Evaluation of the proteomic landscape of HPV E7-induced alterations in human keratinocytes reveal therapeutically relevant pathways for cervical cancer

• Main Authors: Gandhi, Sivasangkary, Mohamad Razif, Muhammad Fazril, Othman, Shatrah, Chakraborty, Sajib, Nor Rashid, Nurshamimi
• Format: Article
• Published: Spandidos Publ Ltd 2023
• Subjects: RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Online Access: http://eprints.um.edu.my/38689/
• Institution: Universiti Malaya

The lack of specific and accurate therapeutic targets poses a challenge in the treatment of cervical cancer (CC). Global proteomics has the potential to characterize the underlying and intricate molecular mechanisms that drive the identification of therapeutic candidates for CC in an unbiased manner. The present study assessed human papillomavirus (HPV)-induced proteomic alterations to identify key cancer hallmark pathways and protein-protein interaction (PPI) networks, which offered the opportunity to evaluate the possibility of using these for targeted therapy in CC. Comparative proteomic profiling of HPV-transfected (HPV16/18 E7), HPV-transformed (CaSki and HeLa) and normal human keratinocyte (HaCaT) cells was performed using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. Both label-free quantification and differential expression analysis were performed to assess differentially regulated proteins in HPV-transformed and -transfected cells. The present study demonstrated that protein expression was upregulated in HPV-transfected cells compared with in HPV-transformed cells. This was probably due to the ectopic expression of E7 protein in the former cell type, in contrast to its constitutive expression in the latter cell type. Subsequent pathway visualization and network construction demonstrated that the upregulated proteins in HPV16/18 E7-transfected cells were predominantly associated with a diverse array of cancer hallmarks, including the mTORC1 signaling pathway, MYC targets V1, hypoxia and glycolysis. Among the various proteins present in the cancer hallmark enrichment pathways, phosphoglycerate kinase 1 (PGK1) was present across all pathways. Therefore, PGK1 may be considered as a potential biomarker. PPI analysis demonstrated a direct interaction between p130 and polyubiquitin B, which may lead to the degradation of p130 via the ubiquitin-proteasome proteolytic pathway. In summary, elucidation of the key signaling pathways in HPV16/18-transfected and -transformed cells may aid in the design of novel therapeutic strategies for clinical application such as targeted therapy and immunotherapy against cervical cancer.