including cell cycle control, proliferation, apoptosis, and has a significant role in angiogenesis and neurite extension. However, the exact function and mechanism of S100A4 in laryngeal carcinogenesis remains to be elucidated. The present study was designed to investigate the potential use of RNA interference to inhibit S100A4 expression and activation, as well as the subsequent effect on human laryngeal cancer cell growth and apoptosis. The present study demonstrated that knockdown of S100A4 decreased the proliferation and growth of the human laryngeal cancer Hep‑2 cell line. The percentages of the apoptotic cells were 4.23±1.22, 4.92±1.85 and 11.70±4.02% in the control, negative control and S100A4 short hairpin RNA (shRNA) groups, respectively, indicating significant differences among the different groups. The S100A4‑mediated induction of apoptosis was demonstrated to be associated with the activation of caspase‑3, caspase‑8 and caspase‑9. Intratumoral injection of S100A4‑shRNA inhibited tumor growth in nude mice. Thus, knockdown of S100A4 inhibited the progression of laryngeal squamous carcinoma, decreased proliferation and promoted apoptosis. S100A4 is a potential candidate for therapeutic targeting of laryngeal carcinoma cells.

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1	Ragin CC, Modugno F and Gollin SM: The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus. J Dent Res. 86:104–114. 2007. View Article : Google Scholar : PubMed/NCBI
2	Jemal A, Siegel R, Ward E, Murray T, Xu J and Thun MJ: Cancer statistics, 2007. CA Cancer J Clin. 57:43–66. 2007. View Article : Google Scholar
3	Marioni G, Marchese-Ragona R, Cartei G, Marchese F and Staffieri A: Current opinion in diagnosis and treatment of laryngeal carcinoma. Cancer Treat Rev. 32:504–515. 2006. View Article : Google Scholar : PubMed/NCBI
4	Mahon PC, Baril P, Bhakta V, et al: S100A4 contributes to the suppression of BNIP3 expression, chemoresistance, and inhibition of apoptosis in pancreatic cancer. Cancer Res. 67:6786–6795. 2007. View Article : Google Scholar : PubMed/NCBI
5	Pedersen MV, Køhler LB, Grigorian M, et al: The Mts1/S100A4 protein is a neuroprotectant. J Neurosci Res. 77:777–786. 2004. View Article : Google Scholar : PubMed/NCBI
6	Sekine H, Chen N, Sato K, et al: S100A4, frequently overexpressed in various human cancers, accelerates cell motility in pancreatic cancer cells. Biochem Biophys Res Commun. 429:214–219. 2012. View Article : Google Scholar : PubMed/NCBI
7	Boye K, Nesland JM, Sandstad B, Haugland Haugen M, Mælandsmo GM and Flatmark K: EMMPRIN is associated with S100A4 and predicts patient outcome in colorectal cancer. Br J Cancer. 107:667–674. 2012. View Article : Google Scholar : PubMed/NCBI
8	Li H, Liu Z, Xu C, et al: Overexpression of S100A4 is closely associated with the progression and prognosis of gastric cancer in young patients. Oncol Lett. 5:1485–1490. 2013.PubMed/NCBI
9	Klingelhöfer J, Grum-Schwensen B, Beck MK, et al: Anti-S100A4 antibody suppresses metastasis formation by blocking stroma cell invasion. Neoplasia. 14:1260–1268. 2012.PubMed/NCBI
10	Wang Z and Griffin M: The role of TG2 in regulating S100A4-mediated mammary tumour cell migration. PLoS One. 8:e570172013. View Article : Google Scholar : PubMed/NCBI
11	Liu J, Guo Y, Fu S, Yang M, Sun KL and Fu WN: Hypomethylation-induced expression of S100A4 increases the invasiveness of laryngeal squamous cell carcinoma. Oncol Rep. 23:1101–1107. 2010.PubMed/NCBI
12	Toolan HW: Transplantable human neoplasms maintained in cortisone-treated laboratory animals: H.S. No. 1; HEp No. 1; HEp No. 2; HEp No. 3; and HEmbRh No. 1. Cancer Res. 14:660–666. 1954.PubMed/NCBI
13	Boehm D, Herold S, Kuechler A, Liehr T and Laccone F: Rapid detection of subtelomeric deletion/duplication by novel real-time quantitative PCR using SYBR-green dye. Hum Mutat. 23:368–378. 2004. View Article : Google Scholar : PubMed/NCBI
14	Zhao Y, Zhang T and Wang Q: S100 calcium-binding protein A4 is a novel independent prognostic factor for the poor prognosis of gastric carcinomas. Oncol Rep. 30:111–118. 2013.
