Department of General Surgery, Drum Tower Hospital, Medical School of Nanjing University, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, China.
State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing, Jiangsu, 210046, China.
Cell Death Dis. 2018 May 1;9(5):522. doi: 10.1038/s41419-018-0611-0.
Gastric cancer (GC) is one of the most common malignant tumors and peritoneal metastasis is the primary cause for advanced GC's mortality. Protein-tyrosine phosphatase 1B (PTP1B) functions as an oncogene and involves in carcinogenesis and cancer dissemination. However, the function and regulation of PTP1B in GC remain poorly understood. In this study, we found that PTP1B was upregulated in GC tissues and overexpression of PTP1B in vitro promoted cell migration and prevented apoptosis. Then, we predicted that PTP1B was a target of miR-338-3p and we revealed an inverse correlation between miR-338-3p levels and PTP1B protein levels in GC tissues. Next, we verified that PTP1B was inhibited by miR-338-3p via direct targeting to its 3'-untranslated regions. Moreover, overexpression of miR-338-3p in vitro attenuated GC cell migration and promoted apoptosis, and these effects could be partially reversed by reintroduction of PTP1B. Finally, we established an orthotopic xenograft model and a peritoneal dissemination model of GC to demonstrate that miR-338-3p restrained tumor growth and dissemination in vivo by targeting PTP1B. Taken together, our results highlight that PTP1B is an oncogene and is negatively regulated by miR-338-3p in GC, which may provide new insights into novel molecular therapeutic targets for GC.
胃癌（GC）是最常见的恶性肿瘤之一，腹膜转移是晚期 GC 患者死亡的主要原因。蛋白酪氨酸磷酸酶 1B（PTP1B）作为一种癌基因，参与了肿瘤的发生和癌症的扩散。然而，PTP1B 在 GC 中的功能和调节作用仍知之甚少。在本研究中，我们发现 PTP1B 在 GC 组织中上调，体外过表达 PTP1B 促进细胞迁移并阻止细胞凋亡。然后，我们预测 PTP1B 是 miR-338-3p 的靶标，并揭示了 miR-338-3p 水平与 GC 组织中 PTP1B 蛋白水平之间的负相关关系。接下来，我们通过直接靶向其 3'非翻译区验证了 PTP1B 受 miR-338-3p 的抑制。此外，体外过表达 miR-338-3p 可减弱 GC 细胞的迁移并促进细胞凋亡，而过表达 PTP1B 可部分逆转这些作用。最后，我们建立了 GC 的原位异种移植模型和腹膜转移模型，证明 miR-338-3p 通过靶向 PTP1B 抑制体内肿瘤的生长和转移。综上所述，我们的研究结果表明 PTP1B 是一种癌基因，在 GC 中受 miR-338-3p 的负调控，这可能为 GC 的新型分子治疗靶点提供新的见解。
