Functional and Topological Properties in Hepatocellular Carcinoma Transcriptome

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality. However, little is known about the precise molecular mechanisms involved in tumor formation and pathogenesis. The primary goal of this study was to elucidate genome-wide molecular networks involved in development of HCC with multiple etiologies by exploring high quality microarray data. We undertook a comparative network analysis across 264 human microarray profiles monitoring transcript changes in healthy liver, liver cirrhosis, and HCC with viral and alcoholic etiologies. Gene co-expression profiling was used to derive a consensus gene relevance network of HCC progression that consisted of 798 genes and 2,012 links. The HCC interactome was further confirmed to be phenotype-specific and non-random. Additionally, we confirmed that co-expressed genes are more likely to share biological function, but not sub-cellular localization. Analysis of individual HCC genes revealed that they are topologically central in a human protein-protein interaction network. We used quantitative RT-PCR in a cohort of normal liver tissue (n = 8), hepatitis C virus (HCV)-induced chronic liver disease (n = 9), and HCC (n = 7) to validate co-expressions of several well-connected genes, namely ASPM, CDKN3, NEK2, RACGAP1, and TOP2A. We show that HCC is a heterogeneous disorder, underpinned by complex cross talk between immune response, cell cycle, and mRNA translation pathways. Our work provides a systems-wide resource for deeper understanding of molecular mechanisms in HCC progression and may be used further to define novel targets for efficient treatment or diagnosis of this disease.

Expression of aurora kinase A correlates with the Wnt‐modulator RACGAP1 in gastric cancer

“…Our PPI network analysis suggests a direct association between AURKA and RACGAP1. RACGAP1 is expressed by a variety of solid tumors, including breast cancer and hepatocellular carcinoma where it is also a prognostic indicator for early recurrence [35,31,38]. In our study, the expression of RACGAP1 in tumor samples was lower compared to noncancer controls, and (similar to AURKA) there was no difference in RACGAP1 gene expression between tumor tissue and nontumorous mucosa in cancer patients.…”

Effects of harmaline on cell growth of human liver cancer through the p53/p21 and Fas/FasL signaling pathways

“…The morbidity rate of HLC is rising, therefore the development of treatments that inhibit the occurrence and development of HLC are required (15). The development of HLC is a complex and relatively slow, and there is no definitive pathological definition of HLC in the clinic (16).…”

Identification of the RNA recognition element of the RBPMS family of RNA-binding proteins and their transcriptome-wide mRNA targets

“…Nuclear (Nuc), cytoplasmic (Cyt), and total cell lysate (Tot) fractions were resolved on a 4%-12% SDS-polyacrylamide gel and then probed using an anti-HA antibody targeting FLAG-HA RBPMS and RBPMS2, and antibodies targeting ELAVL1 (HuR), TUBB (β-tubulin), and LMNB1 (lamin B) as controls for the purity of the cytoplasmic and nuclear fractions. Dysregulation of RBPMS family proteins has been reported in cancer (Skawran et al 2008;Miller and Stamatoyannopoulos 2010;Drozdov et al 2012;Hapkova et al 2013; http://www.cbioportal.org/public-portal/) and chronic intestinal pseudo-obstruction (Notarnicola et al 2012). Manipulation of RBPMS levels during embryogenesis suggested functions in X. laevis oocyte maturation (Zearfoss et al 2003), heart and kidney development (Gerber et al 2002), and retinal ganglion cell development (Hornberg et al 2013).…”