J Exp Clin Cancer Res|赵晓俊团队揭示膀胱癌上皮间质转化中circRNAs的ceRNA机制

2022年8月3日 0条评论 303次阅读 0人点赞

最新细胞功能及机制文献分享

上皮间质转化（EMT）与包括膀胱癌（BCa）在内的多种恶性肿瘤的血管生成和致癌表型相关。环状RNA（circRNA）被认为是EMT中的关键调节因子。2022年1月14日，苏州大学第一附属医院泌尿外科赵晓俊团队在Journal of Experimental and Clinical Cancer Research上发表了题为“Circ_0000658 knockdown inhibits epithelial-mesenchymal transition in bladder cancer via miR-498-induced HMGA2 downregulation”的研究论文。在本研究中，团队旨在阐明环状RNA_0000658（circ_0000658）在BCa中的可能作用及其潜在的分子机制。通过miR-498/HMGA2轴揭示了circ_0000658在BCa中的促肿瘤作用。

BCa作为全球第10位最常见的癌症，具有多种组织学类型，主要包括尿路上皮癌和非尿路上皮BCa，死亡率高。EMT即从上皮细胞特性降低到获得间充质表型的生物学过程，EMT的启动可促进多种恶性肿瘤的血管生成和致癌表型，包括BCa。

circRNA对许多生物功能具有关键作用，可充当miRNA海绵，以及在癌症进展过程中与RNA结合蛋白结合。团队通过大数据分析发现，circ_0000658在BCa中高表达，但很少有研究证明circ_0000658的分子生物学作用。团队通过生物信息学分析，确定了miR-498与circ_0000658的结合位点。

已有研究提出，miR-498可靶向HMGA2的3’UTR区，并抑制其在非小细胞肺癌中的翻译。作为非组蛋白结构转录因子之一，HMGA2通过连接B型DNA小沟中富含AT的序列来调节基因转录，并改变染色质结构。预测结果显示，HMGA2高表达与BCa患者总生存期不佳相关，其可作为顺铂耐药的生物标志物。

基于上述研究基础，团队推测circ_0000658可通过miR-498/HMGA2轴调节BCa细胞的EMT。因此，团队在BCa细胞系和移植BCa细胞的裸鼠模型中进行了系列实验，以验证推测。具体方法为：首先，采用免疫组织化学法检测了BCa患者癌组织及癌旁组织、人BCa细胞系（MGH-U3，T24，5637，SW780）中circ_0000658、miR-498和HMGA2的表达情况；其次，团队采用过表达或shRNA质粒转染BCa细胞，以阐明circ_0000658和miR-498对BCa细胞致癌表型和EMT的作用；最后，建立了异种移植BCa细胞的裸鼠模型，以验证circ_0000658对体内肿瘤生长的作用。

结果发现，circ_0000658在BCa组织样本和细胞系中高表达，提示其与BCa患者预后不良相关；circ_0000658可与miR-498竞争性结合，抑制miR-498表达，并减弱了miR-498与靶基因HMGA2的结合，上调了HMGA2的表达；过表达circ_0000658或敲低miR-498增强了BCa细胞的致癌表型和EMT，而抑制HMGA2可逆转circ_0000658过表达对体内肿瘤生长的影响。

《J Exp Clin Cancer Res|赵晓俊团队揭示膀胱癌上皮间质转化中circRNAs的ceRNA机制》

图 circ_0000658在BCa中的调控网络及作用机制示意图。

期刊及DOI号

J Exp Clin Cancer Res. 2022 Jan 14.

doi: 10.1186/s13046-021-02175-3.

题目

Circ_0000658 knockdown inhibits epithelial-mesenchymal transition in bladder cancer via miR-498-induced HMGA2 downregulation

摘要

背景：Epithelial-mesenchymal transition (EMT) has been associated with the angiogenesis and oncogenic phenotypes of multiple malignant tumors including bladder cancer (BCa). Circular RNAs (circRNAs) are recognized as crucial regulators in the EMT. This study aims to illustrate the possible role of circular RNA_0000658 (circ_0000658) in BCa and the underlying molecular mechanism.

方法：The expression of circ_0000658, microRNA (miR)-498, and high mobility group AT-hook 2 (HMGA2) was assessed in cancer and adjacent normal tissue collected from BCa patients and human BCa cell lines (MGH-U3, T24, 5637 and SW780). BCa cells were transduced with a series of overexpression or shRNA plasmids to clarify the function of circ_0000658 and miR-498 on the oncogenic phenotypes and EMT of BCa cells. Further, we established nude mice xenografted with BCa cells to validate the roles of circ_0000658 on tumor growth in vivo.

结果：Circ_0000658 was highly expressed in BCa tissue samples and cell lines, which indicated a poor prognosis of BCa patients. Circ_0000658 competitively bound to miR-498 and thus restricted miR-498 expression. Meanwhile, circ_0000658 weakened the binding of miR-498 to the target gene HMGA2 and upregulated the HMGA2 expression. Circ_0000658 elevation or miR-498 knockdown augmented oncogenic phenotypes and EMT of BCa cells, correspond-ing to a reduction in the expression of β-catenin and E-cadherin as well as an increase in the expression of N-cad-herin, Slug, Snail, ZEB1 and Twist. Inhibition of HMGA2 reversed the effects of circ_0000658 overexpression on tumor growth in vivo.

结论：Altogether, our study uncovered the tumor-promoting role of circ_0000658 in BCa via the miR-498/HMGA2 axis.

关键词：Bladder cancer, Epithelial-mesenchymal transition, Circular RNA_0000658, microRNA-498, High mobility group AT-hook 2, Oncogenic phenotype, In vitro and in vivo

《J Exp Clin Cancer Res|赵晓俊团队揭示膀胱癌上皮间质转化中circRNAs的ceRNA机制》

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