Infection with high-risk human papillomavirus (HPV), including HPV-16 and HPV-18, is the main cause of malignancies, such as cervical cancer. Viral oncoproteins encoded by HPV are expressed in HPV-positive cancers and associated with the early cancer stages and the transformation of normal cells. The signaling pathways involved in the transformation of normal cells to cancerous form and the subsequently expressed programmed cell death-ligand 1 (PD-L1) on the surface of the transformed cells lead to a disruption in recognition of tumor cells by the immune cell system, including T lymphocytes and dendritic cells which lead to the development of cervical cancer malignancy.These cells also produce modest levels of cytokines during exhaustion, tumor-infiltrating T CD4+ cells with high levels of PD-1 and CD39 release considerable quantities of cytokines. The Wnt/β-catenin signaling pathway, which controls the expression of genes involved in the tumor cells' markers, is demonstrated to be one of the most potent cancer stimulants. It leads to the evasion of the tumor cells from immune cell detection and ultimately avoids being recognized by dendritic cells or T-cells. PD-L1, as an inhibitory immune checkpoint, is essential for controlling immune system activity by inhibiting T-cells' inflammatory function. In the present review, we looked into how Wnt/β-catenin affects the expression of PD-L1 and related genes like c-MYC in cancer cells and its role in the development of HPV-induced malignancy. We hypothesized that blocking these pathways could be a potential immunotherapy and cancer prevention method. Abbreviation List APCs Antigens presenting cells APC Adenomatous polyposis coli SATB1 AT-rich sequence binding protein-1 β-TrCP Beta-transducing repeat-containing protein Brg-1 Brahma-related gene 1 CD Cluster of differentiation c-MYC Cellular myelocytomatosis CIN Cervical intraepithelial neoplasia CREPT Cell cycle-related and expression elevated protein in tumor CBP/p300 CREB-binding protein CK1 Casein kinase 1

Background Persistent infection with high-risk Human papillomaviruses (HPV), such as hr-HPV-16 and hr-HPV-18, lead to cervical cancer, the fourth most common cancer in the world. In the present study, we investigated the alteration of E6 oncogene expression by E6-specific short interfering RNA (siRNA) combined with Oxaliplatin. Methods The cervical cancer cell line, CaSki, was transfected with E6-siRNA, then treated with Oxaliplatin. The cellular genes, such as p53, MMP9, Nanog, and caspases expression, were assessed by quantitative real-time PCR. The cell death rate, cell cycle, and cell viability were assessed by Annexin V/PI staining, DAPI staining, and MTT test, respectively. Furthermore, colony formation assay and scratch test determined the stemness ability and cell metastasis, respectively. Results Combination therapy increased the re-expression of genes involved in the p53-dependent apoptosis pathway (increase in apoptosis to 44.2%), and reduced stemness and metastasis ability compared to either siRNA or Oxaliplatin monotherapy. Together, our results demonstrate that E6-siRNA and Oxaliplatin combination increased the cervical cancer cells’ sensitivity to Oxaliplatin and decreased the survival rate, proliferation, and metastasis, and consequently escalated apoptosis rate, induced cell cycle arrest in the sub-G1 stage, and reduced the chemotherapy drug dosage. Conclusion Inhibition of E6 oncogene expression and subsequent E6-siRNA with Oxaliplatin combination therapy could be a novel strategy for cervical cancer treatment. Graphical Abstract

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