Cellular and Molecular Gastroenterology and Hepatology (Jan 2022)
PHLDB2 Mediates Cetuximab Resistance via Interacting With EGFR in Latent Metastasis of Colorectal CancerSummary
- Maochao Luo,
- Zhao Huang,
- Xingyue Yang,
- Yan Chen,
- Jingwen Jiang,
- Lu Zhang,
- Li Zhou,
- Siyuan Qin,
- Ping Jin,
- Shuyue Fu,
- Liyuan Peng,
- Bowen Li,
- Yongting Fang,
- Wenchen Pu,
- Yanqiu Gong,
- Yu Liu,
- Zhixiang Ren,
- Qiu-Luo Liu,
- Cun Wang,
- Fangqiong Xiao,
- Du He,
- Hongying Zhang,
- Changlong Li,
- Heng Xu,
- Lunzhi Dai,
- Yong Peng,
- Zong-Gung Zhou,
- Canhua Huang,
- Hai-Ning Chen
Affiliations
- Maochao Luo
- 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
- Zhao Huang
- 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
- Xingyue Yang
- 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
- Yan Chen
- 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
- Jingwen Jiang
- 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
- Lu Zhang
- 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 Zhou
- 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
- Siyuan Qin
- 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
- Ping Jin
- 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
- Shuyue Fu
- 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
- Liyuan Peng
- 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
- Bowen Li
- 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
- Yongting Fang
- 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
- Wenchen Pu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
- Yanqiu Gong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
- Yu Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
- Zhixiang Ren
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
- Qiu-Luo Liu
- Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Cun Wang
- Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Fangqiong Xiao
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China
- Du He
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
- Hongying Zhang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
- Changlong Li
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China
- Heng Xu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
- Lunzhi Dai
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
- Yong Peng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
- Zong-Gung Zhou
- Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Canhua Huang
- 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; Canhua Huang, PhD, State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No. 17, Section 3, South Renmin Rd, Chengdu, 610041, P.R. China. Tel: +86-13258370346; fax: +86-28-85164060.
- Hai-Ning Chen
- Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China; Correspondence Address correspondence to: Hai-Ning Chen, MD, PhD, Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China. Tel: +86-18980606468.
- Journal volume & issue
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Vol. 13,
no. 4
pp. 1223 – 1242
Abstract
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.
