乳腺癌外周血循环肿瘤细胞化疗耐药的miR-106b调控机制

..Circulating tumor cells (CTCs) are a key sub-population responsible for the metastasis and chemoresistance of breast cancer.Our previous studies demonstrated that microRNAs play a pivotal role in regulating the chemoresistance of breast cancer.By using microRNA array and real-time PCR,we found that expression of miR-106b was highest upregulated in CTCs compared to primary tumor cells (PTCs), which promoted the chemoresistance of CTCs by targeting the breast cancer metastasis-suppresor 1-like(BRMS1L) and retinoblastomal(RB) protein. In order to clarify the molecular mechanisms of miR-106b and its tagreted genes in the regulation of chemoresistance of CTCs, based on our establised CTCs models in vitro and in vivo, we firstly plan to get the more directly experimental evidence that miR-106b mediates the chemoresistance of CTCs,then clarify how miR-106b and its targeted genes regulate chemoresistance-related genes and contribute to the chemoresistance of CTCs, finally demonstarate the clinical significance of miR-106b and its target genes in CTC chemoresistance of breast cancer.Our study will provide a new insight of chemoresistance and new targets in reversing the chemoresistance of breast cancer by targeting the CTCs.

外周血循环肿瘤细胞(CTC)是乳腺癌转移和化疗耐药的关键细胞群,但CTC化疗耐受的调控机制不明确。本课题组既往研究证实MircroRNAs是调控乳腺癌化疗耐药的关键分子,我们前期研究筛选和验证了CTC中miR-106b表达上调最明显，并证实miR-106b通过其靶基因乳腺癌转移抑制样因子（BRMS1L）和RB促进化疗耐药。为了进一步探索miR-106b调控乳腺癌CTC化疗耐药的分子机制，本项目拟在已建立的CTC体内外研究模型中，通过干预miR-106b及其靶基因，获得它们调节CTC化疗敏感性的直接实验依据，揭示miR-106b通过其靶基因调控耐药相关基因表达而导致CTC化疗耐受的分子机制，阐明miR-106b及其靶基因在乳腺癌CTC耐药中的作用和临床意义，为逆转肿瘤耐药提供靶向CTC的新思路和新靶点。

外周血循环肿瘤细胞(CTC)是乳腺癌转移和化疗耐药的关键细胞群,但 CTC 化疗耐受的调控机制不明确。我们前期的工作证实非编码小分子RNA是调控乳腺癌耐药的关键分子，乳腺癌CTC中高表达miR-106b，其靶基因是乳腺癌转移抑制样因子（BRMS1L）和 RB。基于此，在功能方面，我们进一步通过体内外研究证实悬浮压力下生长的CTC受到化疗打击后能迅速修复受损伤DNA，从而对DNA损伤性化疗药物产生耐受《JBC 2015》，在分子机制方面，我们证实miR-106b通过靶基因之一RB调控乳腺癌细胞的增殖《Oncogene 2013》，通过另一个靶基因BRMS1L表观调控FZD10影响乳腺癌转移《Nature Communications 2014》，从而促进CTC的化疗耐药。本项目的完成不仅获得了 miR-106b 通过靶基因调节 CTC 化疗敏感性的直接实验依据，还揭示了 miR-106b 调控耐药相关基因表达的分子机制，阐明了miR-106b 及其靶基因在乳腺癌 CTC 耐药中的作用和临床意义，这为临床逆转乳腺癌耐药提供了靶向 CTC 的治疗新思路和新靶点。