학술논문
MAD2 activates IGF1R/PI3K/AKT pathway and promotes cholangiocarcinoma progression by interfering USP44/LIMA1 complex.
Document Type
Academic Journal
Author
Jiang W; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China.; Yang X; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Shi K; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Zhang Y; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China.; Shi X; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Wang J; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Wang Y; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Chenyan A; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Shan J; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Wang Y; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Chang J; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Chen R; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Zhou T; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Zhu Y; Personaloncology Biological Technology Co., Ltd, Nanjing, Jiangsu, China.; Yu Y; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China.; Li C; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. doclicx20@163.com.; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China. doclicx20@163.com.; Li X; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. drxcli@njmu.edu.cn.; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China. drxcli@njmu.edu.cn.
Source
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE
Subject
Language
English
Abstract
Spindle assembly checkpoint (SAC) plays an essential part in facilitating normal cell division. However, the clinicopathological and biological significance of mitotic arrest deficient 2 like 1 (MAD2/MAD2L1), a highly conserved member of SAC in cholangiocarcinoma (CCA) remain unclear. We aim to determine the role and mechanism of MAD2 in CCA progression. In the study, we found up-regulated MAD2 facilitated CCA progression and induced lymphatic metastasis dependent on USP44/LIMA1/PI3K/AKT pathway. MAD2 interfered the binding of USP44 to LIMA1 by sequestrating more USP44 in nuclei, causing impaired formation of USP44/LIMA1 complex and enhanced LIMA1 K48 (Lys48)-linked ubiquitination. In therapeutic perspective, the data combined eleven cases of CCA PDTX model showed that high-MAD2 inhibits tumor necrosis and diminishes the inhibition of cell viability after treated with gemcitabine-based regimens. Immunohistochemistry (IHC) analysis of tissue microarray (TMA) for CCA patients revealed that high-MAD2, low-USP44 or low-LIMA1 level are correlated with worse survival for patients. Together, MAD2 activates PI3K/AKT pathway, promotes cancer progression and induces gemcitabine chemo-resistance in CCA. These findings suggest that MAD2 might be an excellent indicator in prognosis analysis and chemotherapy guidance for CCA patients.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)