RAS-GTPase活化蛋白RASAL2促进结直肠癌转移的作用及分子机制研究

Colorectal cancer (CRC) is a worldwide malignant tumor that is also the fourth leading cause of mortality. Although metastasis is the leading cause of colorectal cancer-related death, the molecular mechanisms of tumor progression and metastasis remain largely unknown. In our previous study, we found the increase in DNA copy number and up-regulation of RASAL2 in colorectal cancer by integrated genomic analysis. Multivariate regression analysis confirmed that RASAL2 can be served as a prognostic indicator of poor prognosis in patients with colorectal cancer. Functional studies demonstrated that Hippo pathway was involved in RASAL2-mediated carcinogenesis. Based on the previous research, this study aims to clarify the molecular mechanism underlying the metastatic properties of RASAL2 in colorectal cancer. The following four aspects will be studied: 1. To investigate whether RASAL2 can be used as a molecular biological marker for metastasis in colorectal cancer patients and its clinical significance; 2. Through in vitro and in vivo experiments to reveal the functional role of RASAL2 in metastatic colorectal cancer; 3. To clarify the signal cascade of RASAL2-YAP1 and elucidate the mechanisms underlying the oncogenic properties of RASAL2 via the interaction with Hippo pathway; 4. Further explore the potential molecular mechanisms of RASAL2 affecting tumor metastasis. The proposed study is expected to provide new strategies for prediction, treatment and prognosis for colorectal cancer metastasis.

结直肠癌是一种世界性恶性肿瘤，也是全球导致死亡率第四位的癌症。转移是结直肠癌相关死亡的主要原因，但肿瘤转移的分子机制仍然很大程度上未知。申请人前期研究发现，通过整合基因组分析，结直肠癌中RASAL2的DNA拷贝数增加和表达上调，并且可作为较差预后的标志，RASAL2通过调控Hippo通路发挥其致癌功能。本课题拟在前期研究基础上，着重阐明RASAL2促进结直肠癌转移的作用及分子机制，进行如下四个方面研究：1、分析RASAL2可否作为结直肠癌患者发生转移的分子生物学标志物及其临床意义；2、通过体外和体内功能实验来研究RASAL2在转移性结直肠癌中的生物学功能；3、明确RASAL2-YAP1的信号级联，阐明RASAL2在Hippo信号通路中促进肿瘤转移的分子机制；4、进一步探讨RASAL2影响肿瘤转移的其他分子信号通路。拟议的研究有望对结直肠癌转移的预测、治疗及预后提供新思路与策略。

结直肠癌是一种世界性恶性肿瘤，也是全球导致死亡率第四位的癌症。转移是结直肠癌相关死亡的主要原因，但肿瘤转移的分子机制仍然很大程度上未知。申请人前期研究发现，通过整合基因组分析，结直肠癌中RASAL2的DNA拷贝数增加和表达上调，并且可作为较差预后的标志，RASAL2通过调控Hippo通路发挥其致癌功能。本课题首先发现RASAL2在转移性结直肠癌中的表达显著高于早期结直肠癌，患者预后更差，且RASAL2是转移性结直肠癌的一个独立预后指标；体外和体内功能实验表明RASAL2在转移性结直肠癌中细胞增殖、侵袭和转移能力更强；RASAL2与Hippo通路靶基因的表达呈正相关，且RASAL2沉默导致YAP1和Hippo通路的关键靶基因CTGF和CYR1的RNA表达下降。同时，我们还发现：①RASAL2沉默可导致RHOA-GTP和RAC1-GTP酶的表达水平减少；②IGF1R的促癌功能和STK3的抑癌功能可能均与RASAL2-YAP1-Hippo信号通路轴相关。此外，为了保证此课题中肿瘤患者淋巴结转移状态的准确评估，我们建立了一个基于深度学习的检测肿瘤淋巴结转移的模型，根据术后组织病理学图像区分上皮性恶性肿瘤的良性淋巴结和转移性淋巴结，并验证该系统的诊断性能，从而保证淋巴结转移评估的准确性。以上研究有望对结直肠癌转移的预测、治疗及预后提供新思路与策略。