Shan Xia, Wen Wei, Zhu Danxia, Yan Ting, Cheng Wenfang, Huang Zebo, Zhang Lan, Zhang Huo, Wang Tongshan, Zhu Wei, Zhu Yichao, Zhu Jun
Department of Respiration, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, PR China.
Department of Thoracic Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China.
PLoS One. 2017 Jan 18;12(1):e0170298. doi: 10.1371/journal.pone.0170298. eCollection 2017.
The metastasis of gastric cancer, one of the most common tumors, has a molecular mechanism that is still largely unclear. Here we investigated the role of possible tumor-suppressor miR-1296-5p in the cell migration and invasion of ERBB2-positive gastric cancer. It found that miR-1296-5p was significantly down-regulated in gastric cancer tissues. Moreover, it was down-regulated in lymph node metastatic gastric cancer tissues compared with non-metastatic gastric cancer tissues. The luciferase activity of ERBB2 3'-untranslated region-based reporters constructed in SNU-216 and NUGC-4 gastric cancer cells suggested that ERBB2 was the target gene of miR-1296-5p. Overexpressed miR-1296-5p reduced its target protein level and Rac1 activation, and inhibited the migration and invasion of SNU-216 and NUGC-4 gastric cancer cells. MiR-1296-5p was down-regulated in ERBB2-positive gastric cancer tissues compared with ERBB2-negative gastric cancer tissues. In ERBB2-positive gastric cancers, the miR-1296-5p expression was suppressed in a majority of metastatic lymph node tissues compared to non-metastatic gastric cancer samples. The migration and invasion of gastric cancer cells was inhibited by miR-1296-5p overexpression or herceptin treatment, and rescued by the overexpression of constitutively active Rac1-Q61L or ERBB2. Taken together, our findings first suggest that miR-1296-5p might be involved in the regulation on the migration and invasion of human gastric cancer cells at least in part via targeting ERBB2/Rac1 signaling pathway.
胃癌是最常见的肿瘤之一，其转移的分子机制在很大程度上仍不清楚。在此，我们研究了潜在的肿瘤抑制因子miR-1296-5p在ERBB2阳性胃癌细胞迁移和侵袭中的作用。研究发现，miR-1296-5p在胃癌组织中显著下调。此外，与非转移性胃癌组织相比，其在淋巴结转移性胃癌组织中也下调。在SNU-216和NUGC-4胃癌细胞中构建的基于ERBB2 3'-非翻译区的报告基因的荧光素酶活性表明，ERBB2是miR-1296-5p的靶基因。过表达miR-1296-5p可降低其靶蛋白水平和Rac1激活，并抑制SNU-216和NUGC-4胃癌细胞的迁移和侵袭。与ERBB2阴性胃癌组织相比，miR-1296-5p在ERBB2阳性胃癌组织中下调。在ERBB2阳性胃癌中，与非转移性胃癌样本相比，大多数转移性淋巴结组织中miR-1296-5p表达受到抑制。miR-1296-5p过表达或赫赛汀治疗可抑制胃癌细胞的迁移和侵袭，而组成型活性Rac1-Q61L或ERBB2的过表达可使其恢复。综上所述，我们的研究结果首次表明，miR-1296-5p可能至少部分通过靶向ERBB2/Rac1信号通路参与调控人胃癌细胞的迁移和侵袭。
