Identification of miR-30e* regulation of Bmi1 expression mediated by tumor-associated macrophages in gastrointestinal cancer.
Identification of miR-30e* regulation of Bmi1 expression mediated by tumor-associated macrophages in gastrointestinal cancer.
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DOI：
10.1371/journal.pone.0081839
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Baba H
中科院分区：
文献类型：
--
作者：
Sugihara H;Ishimoto T;Watanabe M;Sawayama H;Iwatsuki M;Baba Y;Komohara Y;Takeya M;Baba H
Bmi1 在包括胃肠癌在内的多种人类癌症中过度表达。 Bmi1蛋白的高表达与胃肠道癌症患者的不良预后相关。另一方面，肿瘤相关巨噬细胞（TAM）通过在肿瘤微环境中产生各种介质来促进肿瘤生长、侵袭和转移。本研究的目的是探讨胃肠癌中 TAM 介导的 Bmi1 表达调节。通过免疫组织化学和实时定量PCR（qRT-PCR）分析TAM和Bmi1表达之间的关系，结果显示与肿瘤浸润巨噬细胞（CD68和CD163）和癌细胞中Bmi1表达呈正相关。与 TAM 共培养可触发癌细胞系中的 Bmi1 表达并增强球体形成能力。对与巨噬细胞共培养的胃癌细胞系进行 miRNA 微阵列分析，并使用计算机方法分析结果，我们确定 miR-30e* 是 Bmi1 表达的潜在调节因子。使用 miR-30e* 模拟物进行的荧光素酶测定表明，Bmi1 通过与 Bmi1 3' 非翻译区中推定的 miR-30e* 结合位点相互作用，成为 miR-30e* 的直接靶标。对切除的癌症标本进行qRT-PCR分析显示，与非肿瘤区域相比，肿瘤区域中miR-30e*表达量下调，并且胃癌组织中Bmi1表达量与miR-30e*表达量呈负相关，但结肠癌组织中Bmi1表达量与miR-30e*表达量不呈负相关。我们的研究结果表明，TAM 可能通过抑制 miR-30e* 导致 Bmi1 表达增加，从而导致肿瘤进展。因此，TAM 介导的 Bmi1 表达抑制可能是治疗胃肠癌的一种可能策略。
Bmi1 is overexpressed in a variety of human cancers including gastrointestinal cancer. The high expression level of Bmi1 protein is associated with poor prognosis of gastrointestinal cancer patients. On the other hand, tumor-associated macrophages (TAMs) contribute to tumor growth, invasion, and metastasis by producing various mediators in the tumor microenvironment. The aim of this study was to investigate TAM-mediated regulation of Bmi1 expression in gastrointestinal cancer. The relationship between TAMs and Bmi1 expression was analyzed by immunohistochemistry and quantitative real-time PCR (qRT-PCR), and results showed a positive correlation with tumor-infiltrating macrophages (CD68 and CD163) and Bmi1 expression in cancer cells. Co-culture with TAMs triggered Bmi1 expression in cancer cell lines and enhanced sphere formation ability. miRNA microarray analysis of a gastric cancer cell line co-cultured with macrophages was conducted, and using in silico methods to analyze the results, we identified miR-30e* as a potential regulator of Bmi1 expression. Luciferase assays using miR-30e* mimic revealed that Bmi1 was a direct target for miR-30e* by interactions with the putative miR-30e* binding sites in the Bmi1 3′ untranslated region. qRT-PCR analysis of resected cancer specimens showed that miR-30e* expression was downregulated in tumor regions compared with non-tumor regions, and Bmi1 expression was inversely correlated with miR-30e* expression in gastric cancer tissues, but not in colon cancer tissues. Our findings suggest that TAMs may cause increased Bmi1 expression through miR-30e* suppression, leading to tumor progression. The suppression of Bmi1 expression mediated by TAMs may thus represent a possible strategy as the treatment of gastrointestinal cancer.
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影响因子：
8
作者：
Schepeler, T.;Holm, A.;Andersen, C. L.
通讯作者：
Andersen, C. L.
影响因子：
30.8
作者：
Sangiorgi, Eugenio;Capecchi, Mario R.
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Capecchi, Mario R.
影响因子：
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作者：
Martinez, Fernando O.;Gordon, Siamon;Mantovani, Alberto
通讯作者：
Mantovani, Alberto
影响因子：
50.3
作者：
Rolny, Charlotte;Mazzone, Massimiliano;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
MicroRNA-218 通过下调 BMI1 多梳环指癌基因抑制结肠癌细胞周期进程并促进细胞凋亡
影响因子：
5.7
作者：
He, Xinqi;Dong, Yujuan;Yu, Jun
通讯作者：
Yu, Jun