The effects of HPV oncoproteins on host communication networks: Therapeutic connotations.

Human papillomavirus (HPV) infections are a leading cause of viral-induced malignancies worldwide, with a prominent association with cervical and head and neck cancers. The pivotal role of HPV oncoproteins, E5, E6, and E7, in manipulating cellular events, which contribute to viral pathogenesis in various ways, has been extensively documented. This article reviews the influence of HPV oncoproteins on cellular signaling pathways within the host cell, shedding light on the underlying molecular mechanisms. A comprehensive understanding of these molecular alterations is essential for the development of targeted therapies and strategies to combat HPV-induced premalignancies and prevent their progress to cancer. Furthermore, this review underscores the intricate interplay between HPV oncoproteins and some of the most important cellular signaling pathways: Notch, Wnt/ß-catenin, MAPK, JAK/STAT, and PI3K AKT/mTOR. The treatment efficacies of the currently available inhibitors on these pathways in an HPV-positive context are also discussed. This review also highlights the importance of continued research to advance our knowledge and enhance therapeutic interventions for HPV-associated diseases.

The ubiquitin specific protease 7 stabilizes HPV16E7 to promote HPV-mediated carcinogenesis.

Human papillomavirus (HPV) encoded E7 oncoprotein plays an important role in supporting the viral productive cycle and inducing cancer phenotypes. The ability of E7 to exercise these functions, partly, depends upon its steady-state level. HPV manipulates the host de-ubiquitination pathway to maintain the stability of its viral proteins. In this study, we uncovered that HPV interacts with the host ubiquitin specific protease 7 (USP7), a universal de-ubiquitinating enzyme, leading to the stabilization of E7 oncoprotein. We observed that HPV16E7 complexes with USP7 via the E7-CR3 domain, and this E7-USP7 complex exists predominantly in the nucleus. Our results showed that USP7 stabilizes and prolongs the half-life of HPV16E7 by antagonizing ubiquitination and proteasomal degradation. Consistently, when we inhibited USP7 activity using HBX 19818, HPV16E7 protein level was reduced and its turnover was increased. We also provide evidence that HBX 19818-induced USP7 inhibition can halt HPV-mediated carcinogenesis, including cell proliferation, invasion, migration and transformation. These findings indicate that USP7 plays an essential role in stabilizing E7. The specific and potent inhibitory effects of HBX 19818 on HPV-induced carcinogenesis provide a molecular insight, suggesting the potential of targeting USP7 as a new therapeutic approach for the treatment of HPV-associated cancers.

Interaction between Human Papillomavirus-Encoded E6 Protein and AurB Induces Cell Immortalization and Proliferation-A Potential Target of Intervention.

The human papillomavirus E6 and E7 oncoproteins interact with a different subset of host proteins, leading to dysregulation of the apoptotic, cell cycle, and signaling pathways. In this study, we identified, for the first time, that Aurora kinase B (AurB) is a bona fide interacting partner of E6. We systematically characterized the AurB-E6 complex formation and its consequences in carcinogenesis using a series of in vitro and cell-based assays. We also assessed the efficacy of Aurora kinase inhibitors in halting HPV-mediated carcinogenesis using in vitro and in vivo models. We showed that AurB activity was elevated in HPV-positive cells, and this correlated positively with the E6 protein level. E6 interacted directly with AurB in the nucleus or mitotic cells. A previously unidentified region of E6, located upstream of C-terminal E6-PBM, was important for AurB-E6 complex formation. AurB-E6 complex led to reduced AurB kinase activity. However, the AurB-E6 complex increased the hTERT protein level and its telomerase activity. On the other hand, AurB inhibition led to the inhibition of telomerase activity, cell proliferation, and tumor formation, even though this may occur in an HPV-independent manner. In summary, this study dissected the molecular mechanism of how E6 recruits AurB to induce cell immortalization and proliferation, leading to the eventual cancer development. Our findings revealed that the treatment of AZD1152 exerted a non-specific anti-tumor effect. Hence, a continuous effort to seek a specific and selective inhibitor that can halt HPV-mediated carcinogenesis should be warranted.

