journal contribution
posted on 2024-02-20, 16:40 authored by Zhen-Zhen Zhang, Wei-Xing Yu, Min Zheng, Xin-Hua Liao, Ji-Chuang Wang, Da-Yun Yang, Wen-Xian Lu, Long Wang, Sheng Zhang, He-Kun Liu, Xiao Zhen Zhou, Kun Ping Lu Supplementary Table 1: Antibodies for Western Blot analysis; Supplementary Figure 1. Effects and EC50 value of ATRA, 5-FU and L-OHP singly or in combination in HGC-27 and MKN45 gastric cancer cells; Supplementary Figure 2. Genetic and chemical Pin1 inhibition suppresses the EMT, cell invasion and migration of gastric cancer cells in vitro; Supplementary Figure 3. Pin1 inhibition suppresses EMT induced MKN45 gastric cancer cell invasion and migration in vitro; Supplementary Figure 4. In vivo fluorescence imaging assay of lung metastasis before ATRA treatment; Supplementary Figure 5. Reduced CD44/ALDH activity of MKN45 cancer stem cell subpopulation with Pin1 inhibition in vitro; Supplementary Figure 6. Immunofluorescence staining of tumorspheres for Pin1, CD44 and β-catenin; Supplementary Figure 7. Pin1 inhibition induced MKN45 gastric cancer cells apoptosis in vitro
Funding
National Natural Science Foundation of China
Joint Funds for Health and Education of Fujian Province
Fujian Provincial Health and Family Planning
Innovation of Science and Technology, Fujian province
Joint Funds for the Innovation of Science and Technology, Fujian province
History
ARTICLE 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.
