癌基因Suprabasin促乳腺癌转移的生物学功能及其分子机制研究

Tumor metastasis is the main cause of malignant death. It is of great importance to find diagnostic factor for tumor metastasis. Our previous published article reported Suprabasin promotes tumor proliferation. However, the function and mechanism of Suprabasin in breast cancer remains unknown. Recently, we found that the expression of Suprabasin was significantly correlated the N and M classification in breast cancer, indicating the potential function of Suprabasin on breast cancer metastasis. The results of in vitro and in vivo experiments in breast cancer showed that upregulation of Suprabasin induced epithelial-mesenchymal transition, promoted lyphmtic, distant metastasis and angiogenesis, enhanced breast cancer stem cell characterics. The results also showed Wnt/β-catenin, NF-κB and Akt signaling pathway might play roles in Suprabasin function and regulation. In current study, we will combine both in vitro and in vivo experimental systems with data from clinical samples, in order to investigate the mechanisms of Suprabasin-induced breast cancer metastasis. It will help to identify novel diagnostic markers and therapeutic targets for breast metastasis.

转移是恶性肿瘤的致死的主要原因，并严重影响患者的生存质量和预后。因此寻找促肿瘤转移的关键分子对肿瘤的早期诊断和治疗具有重要的意义。前期我们已发表文章证明高表达癌基因Suprabasin可促进肿瘤恶性增殖。近期通过分析临床乳腺癌样品，我们发现Suprabasin表达与乳腺癌N、M分期显著相关，提示Suprabasin可能促进肿瘤转移。体内、外生物学功能试验结果显示：上调Suprabasin可①诱导乳腺癌细胞发生EMT；②驱动乳腺癌淋巴结、远处器官转移并促血管增生；③增强乳腺癌细胞“干细胞”特性。结合免疫共沉淀耦联质谱等多种方法进行调控机制探讨，结果发现：Suprabasin与Wnt/β-catenin、NF-κB 和AKT信号通路相关调控因子结合并激活其活性。本研究将深层次解析癌基因Suprabasin多层面驱动乳腺癌转移的分子机制，并与临床相结合，为乳腺癌转移提供新的诊断标记物及治疗靶标。

乳腺癌转移不仅是根治性手术失败的主要原因，也是最终导致患者死亡的主要原因之一。抑制乳腺癌转移是其治疗中重要而迫切的任务。前期研究发现Suprabasin在转移乳腺癌组织中的表达水平增高；Suprabasin高表达可增强乳腺癌细胞运动迁移，可能在多个步骤、多种层面驱动乳腺癌远处转移。主要研究内容包括：(1)Suprabasin是否与肿瘤转移相关，参与肿瘤转移中哪些生物学过程;(2)Suprabasin如何调控信号通路而促进肿瘤转移发生；(3)Suprabasin在乳腺癌中表达上调的分子机制如何；(4)Suprabasin及其调控基因在乳腺癌的临床诊断、预后及治疗中的意义如何。研究结果证实：①确认Suprabasin参与促进乳腺癌体内外的转移过程，包括促进乳腺癌细胞生长增殖、增强乳腺癌的运动和侵袭能力；②Suprabasin持续激活NF-κB信号通路而促进肿瘤转移发生；③Suprabasin具有分泌特性，而分泌性的Suprabasin具有生物学功能和激活NF-κB信号通路的作用；④ TYRO3介导Suprabasin激活NF-κB信号通路的作用；⑤Suprabasin在乳腺癌中表达上调可能与KMT2B甲基转移酶介导的组蛋白甲基化过程有关；⑥Suprabasin在乳腺癌临床样本中表达上调，并与乳腺癌的临床分期、转移状况和患者的不良生存预后存在密切的正相关联。总结项目结果证实Suprabasin在乳腺癌中表达上调，具有促进乳腺癌侵袭和转移的生物学作用，TYRO3介导的NF-κB信号通路活化参与了Suprabasin的调控作用。研究初步证实Suprabasin在乳腺癌诊断、预后及治疗中的具有临床转化和应用的潜力。