PHLDB2 通过与结直肠癌细胞潜伏转移中的 EGFR 相互作用介导西妥昔单抗耐药。

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

机构信息

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.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.

出版信息

Cell Mol Gastroenterol Hepatol. 2022;13(4):1223-1242. doi: 10.1016/j.jcmgh.2021.12.011. Epub 2021 Dec 22.

DOI:10.1016/j.jcmgh.2021.12.011

PMID:34952201

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8881668/

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.

摘要

背景与目的

结直肠癌（CRC）的潜伏转移通常在原发手术后数月或数年后发生，并在辅助治疗后进展，即使给予靶向治疗也可能迅速进展，但潜在机制尚不清楚。在这里，我们旨在探索 CRC 潜伏转移侵袭性行为的分子基础。

方法

对配对的原发和转移瘤样本进行转录谱分析和通路富集分析。通过 RNA 免疫沉淀实验、免疫组织化学、质谱分析和 Sigma-Aldrich（上海，中国）的 Duolink 原位邻近连接分析研究 PH 结构域家族 B 成员 2（PHLDB2）在 CRC 中的潜在机制。在 CRC 细胞系和小鼠模型中阐明了针对 PHLDB2 的疗效。

结果

根据配对的原发和转移瘤样本的转录谱，我们确定 PHLDB2 是潜伏肝转移的潜在调节剂。一项详细的机制研究表明，化疗药物诱导的氧化应激促进甲基转移酶样 14（METTL14）介导的 PHLDB2 信使 RNA 的 N6-甲基腺苷修饰，促进其蛋白表达。上调的 PHLDB2 稳定表皮生长因子受体（EGFR）并促进其核转位，进而导致 EGFR 信号激活和随后的西妥昔单抗耐药。此外，PHLDB2 的 Arg1163（R1163）对于与 EGFR 的相互作用至关重要，而 R1163A 突变则消除了其在 EGFR 信号中的调节功能。