CTHRC1 in Ovarian Cancer Promotes M2-Like Polarization of Tumor-Associated Macrophages via Regulation of the STAT6 Signaling Pathway

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Abstract
Purpose: The infiltration of tumor-associated macrophages (TAMs) facilitates the progression of epithelial ovarian cancer (EOC). TAMs are mainly M2-like due to exposure to various factors in the tumor microenvironment. In our previous study, we reported that collagen triple helix repeat containing 1(CTHRC1), a secreted protein, is associated with ovarian cancer progression and metastasis. However, the correlation between CTHRC1 and the immunological microenvironment in EOC remains unknown. Methods: The association with the expression of CTHRC1 and CD68+CD163+ TAMs infiltration density and phosphorylation of STAT6 was analyzed in tumor tissues of ovarian cancer patients by immunohistochemistry. Western blot and flow cytometry analysis were used to analyze M2-like macrophage polarization induced by CTHRC1. Cell Counting Kit-8 and adhesion assays were used to detect cell proliferation and adhesion, respectively. Cell migration and invasion were detected using transwell assays. Results: In the present study, we observed that the overexpression of CTHRC1 and increased TAMs infiltration density are closely correlated to an advanced stage of EOC. Meanwhile, CTHRC1 expression was positively associated with the infiltration density of M2-like CD68+CD163+TAMs and phosphorylation of STAT6 in EOC. In human PBMC-derived monocytes, recombinant CTHRC1 protein (rCTHRC1) induces an M2-like macrophage phenotype, in a dose-dependent manner, characterized by activating the STAT6 signaling pathway. The conditioned culture medium of Lenti-CTHRC1 EOC cells promoted M2 polarization of macrophages, and by contrast, CTHRC1 knockdown abolished STAT6-mediated M2 polarization of macrophages. Moreover, the culture supernatants of rCTHRC1-treated macrophages efficiently increased the migration and invasion abilities of ovarian cancer cells. Conclusion: Our data indicate that CTHRC1 might play an important role in regulating M2 polarization of macrophages in the ovarian tumor microenvironment and suggest that it is a potential therapeutic target for antitumor immunity.

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