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

Xiaoxiao Zheng; Jiabin Chen; Tianhao Nan; Li Zheng; Jiahua Lan; Xiaoqin Jin; Ying Cai; Hao Liu; Wei Chen

doi:10.1080/21655979.2022.2075300

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

Bioengineered. 2022 May;13(5):12435-12445. doi: 10.1080/21655979.2022.2075300.

Authors

Xiaoxiao Zheng^{1

2}, Jiabin Chen², Tianhao Nan¹, Li Zheng², Jiahua Lan², Xiaoqin Jin³, Ying Cai², Hao Liu², Wei Chen^{1

2}

Affiliations

¹ College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
² Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, China.
³ Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.

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.

Keywords: Colorectal cancer (CRC); FAM198B; SAMD2; macrophage polarization; tumor-associated macrophages (TAMs).

MeSH terms

Cell Line, Tumor
Cell Proliferation / genetics
Colorectal Neoplasms* / metabolism
Humans
Signal Transduction / genetics
Smad2 Protein / genetics
Smad2 Protein / metabolism
Tumor Microenvironment
Tumor-Associated Macrophages*

Substances

SMAD2 protein, human
Smad2 Protein

Grants and funding

This work was supported by the Zhejiang Provincial Nature Science Foundation of China (LR20H160001 to Wei Chen, LQ21H290003 to Jiabin Chen), the Key R&D Projects of Zhejiang Province (2021C03012 to Wei Chen), the Young Qihuang Scholar of National Administration of Traditional Chinese Medicine (to Wei Chen), the Zhejiang Provincial Ten Thousand Plan for Young Top Talents (to Wei Chen), the Training Objects of Health Innovative Talents of Zhejiang Health (to Wei Chen), the Key Project Co-constructed by Zhejiang Province and Ministry (WKJ-ZJ-1916 to Wei Chen), the Natural Science Foundation of China (81972693, 81802383, 81972674, 81973654 and 31900543), the Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project (2020ZZ004 to Wei Chen), and the Zhejiang Provincial Traditional Chinese Medicine Outstanding Young Talents Fund Project (2021ZQ016 to Jiabin Chen).