气候变化领域集成服务门户(CCPortal): Cellular microRNA-127-3p suppresses oncogenic herpesvirus-induced transformation and tumorigenesis via down-regulation of SKP2

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DOI	10.1073/pnas.2105428118
	Cellular microRNA-127-3p suppresses oncogenic herpesvirus-induced transformation and tumorigenesis via down-regulation of SKP2
	Lee S.M.; Kaye K.M.; Slack F.J.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:45
英文摘要	Kaposi's sarcoma-associated herpesvirus (KSHV) causes the endothelial tumor KS, a leading cause of morbidity and mortality in sub-Saharan Africa. KSHV-encoded microRNAs (miRNAs) are known to play an important role in viral oncogenesis; however, the role of host miRNAs in KS tumorigenesis remains largely unknown. Here, high-throughput small-RNA sequencing of the cellular transcriptome in a KS xenograft model revealed miR-127-3p as one of the most significantly down-regulated miRNAs, which we validated in KS patient tissues. We show that restoration of miR-127-3p suppresses KSHV-driven cellular transformation and proliferation and induces G1 cell cycle arrest by directly targeting the oncogene SKP2. This miR-127-3p-induced G1 arrest is rescued by disrupting the miR-127-3p target site in SKP2 messenger RNA (mRNA) using gene editing. Mechanistically, miR-127-3p-mediated SKP2 repression elevates cyclin-dependent kinase (CDK) inhibitor p21Cip1 and down-regulates cyclin E, cyclin A, and CDK2, leading to activation of the RB protein tumor suppressor pathway and suppression of the transcriptional activities of E2F and Myc, key oncoprotein transcription factors crucial for KSHV tumorigenesis. Consequently, metabolomics analysis during miR-127-3p-induced cell cycle arrest revealed significant depletion of dNTP pools, consistent with RB-mediated repression of key dNTP biosynthesis enzymes. Furthermore, miR-127-3p reconstitution in a KS xenograft mouse model suppresses KSHV-positive tumor growth by targeting SKP2 in vivo. These findings identify a previously unrecognized tumor suppressor function for miR-127-3p in KS and demonstrate that the miR-127-3p/SKP2 axis is a viable therapeutic strategy for KS. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Kaposi's sarcoma (KS); Kaposi's sarcoma-associated herpesvirus (KSHV); MiR-127; SKP2
语种	英语
scopus关键词	cyclin A; cyclin dependent kinase 2; cyclin dependent kinase inhibitor 1; cyclin E; deoxyribonucleoside triphosphate; messenger RNA; microRNA; microRNA 127 3p; Myc protein; retinoblastoma protein; S phase kinase associated protein 2; transcription factor E2F; unclassified drug; microRNA; MIRN127 microRNA, human; S phase kinase associated protein; SKP2 protein, human; animal experiment; animal model; animal tissue; Article; biosynthesis; cancer inhibition; cell proliferation; controlled study; down regulation; G1 phase cell cycle checkpoint; gene editing; gene function; gene repression; high throughput sequencing; human; human cell; Human herpesvirus 8; human tissue; in vitro study; in vivo study; Kaposi sarcoma; malignant transformation; mouse; mouse model; nonhuman; oncogene; protein targeting; RNA sequencing; signal transduction; SKP2 gene; virus carcinogenesis; animal; carcinogenesis; cell transformation; female; gene expression regulation; Human herpesvirus 8; metabolism; nude mouse; physiology; virology; Animals; Carcinogenesis; Cell Transformation, Neoplastic; Female; Gene Expression Regulation, Neoplastic; Herpesvirus 8, Human; Humans; Mice, Nude; MicroRNAs; S-Phase Kinase-Associated Proteins; Sarcoma, Kaposi
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/250996
作者单位	Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; Program in Virology, Division of Medical Sciences, Graduate School of Arts and Sciences, Harvard University, Cambridge, MA 02138, United States; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
推荐引用方式 GB/T 7714	Lee S.M.,Kaye K.M.,Slack F.J.. Cellular microRNA-127-3p suppresses oncogenic herpesvirus-induced transformation and tumorigenesis via down-regulation of SKP2[J],2021,118(45).
APA	Lee S.M.,Kaye K.M.,&Slack F.J..(2021).Cellular microRNA-127-3p suppresses oncogenic herpesvirus-induced transformation and tumorigenesis via down-regulation of SKP2.Proceedings of the National Academy of Sciences of the United States of America,118(45).
MLA	Lee S.M.,et al."Cellular microRNA-127-3p suppresses oncogenic herpesvirus-induced transformation and tumorigenesis via down-regulation of SKP2".Proceedings of the National Academy of Sciences of the United States of America 118.45(2021).