Jin Jie, Shen Xian, Chen Lei, Bao Luo-wen, Zhu Li-ming
Department of Digestive Diseases, Wenzhou Central Hospital, Wenzhou, China.
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Biomed Pharmacother. 2016 Feb;77:30-6. doi: 10.1016/j.biopha.2015.11.002. Epub 2015 Dec 11.
Transmembrane protease serine 4 (TMPRSS4) is a type-II transmembrane serine protease that is frequently upregulated in human cancers. However, little is known about the biological roles of TMPRSS4 in gastric cancer. In this study, we examined the effect of TMPRSS4 on gastric cancer cell proliferation, migration, and invasion. The expression and secretion of matrix metalloproteinase-9 (MMP-9) and activation of nuclear factor-κB (NF-κB) were determined. The involvement of NF-κB/MMP-9 signaling was checked. Our data showed that TMPRSS4 silencing significantly (P<0.05) reduced the migration and invasion of AGS and MKN-45 gastric cancer cells, without affecting cell proliferation. Overexpression of TMPRSS4 significantly promoted cell migration and invasion. The expression and secretion of MMP-9 was significantly (P<0.05) enhanced in TMPRSS4-overexpressing cells. TMPRSS4-overexpressing cells had a significantly (P<0.05) lower level of IκBα and higher level of nuclear NF-κB. Luciferase reporter assay confirmed that overexpression of TMPRSS4 resulted in a 3-5-fold increase in NF-κB-dependent luciferase activity. Downregulation of MMP-9 significantly (P<0.05) reversed the invasiveness of gastric cancer cells induced by TMPRSS4 overexpression. Moreover, pharmacological inhibition of NF-κB attenuated the invasion of TMPRSS4-overexpressing cells and the expression of MMP-9. Upregulation of TMPRSS4 enhances the invasiveness of gastric cancer cells, largely through activation of NF-κB and induction of MMP-9 expression. Our study provides the rationale for targeting TMPRSS4 in the treatment of gastric cancer.
跨膜蛋白酶丝氨酸4（TMPRSS4）是一种II型跨膜丝氨酸蛋白酶，在人类癌症中经常上调。然而，关于TMPRSS4在胃癌中的生物学作用知之甚少。在本研究中，我们研究了TMPRSS4对胃癌细胞增殖、迁移和侵袭的影响。测定了基质金属蛋白酶-9（MMP-9）的表达和分泌以及核因子-κB（NF-κB）的激活情况。检测了NF-κB/MMP-9信号通路的参与情况。我们的数据表明，TMPRSS4沉默显著（P<0.05）降低了AGS和MKN-45胃癌细胞的迁移和侵袭能力，但不影响细胞增殖。TMPRSS4过表达显著促进了细胞迁移和侵袭。在TMPRSS4过表达的细胞中，MMP-9的表达和分泌显著（P<0.05）增强。TMPRSS4过表达的细胞中IκBα水平显著（P<0.05）降低，核NF-κB水平升高。荧光素酶报告基因检测证实，TMPRSS4过表达导致NF-κB依赖性荧光素酶活性增加3至5倍。MMP-9的下调显著（P<0.05）逆转了TMPRSS4过表达诱导的胃癌细胞侵袭能力。此外，NF-κB的药理学抑制减弱了TMPRSS4过表达细胞的侵袭能力以及MMP-9的表达。TMPRSS4的上调增强了胃癌细胞的侵袭能力，主要是通过激活NF-κB和诱导MMP-9表达实现的。我们的研究为在胃癌治疗中靶向TMPRSS4提供了理论依据。
