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  2. PIN1 Inhibition Sensitizes Chemotherapy in Gastric Cancer Cells by Targeting Stem Cell-like Traits and Multiple Biomarkers

PIN1 Inhibition Sensitizes Chemotherapy in Gastric Cancer Cells by Targeting Stem Cell-like Traits and Multiple Biomarkers

  • Mol Cancer Ther. 2020 Mar;19(3):906-919. doi: 10.1158/1535-7163.MCT-19-0656.
Zhen-Zhen Zhang 1 2 Wei-Xing Yu 3 Min Zheng 3 Xin-Hua Liao 3 Ji-Chuang Wang 3 Da-Yun Yang 3 Wen-Xian Lu 3 Long Wang 3 Sheng Zhang 2 He-Kun Liu 3 Xiao Zhen Zhou 4 Kun Ping Lu 4
Affiliations

Affiliations

  • 1 Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China. zzz333858@fjmu.edu.cn zzz333858@126.com.
  • 2 Department of Pathology of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
  • 3 Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, China.
  • 4 Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Abstract

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.

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