S100A4 influences cancer stem cell-like properties of MGC803 gastric cancer cells by regulating GDF15 expression

Guo,Junfu; Bian,Yue; Wang,Yu; Chen,Lisha; Yu,Aiwen; Sun,Xiuju

doi:10.3892/ijo.2016.3556

S100A4 influences cancer stem cell-like properties of MGC803 gastric cancer cells by regulating GDF15 expression

Authors:
- Junfu Guo
- Yue Bian
- Yu Wang
- Lisha Chen
- Aiwen Yu
- Xiuju Sun
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Affiliations: Department of Medical Genetics, China Medical University, Shenyang, Liaoning 110122, P.R. China
Published online on: June 2, 2016 https://doi.org/10.3892/ijo.2016.3556
Pages: 559-568

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Abstract

Many studies have revealed that S100A4 is involved in cancer progression by affecting a variety of biological functions. Our previous study showed that S100A4 influences many biological properties of gastric cancer cells; however, the underlying mechanisms are far from clear. In this study, we used cDNA microarray analysis to investigate the global alterations in gene expression in MGC803 gastric cancer cells after siRNA-mediated S100A4 inhibition. Among the total genes investigated, 179 differentially expressed genes (38 upregulated and 141 downregulated) were detected in S100A4-siRNA transfected MGC803 cells compared with NC-siRNA transfected cells. We focused on the GDF15 gene, which was significantly downregulated after S100A4 inhibition. ChIP studies showed that the S100A4 protein binds to the GDF15 promoter, implicating S100A4 in GDF15 regulation at the transcriptional level. GDF15 overexpression promoted CSC-like properties of MGC803 cells, such as spheroid and soft-agar colony forming abilities. S100A4 inhibition suppressed the CSC-like properties of the cells, whereas, GV141-GDF15 vector transfection reversed these effects. Our results suggest that S100A4 influences the CSC-like properties of MGC803 gastric cancer cells by regulating GDF15 expression.