15	Roh J, Knight S, Chung JY, et al: S100A4 expression is a prognostic indicator in small intestine adenocarcinoma. J Clin Pathol. 67:216–221. 2014. View Article : Google Scholar : PubMed/NCBI
16	Berge G, Pettersen S, Grotterød I, Bettum IJ, Boye K and Mælandsmo GM: Osteopontin - an important downstream effector of S100A4-mediated invasion and metastasis. Int J Cancer. 129:780–790. 2011. View Article : Google Scholar : PubMed/NCBI
17	Sack U, Walther W, Scudiero D, et al: S100A4-induced cell motility and metastasis is restricted by the Wnt/beta-catenin pathway inhibitor calcimycin in colon cancer cells. Mol Biol Cell. 22:3344–3354. 2011. View Article : Google Scholar : PubMed/NCBI
18	Chen X, Luther G, Zhang W, et al: The E-F hand calcium-binding protein S100A4 regulates the proliferation, survival and differentiation potential of human osteosarcoma cells. Cell Physiol Biochem. 32:1083–1096. 2013. View Article : Google Scholar : PubMed/NCBI
19	Yang XC, Wang X, Luo L, et al: RNA interference suppression of A100A4 reduces the growth and metastatic phenotype of human renal cancer cells via NF-kB-dependent MMP-2 and bcl-2 pathway. Eur Rev Med Pharmacol Sci. 17:1669–1680. 2013.PubMed/NCBI
20	Tabata T, Tsukamoto N, Fooladi AA, et al: RNA interference targeting against S100A4 suppresses cell growth and motility and induces apoptosis in human pancreatic cancer cells. Biochem Biophys Res Commun. 390:475–480. 2009. View Article : Google Scholar : PubMed/NCBI
21	Hua J, Chen D, Fu H, et al: Short hairpin RNA-mediated inhibition of S100A4 promotes apoptosis and suppresses proliferation of BGC823 gastric cancer cells in vitro and in vivo. Cancer Lett. 292:41–47. 2010. View Article : Google Scholar : PubMed/NCBI
22	Maelandsmo GM, Hovig E, Skrede M, et al: Reversal of the in vivo metastatic phenotype of human tumor cells by an anti-CAPL (mts1) ribozyme. Cancer Res. 56:5490–5498. 1996.PubMed/NCBI
23	Pedersen KB, Andersen K, Fodstad Ø and Maelandsmo GM: Sensitization of interferon-gamma induced apoptosis in human osteosarcoma cells by extracellular S100A4. BMC Cancer. 4:522004. View Article : Google Scholar : PubMed/NCBI
24	Grigorian M, Andresen S, Tulchinsky E, et al: Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. J Biol Chem. 276:22699–22708. 2001. View Article : Google Scholar
25	Orre LM, Panizza E, Kaminskyy VO, et al: S100A4 interacts with p53 in the nucleus and promotes p53 degradation. Oncogene. 32:5531–5540. 2013. View Article : Google Scholar : PubMed/NCBI
26	Cho SG and Choi EJ: Apoptotic signaling pathways: caspases and stress-activated protein kinases. J Biochem Mol Biol. 35:24–27. 2002. View Article : Google Scholar : PubMed/NCBI
27	Fan TJ, Han LH, Cong RS and Liang J: Caspase family proteases and apoptosis. Acta Biochim Biophys Sin (Shanghai). 37:719–727. 2005. View Article : Google Scholar : PubMed/NCBI
28	Slee EA, Harte MT, Kluck RM, et al: Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol. 144:281–292. 1999. View Article : Google Scholar : PubMed/NCBI
29	Shi Y, Zou M, Collison K, et al: Ribonucleic acid interference targeting S100A4 (Mts1) suppresses tumor growth and metastasis of anaplastic thyroid carcinoma in a mouse model. J Clin Endocrinol Metab. 91:2373–2379. 2006. View Article : Google Scholar : PubMed/NCBI
30	Lo JF, Yu CC, Chiou SH, et al: The epithelial-mesenchymal transition mediator S100A4 maintains cancer-initiating cells in head and neck cancers. Cancer Res. 71:1912–1923. 2011. View Article : Google Scholar : PubMed/NCBI