EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN

Abstract

The epithelial-mesenchymal transition (EMT) is crucial to cancer progression and metastasis. Although multiple cellular miRNAs have been identified to regulate the EMT and metastasis in cancers, the role of viral miRNAs in cancer progression remains largely unknown. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy typically characterized by its early metastasis. In the present study, we have discovered the involvement of a viral miRNA, EBV-miR-BART7-3p, in the EMT and metastasis of NPC cells. Initially, we observed that EBV-miR-BART7-3p was highly expressed in NPC and positively correlated with lymph node metastasis and clinical stage of NPC. Subsequently, we demonstrated that EBV-miR-BART7-3p enhanced cell migration/invasion in vitro, cancer metastasis in vivo, and particularly the EMT characterized by loss of epithelial markers and gain of mesenchymal features in NPC cells. Furthermore, mechanistic studies disclosed that EBV-miR-BART7-3p targeted a major human tumor suppressor PTEN, modulating PI3K/Akt/GSK-3β signaling and eventually leading to the high expression and nuclear accumulation of Snail and β-catenin, which favor EMT. Knockdown of PTEN could phenocopy the effect of EBV-miR-BART7-3p, whereas re-expression of PTEN resulted in a phenotypic reversion. Moreover, these findings were supported by an observation of an EBV-positive cell model in which silencing of endogenous EBV-miR-BART7-3p partially attenuated cell migration/invasion and altered EMT protein expression pattern via reverting PI3K/Akt, Snail and β-catenin expression. Thus, this study suggests a novel mechanism by which EBV-miR-BART7-3p modulates the EMT and metastasis of NPC cells, and a clinical implication of EBV-miR-BART7-3p as a potential biomarker or therapeutic target.

miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop modulated by PDCD4 suppresses cell growth, metastasis, and sensitizes nasopharyngeal carcinoma to cisplatin

“…EBV-positive NPC cell line HONE1 was kindly provided by Professor George SW Tsao from the University of Hong Kong. 15 shPDCD4-SUNE1, shPDCD4-HONE1 and miR-374a and PDCD4 in nasopharyngeal carcinoma Y Zhen et al…”

“…Immunohistochemistry Immunohistochemistry of CCND1 (Santa Cruz Biotechnology, Santa Cruz, USA) was performed in NPC tissues according to a previous description. 6,[12][13][14][15]34 Stained tissue sections were evaluated separately by two pathologists blinded to the clinical parameters. For cytoplasmic staining, scoring was assessed based on the sum of cytoplasm staining intensity and the percentage of positive staining areas of cells.…”

“…In recent studies, abnormal expression of miRNAs was broadly implicated in NPC pathogenesis. [12][13][14][15][16][17] However, the role of miR-374a in NPC still remains largely unknown.…”

Epstein-Barr Virus-Associated Gastric Carcinoma: Use of Host Cell Machineries and Somatic Gene Mutations

“…Subsequent experiments demonstrated that ebv-miR-BART4-5p regulates Bid expression in EBVaGC [65]. Cai et al [66] recently demonstrated in nasopharyngeal carcinoma that ebv-miR-BART7-3p, one of the most abundant viral miRNAs in EBVaGC, targets the tumor suppressor gene PTEN , and promotes epithelial-to-mesenchymal transition and tumor metastasis. …”

Small RNAs growing tall: miRNAs as drug targets in herpesvirus infections

“…EBV and KSHV miRNAs deregulate the cell cycle [27,28,30 ,81], inhibit apoptosis [27,28,30 ,41,42 ,82-85] and promote cell migration and metastasis [86][87][88], all hallmarks of cancer. Based on the current knowledge, therapies targeting induced cellular oncomiRs and their viral orthologues are warranted to treat not only EBVinduced and KSHV-induced tumors but also non-viral lymphoproliferative diseases (Figure 1).…”