Interaction between laminin-5γ2 and integrin β1 promotes the tumor budding of colorectal cancer via the activation of Yes-associated proteins
Interaction between laminin-5γ2 and integrin β1 promotes the tumor budding of colorectal cancer via the activation of Yes-associated proteins
复制标题
层粘连蛋白 5 γ 2 和整合素 β 1 之间的相互作用通过激活 Yes 相关蛋白促进结直肠癌的肿瘤出芽
DOI：
10.1038/s41388-019-1082-1
复制
发表时间：
2020-02-01
期刊：
影响因子：
8
通讯作者：
Liu, Yanrong
中科院分区：
文献类型：
--
作者：
Zhou, Bijiao;Zong, Shumin;Liu, Yanrong
结直肠癌（Colorectal cancer，CRC）是一种常见的恶性肿瘤，严重威胁着人类的健康。肿瘤出芽（TB）是在侵袭性癌的侵袭性前沿之前存在单个癌细胞或多达五个癌细胞的簇，并且是CRC的独立预后因素。结核病的分子机制尚不清楚，抑制这一过程的药物仍处于空白阶段。本研究发现结核分枝杆菌表现出部分EMT的特征，E-cadherin的表达减少，而N-cadherin和vimentin的表达没有实质性差异。我们还观察到整合素与细胞外基质组分层粘连蛋白-5 γ 2（LN-5 γ 2）的相互作用在CRC的TB中起重要作用。然后，我们证实LN-5 γ 2和整合素β 1之间的相互作用通过激活FAK和Yes相关蛋白（雅普）促进CRC的TB。利用蛋白质相互作用界面虚拟筛选方法对天然药物单体葫芦素B进行了筛选。我们发现，该单体可以阻断LN-5 γ 2和整合素β 1之间的相互作用界面，并通过灭活雅普而显著抑制CRC细胞的TB。本研究为探讨结直肠癌结核病的发病机制和开发针对结直肠癌结核病的药物提供了新的思路。
Colorectal cancer (CRC) is a common cancer type and a threat to human health. Tumor budding (TB) is the presence of a single cancer cell or clusters of up to five cancer cells prior to the invasive front of an aggressive carcinoma and is an independent prognosis factor for CRC. The molecular mechanism of TB is still unclear, and drugs that inhibit this process are still in the blank stage. This study found that TBs exhibit characteristics of partial EMT with a decreased expression of E-cadherin and no substantial differences in the expression of N-cadherin and vimentin. We also observed the interaction of integrin with extracellular matrix components, laminin-5 gamma 2 (LN-5 gamma 2), play essential roles in the TB of CRC. We then verified that the interaction between LN-5 gamma 2 and integrin beta 1 promotes the TB of CRC via the activation of FAK and Yes-associated proteins (YAP). A natural drug monomer, cucurbitacin B, was screened using virtual screening methods for the interaction interface of proteins. We found that this monomer could block the interaction interface between LN-5 gamma 2 and integrin beta 1 and substantially inhibit the TB of CRC cells via inactivation of YAP. This study provides new insights into the mechanism of TB mechanism and the development of drugs targeting the TB of CRC.