ALKBH5 Inhibits Pancreatic Cancer Motility by Decreasing Long Non-Coding RNA KCNK15-AS1 Methylation
ALKBH5 Inhibits Pancreatic Cancer Motility by Decreasing Long Non-Coding RNA KCNK15-AS1 Methylation
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DOI：
10.1159/000491915
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Miao, Yi
中科院分区：
文献类型：
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作者：
He, Yuan;Hu, Hao;Miao, Yi
背景/目的：越来越多的证据表明，外转录修饰调节多种细胞过程。n -6-甲基腺苷（m(6)A）是mRNA中最丰富的可逆甲基化，在癌症发病中起关键作用。然而，长链非编码RNA （lncRNA）甲基化的机制和功能尚不清楚。2015年，全球有41.16万人死于胰腺癌。胰腺癌确诊时，转移往往发生在身体的其他部位。本研究旨在探讨lncRNA m(6)A修饰及其在胰腺癌中的作用。方法：评估癌细胞与匹配的正常细胞之间的差异表达，鉴定候选lncrna。利用RT-qPCR技术在肿瘤组织和各种胰腺细胞中检测到lncRNA KCNK15-AS1。将KCNK15-AS1转染到细胞中，探讨其在迁移和侵袭中的作用。然后，m(6)A RNA免疫沉淀检测组织和细胞中甲基化的KCNK15-AS1。上皮-间质转化（EMT）标志物用于评估kcnk15 - as1介导的EMT过程。结果：与配对的邻近正常组织相比，KCNK15-AS1在胰腺癌组织中表达下调。KCNK15-AS1抑制MIA PaCa-2和BxPC-3细胞的迁移和侵袭。此外，与人胰管上皮细胞（HPDE6-C7）相比，癌细胞中的总RNA甲基化显著增强。此外，m(6)A擦除剂ALKBH5在癌细胞中下调，可使KCNK15-AS1去甲基化，调节KCNK15-AS1介导的细胞运动。结论：我们的研究结果揭示了ALKBH5通过去甲基化lncRNA KCNK15-AS1抑制胰腺癌运动的新机制，确定了胰腺癌的潜在治疗靶点。(c) 2018年作者：s . Karger AG， Basel出版
Background/Aims: Mounting evidence suggests that epitranscriptional modifications regulate multiple cellular processes. N-6-Methyladenosine (m(6)A), the most abundant reversible methylation of mRNA, has critical roles in cancer pathogenesis. However, the mechanisms and functions of long non-coding RNA (lncRNA) methylation remain unclear. Pancreatic cancer resulted in 411,600 deaths globally in 2015. By the time of pancreatic cancer diagnosis, metastasis has often occurred in other parts of the body. The present study sought to investigate lncRNA m(6)A modification and its roles in pancreatic cancer. Methods: Differential expression between cancer cells and matched normal cells was evaluated to identify candidate lncRNAs. The lncRNA KCNK15-AS1 was detected in cancer tissues and various pancreatic cells using RT-qPCR. KCNK15-AS1 was transfected into cells to explore its role in migration and invasion. Then, m(6)A RNA immunoprecipitation was performed to detect methylated KCNK15-AS1 in tissues and cells. Epithelial-mesenchymal transition (EMT) markers were used to evaluate KCNK15-AS1-mediated EMT processes. Results: KCNK15-AS1 was downregulated in pancreatic cancer tissues compared with paired adjacent normal tissues. KCNK15-AS1 inhibited migration and invasion in MIA PaCa-2 and BxPC-3 cells. Furthermore, total RNA methylation in cancer cells was significantly enriched relative to that in immortalized human pancreatic duct epithelial (HPDE6-C7) cells. In addition, the m(6)A eraser ALKBH5 was downregulated in cancer cells, which can demethylate KCNK15-AS1 and regulate KCNK15-AS1-mediated cell motility. Conclusion: Our results have revealed a novel mechanism by which ALKBH5 inhibits pancreatic cancer motility by demethylating lncRNA KCNK15-AS1, identifying a potential therapeutic target for pancreatic cancer. (c) 2018 The Author(s) Published by S. Karger AG, Basel