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171 results on '"Cui, Shu-Xiang"'

18. Nuclear translocation of ATG5 induces DNA mismatch repair deficiency (MMR-D)/microsatellite instability (MSI) via interacting with Mis18α in colorectal cancer.

Author

Sun, Shi‐Yue, Hu, Xue‐Tao, Yu, Xin‐Feng, Zhang, Yue‐Ying, Liu, Xiao‐Hui, Liu, Yuan‐Hang, Wu, Shu‐Hua, Li, Yang‐Yang, Cui, Shu‐Xiang, Qu, Xian‐Jun, Sun, Shi-Yue, Hu, Xue-Tao, Yu, Xin-Feng, Zhang, Yue-Ying, Liu, Xiao-Hui, Liu, Yuan-Hang, Wu, Shu-Hua, Li, Yang-Yang, Cui, Shu-Xiang, and Qu, Xian-Jun

Subjects
COLORECTAL cancer, DNA mismatch repair, IRINOTECAN, IMMOBILIZED proteins, NUCLEAR proteins, WESTERN immunoblotting, RESEARCH, DNA, ANIMAL experimentation, RESEARCH methodology, GENETIC disorders, MEDICAL cooperation, EVALUATION research, BRAIN tumors, DNA methylation, COMPARATIVE studies, RESEARCH funding, DEGENERATION (Pathology), HEREDITARY cancer syndromes, MICE, CARRIER proteins
Abstract

Background and Purpose: It is well known that microsatellite instability-high (MSI-H) is associated with 5-fluorouracil (5-FU) resistance in colorectal cancer. MSI-H is the phenotype of DNA mismatch repair deficiency (MMR-D), mainly occurring due to hypermethylation of MLH1 promoter CpG island. However, the mechanisms of MMR-D/MSI-H are unclear. We aim to investigate the pathway of MMR-D/MSI-H involved in 5-FU resistance.Experimental Approach: Human colorectal cancer specimens were diagnosed for MSI-H by immunohistochemistry and western blotting. Proteome microarray interactome assay was performed to screen nuclear proteins interacting with ATG5. Nuclear ATG5 and ATG5-Mis18α overexpression were analysed in ATG5high colorectal cancer bearing mice. The methylation assay determined the hypermethylation of hMLH1 promoter CpG island in freshly isolated human colorectal cancer tissue samples and HT29atg5 and SW480atg5 cancer cells.Key Results: In ATG5high colorectal cancer patients, 5-FU-based therapy resulted in nuclear translocation of ATG5, leading to MSI-H. Colorectal cancer in Atg5 Tg mice demonstrated 5-FU resistance, compared to Atg5+/- and WT mice. Proteome microarray assay identified Mis18α, a protein localized on the centromere and a source for methylation of the underlying chromatin, which responded to the translocated nuclear ATG5 leading to ATG5-Mis18α conjugate overexpression. This resulted in MLH1 deficiency due to hypermethylation of hMLH1 promoter CpG island, while the deletion of nuclear Mis18α failed to induce ATG5-Mis18α complex and MMR-D/MSI-H.Conclusions and Implications: Nuclear ATG5 resulted in MMR-D/MSI-H through its interaction with Mis18α in ATG5high colorectal cancer cells. We suggest that ATG5-Mis18α or Mis18α may be a therapeutic target for treating colorectal cancer. [ABSTRACT FROM AUTHOR]

Published
2021
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40. Metformin inhibited colitis and colitis-associated cancer (CAC) through protecting mitochondrial structures of colorectal epithelial cells in mice.

Author

Wang, Shu-Qing, Cui, Shu-Xiang, and Qu, Xian-Jun

Abstract

Although a mountain of papers have showed that metformin plays a role in inhibiting cancers, but the mechanism underpinning this has not yet fully elucidated. Herein, we used AOM/DSS model, the clinicopathological features are similar to those found in humans, to investigate the effects of metformin as well as combination with 5-FU in the prevention of colitis and colitis associated cancer (CAC). Oral metformin significantly inhibited DSS-induced ulcerative colitis and AOM/DSS-induced CAC. Metformin also ameliorated 5-FU-induced colorectal gastrointestinal symptoms in mice. Metformin combination with 5-FU strongly inhibited colorectal cancer. Metformin reduced levels of the NFκB signaling components p-IKKα/β, p-NFκB, p-IκBα in colorectal mucosal cells. Transmission electron microscopy analysis suggested that the inhibition of metformin on colitis and CAC might associate with its biological activity of protecting mitochondrial structures of colorectal epithelial cells. Further analysis by Mito Tracker Red staining assay indicated that metformin prevented H2O2-induced mitochondrial fission correlated with a decrease of mitochondrial perimeter. In addition, metformin increased the level of NDUFA9, a Q-module subunit required for complex I assembly, in colorectal epithelial cells. These observations of metformin in the inhibition of colitis and CAC might associate with its activity of activating the LKB1/AMPK pathway in colorectal epithelial cells. In conclusion, metformin inhibited colitis and CAC through protecting the mitochondrial structures of colorectal epithelial cells. [ABSTRACT FROM AUTHOR]

Published
2019
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