Department of Prdiatric Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China.
Department of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou, PR China.
Int Immunopharmacol. 2024 Jun 15;134:112139. doi: 10.1016/j.intimp.2024.112139. Epub 2024 May 12.
Capping protein regulatory factor and myosin 1 linker 1 is termed CARMIL1. CARMIL1 is involved in several physiological processes; it forms an actin filament network and plasma membrane-bound cellular projection tissues and positively regulates the cellular components and tissues. CARMIL1 exhibits important biological functions in cancer; nonetheless, these functions have not been completely explored. We aimed to investigate the novel functions of CARMIL1 in liver cancer, particularly in cell proliferation. The cell counting kit-8, 5-ethynyl-2'-deoxyuridine, Component A experiments, and subcutaneous tumor formation model suggest that CARMIL1 is central to the proliferation of liver cancer cells both in vivo and in vitro. We extracted CARMIL1 samples from The Cancer Genome Atlas Program and analyzed its enrichment. CARMIL1 regulated the pathway activity by affecting the expression of star molecular proteins of the extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR). Moreover, it influenced the proliferation ability of liver cancer cells. Western blotting suggested that CARMIL1 downregulation could affect ERK and mTOR phosphorylation. Results of the co-immunoprecipitation demonstrated that CARMIL1 binds to tripartite motif (TRIM)27, which in turn binds to p53. Subsequently, CARMIL1 can regulate p53 stability and promote its degradation through TRIM27. Additionally, CARMIL1 inhibition enhanced the sensitivity of liver cancer cells to sorafenib. Tumor growth was significantly inhibited in the group treated with sorafenib and CARMIL1, compared with the group treated with CARMIL1 alone. Sorafenib is a first-line targeted chemotherapeutic drug for hepatocellular carcinoma treatment. It increases the long-term survival of hepatocellular carcinoma by 44%. In this study, downregulated CARMIL1 combined with sorafenib significantly reduced the tumor volume and weight of the mouse subcutaneous tumor model, indicating the potential possibility of combining CARMIL1 with sorafenib in hepatocellular carcinoma treatment. In summary, CARMIL1 promotes liver cancer cell proliferation by regulating the TRIM27/p53 axis and activating the ERK/mTOR pathway.
衔接蛋白调节因子和肌球蛋白 1 接头蛋白 1 被称为 CARMIL1。CARMIL1 参与了几种生理过程；它形成了一个肌动蛋白丝网络和质膜结合的细胞突起组织，并正向调节细胞成分和组织。CARMIL1 在癌症中表现出重要的生物学功能；然而，这些功能尚未完全被探索。我们旨在研究 CARMIL1 在肝癌中的新功能，特别是在细胞增殖方面。细胞计数试剂盒-8、5-乙炔基-2'-脱氧尿苷、成分 A 实验和皮下肿瘤形成模型表明，CARMIL1 在体内和体外均对肝癌细胞的增殖起着核心作用。我们从癌症基因组图谱计划中提取了 CARMIL1 样本，并分析了其富集情况。CARMIL1 通过影响细胞外信号调节激酶 (ERK) 和雷帕霉素靶蛋白 (mTOR) 的明星分子蛋白的表达来调节通路活性。此外，它还影响肝癌细胞的增殖能力。Western blot 表明，CARMIL1 的下调会影响 ERK 和 mTOR 的磷酸化。共免疫沉淀的结果表明，CARMIL1 与三基序 (TRIM)27 结合，TRIM27 反过来又与 p53 结合。随后，CARMIL1 可以通过 TRIM27 调节 p53 的稳定性并促进其降解。此外，CARMIL1 抑制增强了肝癌细胞对索拉非尼的敏感性。与单独使用 CARMIL1 相比，在使用索拉非尼和 CARMIL1 的组中，肿瘤生长明显受到抑制。索拉非尼是治疗肝细胞癌的一线靶向化疗药物。它将肝细胞癌的长期生存率提高了 44%。在这项研究中，下调的 CARMIL1 与索拉非尼联合使用显著减少了小鼠皮下肿瘤模型的肿瘤体积和重量，这表明在肝细胞癌治疗中联合使用 CARMIL1 和索拉非尼具有潜在的可能性。总之，CARMIL1 通过调节 TRIM27/p53 轴和激活 ERK/mTOR 通路促进肝癌细胞增殖。
