Gastric cancer is the third leading cause of cancer-related death worldwide. Diffuse type gastric cancer has the worst prognosis due to notorious resistance to chemotherapy and enrichment of cancer stem-like cells (CSC) associated with the epithelial-to-mesenchymal transition (EMT). The unique proline isomerase PIN1 is a common regulator of oncogenic signaling networks and is important for gastric cancer development. However, little is known about its roles in CSCs and drug resistance in gastric cancer. In this article, we demonstrate that PIN1 overexpression is closely correlated with advanced tumor stages, poor chemo-response and shorter recurrence-free survival in diffuse type gastric cancer in human patients. Furthermore, shRNA-mediated genetic or all-trans retinoic acid–mediated pharmaceutical inhibition of PIN1 in multiple human gastric cancer cells potently suppresses the EMT, cell migration and invasion, and lung metastasis. Moreover, PIN1 genetic or pharmaceutical inhibition potently eliminates gastric CSCs and suppresses their self-renewal and tumorigenicity in vitro and in vivo. Consistent with these phenotypes, are that PIN1 biochemically targets multiple signaling molecules and biomarkers in EMT and CSCs and that genetic and pharmaceutical PIN1 inhibition functionally and drastically enhances the sensitivity of gastric cancer to multiple chemotherapy drugs in vitro and in vivo. These results demonstrate that PIN1 inhibition sensitizes chemotherapy in gastric cancer cells by targeting CSCs, and suggest that PIN1 inhibitors may be used to overcome drug resistance in gastric cancer.

中文翻译：

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Pin1抑制通过靶向干细胞样特征和多种生物标志物来提高胃癌细胞的化疗敏感性

胃癌是全球癌症相关死亡的第三大原因。弥漫型胃癌的预后最差，因为其对化疗的耐药性和与上皮间质转化 (EMT) 相关的癌症干细胞样细胞 (CSC) 的富集是众所周知的。独特的脯氨酸异构酶 PIN1 是致癌信号网络的常见调节因子，对胃癌的发展很重要。然而，关于其在 CSCs 中的作用和胃癌耐药性知之甚少。在本文中，我们证明了 PIN1 过表达与人类患者弥漫型胃癌晚期肿瘤分期、较差的化疗反应和较短的无复发生存期密切相关。此外，shRNA 介导的遗传或全反式视黄酸介导的药物抑制多种人胃癌细胞中的 PIN1 可有效抑制 EMT、细胞迁移和侵袭以及肺转移。此外，PIN1 基因或药物抑制可有效消除胃 CSCs 并抑制其在体外和体内的自我更新和致瘤性。与这些表型一致的是，PIN1 生化靶向 EMT 和 CSC 中的多个信号分子和生物标志物，并且遗传和药物抑制 PIN1 在功能上和显着增强了胃癌在体外和体内对多种化疗药物的敏感性。这些结果表明 PIN1 抑制通过靶向 CSCs 使胃癌细胞中的化疗敏感，