Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental Models
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 target...
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MDPI AG
2023-01-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/2/342 |
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| author | Loraine Kay D. Cabral Pablo J. Giraudi Gianluigi Giannelli Francesco Dituri Roberto Negro Claudio Tiribelli Caecilia H. C. Sukowati |
| author_facet | Loraine Kay D. Cabral Pablo J. Giraudi Gianluigi Giannelli Francesco Dituri Roberto Negro Claudio Tiribelli Caecilia H. C. Sukowati |
| author_sort | Loraine Kay D. Cabral |
| collection | DOAJ |
| description | 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. |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-07T15:15:39Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-fd1a527f655b4ac3a05267d2ba2027db2024-03-05T17:59:12ZengMDPI AGBiomedicines2227-90592023-01-0111234210.3390/biomedicines11020342Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental ModelsLoraine Kay D. Cabral0Pablo J. Giraudi1Gianluigi Giannelli2Francesco Dituri3Roberto Negro4Claudio Tiribelli5Caecilia H. C. Sukowati6Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, ItalyFondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, ItalyNational Institute of Gastroenterology IRCCS “S. De Bellis” Research Hospital, 70013 Bari, ItalyNational Institute of Gastroenterology IRCCS “S. De Bellis” Research Hospital, 70013 Bari, ItalyNational Institute of Gastroenterology IRCCS “S. De Bellis” Research Hospital, 70013 Bari, ItalyFondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, ItalyFondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, ItalyHepatocellular 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.https://www.mdpi.com/2227-9059/11/2/342hepatocellular carcinomacellular heterogeneitytargeted therapiesexperimental models |
| spellingShingle | Loraine Kay D. Cabral Pablo J. Giraudi Gianluigi Giannelli Francesco Dituri Roberto Negro Claudio Tiribelli Caecilia H. C. Sukowati Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental Models Biomedicines hepatocellular carcinoma cellular heterogeneity targeted therapies experimental models |
| title | Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental Models |
| title_full | Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental Models |
| title_fullStr | Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental Models |
| title_full_unstemmed | Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental Models |
| title_short | Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental Models |
| title_sort | network analysis for the discovery of common oncogenic biomarkers in liver cancer experimental models |
| topic | hepatocellular carcinoma cellular heterogeneity targeted therapies experimental models |
| url | https://www.mdpi.com/2227-9059/11/2/342 |
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