SOCS3 methylation in synergy with Reg3A overexpression promotes cell growth in pancreatic cancer
SOCS3 methylation in synergy with Reg3A overexpression promotes cell growth in pancreatic cancer
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SOCS3 甲基化与 Reg3A 过表达协同促进胰腺癌细胞生长
DOI：
10.1007/s00109-014-1184-8
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发表时间：
2014-12-01
影响因子：
4.7
通讯作者：
Xiang, Ming
中科院分区：
文献类型：
--
作者：
Wang, Jun;Zhou, Hong;Xiang, Ming
胰腺癌（PaC）是世界上第五大癌症死亡原因，但其发展的分子机制仍不清楚。据报道，再生胰岛衍生蛋白3-α（Reg 3A）在胰腺炎症中过表达，并与PaC恶性肿瘤相关，因此被认为是炎症相关胰腺癌发生的潜在靶点。细胞因子信号转导抑制因子SOCS 3是一种众所周知的细胞增殖反馈抑制因子，在许多人类癌症中被发现。在此，我们鉴定了SOCS 3在3/5的人PaC细胞系和11/36的癌组织样品中在其CpG岛中异常甲基化。通过去甲基化剂5-氮杂-2 '-脱氧胞苷恢复SOCS 3，显著抑制细胞增殖并诱导甲基化PaC细胞凋亡。此外，我们还表明Reg 3A在PaC细胞和组织样品中高度表达。体外评估SOCS 3和Reg 3A畸变之间的潜在关系表明，SOCS 3在Reg 3A下游起作用，并调节Reg 3A相关的促肿瘤功能。siRNA介导的SOCS 3在正常胰腺上皮细胞中的敲低和质粒转染的SOCS 3在PaC细胞中的过表达分别导致Reg 3A诱导的细胞增殖的明显促进和抑制，从而表明SOCS 3负调节Reg 3A介导的PaC进展。此外，我们的研究结果还显示JAK/STAT 3/NF-κ B似乎参与了SOCS 3-Reg 3A相互作用对胰腺细胞生长的影响。总之，SOCS 3甲基化失活与Reg 3A过表达协同作用，促进PaC细胞生长，并可能促进炎症相关胰腺癌的发生。
Pancreatic cancer (PaC) is the fifth leading cause of cancer death in the world, but the molecular mechanisms for its development remain unclear. Regenerating islet-derived protein 3-alpha (Reg3A) has been reported overexpressed in pancreatic inflammation and associated with PaC malignancies, thus believed as a potential target in inflammation-linked pancreatic carcinogenesis. Silencing of suppressor of cytokine signaling SOCS3, a well-known feedback inhibitor of cell proliferation, has been found in many human cancers. Here, we identified that SOCS3 was aberrantly methylated in its CpG island in 3/5 human PaC cell lines and 11/36 cancer tissue samples. SOCS3 restoration by a demethylating agent, 5-aza-2'-deoxycytidine, remarkably suppressed cell proliferation and induced apoptosis of methylated PaC cells. Moreover, we also have shown that Reg3A was highly expressed in PaC cells and tissue samples. Assessment of potential relationship between SOCS3 and Reg3A aberrations in vitro revealed that SOCS3 worked downstream of Reg3A and modulated Reg3A-linked pro-tumor functions. siRNA-mediated SOCS3 knock-down in normal pancreatic epithelial cells and plasmid-transfected SOCS3 overexpression in PaC cells, respectively, resulted in the obvious promotion and inhibition of Reg3A-induced cell proliferation, thereby suggesting SOCS3 negatively regulating Reg3A-mediated PaC progression. In addition, our findings also revealed that JAK/STAT3/NF-kappa B appear involved in the effect of SOCS3-Reg3A interaction on pancreatic cell growth. In summary, SOCS3 inactivation by methylation was demonstrated to act in synergy with Reg3A overexpression to promote PaC cell growth and maybe the progress of inflammation-linked pancreatic carcinogenesis.