FAM198B promotes colorectal cancer progression by regulating the polarization of tumor-associated macrophages via the SMAD2 signaling pathway

Abstract

Colorectal cancer (CRC) is one of the most common malignant tumors. Tumor-associated macrophages (TAMs) promote the progression of CRC, but the mechanism is not completely clear. The present study aimed to reveal the expression and function of FAM198B in TAMs, and the role of FAM198B in mediating macrophage polarization in CRC. The role of FAM198B in macrophage activity, cell cycle, and angiogenesis was evaluated by CCK-8 assay, flow cytometry, and vasculogenic mimicry assay. The effects of FAM198B on macrophage polarization were determined by flow cytometry. The function of FAM198B-mediated macrophage polarization on CRC progression was evaluated by transwell assays. Bioinformatic analyses and rescue assays were performed to identify biological functions and signaling pathways involved in FAM198B regulation of macrophage polarization. Increased FAM198B expression in TAMs is negatively associated with poor CRC prognosis. Functional assays showed that FAM198B promotes M2 macrophage polarization, which leads to CRC cell proliferation, migration, and invasion. Mechanistically, FAM198B regulates the M2 polarization of macrophages by targeting SMAD2, identifying the SMAD2 pathway as a mechanism by which FAM198B promotes CRC progression through regulating macrophage polarization. These findings provide a possible molecular mechanism for FAM198B in TAMs in CRC and suggest that FAM198B may be a novel therapeutic target in CRC.

Correlation between SMADs and Colorectal Cancer Expression, Prognosis, and Immune Infiltrates

“…In colorectal cancer, the tumor suppressor gene NIT1 is realized by activating the SMAD2/3 signaling pathway [23]. SMAD2 can promote the development of CRC by regulating the polarization of tumor macrophages [24]. In this study, SMAD2 expression in CRC was low, which was SMAD3 plays the dual role of oncogene and tumor suppressor gene in tumor formation, and can be used as a prognostic marker for tumors [22].…”

Role of CELF2 in ferroptosis: Potential targets for cancer therapy (Review)

“…FAM198B also functions in the tumour microenvironment. For example, Zheng et al ( 53 ) observed that the expression level of FAM198B in macrophages of colon cancer tissues correlated with patient prognosis. FAM198B regulates M2 polarisation in macrophages and promotes colon cancer progression by targeting SMAD2 ( 53 ).…”

“…For example, Zheng et al ( 53 ) observed that the expression level of FAM198B in macrophages of colon cancer tissues correlated with patient prognosis. FAM198B regulates M2 polarisation in macrophages and promotes colon cancer progression by targeting SMAD2 ( 53 ). Existing research demonstrates that FAM198B exerts its tumour-suppressive effects mainly by inhibiting the ERK/MAPK pathway ( 51 , 52 ); however, the exact mechanisms involved remain elusive.…”

Regulation of secretory pathway kinase or kinase-like proteins in human cancers

“…However, recent reports showed that FAM198B can also promote colorectal cancer (CRC) progression ( 99 ). The upregulation of FAM198B was found in macrophages and was considered associated with the poor prognosis of CRC.…”