Effects of LMP1 protein of Epstein-Barr virus isolates B95-8 and M81 in the invasive potential of human carcinoma cells, and regulation of endogenous miRNAs and proteins implicated in cancer progression

Abstract

The Epstein-Barr virus (EBV) is a gammaherpesvirus associated with the development of different human cancers, notably the endemic Burkitt lymphoma and nasopharyngeal carcinoma, as well as a subset of cases of Hodgkin's lymphoma, gastric carcinoma, and some non-Hodgkin lymphomas, particularly in immunocompromised individuals. The carcinogenic potential of the virus is attributed to the activity of different viral products expressed in the infected cell, particularly LMP1, a transmembrane protein expressed in most malignant cells latently infected with EBV. LMP1 exhibits oncogenic properties by activation of several intracellular signaling pathways, notably NF-kB. It has been demonstrated that epithelial cells in vitro expressing LMP1 exhibit enhanced cell motility and increased rates of invasion, key phenomena for cancer progression. Thus, it is assumed that LMP1 may affect the biological aggressiveness of the cancers associated with EBV. It is known that different EBV isolates may exhibit unique biological properties: the M81 isolated, for instance, has higher tropism for epithelial cells and high spontaneous lytic reactivation compared to B95.8. However, it is unknown whether the LMP1 variants derived from these isolates have different properties regarding phenomena and molecules relevant to cancer progression. Therefore, this study aims to investigate whether human carcinoma cells expressing LMP1 from the M81 and B95.8 isolates differ in terms of the rates of cell invasion in vitro or in respect to the expression of known regulators of tumor progression, such as the endogenous microRNAs members of the miR-200 family and the miR-21, as well as proteins involved in the FAK, PI3K/AKT, and NF-kB signaling pathways, and in the epithelial-mesenchymal transition (EMT) program. (AU)