MiR-15a/16-1 deficiency induces IL-10-producing CD19+ TIM-1+ cells in tumor microenvironment
MiR-15a/16-1 deficiency induces IL-10-producing CD19+ TIM-1+ cells in tumor microenvironment
复制标题
MiR-15a/16-1缺陷诱导肿瘤微环境中产生IL-10的CD19 TIM-1细胞
DOI：
10.1111/jcmm.14037
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发表时间：
2019-02-01
影响因子：
5.3
通讯作者：
Gong, Weijuan
中科院分区：
文献类型：
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作者：
Jia, Xiaoqin;Liu, Hao;Gong, Weijuan
产生IL-10的B细胞（B10）与自身免疫性疾病、感染和肿瘤相关。miR-15 a/16作为肿瘤抑制基因在几种肿瘤中下调，如慢性淋巴细胞白血病、垂体腺瘤和前列腺癌。在此，在发生B细胞白血病的老年miR-15 a/16（-/-）小鼠（15-18个月）和移植有肝癌细胞的年轻敲除小鼠（8-12周）中均观察到产生IL-10的CD 19（+）Tim-1（+）细胞的频率增加。CD 19（+）Tim-1（+）细胞下调效应CD 4（+）CD 25（低）T细胞的功能，依赖于IL-10的产生，并且过继转移CD 19（+）Tim-1（+）细胞促进小鼠肿瘤生长。CD 19（+）Tim-1（+）细胞IL-10的产生与STAT 3的激活有关。生物信息学分析表明，miR-16靶向STAT 3 mRNA的3 '-非翻译区（3'-UTR）。miR-16在CD 19（+）Tim-1（+）细胞中过表达抑制STAT 3的转录及其蛋白表达。因此，miR-15 a/16的缺失促进了肿瘤微环境中调节性CD 19（+）Tim-1（+）细胞的诱导。这些结果证实了miR-15 a/16由于其对肿瘤和调节性B细胞的抑制而可用于肿瘤治疗。
IL-10-producing B cells (B10) are associated with autoimmune diseases, infection and tumours. MiR-15a/16 as a tumour-suppressive gene is down-regulated in several tumours, such as chronic lymphocytic leukaemia, pituitary adenomas and prostate carcinoma. Here, increased frequency of IL-10-producing CD19(+) Tim-1(+) cells was seen in both aged miR-15a/16(-/-) mice (15-18 months) with the onset of B cell leukaemia and young knockout mice (8-12 weeks) transplanted with hepatic cancer cells. CD19(+) Tim-1(+) cells down-regulated the function of effector CD4(+) CD25(low) T cells ex vivo dependent on IL-10 production, and adoptive transfer of CD19(+) Tim-1(+) cells promoted tumour growth in mice. IL-10 production by CD19(+) Tim-1(+) cells was involved with the STAT3 activation. Bioinformatics analysis shows that miR-16 targets the 3'-untranslating region (3'-UTR) of STAT3 mRNA. Overexpression of miR-16 in CD19(+) Tim-1(+) cells inhibited STAT3 transcription and its protein expression. Thus, the loss of miR-15a/16 promoted induction of regulatory CD19(+) Tim-1(+) cells in tumour microenvironment. These results confirmed that miR-15a/16 could be used in tumour therapy due to its inhibition of tumour and regulatory B cells.