IGFBP7-AS1 is a p53-responsive long noncoding RNA downregulated by Epstein-Barr virus that contributes to viral tumorigenesis
IGFBP7-AS1 is a p53-responsive long noncoding RNA downregulated by Epstein-Barr virus that contributes to viral tumorigenesis
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DOI：
10.1016/j.canlet.2021.10.006
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发表时间：
2021-10-11
期刊：
影响因子：
9.7
通讯作者：
Lu, Jianhong
中科院分区：
文献类型：
--
作者：
Dang, Wei;Cao, Pengfei;Lu, Jianhong
eb病毒（EBV）与多种恶性肿瘤的发展密切相关，如b细胞淋巴瘤（B-CL），但这些恶性肿瘤发展的机制仍不清楚。我们之前观察到长链非编码RNA (lncRNA) IGFBP7-AS1在EBV感染反应中下调。然而，IGFBP7-AS1在ebv相关癌症中的作用尚未明确。本研究发现，IGFBP7- as1及其意义基因IGFBP7在ebv阳性B-CL细胞和临床组织中的表达降低。IGFBP7- as1通过基于IGFBP7重叠区域形成双工来稳定IGFBP7 mRNA。肿瘤抑制因子p53通过结合lncRNA基因的启动子区转录激活IGFBP7-AS1的表达。IGFBP7-AS1的表达能够在ebv阳性细胞中以野生型（wt） p53依赖的方式被拯救。IGFBP7-AS1抑制B-CL细胞增殖，促进B-CL细胞凋亡。此外，通过外源表达IGFBP7或wt-p53， IGFBP7- as1缺失导致的致瘤性特性得以恢复。此外，功能性p53/IGFBP7- as1 /IGFBP7轴通过抑制NPPB信号肽的产生和分泌，进而调控cGMP-PKG信号通路，促进细胞凋亡。该研究表明EBV通过下调新型p53应答lncRNA IGFBP7-AS1促进肿瘤发生，特别是在B-CL进展中。
Epstein-Barr virus (EBV) is closely related to the development of several malignancies, such as B-cell lymphoma (B-CL), by the mechanism through which these malignancies develop remains largely unknown. We previously observed downregulation of the long noncoding RNA (lncRNA) IGFBP7-AS1 in response to EBV infection. However, the role of IGFBP7-AS1 in EBV-associated cancers has not been clarified. Here, we found that expression of IGFBP7-AS1, as well as its sense gene IGFBP7, is decreased in EBV-positive B-CL cells and clinical tissues. IGFBP7-AS1 stabilizes IGFBP7 mRNA by forming a duplex based on their overlapping regions. The tumour suppressor p53 transcriptionally activates IGFBP7-AS1 expression by binding to the promoter region of the lncRNA gene. The IGFBP7-AS1 expression is able to be rescued in EBV-positive cells in wild-type (wt) p53dependent manner. IGFBP7-AS1 inhibits the proliferation and promotes the apoptosis of B-CL cells. Moreover, tumorigenic properties due to the depletion of IGFBP7-AS1 were restored by exogenous expression of IGFBP7 or wt-p53. Furthermore, the functional p53/IGFBP7-AS1/IGFBP7 axis facilitates apoptosis by suppressing the production and secretion of the NPPB signal peptide and further regulating the cGMP-PKG signalling pathway. This study demonstrates that EBV promotes tumorigenesis, particularly in B-CL progression, by downregulating the novel p53-responsive lncRNA IGFBP7-AS1.