MYL9 expressed in cancer-associated fibroblasts regulate the immune microenvironment of colorectal cancer and promotes tumor progression in an autocrine manner

作者：Shenghe Deng, Denglong Cheng, Jun Wang, Junnan Gu, Yifan Xue, Zhenxing Jiang, Le Qin, Fuwei Mao, Yinghao Cao, Kailin Cai · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2023 · DOI：10.1186/s13046-023-02863-2 · 被引用次数：51 · 研究领域：Immune cells in cancer、Cancer Cells and Metastasis、Ferroptosis and cancer prognosis

BACKGROUND: The tumor microenvironment (TME) is an important factor that regulates the progression of colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs) are the main mesenchymal cells in the TME and play a vital role in tumor progression; however, the specific underlying mechanisms require further study. METHODS: Multiple single-cell and transcriptome data were analyzed and validated. Primary CAFs isolation, CCK8 assay, co-culture assay, western blotting, multiple immunofluorescence, qRT-PCR, ELISA, immunoprecipitation, ChIP, double luciferase, and animal experiments were used to explore the potential mechanism of MYL9 regulation in CRC. RESULTS: Our findings revealed that MYL9 was predominantly localized and expressed in CAFs rather than in CRC cells, and bioinformatics analysis revealed that high MYL9 expression was strongly associated with poor overall and disease-free survival in various tumors. In addition, high MYL9 expression is closely associated with M2 macrophage infiltration, which can lead to an immunosuppressive microenvironment in CRC, making it insensitive to immunotherapy. Mechanically, MYL9 can regulate the secretion of CAFs on CCL2 and TGF-β1, thus affecting the immune microenvironment and progression of CRC. In addition, MYL9 bounded with IQGAP1 to regulate CCL2 and TGF-β1 secretion through the ERK 1/2 pathway, and CCL2 and TGF-β1 synergistically promoted CRC cells progression through the PI3K-AKT pathway. Furthermore, MYL9 promotes epithelial-me...