FAM64A在乳腺癌转移中的作用及分子机制研究

Family with Sequence Similarity 64, Member A (FAM64A), also named Regulator of Chromosome Segregation 1 (RCS1), as a mitotic regulator that controls the metaphase to anaphase transition. Currently, previous studies showed that FAM64A promotes leukemia cell proliferation. However, the role of FAM64A in solid tumors is limited. We found that FAM64A is up-regulated in a variety of malignant tumors by analyzing TCGA database and higher FAM64A expression is associated with poor outcomes in patients with breast cancer by analyzing GOBO database. Furthermore, FAM64A promotes breast cancer migration and invasion, and FAM64A expression is elevated after treatment with TGFβ. Our study also indicated that FAM64A binds to TWIST1 and transcriptionally suppresses E-cadherin expression. TWIST1, a master regulator of EMT, promotes cancer metastasis. Thus, our results suggested that FAM64A plays an important role in TWIST1-mediated breast cancer Epithelial-Mesenchymal Transition (EMT). We aim to investigate the possible molecular mechanisms and biological function of the interasction between FAM64A and TWIST1. We will further verify tha whether FAM64A regulates breast cancer metastasis through FAM64A-TWIST1 interaction-mediated breast cancer EMT.

FAM64A，又名RCS1，主要调控丝分裂中期至后期的转变。目前研究表明FAM64A能促进白血病细胞增殖能力，但其在实体肿瘤中的作用及机制尚无报道。课题组通过查询TCGA数据库，发现FAM64A在多种恶性肿瘤中高表达，且GOBO数据库显示FAM64A高表达与乳腺癌患者不良预后相关。课题组前期研究发现FAM64A促进乳腺癌细胞运动和侵袭能力，外源加入TGFβ后，FAM64表达上调。进一步研究发现FAM64A与TWIST1存在相互作用，转录抑制E-cadherin表达。TWIST1 作为上皮间质转化主要调控因子，促进多种肿瘤细胞转移，提示FAM64A在TWIST1介导的乳腺癌细胞EMT中发挥一定作用。我们将进一步研究FAM64A与TWIST1相互作用的分子机制，并探讨FAM64A是否通过与TWIST1相互作用，转录调控E-cadherin表达，进而诱导乳腺癌上皮间质转化，最终促进乳腺癌转移。

FAM64A，又名PIMREG，主要调控有丝分裂中期至后期的转变。目前研究表明FAM64A可促进白血病细胞增殖能力，但其在实体肿瘤中的作用及机制尚无报道。本研究发现FAM64A在乳腺癌组织中表达上调，且FAM64A高表达患者预后较差。体内体外研究证实FAM64A可促进乳腺癌细胞的增殖和转移能力。过表达FAM64A还可促进乳腺癌细胞的上皮间质转化表型，沉默FAM64A表达可以逆转TGFβ1诱导的乳腺癌上皮间质转化表型。进一步研究发现FAM64A可以与TWIST1相互作用，沉默TWIST1后可消除FAM64A对E-cadherin的转录调控作用，且FAM64A的AA36-74在中发挥着重要的作用，该部分缺失能消除FAM64A对乳腺癌增殖和侵袭的促进作用。本研究初步证实FAM64A在乳腺癌发生发展中起到癌基因的作用，FAM64A是一个乳腺癌治疗的潜在靶点。