Theranostics 2022; 12(2):963-975. doi:10.7150/thno.65411 This issue

Research Paper

HMGA2 facilitates colorectal cancer progression via STAT3-mediated tumor-associated macrophage recruitment

Xin Wang1,2*, Jian Wang3*, Jiahui Zhao1,2, Hao Wang3, Jing Chen3, Jingjing Wu1,2✉

1. Department of Pathology & Pathophysiology, and Department of Colorectal Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2. Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, China.
3. Department of Colorectal Surgery and Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
* These authors contributed equally to this work.

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Citation:
Wang X, Wang J, Zhao J, Wang H, Chen J, Wu J. HMGA2 facilitates colorectal cancer progression via STAT3-mediated tumor-associated macrophage recruitment. Theranostics 2022; 12(2):963-975. doi:10.7150/thno.65411. Available from https://www.thno.org/v12p0963.htm

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Abstract

Graphic abstract

Rationale: Tumor-associated macrophages (TAMs), generally displaying the pro-tumor M2-like phenotype, strongly influence the progression of colorectal cancer (CRC) via their immunosuppressive activities. The high-mobility gene group A2 (HMGA2), an oncoprotein, is aberrantly overexpressed in CRC cells. However, the mechanisms by which tumor-derived HMGA2 modulates tumor microenvironment in CRC remain poorly understood.

Methods: In vivo subcutaneous tumor xenograft model, azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumor mouse model and in vitro co-culture assays were used to investigate the Hmga2 role in TAM recruitment and polarization. Luciferase and chromatin immunoprecipitation (ChIP) assays were applied to examine the mechanism of HMGA2-mediated transcriptional regulation of signal transducer and activator of transcription 3 (STAT3). The CD68 correlation with patient outcome was analyzed in 167 human CRC tissues.

Results: We found that HMGA2 in cancer cells promoted macrophage recruitment and M2 polarization in vitro and in vivo. HMGA2 directly bound to the STAT3 promoter to activate its transcription and subsequently induced CCL2 secretion, thus promoting macrophage recruitment. Our results from human CRC specimens also revealed a strong positive association between HMGA2 expression in tumor cells and CD68 expression in the stroma. We further showed that patients with an elevated CD68 expression had an unfavorable overall survival in all of the patients or in the subgroup with negative distant metastasis.

Conclusion: Our work uncovers new insight into the link between the HMGA2/STAT3/CCL2 axis and macrophage recruitment in CRC. These findings provide a novel therapeutic option for targeting the HMGA2/STAT3/CCL2 axis in CRC.

Keywords: colorectal cancer, HMGA2, STAT3, macrophages