Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University& Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou 310016, Zhejiang, China.
Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
Int J Biol Sci. 2022 Jan 1;18(3):1039-1050. doi: 10.7150/ijbs.68312. eCollection 2022.
Colorectal cancer (CRC) is the most common gastrointestinal cancer, with a high mortality rate but limited therapeutic targets. DIRAS family GTPase 2 () is a member of the Ras-related small G-protein family whose biological functions and underlying mechanism in CRC remain poorly understood. In this study, we identified the crucial roles of DIRAS2 in CRC. DIRAS2 expression was downregulated in CRC and closely correlated with poor prognosis. Functionally, DIRAS2 inhibited CRC cell proliferation and affected cell-cycle protein expression. Mechanistically, DIRAS2 blocked nuclear factor kappa light-chain enhancer of activated B-cell signaling pathways, inducing G0/G1 arrest. Moreover, DIRAS2 interacted with 26S proteasome non-ATPase regulatory subunit 2, which facilitates the degradation of DIRAS2 in a proteasome-mediated way. Together, these results demonstrate potential functions of as a tumor-suppressor gene in CRC and reveal a distinct mechanism of in CRC tumorigenesis, indicating its role as a potential biomarker and target for CRC therapy.
结直肠癌（CRC）是最常见的胃肠道癌症，死亡率高，但治疗靶点有限。DIRAS 家族 GTPase 2 () 是 Ras 相关小 G 蛋白家族的成员，其在 CRC 中的生物学功能和潜在机制仍知之甚少。在本研究中，我们确定了 DIRAS2 在 CRC 中的关键作用。DIRAS2 在 CRC 中表达下调，与预后不良密切相关。功能上，DIRAS2 抑制 CRC 细胞增殖，并影响细胞周期蛋白表达。机制上，DIRAS2 阻断核因子 κB 轻链增强子的激活 B 细胞信号通路，诱导 G0/G1 期阻滞。此外，DIRAS2 与 26S 蛋白酶体非 ATP 酶调节亚基 2 相互作用，促进 DIRAS2 以蛋白酶体介导的方式降解。总之，这些结果表明作为 CRC 中的肿瘤抑制基因具有潜在功能，并揭示了 DIRAS2 在 CRC 肿瘤发生中的独特机制，表明其作为 CRC 治疗的潜在生物标志物和靶标。