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1	Boye K and Maelandsmo GM: S100A4 and metastasis: A small actor playing many roles. Am J Pathol. 176:528–535. 2010. View Article : Google Scholar :
2	Natarajan J, Hunter K, Mutalik VS and Radhakrishnan R: Overexpression of S100A4 as a biomarker of metastasis and recurrence in oral squamous cell carcinoma. J Appl Oral Sci. 22:426–433. 2014. View Article : Google Scholar : PubMed/NCBI
3	Li H, Liu Z, Xu C, Chen Y, Zhang J, Cui B, Chen X, An G, She X, Liu H, 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
4	Niu Y, Wang L, Cheng C, Du C, Lu X, Wang G and Liu J: Increased expressions of SATB1 and S100A4 are associated with poor prognosis in human colorectal carcinoma. APMIS. 123:93–101. 2015. View Article : Google Scholar
5	Zhang K, Zhang M, Zhao H, Yan B, Zhang D and Liang J: S100A4 regulates motility and invasiveness of human esophageal squamous cell carcinoma through modulating the AKT/Slug signal pathway. Dis Esophagus. 25:731–739. 2012. View Article : Google Scholar
6	Wang L, Wang X, Liang Y, Diao X and Chen Q: S100A4 promotes invasion and angiogenesis in breast cancer MDA-MB-231 cells by upregulating matrix metalloproteinase-13. Acta Biochim Pol. 59:593–598. 2012.
7	Che P, Yang Y, Han X, Hu M, Sellers JC, Londono-Joshi AI, Cai GQ, Buchsbaum DJ, Christein JD, Tang Q, et al: S100A4 promotes pancreatic cancer progression through a dual signaling pathway mediated by Src and focal adhesion kinase. Sci Rep. 5:84532015. View Article : Google Scholar : PubMed/NCBI
8	Hua J, Chen D, Fu H, Zhang R, Shen W, Liu S, Sun K and Sun X: 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
9	Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL and Wahl GM: Cancer stem cells - perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66:9339–9344. 2006. View Article : Google Scholar : PubMed/NCBI
10	Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R, Gordon SA, Shimada Y and Wang TC: Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 27:1006–1020. 2009. View Article : Google Scholar : PubMed/NCBI
11	Larzabal L, El-Nikhely N, Redrado M, Seeger W, Savai R and Calvo A: Differential effects of drugs targeting cancer stem cell (CSC) and non-CSC populations on lung primary tumors and metastasis. PLoS One. 8:e797982013. View Article : Google Scholar : PubMed/NCBI
12	Ping YF and Bian XW: Consice review: Contribution of cancer stem cells to neovascularization. Stem Cells. 29:888–894. 2011. View Article : Google Scholar : PubMed/NCBI
13	Liao J, Qian F, Tchabo N, Mhawech-Fauceglia P, Beck A, Qian Z, Wang X, Huss WJ, Lele SB, Morrison CD, et al: Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism. PLoS One. 9:e849412014. View Article : Google Scholar : PubMed/NCBI
14	Lo JF, Yu CC, Chiou SH, Huang CY, Jan CI, Lin SC, Liu CJ, Hu WY and Yu YH: 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
15	Liu Z, Liu H, Pan H, Du Q and Liang J: Clinicopathological significance of S100A4 expression in human hepatocellular carcinoma. J Int Med Res. 41:457–462. 2013. View Article : Google Scholar : PubMed/NCBI
16	Yang H, Zhao K, Yu Q, Wang X, Song Y and Li R: Evaluation of plasma and tissue S100A4 protein and mRNA levels as potential markers of metastasis and prognosis in clear cell renal cell carcinoma. J Int Med Res. 40:475–485. 2012. View Article : Google Scholar : PubMed/NCBI
17	Wang YY, Ye ZY, Zhao ZS, Tao HQ and Chu YQ: High-level expression of S100A4 correlates with lymph node metastasis and poor prognosis in patients with gastric cancer. Ann Surg Oncol. 17:89–97. 2010. View Article : Google Scholar
18	Shen W, Chen D, Fu H, Liu S, Sun K and Sun X: S100A4 protects gastric cancer cells from anoikis through regulation of αv and α5 integrin. Cancer Sci. 102:1014–1018. 2011. View Article : Google Scholar : PubMed/NCBI
19	Chen D, Zhang R, Shen W, Fu H, Liu S, Sun K and Sun X: RPS12-specific shRNA inhibits the proliferation, migration of BGC823 gastric cancer cells with S100A4 as a downstream effector. Int J Oncol. 42:1763–1769. 2013.
20	Saleem M, Kweon MH, Johnson JJ, Adhami VM, Elcheva I, Khan N, Bin Hafeez B, Bhat KM, Sarfaraz S, Reagan-Shaw S, et al: S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9. Proc Natl Acad Sci USA. 103:14825–14830. 2006. View Article : Google Scholar : PubMed/NCBI
21	Huang L, Xu Y, Cai G, Guan Z and Cai S: Downregulation of S100A4 expression by RNA interference suppresses cell growth and invasion in human colorectal cancer cells. Oncol Rep. 27:917–922. 2012.
22	Ochiya T, Takenaga K and Endo H: Silencing of S100A4, a metastasis-associated protein, in endothelial cells inhibits tumor angiogenesis and growth. Angiogenesis. 17:17–26. 2014. View Article : Google Scholar :
23	Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, et al: MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci USA. 94:11514–11519. 1997. View Article : Google Scholar : PubMed/NCBI
