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

Wei Dang; Pengfei Cao; Qijia Yan; Li Yang; Yiwei Wang; Jing Yang; Shuyu Xin; Jing Zhang; Jing Li; Sijing Long; Wentao Zhang; Senmiao Zhang; Jianhong Lu

doi:10.1016/j.canlet.2021.10.006

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

Cancer Lett. 2021 Dec 28:523:135-147. doi: 10.1016/j.canlet.2021.10.006. Epub 2021 Oct 8.

Authors

Wei Dang¹, Pengfei Cao², Qijia Yan³, Li Yang¹, Yiwei Wang¹, Jing Yang⁴, Shuyu Xin⁵, Jing Zhang¹, Jing Li¹, Sijing Long¹, Wentao Zhang¹, Senmiao Zhang¹, Jianhong Lu⁶

Affiliations

¹ Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China.
² Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China.
³ Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China.
⁴ NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China.
⁵ Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China.
⁶ Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China. Electronic address: jianhlu@csu.edu.cn.

PMID: 34634383
DOI: 10.1016/j.canlet.2021.10.006

Abstract

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.

Keywords: Apoptosis; IGFBP7; LncRNA; NPPB; cGMP-PKG signalling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Carcinogenesis
Cell Line, Tumor
Cyclic GMP / physiology
Cyclic GMP-Dependent Protein Kinases / physiology
Down-Regulation
Epstein-Barr Virus Infections / complications*
Female
Herpesvirus 4, Human / pathogenicity*
Humans
Insulin-Like Growth Factor Binding Proteins / genetics*
Lymphoma, B-Cell / etiology*
Lymphoma, B-Cell / pathology
Lymphoma, B-Cell / virology
Mice
Mice, Inbred BALB C
RNA, Long Noncoding / physiology*
Tumor Suppressor Protein p53 / physiology*

Substances

Insulin-Like Growth Factor Binding Proteins
RNA, Long Noncoding
TP53 protein, human
Tumor Suppressor Protein p53
insulin-like growth factor binding protein-related protein 1
Cyclic GMP-Dependent Protein Kinases
Cyclic GMP