Table_1_TMPRSS4 Promotes Cell Proliferation and Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma by Activating ERK1/2 Signaling Pathway.XLSX

Transmembrane protease serine 4 (TMPRSS4) is upregulated in various kinds of human cancers, including pancreatic cancer. However, its biological function in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In the current study, real-time qPCR, immunohistochemical staining, Western blotting, and database (Cancer Genome Atlas and Gene Expression) analysis revealed remarkable overexpression of TMPRSS4 in PDAC tissue as compared to non-tumor tissue. The TMPRSS4 overexpression was associated with poor prognosis of PDAC patients. Moreover, multivariate analysis revealed that TMPRSS4 serves as an independent risk factor in PDAC. We performed gain-and loss-of-function analysis and found that TMPRSS4 promotes cellular proliferation and inhibits apoptosis of PDAC cells both in vitro and in vivo. Furthermore, we showed that TMPRSS4 might promote cell proliferation and inhibit apoptosis through activating ERK1/2 signaling pathway in pancreatic cancer cells. These findings were validated by using ERK1/2 phosphorylation inhibitor SCH772984 both in vitro and in vivo. Taken together, this study suggests that TMPRSS4 is a proto-oncogene, which promotes initiation and progression of PDAC by controlling cell proliferation and apoptosis. Our findings indicate that TMPRSS4 could be a promising prognostic biomarker and a therapeutic target for the treatment of pancreatic cancer.

跨膜丝氨酸蛋白酶4（Transmembrane protease serine 4, TMPRSS4）在包括胰腺癌在内的多种人类癌症中呈高表达状态。然而，其在胰腺导管腺癌（PDAC）中的生物学功能尚未阐明。本研究通过实时定量聚合酶链反应（real-time qPCR）、免疫组织化学染色、蛋白质免疫印迹（Western blotting）以及癌症基因组图谱、基因表达数据库分析，证实相较于非肿瘤组织，TMPRSS4在PDAC组织中存在显著过表达。TMPRSS4过表达与PDAC患者的不良预后显著相关。进一步的多变量分析显示，TMPRSS4可作为PDAC的独立危险因素。本研究开展了功能获得与功能缺失实验，结果表明TMPRSS4在体内外均可促进PDAC细胞增殖并抑制其凋亡。此外，本研究证实TMPRSS4可能通过激活胰腺癌细胞中的细胞外调节蛋白激酶1/2（ERK1/2）信号通路，促进细胞增殖并抑制细胞凋亡，该结论通过在体内外使用ERK1/2磷酸化抑制剂SCH772984得到验证。综上，本研究表明TMPRSS4是一种原癌基因，通过调控细胞增殖与凋亡促进PDAC的发生与进展。本研究结果提示，TMPRSS4有望成为胰腺癌潜在的预后生物标志物与治疗靶点。