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

被引:16
作者
Deng, Shenghe [1 ,2 ]
Cheng, Denglong [2 ]
Wang, Jun [2 ]
Gu, Junnan [2 ]
Xue, Yifan [2 ]
Jiang, Zhenxing [2 ]
Qin, Le [2 ]
Mao, Fuwei [2 ]
Cao, Yinghao [3 ]
Cai, Kailin [2 ]
机构
[1] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Ctr Liver Transplantat, Wuhan 430022, Peoples R China
[2] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Gastrointestinal Surg, Wuhan 430022, Peoples R China
[3] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Canc Ctr,Dept Digest Surg Oncol, Wuhan 430022, Peoples R China
关键词
MYL9; Cancer-associated fibroblasts; Colorectal cancer; Immunosuppressive microenvironment; Metastasis; Epithelial-mesenchymal transition; CELLS; COLON; MACROPHAGES; PHENOTYPE; MIGRATION; INVASION; ERK1/2; CCL2;
D O I
10.1186/s13046-023-02863-2
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BackgroundThe 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.MethodsMultiple 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.ResultsOur 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-beta 1, thus affecting the immune microenvironment and progression of CRC. In addition, MYL9 bounded with IQGAP1 to regulate CCL2 and TGF-beta 1 secretion through the ERK 1/2 pathway, and CCL2 and TGF-beta 1 synergistically promoted CRC cells progression through the PI3K-AKT pathway. Furthermore, MYL9 promotes epithelial-mesenchymal transition (EMT) in CRC. During the upstream regulation of MYL9 in CAFs, we found that the EMT transcription factor ZEB1 could bind to the MYL9 promoter in CAFs, enhancing the activity and function of MYL9. Therefore, MYL9 is predominantly expressed in CAFs and can indirectly influence tumor biology and EMT by affecting CAFs protein expression in CRC.ConclusionsMYL9 regulates the secretion of cytokines and chemokines in CAFs, which can affect the immune microenvironment of CRC and promote CRC progression. The relationship between MYL9 expression and CRC clinical staging and immunotherapy is closer in CAFs than in tumor cells; therefore, studies using CAFs as a model deserve more attention when exploring tumor molecular targets in clinical research.
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页数:20
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共 48 条
  • [1] User's guide to correlation coefficients
    Akoglu, Haldun
    [J]. TURKISH JOURNAL OF EMERGENCY MEDICINE, 2018, 18 (03): : 91 - 93
  • [2] Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: Significance in claudin-low breast cancer cells
    Alsuliman, Abdullah
    Colak, Dilek
    Al-Harazi, Olfat
    Fitwi, Hanaa
    Tulbah, Asma
    Al-Tweigeri, Taher
    Al-Alwan, Monther
    Ghebeh, Hazem
    [J]. MOLECULAR CANCER, 2015, 14
  • [3] The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis
    Asif, Paris Jabeen
    Longobardi, Ciro
    Hahne, Michael
    Medema, Jan Paul
    [J]. CANCERS, 2021, 13 (18)
  • [4] Targeting macrophages: therapeutic approaches in cancer
    Cassetta, Luca
    Pollard, Jeffrey W.
    [J]. NATURE REVIEWS DRUG DISCOVERY, 2018, 17 (12) : 887 - 904
  • [5] Tumor and its microenvironment: A synergistic interplay
    Catalano, Veronica
    Turdo, Alice
    Di Franco, Simone
    Dieli, Francesco
    Todaro, Matilde
    Stassi, Giorgio
    [J]. SEMINARS IN CANCER BIOLOGY, 2013, 23 (06) : 522 - 532
  • [6] High Expression of MYL9 Indicates Poor Clinical Prognosis of Epithelial Ovarian Cancer
    Deng, Yuao
    Liu, Longyang
    Feng, Weifeng
    Lin, Zhongqiu
    Ning, Yingxia
    Luo, Xin
    [J]. RECENT PATENTS ON ANTI-CANCER DRUG DISCOVERY, 2021, 16 (04) : 533 - 539
  • [7] Myosin light chain 9 promotes the proliferation, invasion, migration and angiogenesis of colorectal cancer cells by binding to Yes-associated protein 1 and regulating Hippo signaling
    Feng, Min
    Dong, Ningfei
    Zhou, Xin
    Ma, Lihong
    Xiang, Rui
    [J]. BIOENGINEERED, 2022, 13 (01) : 96 - 106
  • [8] A new aggressive xenograft model of human colon cancer using cancer-associated fibroblasts
    Fernando-Macias, Ester
    Teresa Fernandez-Garcia, Maria
    Garcia-Perez, Eva
    Porrero Guerrero, Belen
    Lopez-Arevalo, Camilo
    Rodriguez-Uria, Raquel
    Sanz-Navarro, Sandra
    Fernando Vazquez-Villa, Jose
    Carmen Muniz-Salgueiro, Maria
    Suarez-Fernandez, Laura
    Galvan, Jose A.
    Barneo-Caragol, Clara
    Garcia-Ocana, Marcos
    de los Toyos, Juan R.
    Barneo-Serra, Luis
    [J]. PEERJ, 2020, 8
  • [9] Decreased expression of myosin light chain MYL9 in stroma predicts malignant progression and poor biochemical recurrence-free survival in prostate cancer
    Huang, Ya-qiang
    Han, Zhao-dong
    Liang, Yu-xiang
    Lin, Zhuo-yuan
    Ling, Xiao-hui
    Fu, Xin
    Cai, Chao
    Bi, Xue-cheng
    Dai, Qi-shan
    Chen, Jia-hong
    He, Hui-chan
    Chen, Yan-ru
    Jiang, Fu-neng
    Zhong, Wei-de
    [J]. MEDICAL ONCOLOGY, 2014, 31 (01)
  • [10] Cancer-associated fibroblasts enhance cell proliferation and metastasis of colorectal cancer SW480 cells by provoking long noncoding RNA UCA1
    Jahangiri, Babak
    Khalaj-kondori, Mohammad
    Asadollahi, Elahe
    Sadeghizadeh, Majid
    [J]. JOURNAL OF CELL COMMUNICATION AND SIGNALING, 2019, 13 (01) : 53 - 64