竞争性长链非编码RNAs调控低氧乳腺癌CAF细胞能量代谢重塑的作用及其机制研究

Cancer-associated fibroblasts（CAF）play an essential role in breast cancer development such as proliferation and metastasis. The hypoxic tumor environment is an important stimulus of the energy metabolism reprogramming phenotype of CAF. Our previous work has shown that the expression levels of long non coding RNAs (lncRNAs) acting as competing endogenous RNA and the status of energy metabolism were changed in hypoxia-treated CAF derived from breast cancer. However, it remains unknown that the role and its mechanisms underlying these lncRNAs in regulating the hypoxia-induced EMR of breast cancer CAF. On the basis of our previous work, we will mimic the hypoxic condition of breast cancer microenvironment to uncover the potential mechanisms of lncRNA acting as ceRNA regulating the hypoxia-induced EMR of breast cancer CAF by using gene microarray and bioinformatics tools. In order to further study its role of the CAF EMR mediated by lncRNA acting as ceRNA, the biological features of CAFs, and the proliferation and metastasis of breast cancer cells in the cross-talking with CAFs will be investigated by using the siRNA or gene-overexpression technology to knock down or upregulate the expression of key lncRNAs acting as ceRNA responsible for the hypoxia-induced EMR of breast cancer CAF. This study will provide new ideas and reliable evidence for uncovering the role of breast cancer microenvironment and looking for new biological targets for preventing and treating of breast cancer.

癌相关成纤维细胞(CAF)能量代谢重塑（EMR）具有促乳癌增殖和转移等功能。低氧肿瘤微环境是CAF EMR重要诱因。前期研究表明：低氧乳癌CAF存在竞争性内源RNA（ceRNA）样长链非编码RNAs（lncRNA）表达和CAF能量代谢改变，但ceRNA样lncRNAs对低氧乳癌CAF EMR的调控作用及其机制不明。本项目拟以乳癌NF和CAF为模型，模拟乳癌肿瘤低氧微环境，采用基因芯片和生物信息手段寻找低氧CAF EMR的ceRNA样责任lncRNAs，以siRNA干扰或过表达技术，研究ceRNA样责任lncRNAs调控低氧CAF EMR的作用及分子机理；探索ceRNA样责任lncRNAs介导的低氧CAF EMR对CAF生物学特征、乳癌增殖转移的作用，研究结果将为揭示乳癌微环境功能、寻求乳癌防治新靶标提供新思路和坚实的实验证据。

四年来，全体课题组成员积极进取与密切协作，顺利完成了本课题的研究内容，获得了较好的成果，主要成果如下：1. 低氧诱导乳腺癌癌相关成纤维细胞能量代谢重塑，通过乳酸代谢耦联，促乳腺癌细胞侵袭和转移。低氧条件下，乳腺CAF细胞中ATM激酶被氧化活化，磷酸化下游GLUT1，增强细胞EMR，促进乳腺CAF乳酸产生并外排。乳腺癌细胞摄取这些乳酸，细胞内TGFbeta1/P38/AMPK/MMP2/9 信号通路活化，癌细胞更具有侵袭性。2. 内源竞争性lncRNAs在低氧诱导乳腺癌CAF细胞EMR中有重要作用。芯片结果显示，低氧乳腺癌CAF细胞中许多lncRNAs表达异常，许多能量代谢基因表达异常。研究结果揭示，内源竞争性lncRNAs可能在乳腺癌CAF细胞EMR起重要作用。3. 低氧乳腺癌CAF细胞内源竞争性lncRNA与低氧血管形成密切相关。本课题研究成果拓展了对低氧条件乳腺癌CAF细胞EMR行为、内在机理和生物学功能的认识，有利于乳腺癌等实体恶性肿瘤的有效防治。本课题已发表SCI收录论文1篇，待发表SCI论文1篇。已资助培养博士研究生1名、在读硕士研究生2名。