Lv Hongjun, Liu Rui, Fu Jiao, Yang Qi, Shi Jing, Chen Pu, Ji Meiju, Shi Bingyin, Hou Peng
a Department of Endocrinology ; The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine ; Xi'an , The People's Republic of China.
Cell Cycle. 2014;13(18):2962-74. doi: 10.4161/15384101.2014.947203.
Periostin is usually considered as an oncogene in diverse human cancers, including breast, prostate, colon, esophagus, and pancreas cancers, whereas it acts as a tumor suppressor in bladder cancer. In gastric cancer, it has been demonstrated that periglandular periostin expression is decreased whereas stromal periostin expression is significantly increased as compared with normal gastric tissues. Moreover, periostin produced by stromal myofibroblasts markedly promotes gastric cancer cell growth. These observations suggest that periostin derived from different types of cells may play distinct biological roles in gastric tumorigenesis. The aim of this study was to explore the biological functions and related molecular mechanisms of epithelial cell-derived periostin in gastric cancer. Our data showed that periglandular periostin was significantly down-regulated in gastric cancer tissues as compared with matched normal gastric mucosa. In addition, its expression in metastatic lymph nodes was significantly lower than that in their primary cancer tissues. Our data also demonstrated that periglandular periostin expression was negatively associated with tumor stage. More importantly, restoration of periostin expression in gastric cancer cells dramatically suppressed cell growth and invasiveness. Elucidation of the mechanisms involved revealed that periostin restoration enhanced Rb phosphorylation and sequentially activated the transcription of E2F1 target gene p14(ARF), leading to Mdm2 inactivation and the stabilization of p53 and E-cadherin proteins. Strikingly, these effects of periostin were abolished upon Rb deletion. Collectively, we have for the first time demonstrated that epithelial cell-derived periostin exerts tumor-suppressor activities in gastric cancer through stabilizing p53 and E-cadherin proteins via the Rb/E2F1/p14(ARF)/Mdm2 signaling pathway.
骨膜蛋白通常被认为是多种人类癌症中的一种癌基因，包括乳腺癌、前列腺癌、结肠癌、食管癌和胰腺癌，而在膀胱癌中它却起着肿瘤抑制作用。在胃癌中，已证实与正常胃组织相比，腺周骨膜蛋白表达降低，而基质骨膜蛋白表达显著增加。此外，基质肌成纤维细胞产生的骨膜蛋白显著促进胃癌细胞生长。这些观察结果表明，源自不同类型细胞的骨膜蛋白可能在胃癌发生过程中发挥不同的生物学作用。本研究的目的是探讨上皮细胞源性骨膜蛋白在胃癌中的生物学功能及相关分子机制。我们的数据显示，与配对的正常胃黏膜相比，胃癌组织中腺周骨膜蛋白显著下调。此外，其在转移淋巴结中的表达明显低于原发癌组织。我们的数据还表明，腺周骨膜蛋白表达与肿瘤分期呈负相关。更重要的是，恢复胃癌细胞中骨膜蛋白的表达可显著抑制细胞生长和侵袭性。对所涉及机制的阐明表明，骨膜蛋白的恢复增强了Rb磷酸化，并依次激活E2F1靶基因p14(ARF)的转录，导致Mdm2失活以及p53和E-钙黏蛋白的稳定。令人惊讶的是，Rb缺失后骨膜蛋白的这些作用被消除。总的来说，我们首次证明上皮细胞源性骨膜蛋白通过Rb/E2F1/p14(ARF)/Mdm2信号通路稳定p53和E-钙黏蛋白，从而在胃癌中发挥肿瘤抑制活性。
