HMGA2 facilitates colorectal cancer progression via STAT3-mediated tumor-associated macrophage recruitment.
HMGA2 facilitates colorectal cancer progression via STAT3-mediated tumor-associated macrophage recruitment.
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HMGA2 通过 STAT3 介导的肿瘤相关巨噬细胞募集促进结直肠癌进展
作者：
Wang X;Wang J;Zhao J;Wang H;Chen J;Wu J
基本原理：肿瘤相关巨噬细胞（TAM）通常表现为促肿瘤M2样表型，通过其免疫抑制活性强烈影响结直肠癌（CRC）的进展。高迁移率基因组A2（HMGA 2）是一种癌蛋白，在CRC细胞中异常过表达。然而，肿瘤源性HMGA 2调节CRC中肿瘤微环境的机制仍然知之甚少。研究方法：采用体内皮下肿瘤异种移植模型、氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的肿瘤小鼠模型和体外共培养试验来研究Hmga 2在TAM募集和极化中的作用。应用荧光素酶和染色质免疫沉淀（ChIP）分析来研究HMGA 2介导的信号转导子和转录激活子3（STAT 3）的转录调节机制。在167例人CRC组织中分析了CD 68与患者结局的相关性。结果：HMGA 2在体内外均能促进巨噬细胞的募集和M2的极化。HMGA 2直接结合到STAT 3启动子上以激活其转录，随后诱导CCL 2分泌，从而促进巨噬细胞募集。我们对人类CRC标本的研究结果也揭示了肿瘤细胞中HMGA 2表达与间质中CD 68表达之间的强正相关性。我们进一步发现，在所有患者或远处转移阴性的亚组中，CD 68表达升高的患者的总体生存率均不利。结论：我们的工作揭示了HMGA 2/STAT 3/CCL 2轴与CRC中巨噬细胞募集之间联系的新见解。这些发现为在CRC中靶向HMGA 2/STAT 3/CCL 2轴提供了新的治疗选择。
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.
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影响因子：
15.3
作者：
Muller, W A
通讯作者：
Muller, W A
影响因子：
7.3
作者：
Pan Y;Yu Y;Wang X;Zhang T
通讯作者：
Zhang T
影响因子：
8
作者：
Niu, GL;Wright, KL;Yu, H
通讯作者：
Yu, H
影响因子：
8
作者：
Kawada, M.;Seno, H.;Kanda, K.;Nakanishi, Y.;Akitake, R.;Komekado, H.;Kawada, K.;Sakai, Y.;Mizoguchi, E.;Chiba, T.
通讯作者：
Chiba, T.
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P