ROC1活化mTOR通路促进膀胱癌侵袭及转移的机制研究

Regulator of Cullin-1 (ROC1) is an essential subunit of Cullin-RING ligase (CRL), participating in mediating degradation of many oncogenic proteins. Our previous study indicated that ROC1 was overexpressed in bladder cancer and ROC1 expression was positively correlated with the recurrence rate of the patients. ROC1 knockdown inhibited the growth of bladder cancer cells by inducing G2 phase arrest and senescence due to accumulation of CRL substrates of p21 and p27. We have recently found that ROC1 expression was positively correlated with invasion ability of bladder cancer cells. ROC1 knockdown suppressed epithelial-mesenchymal transition (EMT), accompanied by accumulation of mTOR-inhibitory protein DEPTOR. We speculated that ROC1 may induce mTOR-dependent EMT to promote invasion and metastasis of bladder cancer. This project intends to research: 1) To define the impact of ROC1 on invasion and metastasis of bladder cancer; 2) To study whether ROC1 regulating DEPTOR protein degradation and mTOR kinase activity to trigger EMT of bladder cancer; 3) To analyze the relationship among ROC1, DEPTOR, EMT phenotype and clinical characteristics in bladder cancer samples. Taken together, this project will reveal a novel mechanism of ROC1→DEPTOR→EMT regulating invasion and metastasis of bladder cancer and provide new strategies for prognosis judgment and targeted therapy of bladder cancer patients.

ROC1是CRL泛素连接酶的核心亚基，参与介导多种癌相关蛋白的泛素化降解。我们前期研究显示：膀胱癌组织中ROC1表达量与患者病情预后密切相关；下调膀胱癌细胞ROC1引起CRL底物积聚，诱导细胞G2期阻滞及衰老从而抑制癌细胞生长。我们最近研究发现膀胱癌细胞ROC1表达量与其侵袭转移能力呈正相关，下调ROC1抑制膀胱癌细胞EMT，伴随mTOR通路负调控因子DEPTOR积聚。我们推测ROC1可能通过活化mTOR通路诱导EMT促进膀胱癌侵袭及转移，本项目拟深入研究：(1)ROC1不同表达状态对膀胱癌侵袭转移的影响；(2)ROC1是否通过调控DEPTOR降解及mTOR通路活性从而诱导膀胱癌细胞EMT；(3)组织样本中ROC1、DEPTOR表达与EMT表型及膀胱癌侵袭转移的相关性。本项目期望初步描绘出膀胱癌侵袭转移调控网络中ROC1→DEPTOR→EMT作用模式，为膀胱癌预后判断及靶向治疗提供新策略。

ROC1是CRL泛素连接酶的核心亚基，参与介导多种癌相关蛋白的泛素化降解。我们前期研究显示：膀胱癌组织中ROC1表达量与患者病情预后密切相关；下调膀胱癌细胞ROC1引起CRL底物积聚，诱导细胞G2期阻滞及衰老从而抑制癌细胞生长。本项目研究发现：(1)下调ROC1抑制膀胱癌细胞迁移活性；(2)下调ROC1是否通过抑制DEPTOR降解活化mTOR通路活性从而抑制膀胱癌细胞EMT；(3) 下调ROC1抑制膀胱癌细胞在裸鼠体内远处转移；(4) 组织样本中ROC1、DEPTOR表达与EMT表型及膀胱癌侵袭转移存在相关性。上述研究结果验证了前期假说：ROC1通过调控DEPTOR/mTOR通路活性，诱导上皮-间质转化，促进膀胱癌恶性进展。本项目描绘出膀胱癌侵袭转移调控网络中ROC1→DEPTOR→EMT新作用模式，为膀胱癌预后判断及靶向治疗提供新策略。