Long non-coding RNA VCAN-AS1 promotes the malignant behaviors of breast cancer by regulating the miR-106a-5p-mediated STAT3/HIF-1α pathway

An accumulating number of studies have found that long noncoding RNAs (lncRNAs) participate in breast cancer (BC) development. LncRNA VCAN-AS1, a novel lncRNA, has been confirmed to regulate the progression of gastric cancer, while its role in BC is elusive. Here, our results illustrate that VCAN-AS1 is overexpressed in BC tissues and cells, while miR-106a-5p was downregulated and negatively correlated with VCAN-AS1. In addition, high VCAN-AS1 expression and low miR-106a-5p expression were closely correlated with poor overall survival in BC patients. Functional experiments confirmed that VCAN-AS1 overexpression notably accelerated BC cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) and enhanced tumor cell growth while also suppressing cell apoptosis. However, overexpression of miR-106a-5p had the opposite effects. In addition, rescue experiments confirmed that overexpression of VCAN-AS1 inhibited the tumor-suppressive effects mediated by miR-106a-5p. Mechanistically, through bioinformatics analysis, we found that VCAN-AS1 functions as a competitive endogenous RNA (ceRNA) of miR-106a-5p, which targets the 3ʹ untranslated region (UTR) of signal transducer and activator of transcription 3 (STAT3). Further experiments indicated that miR-106a-5p downregulated the STAT3/hypoxia-inducible factor-1alpha (HIF-1α) pathway, while activating the STAT3 pathway reversed miR-106a-5p-mediated antitumor effects. Collectively, our data suggest that VCAN-AS1 is upregulated in breast cancer and promotes its progression by regulating the miR-106a-5p-mediated STAT3/HIF-1α pathway. This study provides a new target for BC therapy.

越来越多的研究表明，长链非编码RNA（long noncoding RNAs，lncRNAs）参与乳腺癌（breast cancer，BC）的发生发展。长链非编码RNA VCAN-AS1作为一种新型长链非编码RNA，已被证实可调控胃癌的进展，但其在乳腺癌中的作用尚不清楚。本研究结果显示，VCAN-AS1在乳腺癌组织及细胞中呈高表达，而微小RNA-106a-5p（miR-106a-5p）呈低表达，且与VCAN-AS1呈负相关。此外，VCAN-AS1高表达与miR-106a-5p低表达均与乳腺癌患者的不良总生存期密切相关。功能实验证实，过表达VCAN-AS1可显著促进乳腺癌细胞的增殖、迁移、侵袭及上皮间质转化（epithelial-mesenchymal transition，EMT），增强肿瘤细胞生长并抑制细胞凋亡；而过表达miR-106a-5p则发挥相反的作用。此外，挽救实验证实，过表达VCAN-AS1可抵消miR-106a-5p介导的抑瘤作用。从机制上看，通过生物信息学分析，我们发现VCAN-AS1可作为miR-106a-5p的竞争性内源RNA（competitive endogenous RNA，ceRNA），后者靶向结合信号转导与转录激活因子3（signal transducer and activator of transcription 3，STAT3）的3'非翻译区（3' untranslated region，UTR）。进一步实验表明，miR-106a-5p可抑制STAT3/缺氧诱导因子-1α（hypoxia-inducible factor-1α，HIF-1α）通路的活性，而激活STAT3通路可逆转miR-106a-5p介导的抗肿瘤作用。综上，本研究数据表明，VCAN-AS1在乳腺癌中呈高表达，并通过调控miR-106a-5p介导的STAT3/HIF-1α通路促进乳腺癌进展。本研究为乳腺癌的治疗提供了新的靶点。