IGFBP7-AS1 is a p53-responsive long noncoding RNA downregulated by Epstein-Barr virus that contributes to viral tumorigenesis

• Published in: Cancer letters Vol. 523; pp. 135 - 147
• Main Authors: Dang, Wei, Cao, Pengfei, Yan, Qijia, Yang, Li, Wang, Yiwei, Yang, Jing, Xin, Shuyu, Zhang, Jing, Li, Jing, Long, Sijing, Zhang, Wentao, Zhang, Senmiao, Lu, Jianhong
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.12.2021; Elsevier Limited
• Subjects: Animals; Apoptosis; B-cell lymphoma; Binding sites; Breast cancer; Carcinogenesis; Cell cycle; Cell Line, Tumor; Cell proliferation; cGMP-PKG signalling; Colorectal cancer; Cyclic GMP; Cyclic GMP - physiology; Cyclic GMP-Dependent Protein Kinases - physiology; Down-Regulation; Epstein-Barr virus; Epstein-Barr Virus Infections - complications; Female; Genes; Genomes; Hepatitis; Herpesvirus 4, Human - pathogenicity; Humans; Hybridization; IGFBP7; Infections; Insulin-Like Growth Factor Binding Proteins - genetics; LncRNA; Lymphocytes B; Lymphoma; Lymphoma, B-Cell - etiology; Lymphoma, B-Cell - pathology; Lymphoma, B-Cell - virology; Mice; Mice, Inbred BALB C; NPPB; p53 Protein; Plasmids; Proteins; RNA viruses; RNA, Long Noncoding - physiology; Signal transduction; Transcription; Tumor suppressor genes; Tumor Suppressor Protein p53 - physiology; Tumorigenesis; Tumors; China; NPPB; LncRNA; IGFBP7; cGMP-PKG signalling; Apoptosis
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.10.006

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) p53-dependent 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. •IGFBP7-AS1 is a p53-responsive lncRNA downregulated by EBV in B-cell lymphoma.•IGFBP7-AS1 regulates IGFBP7 expression by stabilizing IGFBP7 mRNA.•IGFBP7 reduces the production and secretion of the signal peptide NPPB.•IGFBP7 promotes apoptosis via inhibiting NPPB-mediated cGMP/PKG pathway.