Background: Molecular targeted drugs are the first line of treatment of advanced hepatocellular carcinoma (HCC) due to its chemo and radio resistant 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 RNA was extracted from 32 Formalin fixed paraffin embedded tissues of human HCV-related HCCs and six healthy liver donors as controls. 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 and VEGFAwere significantly under expressed. 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 Conclusion: 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.
Introduction Gastric mesenchymal tumours are a rare group of neoplasms, which include gastrointestinal stromal tumours (GISTs) and leiomyomas. To date, there is limited information on the tumour microenvironment (TME) in these neoplasms, despite the TME widely known to influence the hallmarks of cancer. In this study we used single cell RNA sequencing (scRNAseq) to profile individual cells of the TME in GIST and leiomyoma. Method The two gastric mesenchymal tumours and two normal gastric samples were analysed using DropSeq, where single cell transcriptomes are captured onto barcoded beads using a microfluidic device before next generation sequencing. For comparison, we performed bulk RNA-sequencing and CIBERSORT to estimate the abundance of 22 immune cell populations. Furthermore, we used immunohistochemistry to elucidate the presence and location of several immune cells. Result Both neoplasms had diverse immune and stromal cell populations with a greater proportion of macrophages but less B cells than normal gastric tissue. ScRNAseq was able to identify subpopulations of B cells and T cells not detected with CIBERSORT. Interstitial cells of cajal, believed to be the pre-cursor to GISTs, were observed through scRNAseq and confirmed through immunohistochemistry. Conclusion To our knowledge, this is the first study to utilise scRNAseq on GISTs and leiomyomas, which enabled characterisation of the TME at a cellular level. Using this platform in future studies will enable better characterisation of the TME and may inform the discovery of therapeutic targets. Take-home message Single cell RNA sequencing enables the ability to explore the tumour microenvironment of mesenchymal tumours at an enhanced resolution, paving the way for potential future therapeutic targets.
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