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Integrative functional genomic delineation of the cascades of transcriptional changes involved in hepatocellular carcinoma progression
Author(s) -
Ramesh Vignesh,
Ganesan Kumaresan
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30195
Subject(s) - hepatocellular carcinoma , biology , cancer research , transcriptome , context (archaeology) , epigenetics , signal transduction , bioinformatics , computational biology , gene , gene expression , genetics , paleontology
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.