Modulation of Cellular MicroRNA by HIV-1 in Burkitt Lymphoma Cells—A Pathway to Promoting Oncogenesis

Abstract

Viruses and viral components have been shown to manipulate the expression of host microRNAs (miRNAs) to their advantage, and in some cases to play essential roles in cancer pathogenesis. Burkitt lymphoma (BL), a highly aggressive B-cell derived cancer, is significantly over-represented among people infected with HIV. This study adds to accumulating evidence demonstrating that the virus plays a direct role in promoting oncogenesis. A custom miRNA PCR was used to identify 32 miRNAs that were differently expressed in Burkitt lymphoma cells exposed to HIV-1, with a majority of these being associated with oncogenic processes. Of those, hsa-miR-200c-3p, a miRNA that plays a crucial role in cancer cell migration, was found to be significantly downregulated in both the array and in single-tube validation assays. Using an in vitro transwell system we found that this downregulation correlated with significantly enhanced migration of BL cells exposed to HIV-1. Furthermore, the expression of the ZEB1 and ZEB2 transcription factors, which are promotors of tumour invasion and metastasis, and which are direct targets of hsa-miR-200c-3p, were found to be enhanced in these cells. This study therefore identifies novel miRNAs as role players in the development of HIV-associated BL, with one of these miRNAs, hsa-miR-200c-3p, being a candidate for further clinical studies as a potential biomarker for prognosis in patients with Burkitt lymphoma, who are HIV positive.

Carcinogenic mechanisms of virus-associated lymphoma

“…Viruses and their components manipulate the expression of host miRNAs and play important roles in cancer pathogenesis. Hsa-miR-200c-3p is significantly downregulated in HIV-associated BL, and the zinc finger E-box binding homeobox epithelial-mesenchymal transition (EMT) transcription factors ZEB1 and ZEB2 are upregulated and actively help to promote tumor metastasis and invasion ( 237 ). Moreover, miRNA-21 is significantly elevated in peripheral B cells of patients infected with HIV, suggesting that it might contribute to the maintenance of B cell hyperactivation ( 238 ).…”

Non-Coding RNAs in Human Health and Diseases

“…In a research paper by Murakami and colleagues, the downregulation of tumor suppressor miRNAs, miR-34a and miR-34b, and the p53 tumor suppressor gene was correlated with increased MYC oncogene expression in multiple myeloma patients [22]. Finally, Ramorola and colleagues characterized 32 miRNAs associated with HIV-1 exposed Burkitt-lymphoma cells, finding that there was, essentially, an even distribution between those that were downregulated and those that were upregulated (16 each) [23]. However, the exposure of Burkett's lymphomas cells to HIV-1 lead to the downregulation of miRNAs, such as miR-200c-3p, which has been shown by this group and others to have a tumor suppressor role.…”