Identification of the possible therapeutic targets in the insulin-like growth factor 1 receptor pathway in a cohort of Egyptian hepatocellular carcinoma complicating chronic hepatitis C type 4

Nada M K Mabrouk; Dalal M Elkaffash; Mona Abdel-Hadi; Salah-ElDin Abdelmoneim; Sameh Saad ElDeen; Gihan Gewaifel; Khaled A Elella; Maher Osman; Nahed Baddour

doi:10.33393/dti.2020.1548

Identification of the possible therapeutic targets in the insulin-like growth factor 1 receptor pathway in a cohort of Egyptian hepatocellular carcinoma complicating chronic hepatitis C type 4

Drug Target Insights. 2020 Apr 8:14:1-11. doi: 10.33393/dti.2020.1548. eCollection 2020.

Authors

Nada M K Mabrouk¹, Dalal M Elkaffash^{2

3}, Mona Abdel-Hadi¹, Salah-ElDin Abdelmoneim⁴, Sameh Saad ElDeen³, Gihan Gewaifel⁵, Khaled A Elella⁶, Maher Osman⁶, Nahed Baddour¹

Affiliations

¹ Department of Pathology, University of Alexandria, Alexandria - Egypt.
² Alexandria Regional Center for Women's Health and Development, Alexandria - Egypt.
³ Department of Clinical and Chemical Pathology, University of Alexandria, Alexandria - Egypt.
⁴ Department of Clinical Oncology and Nuclear Medicine, University of Alexandria, Alexandria - Egypt.
⁵ Public Health Department, Faculty of Medicine, University of Alexandria, Alexandria - Egypt.
⁶ Department of General Surgery, University of Alexandria, Alexandria - Egypt.

Abstract

Background: Molecular targeted drugs are the first line of treatment of advanced hepatocellular carcinoma (HCC) due to its chemo- and radioresistant nature. HCC has several well-documented etiologic factors that drive hepatocarcinogenesis through different molecular pathways. Currently, hepatitis C virus (HCV) is a leading cause of HCC. Therefore, we included a unified cohort of HCV genotype 4-related HCCs to study the expression levels of genes involved in the insulin-like growth factor 1 receptor (IGF1R) pathway, which is known to be involved in all aspects of cancer growth and progression.

Aim: Determine the gene expression patterns of IGF1R pathway genes in a cohort of Egyptian HCV-related HCCs. Correlate them with different patient/tumor characteristics. Determine the activity status of involved pathways.

Methods: Total ribonucleic acid (RNA) was extracted from 32 formalin-fixed paraffin-embedded tissues of human HCV-related HCCs and 6 healthy liver donors as controls. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT² Profiler PCR Array for Human Insulin Signaling Pathway was done to determine significantly up- and downregulated genes with identification of most frequently coregulated genes, followed by correlation of gene expression with different patient/tumor characteristics. Finally, canonical pathway analysis was performed using the Ingenuity Pathway Analysis software.

Results: Six genes - AEBP1, AKT2, C-FOS, PIK3R1, PRKCI, SHC1 - were significantly overexpressed. Thirteen genes - ADRB3, CEBPA, DUSP14, ERCC1, FRS3, IGF2, INS, IRS1, JUN, MTOR, PIK3R2, PPP1CA, RPS6KA1 - were significantly underexpressed. Several differentially expressed genes were related to different tumor/patient characteristics. Nitric oxide and reactive oxygen species production pathway was significantly activated in the present cohort, while the growth hormone signaling pathway was inactive.

Conclusions: The gene expression patterns identified in this study may serve as possible therapeutic targets in HCV-related HCCs. The most frequently coregulated genes may serve to guide combined molecular targeted therapies. The IGF1R pathway showed evidence of inactivity in the present cohort of HCV-related HCCs, so targeting this pathway in therapy may not be effective.

Keywords: Gene expression; Hepatitis C virus; Hepatocellular carcinoma; Molecular therapeutic targets.