Abstract
Cancer stem-like cells, possessing “stemness” properties, play crucial roles in progression, metastasis, and drug resistance in various cancers. Viral microRNAs (such as EBV-miR-BART7-3p), as exogenous regulators, have been discovered to regulate malignant progression of nasopharyngeal carcinoma (NPC), suggesting a possible role of viral microRNAs in imposing stemness. In this study, we found that EBV-miR-BART7-3p induce stemness of NPC cells. We firstly reported that EBV-miR-BART7-3p increased the percentage of side population cells, the development of tumor spheres, and the expression level of stemness markers in vitro. This viral microRNA also enhanced stem-like or cancer-initiating properties of NPC cells in vivo. Besides, we identified SMAD7 as a novel target gene of EBV-miR-BART7-3p in addition to PTEN gene we previously reported; this viral microRNA suppressed SMAD7, led to activation of TGF-β signaling, and eventually enhanced the stemness of NPC cells. Silencing of SMAD7 resembled the effects generated by EBV-miR-BART7-3p in NPC cells. After reconstitution of SMAD7, EBV-miR-BART7-3p-expressing cells underwent a phenotypic reversion. EBV-positive NPC cells were used to enable experimental validation. Finally, we further discovered that EBV-miR-BART7-3p increased chemo-resistance of NPC in vitro and in vivo, supporting that EBV-miR-BART7-3 resulted in increased stemness of NPC cells and lead to drug resistance and cancer recurrence. Overall, this study uncovered a novel mechanism underlying viral microRNA-associated stemness of NPC cells. This viral microRNA and its associated cellular genes may be potential therapeutic targets for restraining chemo-resistance and recurrence of NPC.
Highlights
Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy arising from the nasopharynx
We first detected the presence of side population (SP) cells, which were reported as primitive stem cell-like populations, in the control and miR-BART7-3poverexpressing cells
The results showed that stable expression of EBV-miR-BART7-3p increased the percentage of SP cells (Figure 1A)
Summary
Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy arising from the nasopharynx. There is an unbalanced distribution of its morbidity in different regions of the world with a high incident rate of approximately 30 per 100,000 being observed in Southern China, Southeast Asia and North Africa (Spano et al, 2003; Cho, 2010). EBV-miR-BART7-3p Imposes Stemness in NPC (CCRT) are the preferential treatments for NPC. Despite improved diagnostic and therapeutic strategies, 30–60% of NPC progresses to be a recurrent and chemoradiotherapy-resistant disease. The “stemness” refers to the integrated functioning of molecular programs that govern and maintain the stem cell state. Cancer stem-like cells are a small population of cells within tumor holding “stemness” properties that facilitate tumor growth, invasion, and treatment failure (Aponte and Caicedo, 2017).
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