title: Integrative functional genomic delineation of the cascades of transcriptional changes involved in hepatocellular carcinoma progression.
abstract: Development of targeted therapeutics is still at its early stage for hepatocellular carcinoma (HCC) due to the incomplete understanding of the confounding regulations at signaling pathway level. In this investigation, gene co-expression-based networking and integrative functional genomic modeling of HCC mRNA profiles as signaling processes were employed to understand the complex signaling cascades involved in HCC development toward understanding the avenues for targeted therapeutics. Multiple sets of genes and molecular biological processes involved during HCC development were identified from this integrative analysis: (i) Loss of liver cellular features due to the reduced HNF4A & PPAR signaling in the early stages of HCC, (ii) activated inflammatory and stress signals in the cirrhosis stages and (iii) highly activated cellular proliferation with the activated E2F-MYC oncogenic signaling with the gain of embryonic liver stem cell-like features in the advanced stage tumors. Upon connecting these gene-sets with the established drug sensitivity-related gene signatures, targeted therapeutic strategies for the heterogeneous HCC conditions have been identified. PPAR agonist class of drugs for early stage HCC conditions, anti-inflammatory drugs for cirrhosis and topoisomerase inhibitors for the advanced HCC conditions were inferred. Integrative functional genomic analysis of HCC transcriptome profiles at the context of signaling pathways has defined the key molecular processes involved in HCC development. Further, the study highlights the stage-specific and pathway focused targeted therapeutics for HCC. These findings deserve extensive preclinical explorations toward the establishment of targeted therapeutics.
authors.affiliation: Cancer Genetics Laboratory, Department of Genetics, School of Biological Sciences, Madurai Kamaraj University, Madurai, India.
authors.forename: Vignesh
authors.initials: V
authors.lastname: Ramesh
authors.affiliation: Cancer Genetics Laboratory, Department of Genetics, School of Biological Sciences, Madurai Kamaraj University, Madurai, India.
authors.forename: Kumaresan
authors.initials: K
authors.lastname: Ganesan
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D012333:RNA, Messenger
keywords: embryonic liver; hepatocellular carcinoma; integrative genomics; liver development; network; signaling pathways