The LINC01119-SOCS5 axis as a critical theranostic in triple-negative breast cancer

The development of triple-negative breast cancer (TNBC) is critically regulated by certain tumor-microenvironment-associated cells called mesenchymal stem/stromal cells (MSCs), which we and others have shown promoted TNBC progression by activating pro-malignant signaling in neighboring cancer cells. Characterization of these cascades will better our understanding of TNBC biology, and stands to bring about therapeutics that can eliminate the morbidity and mortality associated with advanced disease. Here, we focused on the emerging class of non-coding RNAs called long non-coding RNAs or lncRNAs, and utilized a MSC-supported TNBC progression model to identify specific family members of functional relevance to TNBC pathogenesis. Indeed, although some have been described to play functional roles in TNBC, activities for lncRNAs as mediators of tumor-microenvironment-driven TNBC development remain to be fully explored. We report that MSCs stimulated robust expression of LINC01119 in TNBC cells, which in turn induced suppressor of cytokine signaling 5 (SOCS5), leading to accelerated cancer cell growth and tumorigenesis. We show that LINC01119 and SOCS5 exhibited tight correlation across multiple breast cancer gene sets and that they were highly enriched in TNBC patient cohorts. Importantly, we present evidence that the LINC01119-SOCS5 axis served as a powerful prognostic indicator of adverse outcome in TNBC patients, and we demonstrate that its repression severely impaired cancer cell growth. Altogether, our findings identify LINC01119 as a major driver of TNBC development, and delineate critical non-coding RNA theranostics of potential translational utility in the management of advanced TNBC, a class of tumors in most need of effective and targeted therapy.

三阴性乳腺癌（triple-negative breast cancer, TNBC）的发生发展受到一类名为间充质干细胞/基质细胞（mesenchymal stem/stromal cells, MSCs）的肿瘤微环境相关细胞的关键调控，我们及其他研究团队已证实，这类细胞可通过激活邻近癌细胞内的促恶性信号通路，促进TNBC的进展。对这些信号级联反应的解析，将深化我们对TNBC生物学特性的认知，并有望开发出可消除晚期疾病相关发病率与死亡率的治疗手段。本研究聚焦于一类新兴的非编码RNA——长链非编码RNA（long non-coding RNAs, lncRNAs），并利用MSC支持的TNBC进展模型，筛选出与TNBC发病机制具有功能相关性的特定家族成员。尽管已有部分lncRNAs被报道在TNBC中发挥功能，但作为肿瘤微环境驱动TNBC发生发展介质的lncRNAs的具体作用仍有待全面探索。本研究发现，MSCs可显著诱导TNBC细胞内LINC01119的表达，而LINC01119又可上调细胞因子信号抑制因子5（suppressor of cytokine signaling 5, SOCS5）的表达，进而加速癌细胞增殖与肿瘤发生。我们证实，LINC01119与SOCS5在多组乳腺癌基因数据集中呈现紧密的表达相关性，且二者在TNBC患者队列中呈高表达状态。尤为重要的是，本研究提供的证据表明，LINC01119-SOCS5轴可作为TNBC患者不良预后的强有力预测指标，同时我们证明，抑制该轴的表达会严重削弱癌细胞的增殖能力。综上，本研究的发现确定LINC01119是TNBC发生发展的关键驱动因子，并阐明了具有潜在临床转化价值的非编码RNA诊疗靶点，为目前亟需有效靶向治疗的晚期TNBC的临床管理提供了新的思路。