EBV–encoded miRNAs can sensitize nasopharyngeal carcinoma to chemotherapeutic drugs by targeting BRCA1
| Autor: | Lok-Man Ip, Lau-Ying Chung, Ka Fai To, Raymond W.M. Lung, Sai Wah Tsao, Kwok Wai Lo, Joanna H.M. Tong, Anthony W.H. Chan, Kin-Mang Lau, Shuk-Ling Chau, Walter Wai Yeung, Wing-Po Chak, Pok Man Hau, Ka-Hei Lam |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Epstein-Barr Virus Infections Herpesvirus 4 Human DNA repair DNA damage Epstein‐Barr virus Biology medicine.disease_cause Mice 03 medical and health sciences 0302 clinical medicine Genes Reporter Cell Line Tumor microRNA medicine Animals Humans miR‐BARTs Cisplatin Nasopharyngeal Carcinoma BRCA1 Protein Cell Cycle Cancer Nasopharyngeal Neoplasms Original Articles Cell Biology BRCA1 medicine.disease Immunohistochemistry Epstein–Barr virus Gene Expression Regulation Neoplastic MicroRNAs 030104 developmental biology Nasopharyngeal carcinoma Drug Resistance Neoplasm 030220 oncology & carcinogenesis Host-Pathogen Interactions Cancer research RNA Viral Molecular Medicine RNA Interference Original Article Ectopic expression medicine.drug |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| ISSN: | 1582-4934 1582-1838 |
| DOI: | 10.1111/jcmm.16007 |
| Popis: | Nasopharyngeal carcinoma (NPC) is an Epstein‐Barr virus (EBV)‐associated epithelial malignancy. The high expression of BART‐miRNAs (miR‐BARTs) during latent EBV infection in NPC strongly supports their pathological importance in cancer progression. Recently, we found that several BART‐miRNAs work co‐operatively to modulate the DNA damage response (DDR) by reducing Ataxia‐telangiectasia‐mutated (ATM) activity. In this study, we further investigated the role of miR‐BARTs on DDR. The immunohistochemical study showed that the DNA repair gene, BRCA1, is consistently down‐regulated in primary NPCs. Using computer prediction programs and a series of reporter assays, we subsequently identified the negative regulatory role of BART2‐3p, BART12, BART17‐5p and BART19‐3p in BRCA1 expression. The ectopic expression of these four miR‐BARTs suppressed endogenous BRCA1 expression in EBV‐negative epithelial cell lines, whereas BRCA1 expression was enhanced by repressing endogenous miR‐BARTs activities in C666‐1 cells. More importantly, suppressing BRCA1 expression in nasopharyngeal epithelial cell lines using miR‐BART17‐5p and miR‐BART19‐3p mimics reduced the DNA repair capability and increased the cell sensitivity to the DNA‐damaging chemotherapeutic drugs, cisplatin and doxorubicin. Our findings suggest that miR‐BARTs play a novel role in DDR and may facilitate the development of effective NPC therapies. |
| Databáze: | OpenAIRE |
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