Zhang Yan, Yang Mei, Wang Yiping, Zhao Junhao, Lee Pei Yao, Ma Yuhua, Qu Shaohua
Department of Breast Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510630, People's Republic of China.
Department of Breast Surgery, JiangMen Maternity and Child Health Care Hospital, Jiangmen, 529000, People's Republic of China.
Breast Cancer (Dove Med Press). 2024 Nov 26;16:795-810. doi: 10.2147/BCTT.S495517. eCollection 2024.
Non-coding RNAs have received increasing attention in human tumors, with RNA interaction networks playing important roles in breast cancer. This study aims to explore novel circular RNAs and their mechanisms of biological function in breast cancer.
Six HER2-positive breast cancer tissues and paired normal tissues were obtained for the whole transcriptome RNA sequencing. Differentially expressed (DE) circRNAs, miRNAs and mRNAs were identified and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DERNAs were performed. DECircRNAs- DEmiRNAs- DEmRNAs networks were constructed and further verified by bioinformatics database analyses, luciferase assays and RIP assays. The expression level of circDOCK1 in breast cancer specimens was measured using qRT-PCR. Functional rescue experiments were conducted to explore the role of circDOCK1/miR-138-5p/GRB7 axis in breast cancer cells. The correlation of circDOCK1 expression and clinicopathologic features of 102 HER2 positive breast cancer patients was analyzed.
A total of 6960 DEmRNAs, 133 DE miRNAs and 1691 DE circRNAs were identified from HER2-positive breast cancer tissues and paracancerous tissues. Enrichment Analysis showed that the differential mRNAs were associated with cell division in biological processes and cell cycle and signaling pathways. GO and KEGG analysis demonstrated that DE circRNAs were mainly enriched in double-strand break repair, positive regulation of transcription by RNA polymerase II, nucleoplasma, nucleus, chromatin binding and protein binding. Forty networks of competing endogenous RNAs (ceRNAs) were constructed and circDOCK1/miR-138-5p/GRB7 axis was verified. Functional experiments revealed that the axis promotes migration and invasion of breast cancer cells. CircDOCK1 expression was elevated in breast cancer patients and correlated with adverse clinicopathologic parameters. Patients with high circDOCK1 level had poor outcomes.
A novel circDOCK1/miR-138-5p/GRB7 axis promotes HER2 positive breast cancer metastasis and progression, providing a potential therapeutic target in the treatment of breast cancer.
非编码RNA在人类肿瘤中受到越来越多的关注，RNA相互作用网络在乳腺癌中发挥着重要作用。本研究旨在探索乳腺癌中新型环状RNA及其生物学功能机制。
获取6例HER2阳性乳腺癌组织及配对的正常组织进行全转录组RNA测序。鉴定差异表达的环状RNA、微小RNA和信使RNA，并对差异表达RNA进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析。构建差异表达环状RNA-差异表达微小RNA-差异表达信使RNA网络，并通过生物信息学数据库分析、荧光素酶测定和RNA免疫沉淀测定进一步验证。采用qRT-PCR检测乳腺癌标本中circDOCK1的表达水平。进行功能挽救实验以探讨circDOCK1/miR-138-5p/GRB7轴在乳腺癌细胞中的作用。分析102例HER2阳性乳腺癌患者中circDOCK1表达与临床病理特征的相关性。
从HER2阳性乳腺癌组织和癌旁组织中鉴定出6960个差异表达信使RNA、133个差异表达微小RNA和1691个差异表达环状RNA。富集分析表明，差异表达信使RNA在生物学过程中与细胞分裂以及细胞周期和信号通路相关。GO和KEGG分析表明，差异表达环状RNA主要富集于双链断裂修复、RNA聚合酶II对转录的正调控、核质、细胞核、染色质结合和蛋白质结合。构建了40个竞争性内源RNA（ceRNA）网络，并验证了circDOCK1/miR-138-5p/GRB7轴。功能实验表明，该轴促进乳腺癌细胞的迁移和侵袭。circDOCK1在乳腺癌患者中表达升高，并与不良临床病理参数相关。circDOCK1水平高的患者预后较差。
一种新型的circDOCK1/miR-138-5p/GRB7轴促进HER2阳性乳腺癌转移和进展，为乳腺癌治疗提供了一个潜在的治疗靶点。
