Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental Models

• Published in: Biomedicines Vol. 11; no. 2; p. 342
• Main Authors: Cabral, Loraine Kay D, Giraudi, Pablo J, Giannelli, Gianluigi, Dituri, Francesco, Negro, Roberto, Tiribelli, Claudio, Sukowati, Caecilia H C
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25-01-2023; MDPI
• Subjects: Antibodies; Azacytidine; Cancer therapies; Cells; cellular heterogeneity; Datasets; experimental models; Experiments; Gene amplification; Gene expression; Gene silencing; Growth factors; Hepatocellular carcinoma; Hepatocytes; Kinases; L1 gene; Liver cancer; Malignancy; Medical research; PD-L1 protein; Physiological aspects; Proteins; Proto-oncogenes; Software; Statistical significance; targeted therapies; Tumors; Wnt protein; United States; United States > US; cellular heterogeneity; experimental models; targeted therapies; hepatocellular carcinoma
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines11020342

Hepatocellular carcinoma (HCC) is a malignancy marked by heterogeneity. This study aimed to discover target molecules for potential therapeutic efficacy that may encompass HCC heterogeneity. In silico analysis using published datasets identified 16 proto-oncogenes as potential pharmacological targets. We used an immortalized hepatocyte (IHH) and five HCC cell lines under two subtypes: S1/TGFβ-Wnt-activated (HLE, HLF, and JHH6) and the S2/progenitor subtype (HepG2 and Huh7). Three treatment modalities, 5 µM 5-Azacytidine, 50 µM Sorafenib, and 20 nM PD-L1 gene silencing, were evaluated in vitro. The effect of treatments on the proto-oncogene targets was assessed by gene expression and Western blot analysis. Our results showed that 10/16 targets were upregulated in HCC cells, where cells belonging to the S2/progenitor subtype had more upregulated targets compared to the S1/TGFβ-Wnt-activated subtype (81% vs. 62%, respectively). Among the targets, FGR was consistently down-regulated in the cell lines following the three different treatments. Sorafenib was effective to down-regulate targets in S2/progenitor subtype while PD-L1 silencing was able to decrease targets in all HCC subtypes, suggesting that this treatment strategy may comprise cellular heterogeneity. This study strengthens the relevance of liver cancer cellular heterogeneity in response to cancer therapies.