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Expression of Transgenes in Native Bladder Urothelium Using Adenovirus-Mediated Transduction
Published on: October 6, 2022
Analysis of PPI networks of transcriptomic expression identifies hub genes associated with Newcastle disease virus
Umar Ahmad1,2, Syahril Abdullah1,3, De Ming Chau1
1Medical Genetics Laboratory, Genetics and Regenerative Medicine Research Centre, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.
Abstract:
Bladder cancer cells can acquire persistent infection of oncolytic Newcastle disease virus (NDV) but the molecular mechanism(s) remain unelucidated. This poses a major barrier to the effective clinical translation of oncolytic NDV virotherapy of cancers. To improve our understanding of the molecular mechanism(s) associated with the development of NDV persistent infection in bladder cancer, we used mRNA expression profiles of persistently infected bladder cancer cells to construct PPI networks. Based on paths and modules in the PPI network, the bridges were found mainly in the upregulated mRNA-pathways of p53 signalling, ECM-receptor interaction, and TGF-beta signalling and downregulated mRNA-pathways of antigen processing and presentation, protein processing in endoplasmic reticulum, completement and coagulation cascades in persistent TCCSUPPi cells. In persistent EJ28Pi cells, connections were identified mainly through upregulated mRNA-pathways of renal carcinoma, viral carcinogenesis, Ras signalling and cell cycle and the downregulated mRNA-pathways of Wnt signalling, HTLV-I infection and pathways in cancers. These connections were mainly dependent on RPL8-HSPA1A/HSPA4 in TCCSUPPi cells and EP300, PTPN11, RAC1-TP53, SP1, CCND1 and XPO1 in EJ28Pi cells. Oncomine validation showed that the top hub genes identified in the networks that include RPL8, THBS1, F2 from TCCSUPPi and TP53 and RAC1 from EJ28Pi are involved in the development and progression of bladder cancer. Protein-drug interaction networks identified several putative drug targets that could be used to disrupt the linkages between the modules and prevent bladder cancer cells from acquiring NDV persistent infection. This novel PPI network analysis of differentially expressed mRNAs of NDV persistently infected bladder cancer cell lines provide an insight into the molecular mechanisms of NDV persistency of infection in bladder cancers and the future screening of drugs that can be used together with NDV to enhance its oncolytic efficacy.
Insights
Newcastle disease virus (NDV) can persist in bladder cancer cells, hindering effective virotherapy. This study reveals molecular pathways and potential drug targets to overcome NDV persistence and enhance cancer treatment.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Oncolytic Newcastle disease virus (NDV) shows promise for cancer therapy, but its persistent infection in bladder cancer cells impedes clinical application.
- Understanding the molecular mechanisms behind NDV persistence is crucial for improving virotherapy efficacy.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying persistent Newcastle disease virus (NDV) infection in bladder cancer cells.
- To identify potential therapeutic targets for disrupting NDV persistence and enhancing oncolytic efficacy.
Main Methods:
- Construction and analysis of protein-protein interaction (PPI) networks using mRNA expression profiles of persistently infected bladder cancer cell lines (TCCSUPPi and EJ28Pi).
- Identification of key signaling pathways and hub genes involved in NDV persistence.
- Oncomine validation of identified hub genes.
- Construction of protein-drug interaction networks to identify potential drug targets.
Main Results:
- Differentially expressed mRNA pathways associated with NDV persistence were identified, including upregulated p53 signaling, ECM-receptor interaction, TGF-beta signaling, and downregulated antigen processing and presentation in TCCSUPPi cells.
- In EJ28Pi cells, upregulated pathways included renal carcinoma, viral carcinogenesis, Ras signaling, and cell cycle, while Wnt signaling and HTLV-I infection pathways were downregulated.
- Key molecular connections involved RPL8-HSPA1A/HSPA1A and EP300, PTPN11, RAC1-TP53, SP1, CCND1, XPO1.
- Hub genes like RPL8, THBS1, F2, TP53, and RAC1 were validated and found to be involved in bladder cancer development.
- Several potential drug targets were identified to disrupt NDV persistence.
Conclusions:
- This PPI network analysis provides novel insights into the molecular mechanisms of NDV persistence in bladder cancer.
- Identified drug targets offer potential strategies to overcome NDV resistance and improve oncolytic virotherapy outcomes.
- Further research can focus on screening drugs targeting these pathways to enhance NDV's anti-cancer efficacy.
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