مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
The Regulatory Nexus: Unraveling the E6/E7-hnRNP Axis in Orchestrating Transcriptional Escape and PD-L1-Driven Immune Evasion in High-Risk HPV Carcinogenesis
The Regulatory Nexus: Unraveling the E6/E7-hnRNP Axis in Orchestrating Transcriptional Escape and PD-L1-Driven Immune Evasion in High-Risk HPV Carcinogenesis
Kiana Mohammedi,1,*Mohammad Zahiri,2Ali Dolatian,3Melika Rouzbahani,4Mani Sohrabfar,5
1. Ph.D. Candidate of Molecular Genetics,Islamic Azad University, Damghan Branch 2. Bachelor of Science in Cellular and Molecular Biology, Islamic Azad University, Shahre Qods Branch 3. Bachelor of Science in Cellular and Molecular Biology, Islamic Azad University, Shahre Qods Branch 4. Bachelor of Science in Cellular and Molecular Biology, Islamic Azad University, Shahre Qods Branch 5. Bachelor of Science in Cellular and Molecular Biology, Islamic Azad University, Shahre Qods Branch
Introduction: Despite progress in identifying the molecular targets of E6 and E7, the transformation of high-risk HPV infection into invasive cancer requires careful coordination between genomic alterations and manipulations of the immune environment. It is not yet clear how the virus maintains the expression of E6/E7 and creates a suppressive environment for the immune response by coordinating the cellular machinery. This study shows the Regulatory Nexus; A key junction where hnRNP regulates gene pathways and activates immunosuppressive pathways (PD-1/PD-L1), thereby explaining viral evasion of the immune response in the pre-proliferative and invasive stages of HPV.
Methods: Using the integrative analytical approach, two molecular levels were investigated:
1. Regulation of viral expression: the role of hnRNP proteins (A1, A2, D) in alternative splicing of viral pre-mRNA, which optimizes E6/E7 expression in different stages of infection.
2. Immune engineering: Investigating the direct involvement of E6/E7 in the weakening of antigen presentation pathways (reduction of MHC-I), induction of tumor suppressor cells (Tregs, MDSCs) and increased expression of PD-L1 on the surface of tumor cells.
Results: The findings showed that hnRNP L performs fine-tuning of splicing and maintains the optimal level of E6/E7 for simultaneous activation of metabolic pathways and inhibition of apoptosis. This situation, together with the creation of an anergic immune niche through increased PD-L1, creates a destructive synergy that facilitates viral escape from the immune response and tumor progression. This mechanism suggests that targeted therapies should address both E6/E7 intracellular pathways and tumor intrinsic resistance to PD-1-based immunotherapies.
Conclusion: This study elucidates the synergistic mechanism between transcriptional evasion and immunosuppression of high-risk HPV. The findings suggest that hnRNP protein as a critical mediator both optimizes E6/E7 expression and facilitates PD-L1 upregulation, leading to the establishment of a passive immune environment and tumor progression. Understanding this central junction of transcriptional and immune pathways provides an opportunity to develop novel therapeutic strategies that can significantly increase the efficacy of current therapies. This perspective provides a new framework for tackling HPV-related cancers and emphasizes the importance of simultaneously targeting viral and immune pathways.