Hoxc10调控miR-181a/Nanog影响三阴性乳腺癌化疗耐药及干性的机制研究

Previous studies showed that Hoxc10 was an important regulator in endocrine therapy resistant of breast cancer with ER positive. However, the role of Hoxc10 in triple-negative breast cancer (TNBC) is limited. Our previous study indicated that Hoxc10 up-regulated was correlated with poor survival and over-expression of miR-181a and Nanog in TNBC, putative Hoxc10 binding sites existed in miR-181a gene promoter, and Nanog repression reduced the proportion of stem cell and reversed chemotherapy resistance in TNBC.Furthermore, Nanog was a direct target gene for miR-181a. Accordingly, we propose the hypothesis that Hoxc10/miR-181a/Nanog as a biological axis synergistically regulates the drug resistance and stem cell enrichment of stem cells in TNBC. The present study intends to illuminate the Hoxc10 funcion as the starting point verifying the chemotherapy resistance and stem cell enrichment of TNBC through miR-181a/Nanog. Meanwhile, we will also establish the regulatory network mediated by Hoxc10 and explore its role in drug resistance and stem cell enrichment in TNBC. In conclusion, our finding may enrich the insides of mechanism of TNBC resistant and stem cells， and provide rations for seeking the effective therapeutic targets of TNBC.

Hoxc10在ER阳性乳腺癌内分泌治疗耐药中发挥着重要的作用，但其在三阴性乳腺癌化疗耐药及干性特征的作用和机制尚无报道。课题组前期研究结果发现在三阴性乳腺癌中，Hoxc10上调与不良预后相关，且Hoxc10与miR-181a、Nanog之间表达具有相关性；miR-181a的启动子区存在Hoxc10的结合位点；敲低Nanog可有效抑制三阴性乳腺癌干细胞干性特征并逆转化疗耐药。而Nanog是miR-181a的直接靶基因。据此我们提出假说“Hoxc10/miR-181a/Nanog作为生物轴协同调控三阴性乳腺癌细胞的干性特征和化疗耐药”。本课题拟以Hoxc10在三阴性乳腺癌细胞耐药及干性所发挥功能为出发点，验证Hoxc10对miR-181a/Nanog的调控关系，建立以Hoxc10为核心的通路调控体系，探讨其在三阴性乳腺癌干性特征及治疗耐药的重要作用，为寻找三阴性乳腺癌治疗靶点提供理论依据。

由于乳腺癌具有高度的异质性，根据基因表达谱特征可将乳腺癌分为Luminal A、Luminal B、Basal-like、HER2-positive和Normal-like五种亚型。HOXC10在雌激素受体（estrogen receptor，ER）阳性乳腺癌内分泌治疗敏感性中发挥着重要作用，但HOXC10在三阴性乳腺癌（triple-negative breast cancer，TNBC）干性及耐药中的作用未见报告。本研究发现HOXC10在转移性TNBC乳腺癌中表达显著上调，且HOXC10高表达与TNBC患者不良预后相关。沉默HOX10C表达TNBC细胞的干样细胞比例显著降低，对化疗药物敏感性显著增强。miR-181a-5p在TNBC组织中表达显著上调，且与患者不良预后相关。沉默miR-181a-5p表达降低TNBC细胞干性、运动能力，干性标志Nanog、Sox2和Oct-4等表达显著降低，且细胞体内成瘤能力也显著降低。进一步研究发现抑癌基因PTEN是miR-181a-5p下游调控的靶基因，且沉默HOXC10下调miR-181a-5p表达。本研究初步证实HOXC10通过上调miR-181a-5p，导致PTEN表达下调，诱导乳腺癌干样表型，促进乳腺癌发生发展。