Correlation between S100A11 and the TGF-β1/SMAD4 pathway and its effects on the proliferation and apoptosis of pancreatic cancer cell line PANC-1
S100A11 as a S100 protein family member has been documented to play dual-direction regulation over cancer cell proliferation. We explored the role of S100A11 in the proliferation and apoptosis of pancreatic cancer cell line PANC-1 and the potential mechanisms involving the TGF-β1/SMAD4/p21 pathway. S100A11 and TGF-β1 protein expressions in 30 paraffin-embedded specimens were evaluated by immunohistochemistry. S100A11 and TGF-β1 expression in PANC-1 cell line was suppressed using small interfering RNA (siRNA), respectively. Subsequently, pancreatic cancer cell apoptosis was measured by Cell Counting Kit-8 and flow cytometry, and S100A11 and TGF-β1/SMAD4/p21 pathway proteins and genes were detected with Western blotting and quantitative polymerase chain reaction (qPCR). S100A11 cytoplasmic/nuclear protein translocation was examined using NE-PER® cytoplasm/nuclear protein extraction in cells interfered with TGF-β1 siRNA. Our results showed that S100A11 expression was positively correlated with TGF-β1 expression in pancreatic cancerous tissue. Silencing TGF-β1 down-regulated intracellular P21WAF1 expression by 90%, blocked S100A11 from cytoplasm entering nucleus, and enhanced cell proliferation. Silencing S100A11 down-regulated intracellular P21 expression and promoted cell apoptosis without significantly changing TGF-β1 and SMAD4 expression. Our findings revealed that S100A11 and TGF-β1/SMAD4 signaling pathway were related but mutually independent in regulating PANC-1 cells proliferation and apoptosis. Other independent mechanisms might be involved in S100A11’s regulation of pancreatic cell growth. S100A11 could be a potential gene therapy target for pancreatic cancer.
KeywordsPancreatic cancer S100A11 protein TGF-β1/SMAD4 pathway P21WAF1 Proliferation ·apoptosis
This study was supported by Grants from the Natural Youth Science Foundation of China (Grant No. 81502055), the Natural Science Foundation of Jiangsu Province (Grant No. BK20161286), the Health Project of Jiangsu Province (Grant No. H201624) and the Social Development Foundation of Nantong City (Grant Nos. MS22016056, MS22015062, HS2014072, and MS22015044).
YFJ, TL, FJ, WKN, and CQG carried out the studies, participated in collecting data, and drafted the manuscript. WW and MBX performed the statistical analysis and participated in its design. ZXL, CHL, and RZN helped to draft the manuscript. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- 1.Ercan G, Karlitepe A, Ozpolat B (2017) Pancreatic cancer stem cells and therapeutic approaches. Anticancer Res 37:2761–2775Google Scholar
- 4.Rezvanpour A, Shaw GS (2009) Unique S100 target protein interactions. Gen Physiol Biophys Focus Issue 28:F39-46Google Scholar
- 6.Kondo A, Sakaguchi M, Makino E, Namba M, Okada S, Huh NH (2002) Localization of S100C immunoreactivity in various human tissues. Acta Med Okayama 56:31–34Google Scholar
- 11.Chen JH, Ni RZ, Xiao MB, Guo JG, Zhou JW (2009) Comparative proteomic analysis of differentially expressed proteins in human pancreatic cancer tissue. Hepatobiliary Pancreat Dis Int 8:193–200Google Scholar
- 12.Saho S, Satoh H, Kondo E, Inoue Y, Yamauchi A, Murata H, Kinoshita R, Yamamoto KI, Futami J, Putranto EW, Ruma IM, Sumardika IW, Youyi C, Suzawa K, Yamamoto H, Soh J, Tomida S, Sakaguchi Y, Saito K, Iioka H, Huh NH, Toyooka S, Sakaguchi M (2016) Active secretion of dimerized S100A11 induced by the peroxisome in mesothelioma cells. Cancer Microenviron 9:93–105. https://doi.org/10.1007/s12307-016-0185-2 CrossRefGoogle Scholar
- 21.Moz S, Basso D, Bozzato D, Galozzi P, Navaglia F, Negm OH, Arrigoni G, Zambon CF, Padoan A, Tighe P, Todd I, Franchin C, Pedrazzoli S, Punzi L, Plebani M (2016) SMAD4 loss enables EGF, TGFbeta1 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells. Oncotarget 7:69927–69944. https://doi.org/10.18632/oncotarget.12068 CrossRefGoogle Scholar
- 24.Sakaguchi M, Murata H, Sonegawa H, Sakaguchi Y, Futami J, Kitazoe M, Yamada H, Huh NH (2007) Truncation of annexin A1 is a regulatory lever for linking epidermal growth factor signaling with cytosolic phospholipase A2 in normal and malignant squamous epithelial cells. J Biol Chem 282:35679–35686. https://doi.org/10.1074/jbc.M707538200 CrossRefGoogle Scholar
- 28.Melchionna R, Iapicca P, Di Modugno F, Trono P, Sperduti I, Fassan M, Cataldo I, Rusev BC, Lawlor RT, Diodoro MG, Milella M, Grazi GL, Bissell MJ, Scarpa A, Nistico P (2016) The pattern of hMENA isoforms is regulated by TGF-beta1 in pancreatic cancer and may predict patient outcome. Oncoimmunology 5:e1221556. https://doi.org/10.1080/2162402X.2016.1221556 CrossRefGoogle Scholar
- 29.Aletaha M, Mansoori B, Mohammadi A, Fazeli M, Baradaran B (2017) The effect of snail1 gene silencing by siRNA in metastatic breast cancer cell lines. Iran J Public Health 46:659–670Google Scholar
- 31.Liu L, Miao L, Liu Y, Qi A, Xie P, Chen J, Zhu H (2017) S100A11 regulates renal carcinoma cell proliferation, invasion, and migration via the EGFR/Akt signaling pathway and E-cadherin. Tumour Biol 39:1010428317705337Google Scholar