Journal
CELL DEATH & DISEASE
Volume 13, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-021-04461-6
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Funding
- National Natural Science Foundation of China [81972818, 82003163, 81972212, 82003197]
- Fundamental Research Funds for the Central Universities, Sun Yat-Sen University [20ykzd01]
- Key-Area Research and Development Program of Guangdong Province [2019B020229002]
- Science & Technology program of Guangdong Province [2021A0505030028]
- National Key Clinical Discipline of China
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Cancer-associated fibroblasts (CAFs) play a crucial role in colorectal cancer (CRC) metastasis by inducing the expression of Leucine Rich Alpha-2-Glycoprotein 1 (LRG1), which promotes CRC migration and invasion through epithelial-mesenchymal transition (EMT). The CAFs-mediated IL-6-STAT3-LRG1 axis is responsible for the up-regulation of LRG1 in CRC, and higher LRG1 expression predicts poor clinical outcomes, especially distant metastasis free survival in CRC patients.
Cancer-associated fibroblasts (CAFs) have been shown to play a strong role in colorectal cancer metastasis, yet the underlying mechanism remains to be fully elucidated. Using CRC clinical samples together with ex vivo CAFs-CRC co-culture models, we found that CAFs induce expression of Leucine Rich Alpha-2-Glycoprotein 1(LRG1) in CRC, where it shows markedly higher expression in metastatic CRC tissues compared to primary tumors. We further show that CAFs-induced LRG1 promotes CRC migration and invasion that is concomitant with EMT (epithelial-mesenchymal transition) induction. In addition, this signaling axis has also been confirmed in the liver metastatic mouse model which displayed CAFs-induced LRG1 substantially accelerates metastasis. Mechanistically, we demonstrate that CAFs-secreted IL-6 (interleukin-6) is responsible for LRG1 up-regulation in CRC, which occurs through a direct transactivation by STAT3 following JAK2 activation. In clinical CRC tumor samples, LRG1 expression was positively correlated with CAFs-specific marker, alpha-SMA, and a higher LRG1 expression predicted poor clinical outcomes especially distant metastasis free survival, supporting the role of LRG1 in CRC progression. Collectively, this study provided a novel insight into CAFs-mediated metastasis in CRC and indicated that therapeutic targeting of CAFs-mediated IL-6-STAT3-LRG1 axis might be a potential strategy to mitigate metastasis in CRC.
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