丹参酮类成分通过抑制miR-9/STARD13信号轴削弱乳腺癌干细胞样特性及化疗耐药的机制研究

Chemoresistance is a major issue needed to be solved in breast cancer treatment. Blood-activating and stasis-resolving component tanshinones can reverse the chemoresistance of breast cancer, however, the underlying mechanisms are still confused. Cancer stem cells (CSCs) have been shown as the critical contributor to chemoresistance, and miRNA plays an important role in regulating CSCs. Pre-experiment found that tanshinones attenuated the stem-like traits of breast cancer cells. High-throughput sequencing showed that tanshinones could downregulate miR-9 level in breast cancer, and the effect of tanshinones on the stem-like traits of breast cancer cells was rescued by miR-9 overexpression. We previously confirmed that miR-9 promoted breast cancer metastasis via targeting STARD13, which could attenuate the stem-like traits of breast cancer cells. Moreover, tanshinones upregulated STADR13 level of breast cancer cells. Therefore, we assume that tanshinones could attenuate the stem-like traits and chemoresistance of breast cancer through inhibiting miR-9/STARD13 signaling. To confirm this speculation, CSCs was selected as the breakthrough of study point. This work will perform positive and negative genetics methods combined with MMTV-PyMT mice and mice with miR-9 knockout to explore the effects and the corresponding mechanism of tanshinones suppressing the stem-like traits and chemoresistance of breast cancer, and thus provide important academic foundations for treating breast cancer chemoresistance using blood-activating and stasis-resolving herbs.

化疗耐药是乳腺癌治疗亟待解决的难题，活血化瘀成分丹参酮类可逆转乳腺癌化疗耐药，机制尚不清楚。肿瘤干细胞（Cancer stem cells, CSCs）被认为是肿瘤耐药的根源，miRNA在调控CSCs活性中起关键作用。预实验发现丹参酮类成分可削弱乳腺癌CSCs样特性，高通量测序表明其可下调miR-9水平，过表达miR-9上述作用被削弱；申请者已证实miR-9靶向抑制STARD13促乳腺癌转移，且STARD13可削弱乳腺癌CSCs样特性；进一步研究发现丹参酮类成分尚可上调STARD13水平。由此我们设想：丹参酮类成分通过抑制miR-9/STARD13信号轴削弱乳腺癌CSCs样特性，逆转化疗耐药。为此，本项目以CSCs为切入点，结合miR-9基因敲除鼠和自发乳腺癌MMTV-PyMT小鼠，利用正/反向遗传学手段，研究丹参酮类成分调控乳腺癌化疗耐药机制，为活血化瘀药治疗乳腺癌化疗耐药积累学术基础。

化疗耐药是乳腺癌治疗亟待解决的难题，活血化瘀成分丹参酮类可逆转乳腺癌化疗耐药，机制尚不清楚。肿瘤干细胞（Cancer stem cells, CSCs）被认为是肿瘤耐药的根源，miRNA在调控CSCs活性中起关键作用。本研究发现丹参酮类代表性成分丹参酮ⅡA可削弱乳腺癌CSCs样特性，高通量测序表明其可下调miR-125b水平，上调miR-125b上述作用被削弱；申请者已证实miR-125b靶向抑制STARD13促乳腺癌转移，且STARD13可削弱乳腺癌CSCs样特性；进一步研究发现丹参酮ⅡA尚可上调STARD13水平。以上结果提示我们丹参酮ⅡA可能通过抑制miR-125b/STARD13信号轴削弱乳腺癌CSCs样特性，逆转化疗耐药。进一步研究发现，上调miR-125b或敲除STARD13可削弱丹参酮ⅡA对乳腺癌细胞干性及化疗耐药的抑制作用。本研究表明丹参酮ⅡA通过抑制miR-125b，增强STARD13表达，削弱乳腺癌CSCs样特性，逆转化疗耐药。本研究以CSCs为切入点，阐明丹参酮ⅡA调控乳腺癌化疗耐药机制，为活血化瘀药治疗乳腺癌化疗耐药积累学术基础。