24	Li PX, Wong J, Ayed A, Ngo D, Brade AM, Arrowsmith C, Austin RC and Klamut HJ: Placental transforming growth factor-beta is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression. J Biol Chem. 275:20127–20135. 2000. View Article : Google Scholar
25	Hromas R, Hufford M, Sutton J, Xu D, Li Y and Lu L: PLAB, a novel placental bone morphogenetic protein. Biochim Biophys Acta. 1354:40–44. 1997. View Article : Google Scholar : PubMed/NCBI
26	Bauskin AR, Brown DA, Junankar S, Rasiah KK, Eggleton S, Hunter M, Liu T, Smith D, Kuffner T, Pankhurst GJ, et al: The propeptide mediates formation of stromal stores of PROMIC-1: Role in determining prostate cancer outcome. Cancer Res. 65:2330–2336. 2005. View Article : Google Scholar : PubMed/NCBI
27	Welsh JB, Sapinoso LM, Kern SG, Brown DA, Liu T, Bauskin AR, Ward RL, Hawkins NJ, Quinn DI, Russell PJ, et al: Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc Natl Acad Sci USA. 100:3410–3415. 2003. View Article : Google Scholar : PubMed/NCBI
28	Paralkar VM, Vail AL, Grasser WA, Brown TA, Xu H, Vukicevic S, Ke HZ, Qi H, Owen TA and Thompson DD: Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family. J Biol Chem. 273:13760–13767. 1998. View Article : Google Scholar : PubMed/NCBI
29	Yin T, Cho SJ and Chen X: RNPC1, an RNA-binding protein and a p53 target, regulates macrophage inhibitory cytokine-1 (MIC-1) expression through mRNA stability. J Biol Chem. 288:23680–23686. 2013. View Article : Google Scholar : PubMed/NCBI
30	Wiklund FE, Bennet AM, Magnusson PK, Eriksson UK, Lindmark F, Wu L, Yaghoutyfam N, Marquis CP, Stattin P, Pedersen NL, et al: Macrophage inhibitory cytokine-1 (MIC-1/ GDF15): A new marker of all-cause mortality. Aging Cell. 9:1057–1064. 2010. View Article : Google Scholar : PubMed/NCBI
31	Staff AC, Trovik J, Eriksson AG, Wik E, Wollert KC, Kempf T and Salvesen HB: Elevated plasma growth differentiation factor-15 correlates with lymph node metastases and poor survival in endometrial cancer. Clin Cancer Res. 17:4825–4833. 2011. View Article : Google Scholar : PubMed/NCBI
32	Schiegnitz E, Kämmerer PW, Koch FP, Krüger M, Berres M and Al-Nawas B: GDF 15 as an anti-apoptotic, diagnostic and prognostic marker in oral squamous cell carcinoma. Oral Oncol. 48:608–614. 2012. View Article : Google Scholar : PubMed/NCBI
33	Tsui KH, Chang YL, Feng TH, Chung LC, Lee TY, Chang PL and Juang HH: Growth differentiation factor-15 upregulates interleukin-6 to promote tumorigenesis of prostate carcinoma PC-3 cells. J Mol Endocrinol. 49:153–163. 2012. View Article : Google Scholar : PubMed/NCBI
34	Grigorian M, Andresen S, Tulchinsky E, Kriajevska M, Carlberg C, Kruse C, Cohn M, Ambartsumian N, Christensen A, Selivanova G, 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 : PubMed/NCBI
35	Tan M, Wang Y, Guan K and Sun Y: PTGF-beta, a type beta transforming growth factor (TGF-beta) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-beta signaling pathway. Proc Natl Acad Sci USA. 97:109–114. 2000. View Article : Google Scholar : PubMed/NCBI
36	Osada M, Park HL, Park MJ, Liu JW, Wu G, Trink B and Sidransky D: A p53-type response element in the GDF15 promoter confers high specificity for p53 activation. Biochem Biophys Res Commun. 354:913–918. 2007. View Article : Google Scholar : PubMed/NCBI
37	Baek SJ, Horowitz JM and Eling TE: Molecular cloning and characterization of human nonsteroidal anti-inflammatory drug-activated gene promoter. Basal transcription is mediated by Sp1 and Sp3. J Biol Chem. 276:33384–33392. 2001. View Article : Google Scholar : PubMed/NCBI
38	Baek SJ, Kim JS, Moore SM, Lee SH, Martinez J and Eling TE: Cyclooxygenase inhibitors induce the expression of the tumor suppressor gene EGR-1, which results in the up-regulation of NAG-1, an antitumorigenic protein. Mol Pharmacol. 67:356–364. 2005. View Article : Google Scholar
39	Lee DH, Yang Y, Lee SJ, Kim KY, Koo TH, Shin SM, Song KS, Lee YH, Kim YJ, Lee JJ, et al: Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system. Cancer Res. 63:4648–4655. 2003.PubMed/NCBI
40	Baek KE, Yoon SR, Kim JT, Kim KS, Kang SH, Yang Y, Lim JS, Choi I, Nam MS, Yoon M, et al: Upregulation and secretion of macrophage inhibitory cytokine-1 (MIC-1) in gastric cancers. Clin Chim Acta. 401:128–133. 2009. View Article : Google Scholar : PubMed/NCBI
41	Blanco-Calvo M, Tarrío N, Reboredo M, Haz-Conde M, García J, Quindós M, Figueroa A, Antón-Aparicio L, Calvo L and Valladares-Ayerbes M: Circulating levels of GDF15, MMP7 and miR-200c as a poor prognostic signature in gastric cancer. Future Oncol. 10:1187–1202. 2014. View Article : Google Scholar : PubMed/NCBI
42	Tanno T, Lim Y, Wang Q, Chesi M, Bergsagel PL, Matthews G, Johnstone RW, Ghosh N, Borrello I, Huff CA, et al: Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells. Blood. 123:725–733. 2014. View Article : Google Scholar :