PHLDB2 Mediates Cetuximab Resistance via Interacting With EGFR in Latent Metastasis of Colorectal Cancer.
PHLDB2 Mediates Cetuximab Resistance via Interacting With EGFR in Latent Metastasis of Colorectal Cancer.
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DOI：
10.1016/j.jcmgh.2021.12.011
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发表时间：
2022
影响因子：
7.2
通讯作者：
Chen HN
中科院分区：
文献类型：
--
作者：
Luo M;Huang Z;Yang X;Chen Y;Jiang J;Zhang L;Zhou L;Qin S;Jin P;Fu S;Peng L;Li B;Fang Y;Pu W;Gong Y;Liu Y;Ren Z;Liu QL;Wang C;Xiao F;He D;Zhang H;Li C;Xu H;Dai L;Peng Y;Zhou ZG;Huang C;Chen HN
结直肠癌的潜伏转移通常在初次手术后数月或数年发生，随后进行辅助治疗，即使进行靶向治疗也可能进展迅速，但其潜在的机制尚不清楚。在此，我们旨在探讨大肠癌潜伏转移侵袭行为的分子基础。对配对的原发和转移肿瘤样本进行转录图谱和途径富集化分析。应用核糖核酸免疫沉淀分析、免疫组织化学、质谱分析和双链原位邻近连接分析(Sigma-Aldrich，Shanghai，中国)对结直肠癌中Pleckstrin同源结构域，家族B，成员2(PHLDB2)的可能机制进行了研究。靶向PHLDB2在西妥昔单抗治疗中的疗效在结直肠癌细胞系和小鼠模型中得到阐明。根据配对的原发和转移肿瘤样本的转录图谱，我们确定PHLDB2是潜在的肝转移调节因子。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N6-甲基腺苷修饰PHLDB2信使RNA，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)在与EGFR的相互作用中起关键作用，R1163A突变使其在EGFR信号转导中的调节功能丧失。PHLDB2在西妥昔单抗耐药中起关键作用，被认为是治疗结直肠癌的潜在靶点。
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. 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. 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. PHLDB2 plays a crucial role in cetuximab resistance and is proposed to be a potential target for the treatment of CRC.
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
4.8
作者：
Grimsey, Neil J.;Coronel, Luisa J.;Trejo, JoAnn
通讯作者：
Trejo, JoAnn
DOI：
10.1056/nejmcibr1606716
发表时间：
2016-07-21
期刊：
The New England journal of medicine
影响因子：
--
作者：
Pollard JW
通讯作者：
Pollard JW
影响因子：
8.8
作者：
Frattini, M;Saletti, P;Romagnani, E;Martin, V;Molinari, F;Ghisletta, M;Camponovo, A;Etienne, L L;Cavalli, F;Mazzucchelli, L
通讯作者：
Mazzucchelli, L
影响因子：
64.8
作者：
Huttlin EL;Bruckner RJ;Paulo JA;Cannon JR;Ting L;Baltier K;Colby G;Gebreab F;Gygi MP;Parzen H;Szpyt J;Tam S;Zarraga G;Pontano-Vaites L;Swarup S;White AE;Schweppe DK;Rad R;Erickson BK;Obar RA;Guruharsha KG;Li K;Artavanis-Tsakonas S;Gygi SP;Harper JW
通讯作者：
Harper JW