RNA demethylase ALKBH5 promotes ovarian carcinogenesis in a simulated tumour microenvironment through stimulating NF-κB pathway
RNA demethylase ALKBH5 promotes ovarian carcinogenesis in a simulated tumour microenvironment through stimulating NF-κB pathway
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DOI：
10.1111/jcmm.15228
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发表时间：
2020-04-24
影响因子：
5.3
通讯作者：
Cheng, Wenjun
中科院分区：
文献类型：
--
作者：
Jiang, Yi;Wan, Yicong;Cheng, Wenjun
甲基化是RNA修饰的主要形式。n6 -甲基腺嘌呤（m6A）调控mRNA的剪接和翻译。Alk B同源物5 （ALKBH5）参与多种癌症的生物学调控。然而，其在卵巢癌发生中的作用尚未被揭示。在本研究中，ALKBH5在卵巢癌组织中的表达高于正常卵巢组织，但在卵巢癌细胞系中的表达低于正常卵巢细胞系。有趣的是，toll样受体（TLR4），肿瘤微环境（TME）中的分子功能，也表现出相同的表达趋势。为了研究TME异常对卵巢癌发生的影响，我们建立了巨噬细胞与卵巢癌细胞共培养的体外模型。在与M2巨噬细胞共培养的卵巢癌细胞中，ALKBH5和TLR4的表达增加。我们还验证了TLR4通过激活NF-kappa B通路上调ALKBH5的表达。通过转录组测序、m6A- seq和m6A MeRIP，我们发现NANOG是alkbh5介导的m6A修饰的靶标。在mRNA去甲基化后，NANOG表达增加，从而增强卵巢癌细胞的侵袭性。综上所述，高表达的TLR4激活了NF-kappa B通路，上调了ALKBH5的表达，增加了m6A水平和NANOG的表达，这些都参与了卵巢癌的发生。我们的研究揭示了m6A在卵巢癌发生中的作用，为发明新的靶向治疗提供了线索。
Methylation is the main form of RNA modification. N6-methyladenine (m6A) regulates the splicing and translation of mRNA. Alk B homologue 5 (ALKBH5) participates in the biological regulation of various cancers. However, its role in ovarian carcinogenesis has not been unveiled. In the present study, ALKBH5 showed higher expression in ovarian cancer tissue than in normal ovarian tissue, but lower expression in ovarian cancer cell lines than in normal ovarian cell lines. Interestingly, Toll-like receptor (TLR4), a molecular functioning in tumour microenvironment (TME), demonstrated the same expression trend. To investigate the effect of abnormal TME on ovarian carcinogenesis, we established an in vitro model in which macrophages and ovarian cancer cells were co-cultured. In the ovarian cancer cells co-cultured with M2 macrophages, the expression of ALKBH5 and TLR4 increased. We also verified that TLR4 up-regulated ALKBH5 expression via activating NF-kappa B pathway. Depending on transcriptome sequencing, m6A-Seq and m6A MeRIP, we found that NANOG served as a target in ALKBH5-mediated m6A modification. NANOG expression increased after mRNA demethylation, consequently enhancing the aggressiveness of ovarian cancer cells. In conclusion, highly expressed TLR4 activated NF-kappa B pathway, up-regulated ALKBH5 expression and increased m6A level and NANOG expression, all contributing to ovarian carcinogenesis. Our study revealed the role of m6A in ovarian carcinogenesis, providing a clue for inventing new target therapy.