Quercetin Inhibits Colorectal Cancer Progression By Regulating The Polarization Of Tumor-associated Macrophages Via The FAM198B Signaling Pathway

Objective Colorectal cancer(CRC)is a prevalent gastrointestinal malignancy,ranking third in morbidity and second in mortality globally.Despite significant progress in treatment due to modern medicine,the mortality rate remains high,primarily due to metastasis.Macrophages are crucial in tumorigenesis,development,and remodeling of the immunosuppressive environment in the tumor microenvironment.Targeting tumorassociated macrophages(TAMs)to explore new therapeutic strategies for CRC is a promising avenue of research.This study aimed to investigate the role of FAM198B in the polarization change of TAMs and its effect on CRC cells.The findings suggest that quercetin can regulate TAM polarization and inhibit CRC progression by targeting FAM198B through a molecular mechanism.The results of this study are expected to provide new targets and potential drugs for the treatment of colorectal cancer,which has important theoretical significance and practical value.Methods Bioinformatics was used to analyze the enrichment degree of macrophages in colorectal cancer tissues,and to study the correlation between increased expression of FAM198B in macrophages and poor prognosis.siRNA interference and plasmid overexpression were used to interfere with the level of FAM198B,and the function of FAM198B in macrophages was explored in combination with CCK-8 detection of cell activity,flow cytometry detection of cell cycle and phenotypic changes,and vascular mimicry test.Cytokine induced macrophage polarity change,combined with siRNA intervention of FAM198B level,flow cytometry CD 163/206,Elisa detection of M2type related cytokines,to study the relationship between FAM198B and M2-type polarization of macrophages.The co-culture system was used to study the influence of macrophages on the migration,invasion and clonogenesis of tumor cells under different levels of FAM198B,and to study the correlation between the expression level of FAM198B in macrophages and the metastasis ability of colorectal cancer cells.Bioinformatics predicted the possible signaling pathways and key proteins regulated by FAM198B and investigated the molecular mechanism of FAM198B regulating macrophage polarization by rescue test.Results Bioinformatics analysis showed that increased macrophage FAM198B expression was associated with poor prognosis in colorectal cancer.Protein electrophoresis and flow cytometry were used to detect phenotypic markers of macrophages.The results showed that after FAM198B knockdown,macrophages had decreased cell activity,prolonged cell cycle and decreased angiogenesis ability.It was also found that knockout FAM198B blocked cytokine induced M2 phenotype polarization in macrophages,and CD163/206 expression was decreased,inhibiting M2type polarization in macrophages.The co-culture system showed that the level of FAM198B in macrophages was positively correlated with the ability of tumor cell migration,invasion and clonogenesis,and the high expression of FAM198B in macrophages promoted the metastasis of colorectal cancer cells.Rescue experiments clarified the molecular mechanism of FAM198B regulating macrophage polarization by targeting SMAD2 pathway and quercetin inhibiting FAM198B expression,thus blocking macrophage M2 type polarization.Conclusion Quercetin inhibits the expression of FAM198B mRNA and protein,blocks FAM198B from regulating M2 polarization of macrophages through SMAD2 pathway,and delay the progression of colorectal cancer.