Research Overview, Vison and Aim:
The Molecular Pathology Research Group (MPRG) and laboratory was established in 2007. Our main research emphasis is in translational medicine which encompasses pharmacogenomics and epigenetic regulation of the host immune response in Hepatocellular Carcinoma (HCC), Hepatitis C Virus (HCV) and Systemic Lupus Erythematosus (SLE). We are finally aiming at personalized medicine for Egyptian patients.
Systemic Lupus Erythematosus (SLE) is an autoimmune disease manifested by self-reactive antibodies due to failure of selection in both B and T lymphocytes leading to immune intolerance accompanied by increased rate of apoptosis and deficiency in the clearance of the apoptotic cells. We are interested in the molecular pathogenesis of pediatric/adult SLE. Our emphasis is mainly on the role of microRNAs (miRs) in SLE pathogenesis by screening and functional analysis of those small non-coding RNAs and their down-stream signaling pathways. We have recently demonstrated the downregulation of miR-181-a in children with SLE resulting in upregulation of the miR-181-a target gene P300/CBP-associated factor (PCAF). We proposed that upregulation of PCAF may impact ubiquitination levels of Hdm2, a negative regulator of tumor suppressor protein p53, resulting in the induction of apoptosis in children with SLE. We have also suggested, for the first time, a unique pattern of expression for miR-17-5-p and its downstream target E2F1 transcriptional factor, where both were downregulated with the reduction of E2F1 expression on both the mRNA and protein levels. This expression correlation is specific to SLE where it shows an inverse correlation in several cancers. We are currently extending our work by analyzing the impact of those microRNAs on the cell cycle and by functionally analyzing the B and T lymphocyte’s behavior after ex-vivo correction of microRNA expression.
Our research interests in hepatology are focused on the molecular pathology & pharmacogenomics of Hepatitis C Virus (HCV), with particular emphasis on epigenetics (microRNAs and genetic methylation). We are concerned with the microRNAs regulation of the cell surface receptors and the viral life cycle in the hepatocytes and peripheral blood lymphocytes (PBMCs), both in terms of the primary interaction of the virus with the host and with reference to the host-mediated immune response to HCV, which involves the release of interferon (IFN) and cytokines and the progression to hepatocellular carcinoma. We have recently shown the transcriptional induction of IFN-stimulated genes (ISGs) MxA and PKR during IFN treatment which may distinguish early virologic responders (EVRs) from non-EVRs in HCV genotype 4 patients. Furthermore, we clearly demonstrated that host genetic response to HCV varies between sexes with premenopausal women having the highest MxA expression. We denied any role of estrogen or progesterone in enhancing the genetic response to interferon. But we have shown that Tamoxifen alleviates the inhibition of the IFN signaling pathway in PBMCs of HCV-infected premenopausal females.
Currently, we are investigating the role of important microRNAs on the host response to HCV infection and on the viral life cycle. For that purpose we are using genotype 4-HCV-infected PBMCs as well as HCC cell replicons for Genotypes 2 and 4. We have shown that HCV infection might repress the induction of miR-146a and miR-155 by interfering with TLR-7 signaling.
Our research group is interested in the genetic/epigenetic regulation of Hepatocellular Carcinoma (HCC) mitogenic signaling pathways and its progression from HCV e.g. Insulin-like growth factor (IGF) signaling pathway and its role in the pathogenesis of HCC. We have highlighted the elevated expression of IGF-II in the PBMCs of HCC patients with the aberrant expression of its key regulators, matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinase-1 (TIMP-1). This was associated with a significant correlation between MMP-9 & TIMP-1 and different HCC stages. We have also designed cell models harboring important microRNAs and cell cycle proteins tagged with various reporter genes and we have investigated the impact of photodynamic therapy (PDT) on HCC. We showed that PDT decreases both viability and proliferation of Huh-7 cells while p53 levels show a significant increase following PDT.
We are currently studying the role of microRNAs on cell cycle induction/repression, as well their role in regulating several mitogenic signaling pathways, aiming for molecular-targeted therapies for HCC. We have proven, for the first time, that forcing the expression of miR-615-5p downregulates IGF-II mRNA, and also inhibits the luciferase activity in a luciferase reporter vector harboring the IGF-II-3’UTR target sequence. This highlights one of our novel findings that miR-615-5p acts as tumor-suppressor in HCC through targeting IGF-II.
HCV: gender variation in genetic response to interferon therapy
Epigenetic regulation and role of microRNAs in HCV replication and host genetic response to infection
Personalized response to therapy of genotype 4 HCV infection
New molecular targeted therapies for HCV infection
Role of microRNAs and their downstream genes/proteins in the pathogenesis of SLE
Role of microRNAs in the regulation of the expression of components of the insulin like-growth factor axis (IGF-II, IGF receptors & ligands) in HCC
Role of PDT in the regulation of cell cycle proteins in HCC