APOBEC3B expression is promoted by lincNMR collaborating with TGF-β-Smad pathway
APOBEC3B expression is promoted by lincNMR collaborating with TGF-β-Smad pathway
复制标题
lincNMR协同TGF-β-Smad通路促进APOBEC 3B表达
DOI：
10.1093/carcin/bgac086
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发表时间：
2022-11-06
期刊：
影响因子：
4.7
通讯作者：
Kitagawa, Masatoshi
中科院分区：
文献类型：
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作者：
Ota, Kosuke;Sakai, Satoshi;Kitagawa, Masatoshi
我们发现lincNMR的表达通过TGF-β-Smad途径被促进，并且lincNMR参与了与恶性肿瘤相关的胞苷脱氨酶APOBEC 3B的表达，长链非编码RNA（lncRNA）参与了肿瘤的发生和恶性肿瘤的发生。转化生长因子-β（TGF-β）参与各种细胞过程，包括癌症进展。我们进行了全面的RNA测序分析，以确定由TGF-β调节的lncRNA，并发现lincNMR（长基因间非编码RNA-核苷酸代谢调节因子，也被鉴定为MAP 3 K9-DT）在各种细胞系中由TGF-β诱导。在lincNMR/MAP 3 K9-DT基因座中存在lincNMR的几种变体（下文称为lincNMR），并且它们的表达通过TGF-β增加。TGF-β介导的lincNMR诱导通过Huh 7中Smad 2/3的耗尽而降低，表明TGF-β-Smad途径参与lincNMR表达。我们还发现APOBEC 3B而不是其他APOBEC家族成员是lincNMR的靶基因。APOBEC 3B是一种胞苷脱氨酶，促进C至U突变，并在多种人类癌症中高度表达。虽然它与癌症进展有关，但APOBEC 3B表达的调控机制尚未完全阐明。我们进行了RNA免疫沉淀测定，并证明lincNMR结合到Huh 7细胞中的内源性Smad 2。Smad 2/3过表达诱导的APOBEC 3B启动子活性的增加被lincNMR的耗尽所抑制。这些数据表明，lincNMR通过与TGF-β-Smad通路协作参与APOBEC 3B表达。在各种癌细胞系中，lincNMR的高表达与APOBEC 3B的高表达正相关。APOBEC 3B以及lincNMR的过表达在人类癌症如肝癌和肺癌中被发现，并且与它们的不良预后相关，这表明lincNMR可能通过增强APOBEC 3B的表达而导致肿瘤恶性。
We found that lincNMRexpression is promoted via TGF-beta-Smad pathway and that lincNMRparticipates in expression of APOBEC3B which is a cytidine deaminase associated with cancer malignancies.Long non-coding RNAs (lncRNAs) participate in carcinogenesis and cancer malignancies. Transforming growth factor-beta (TGF-beta) is involved in various cellular processes including cancer progression. We performed comprehensive RNA sequencing analyses to identify lncRNAs regulated by TGF-beta and found that lincNMR (long intergenic noncoding RNA-nucleotide metabolism regulator, also identified as MAP3K9-DT) was induced by TGF-beta in various cell lines. There are several variants of lincNMR (hereafter lincNMRs) in the lincNMR/MAP3K9-DT locus, and their expression was increased by TGF-beta. TGF-beta-mediated induction of lincNMRs was decreased by depletion of Smad2/3 in Huh7, suggesting that the TGF-beta-Smad pathway is involved in lincNMRs expression. We also found that APOBEC3B but not other APOBEC family members were a target gene of lincNMRs. APOBEC3B, a cytidine deaminase, promotes C to U mutation and highly expressed in various human cancers. Although it is associated with cancer progression, regulatory mechanisms of APOBEC3B expression have not been fully elucidated. We performed RNA immunoprecipitation assays and proved that lincNMRs bound to endogenous Smad2 in Huh7 cells. The increased activity of the promoter of APOBEC3B induced by overexpression of Smad2/3 was inhibited by depletion of lincNMRs. These data suggest that lincNMRs participate in APOBEC3B expression by collaborating with TGF-beta-Smad pathway. High expression of lincNMRs was positively correlated with high expression of APOBEC3B in various cancer cell lines. Overexpression of APOBEC3B as well as lincNMR was found in human cancers such as hepatic and lung cancers and was associated with their poor prognosis, suggesting that lincNMR may contribute to tumor malignancy via enhanced expression of APOBEC3B.