PHLDB2 Mediates Cetuximab Resistance via Interacting With EGFR in Latent Metastasis of Colorectal Cancer.

Autor:	Luo M; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Huang Z; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Yang X; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Chen Y; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Jiang J; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Zhang L; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Zhou L; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Qin S; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Jin P; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Fu S; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Peng L; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Li B; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Fang Y; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Pu W; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China., Gong Y; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China., Liu Y; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China., Ren Z; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China., Liu QL; Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China., Wang C; Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China., Xiao F; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., He D; Department of Pathology, West China Hospital, Sichuan University, Chengdu, China., Zhang H; Department of Pathology, West China Hospital, Sichuan University, Chengdu, China., Li C; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China., Xu H; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China., Dai L; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China., Peng Y; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China., Zhou ZG; Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China., Huang C; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China. Electronic address: hcanhua@hotmail.com., Chen HN; Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China. Electronic address: hnchen@scu.edu.cn.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2022; Vol. 13 (4), pp. 1223-1242. Date of Electronic Publication: 2021 Dec 22.
DOI:	10.1016/j.jcmgh.2021.12.011
Abstrakt:	Background & Aims: Latent metastasis of colorectal cancer (CRC) frequently develops months or years after primary surgery, followed by adjuvant therapies, and may progress rapidly even with targeted therapy administered, but the underlying mechanism remains unclear. Here, we aim to explore the molecular basis for the aggressive behavior of latent metastasis in CRC. Methods: Transcriptional profiling and pathway enrichment analysis of paired primary and metastatic tumor samples were performed. The underlying mechanisms of pleckstrin homology-like domain, family B, member 2 (PHLDB2) in CRC were investigated by RNA immunoprecipitation assay, immunohistochemistry, mass spectrometry analysis, and Duolink in situ proximity ligation assay (Sigma-Aldrich, Shanghai, China). The efficacy of targeting PHLDB2 in cetuximab treatment was elucidated in CRC cell lines and mouse models. Results: Based on the transcriptional profile of paired primary and metastatic tumor samples, we identified PHLDB2 as a potential regulator in latent liver metastasis. A detailed mechanistic study showed that chemotherapeutic agent-induced oxidative stress promotes methyltransferase-like 14 (METTL14)-mediated N6-methyladenosine modification of PHLDB2 messenger RNA, facilitating its protein expression. Up-regulated PHLDB2 stabilizes epidermal growth factor receptor (EGFR) and promotes its nuclear translocation, which in turn results in EGFR signaling activation and consequent cetuximab resistance. Moreover, Arg1163 (R1163) of PHLDB2 is crucial for interaction with EGFR, and the R1163A mutation abrogates its regulatory function in EGFR signaling. Conclusions: PHLDB2 plays a crucial role in cetuximab resistance and is proposed to be a potential target for the treatment of CRC. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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