Analysis of Genomes and Transcriptomes of Hepatocellular Carcinomas Identifies Mutations and Gene Expression Changes in the Transforming Growth Factor-β Pathway

Abstract

In genome and transcriptome analyses of HCC samples, we found mutations in genes in the TGF-β signaling pathway in almost 40% of samples. These correlated with changes in expression of genes in the pathways; up-regulation of genes in this pathway would contribute to inflammation and fibrosis, whereas down-regulation would indicate loss of TGF-β tumor suppressor activity. Our findings indicate that therapeutic agents for HCCs can be effective, based on genetic features of the TGF-β pathway; agents that block TGF-β should be used only in patients with specific types of HCCs.

Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases

“…These include the following markers: epithelial cell adhesion molecule, osteopontin, surface marker vimentin, transforming growth factor beta/sirtuin, and DNA repair pathway members. These novel biomarkers reflect biological significance in HCC …”

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily

“…The TGF-β pathways are context-dependent signal transduction cascades that can promote seemingly contradictory cell processes, including promotion of differentiation and tumor growth, inhibition of cell proliferation, suppression of immune response, and maintenance of stem cell homeostasis (Akhurst, 2017; Colak and Dijke, 2017; Seoane and Gomis, 2017; Christian and Heldin, 2017; Moustakas and Heldin, 2016; Mishra et al, 2005; Wakefield and Roberts, 2002). Animal models of mammary gland tumorigenesis support a pro-tumorigenic role for signaling by the TGF-β1-Smad2 pathway (Muraoka-Cook et al, 2004), whereas mouse models of gastrointestinal (GI) cancers and hepatocellular cancers indicate a primarily tumor-suppressive role (Chen et al, 2018; Chen et al, 2016b; David et al, 2016; Katz et al, 2016). In pancreatic KRAS-mutant premalignant cells, TGF-β signaling induces expression of metastasis-promoting genes (David et al, 2016) and apoptosis-regulatory genes.…”

Silencing the expression of copine-III enhances the sensitivity of hepatocellular carcinoma cells to the molecular targeted agent sorafenib

“…Hepatocellular carcinoma (HCC) is one of the most fatal malignancies in the Asia-Pacific region, especially in the People’s Republic of China 1,2. Most patients suffering from advanced HCC at initial diagnosis have poor prognosis due to tumor insensitivity against radiation therapy and chemotherapy 3–5.…”