J Exp Clin Cancer Res|上海同济医院周永新团队揭示circRNA介导食管癌细胞化疗敏感性作用机制

2022年8月4日 0条评论 487次阅读 0人点赞

最新细胞功能及机制文献分享

以顺铂为基础的化疗是晚期食管鳞癌（ESCC）主要的系统性治疗方法，而顺铂耐药是影响患者预后的主要原因。近年来的研究指明，环状RNA（circRNAs）作为一种新型RNA分子可参与癌症进展有关，但它们在ESCC中是否可调节顺铂耐药性及其调节机制尚不清楚。2021年11月15日，同济大学医学院上海同济医院胸外科周永新团队在Journal of Experimental and Clinical Cancer Research上发表了题为“CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation”的研究论文。

食管癌（EC）是最常见的恶性肿瘤之一，也是全球癌症相关死亡的主要原因，其中，ESCC是EC最常见的组织学亚型。大多ESCC患者在诊断时就表现为局部晚期，需采用放疗或化疗方式进行治疗。顺铂是ESCC患者使用最广泛、最有效的化疗药物之一，但在长期使用过程中，肿瘤细胞已获得顺铂化疗抗性。circRNAs具有共价闭合单链环构象，起源于premRNA外显子的反向剪接，先前的研究表明，其可通过作为miRNAs的“分子海绵”在转录或剪接水平调节基因表达，以及作为蛋白质支架甚至直接编码功能多肽在基本过程中发挥作用。Mcl-1属抗凋亡Bcl-2蛋白家族，可促进细胞存活和抑制凋亡，越来越多的证据表明，持续的Mcl-1表达是癌细胞逃避化疗试剂诱导死亡的关键决定因素。最关键的是，在所有Bcl-2抗凋亡家族成员中，仅发现Mcl-1在大多数顺铂抗性细胞中上调，并且，在ESCC中靶向Mcl-1可恢复其化疗敏感性并抑制其进展。

在本研究中，团队应用生物信息学分析了参与ESCC顺铂耐药反应的circRNAs，并通过体内外实验证实其对ESCC化疗敏感性的影响，之后，通过质谱、免疫沉淀法和泛素化分析研究了circRNAs的分子作用机制。研究结果表明，与亲代化学敏感细胞相比，新型circRNA cDOPYE2即hsa_circ_0008078在顺铂耐药ESCC细胞株（ESCC-cr）中显著下调。临床数据显示，低表达的cDOPEY2与不利的总生存期和低顺铂反应性显著正相关。接下来的围绕cDOPYE2展开的系列实验表明，cDOPEY2可通过促进TRIM25介导的转录后调节因子CPEB4的泛素化和降解，从而抑制CPEB4下游蛋白Mcl-1的翻译和表达，从而缓解顺铂耐药，证明cDOPEY2可能是ESCC中一个有价值的生物标志物和潜在的治疗靶点。

《J Exp Clin Cancer Res|上海同济医院周永新团队揭示circRNA介导食管癌细胞化疗敏感性作用机制》

图 cDOPEY2抑制ESCC顺铂耐药作用的示意图。cDOPEY2作为支架以TRIM25依赖性方式促进 CPEB4的泛素化和降解，抑制Mcl-1翻译，减轻ESCC细胞的顺铂耐药性，促进顺铂诱导的细胞凋亡。

期刊及DOI号

J Exp Clin Cancer Res. 2021 Nov 15.

doi: 10.1186/s13046-021-02149-5.

题目

CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation

摘要

背景：Cisplatin-based chemotherapy is a mainstay systematic therapy for advanced esophageal squamous cell carcinoma (ESCC), and cisplatin resistance, which is not uncommon, is the major barrier to improving patient outcomes. Circular RNAs (circRNAs) are novel noncoding RNAs that are implicated in cancer progression, but their involvement in modulating cisplatin responsiveness in ESCC remains unknown.

方法：Bioinformatics analysis was used to profile and identify the circRNAs involved in cisplatin responsiveness in ESCC. The chemosensitive role of cDOPEY2 was confirmed both in vitro and in vivo. The molecular mechanism of cDOPEY2 was investigated by mass spectrometry, immunoprecipitation, and ubiquitination analyses.

结果：We report that a novel circRNA (cDOPYE2, hsa_circ_0008078) was markedly downregulated in cisplatin-resistant ESCC cells (ESCC-CR) compared with parental chemosensitive cells. Re-expression of cDOPEY2 substan-tially enhanced the cell-killing ability of cisplatin by augmenting the apoptotic process in ESCC-CR cells, which was achieved by decreasing the abundance of the antiapoptotic protein Mcl-1. Mechanistically, we showed that cDOPEY2 acted as a protein scaffold to enhance the interaction between the cytoplasmic polyadenylation element binding protein (CPEB4) and the E3 ligase TRIM25, which in turn facilitated the ubiquitination and degradation of CPEB4. The increased Mcl-1 expression in ESCC-CR cells was dependent on the binding of CPEB4 to its untranslated mRNA, and depletion of CPEB4 mediated by cDOPEY2 reversed this effect. Rescue experiments confirmed that the critical role of cDOPEY2 in maintaining cisplatin sensitivity was dependent on the depletion of CEPB4 and its downstream target Mcl-1. Clinical and in vivo data further corroborated the significant relevance of cDOPEY2 to cisplatin responsiveness in ESCC.

结论：We provide evidence that cDOPEY2 inhibits CPEB4-mediated Mcl-1 translation by promoting the ubiq-uitination and degradation of CPEB4 to alleviate cisplatin resistance, indicating that cDOPEY2 may serve as a valuable biomarker and potential therapeutic target in ESCC.

关键词：Circular RNA, Esophageal squamous cell carcinoma, Cisplatin resistance, CPEB4, Mcl-1