Molecular Pathology Institute of Gastrointestinal Tumors, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272029, Shandong, China.
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, China.
Oncogene. 2020 Feb;39(7):1527-1542. doi: 10.1038/s41388-019-1082-1. Epub 2019 Nov 1.
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-5γ2 (LN-5γ2), play essential roles in the TB of CRC. We then verified that the interaction between LN-5γ2 and integrin β1 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-5γ2 and integrin β1 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.
结直肠癌（CRC）是一种常见的癌症类型，严重威胁人类健康。肿瘤芽（TB）是指在侵袭性癌的浸润前沿之前，单个癌细胞或多达 5 个癌细胞簇的存在，是 CRC 的独立预后因素。TB 的分子机制尚不清楚，抑制该过程的药物仍处于空白阶段。本研究发现，TB 表现出部分 EMT 的特征，E-钙黏蛋白表达降低，而 N-钙黏蛋白和波形蛋白的表达没有明显差异。我们还观察到整合素与细胞外基质成分层粘连蛋白-5γ2（LN-5γ2）的相互作用在 CRC 的 TB 中发挥着重要作用。然后我们验证了 LN-5γ2 与整合素β1 的相互作用通过激活 FAK 和 Yes 相关蛋白（YAP）促进 CRC 的 TB。我们使用虚拟筛选方法筛选出一种天然药物单体葫芦素 B，以寻找蛋白质相互作用界面。我们发现，这种单体可以阻断 LN-5γ2 和整合素β1 之间的相互作用界面，并通过失活 YAP 来显著抑制 CRC 细胞的 TB。本研究为 TB 机制和针对 CRC 的 TB 的药物开发提供了新的见解。
