长链非编码RNA 结合膜脂分子PIP3调控乳腺癌发生及其临床耐药机制研究

Breast cancer continues to be a serious healthcare problem. The PI3K/AKT/mTOR pathway is known to drive the progression of TNBC（Lin, A et al 2013, Oncogene）; however, recent failures of clinical trials testing small molecule inhibitors that target the PI3K or AKT pathway, such as Perifosine, demands novel, alternative therapeutic strategies（Lin, A et al 2014, Cancer Research）. Extensive genomic profiling studies have identified hundreds of long noncoding RNAs (lncRNAs) associated with cancer. Therefore, lncRNAs must be examined to clarify the reason that breast cancer recurs after the administration of targeted therapeutic regiments. A point-of-view that lncRNA could be the conceptual advance that makes such breakthroughs feasible. However, characterizing the function of individual lncRNAs remains a challenge. Recently, we have investigated a novel lncRNA-dependent signaling pathway that is involved in breast cancer metastasis (Lin et al co-first 2014, Cell). Another study even uncovered a plasma lncRNA that controls normoxic HIF1α stabilization (Lin et al 2014, Nature Cell Biology). These studies indicate the crucial role of noncoding RNA in the field of cancer research. Our recent findings demonstrate that the screened lncRNA, Lipid-Interacting Non-coding RNA for Kinase Activation (LINK-A), is involved in the AKT signaling and downstream cellular processes. We hypothesize that lncRNAs are involved in signal transduction crucial for cancer development and cancer therapy. We propose to investigate the hypothesis with three specific aims: 1) To define PIP3- LINK-A mediated regulation of AKT activation. 2) To determine the potential role of LINK-A in metabolism reprogramming in vivo. 3) To investigate the potential approach of LINK-A as a novel biomarker to stratify patients for PI3K or AKT inhibitor treatment or as a novel therapeutic target to synergize with PI3K-AKT inhibition in breast cancer treatment. Collectively, these proposed studies will focus on the role of LINK-A, or other new candidate lncRNAs, in the essential cell signaling pathway. By conducting a series of molecular and cellular studies on LINK-A, I hope to elucidate a lncRNA that is involved in new molecular mechanisms that underlie cell metabolism and tumorigenesis of the PI3K-PIP3-AKT signaling network. By further analyzing my transcriptomic results, I hope to identify novel lncRNAs that contribute to this signaling in cancer development and cancer therapy, and to detect novel therapeutic targets and biomarkers in this new field of RNA-cancer research. The proposed study will address these overarching challenges in breast cancer by providing new insights into the previously unsuspected “lncRNA circuits”. We hope this proposed study will reveal the global properties of lncRNAs as regulators, therapeutic targets and biomarkers, facilitating research studies and furthering clinical trials.

乳腺癌是长期困扰人类健康的重要疾病隐患。针对关键信号及激酶PI3K/mTOR抑制剂如NVP-BEZ235和Perifosine等在治疗后期业已出现临床耐药现象，迫切需要研究可替代分子靶点。长链非编码RNA（LncRNAs）作为最新关注热点，其对肿瘤发生发挥重要作用。最近我们利用乳腺癌病患样品及高通量测序，发现了与脂类PIP3结合lncRNA-LINK-A， 该LncRNA参与AKT信号活化，暗示其对肿瘤代谢和发生起重要调节作用。本课题拟在前期工作基础上，运用生化、分子及细胞学技术，在细胞和动物模型上研究（1）LncRNA-PIP3特异结合调控 AKT激酶活化机制；（2）LncRNA-PIP3特异结合对体内乳腺癌细胞代谢、增殖影响；（3）LncRNA 作为临床标记物及其与AKT共同靶点研究。通过上述研究，揭示LncRNA对肿瘤信号调控机制，探讨将LncRNAs作为一类新的治疗靶标的潜在价值。

乳腺癌是长期困扰人类健康的重要疾病隐患。针对关键信号及激酶PI3K/mTOR抑制剂在治疗后期业已出现临床耐药现象，迫切需要研究可替代分子靶点。长链非编码RNA（LncRNAs）作为最新关注热点，其对肿瘤发生发挥重要作用。前期我们利用乳腺癌病患样品及高通量测序，发现了与脂类PIP3结合lncRNA-LINK-A，以及与PA结合的SNHG9。LncRNA-LINK-A参与AKT信号活化，SNHG9参与Hippo信号通路的激活，暗示LncRNA对肿瘤代谢和发生起重要调节作用。本课题在前期工作基础上，在细胞和动物模型上深入研究膜脂结合的LncRNA-LINK-A在肥胖诱导的乳腺癌发生发展中的分子机制。我们发现：（1）发现肥胖导致肿瘤发生的重要HIF通路调控机制；（2）通过构建非编码LINK-A转基因小鼠模型，我们发现肥胖诱导的LINK-A-HIF通路对肿瘤发生具有调控作用；（3）结合临床样本大数据，我们发现了LINK-A-HIF调控节点对肥胖导致的肿瘤发生的调控作用，具有作为临床靶点和检测标志物的潜能。上述系列研究发现丰富了细胞信号研究领域，提示深入挖掘细胞膜脂相关LncRNAs通过与多类生物分子结合调控细胞代谢信号的机理机制，开发节点LncRNA在内的联合靶向抑制剂，实现进一步提高癌症临床治疗药效，很有可能成为下一个临床用药的新突破。