Abstract
BackgroundCartilage oligomeric matrix protein (COMP) is known to promote fibrosis in skin, lung and liver. Emerging evidence shows that COMP plays critical roles in tumor development, including breast cancer, colon cancer and hepatocellular carcinoma (HCC). Nevertheless, the role of COMP in HCC proliferation and metastasis and its underlying mechanisms remain fully unclear.MethodsSerum COMP was determined by ELISA. Cell Counting Kit-8 and plate colony formation were performed to evaluate cell proliferation. Wound healing and transwell assays were used to determine migration and invasion of HCC cells. Western blotting and immunofluorescence were carried out for detection of epithelial-to-mesenchymal transition (EMT) markers and MMPs in HCC cells. The in vivo role of COMP was evaluated using mouse models. We also measured effects of hepatic stellate cells (HSCs)-conditioned medium (CM) on HCC progression using transwell coculture system.ResultsHere, we found that serum COMP levels in HCC patients were significantly higher than those in healthy controls. Accordingly, high serum COMP levels in HCC patients significantly correlated with malignant clinical characteristics and poor clinical outcomes. Next, we investigated that recombinant human COMP protein (rCOMP) treatment resulted in increased abilities of proliferation, invasion and migration of HCC cells. Furthermore, rCOMP treatment enhanced proliferative and metastatic colonization of HCC cells in vivo. Mechanistically, CD36 receptor played an essential role in COMP-mediated HCC cell proliferation and metastasis. Functionally, COMP/CD36 signaling caused phosphorylation of ERK and AKT, resulting in the upregulation of tumor-progressive genes such as EMT markers, MMP-2/9, Slug and Twist in HCC cells. Interestingly, we revealed that COMP was secreted by HSCs. CM of LX2 cells with COMP knockdown showed weaker effects on the activation of MEK/ERK and PI3K/AKT signaling pathways in HCC cells compared to control CM.ConclusionsOur findings indicated that HSCs-derived COMP collaborated with CD36 and subsequently played an essential role in MEK/ERK and PI3K/AKT-mediated HCC progression. COMP might act as a promising target for the diagnosis and treatment of aggressive HCC.
Highlights
Cartilage oligomeric matrix protein (COMP) is known to promote fibrosis in skin, lung and liver
Increased serum level of COMP is associated with poor clinicopathological features and clinical outcomes of hepatocellular carcinoma (HCC) patients Our Enzyme-linked immunosorbent assay (ELISA) data showed that the serum content of COMP in the 100 HCC samples ranged from 41.9 ng/ml to 494.3 ng/ml with a median of 170.7 ng/ml
Serum COMP level ranged from 44.2 ng/ml to 270.3 ng/ ml with a median of 127.1 ng/ml in the 30 healthy controls, and a significant difference was observed between HCCs and healthy controls (P = 0.0115, Fig. 1a)
Summary
Cartilage oligomeric matrix protein (COMP) is known to promote fibrosis in skin, lung and liver. Cartilage oligomeric matrix protein (COMP), a cartilage metabolism marker, is an extracellular matrix protein that modulates the cellular phenotype during tissue genesis and remodeling. It has been extensively studied for its pro-fibrosis potential against various internal organs, for instance, pulmonary fibrosis [3], and liver cirrhosis [4]. Recent studies have shown that COMP promotes the progression of breast cancer, colon cancer and prostate cancer [7,8,9] These results suggest that COMP may be an important pro-HCC molecule, but the mechanism by which COMP plays a role in HCC still needs to be further studied
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