p120 Catenin 通过CXCR4和RANKL调控乳腺癌细胞骨转移的研究

Bone is the most frequent site of breast cancer metastasis, however, at present, the clinical diagnosis and therapies for bone metastases were limited due to its unclear mechanism. In our preliminary experiments, we found that bone metastases of breast cancer patients were associated with the low expression level of p120 Catenin detected by high-throughput sequence and qPCR, and culturing breast cancer cells with human bone matrix extract in vitro resulted in decreased p120 Catenin expression of breast cancer cells. Knockdowning p120 Catenin of breast cancer cells promoted their interaction with osteoblasts, accompanied with upregulation of bone tissue chemokine CXCR4 and osteoclast activation factor RANKL. Based on these, we further plan to demonstrate that breast cancer cells with reduced p120 Catenin are easier to home to bone via upregulation of CXCR4 and activate osteoclasts trough increasing RANKL secretion both in vitro and in vivo.The molecular mechanism how p120 Catenin regulates CXCR4 and RANKL expression and its clinical significance in bone metastases of breast cancer will be investigated as well. The completion of this project will provide new ideas for clinical therapies and new biomarkers for diagnosis of bone metastases.

骨是乳腺癌最常见转移部位，然而目前临床缺乏有效诊治乳腺癌骨转移的手段，主要原因是乳腺癌骨转移的机制尚不明确。我们前期通过高通量测序和qPCR检测发现临床乳腺癌骨转移与乳腺癌组织p120 Catenin表达水平下调相关，体外实验发现与人骨基质提取物共培养的乳腺癌细胞p120 Catenin表达下调，敲低乳腺癌细胞p120 Catenin能促进其粘附成骨细胞，且伴有骨组织趋化因子CXCR4和破骨细胞激活因子RANKL表达增加。因此，我们拟进一步通过体内外研究证实p120 Catenin表达下调的乳腺癌细胞可通过上调CXCR4表达驱使其自身归巢至骨组织，通过上调其自身RANKL分泌激活破骨细胞促进骨损伤，同时探索p120 Catenin调控CXCR4和RANKL表达和分泌的分子机制及其在乳腺癌骨转移中的临床意义。本项目的完成将为临床诊治乳腺癌骨转移提供新思路和新的分子标记物。

三阴性乳腺癌(triple-negative breast cancer, TNBC)骨转移由于诊断和干预的延迟、缺乏有效治疗及更多的骨相关并发症，往往比其他类型的乳腺癌预后更差。 在本研究中，我们通过对TNBC患者临床标本进行高通量测序发现CTNND1在TNBC骨转移标本中显著低表达。体内实验证实，敲除CTNND1可促进肿瘤细胞向骨的转移，并增加中性粒细胞在骨中的浸润。体外实验证实抑制CTNND1可以加速肿瘤细胞的上皮间充质转化(EMT)和肿瘤细胞募集至骨。 CTNND1参与EMT和骨归巢是通过激活PI3K/AKT/ hif -1α通路上调CXCR4实现的。 此外，CTNND1低表达的TNBC细胞通过分泌更多GM-CSF和IL-8来加速中性粒细胞的浸润从而抑制细胞毒性t细胞的抗肿瘤免疫功能。通过分析TCGA数据库中TNBC患者CTNND1表达与预后关系发现，CTNND1低表达患者总生存期(OS)和无远处转移生存期(DMFS)显著缩短。 因此，CTNND1的下调在促进TNBC骨转移中发挥了重要作用，CTNND1可能是预测TNBC骨转移风险的潜在生物标志物。