E6-Encoded by Cancer-Causing Human Papillomavirus Interacts with Aurora Kinase A To Promote HPV-Mediated Carcinogenesis.

The expression of human papillomavirus (HPV) oncoproteins perturbed multiple cellular events of the host cells, leading to the formation of cancer phenotypes. Our current and previous studies indicated that Aurora kinase A (AurA), a mitotic regulator that is often aberrantly expressed in human cancers, is preferentially bound to E6-encoded by cancer-causing HPV. AurA is believed to be important for the proliferation and survival of HPV-positive cells. Nonetheless, the interaction between AurA and E6, and the mechanism of how this association is involved in carcinogenesis, have not been elucidated clearly. Hence, we performed a series of biochemical assays to characterize the AurA-E6 association and complex formation. We found the C-terminus of E6, upstream of the PDZ binding motif of E6, is important to forming the AurA-E6 complex in the nucleus. We also showed that the expression level of E6 corresponded positively with AurA expression. Meanwhile, the functional consequences of the AurA-E6 association to AurA kinase function and host cellular events were also delineated. Intriguingly, we revealed that AurA-E6 association regulated the expression of cyclin E and phosphor-Histone H3, which are involved in G1/S and mitotic phases of the cell cycle, respectively. Depletion of AurA also reduced the invasive ability of HPV-positive cells. AurA inhibition may not be sufficient to reduce the oncogenic potential exerted by E6. Altogether, our study unleashed the mechanism of how HPVE6 deploy AurA to promote cancer phenotypes, particularly through dysregulation of cell cycle checkpoints and suggests that the AurA-E6 complex possesses a therapeutic value. IMPORTANCE We unveiled the mechanism of how HPV employs Aurora kinase A (AurA) of host cells to exert its oncogenic capability synergistically. We systematically characterized the mode of interaction between E6-encoded by cancer-causing HPV and AurA. Then, we delineated the consequences of AurA-E6 complex formation on AurA kinase function and changes to cellular events at molecular levels. Using a cell-based approach, we unleashed that disruption of AurA-E6 association can halt cancer phenotype exhibited by HPV-positive cancer cells. Our findings are vital for the designing of state-of-the-art therapies for HPV-associated cancers.

Review of the Standard and Advanced Screening, Staging Systems and Treatment Modalities for Cervical Cancer.

Cancer arising from the uterine cervix is the fourth most common cause of cancer death among women worldwide. Almost 90% of cervical cancer mortality has occurred in low- and middle-income countries. One of the major aetiologies contributing to cervical cancer is the persistent infection by the cancer-causing types of the human papillomavirus. The disease is preventable if the premalignant lesion is detected early and managed effectively. In this review, we outlined the standard guidelines that have been introduced and implemented worldwide for decades, including the cytology, the HPV detection and genotyping, and the immunostaining of surrogate markers. In addition, the staging system used to classify the premalignancy and malignancy of the uterine cervix, as well as the safety and efficacy of the various treatment modalities in clinical trials for cervical cancers, are also discussed. In this millennial world, the advancements in computer-aided technology, including robotic modules and artificial intelligence (AI), are also incorporated into the screening, diagnostic, and treatment platforms. These innovations reduce the dependence on specialists and technologists, as well as the work burden and time incurred for sample processing. However, concerns over the practicality of these advancements remain, due to the high cost, lack of flexibility, and the judgment of a trained professional that is currently not replaceable by a machine.

Oesophageal carcinoma: The prevalence of DNA tumour viruses and therapy.

Oesophageal carcinoma ranks the sixth leading cause of cancer death and affected 544,000 - 604,000 people in 2020. Patients often presented with a poor cancer prognosis with a low survival rate of 15-25%. Depending upon the cell type, oesophageal carcinoma is categorised into oesophageal squamous cell carcinoma (ESCC) and oesophageal adenocarcinoma (EAC). ESCC is predominantly reported in developing countries, while EAC is more common in developed countries. Aside from the presence of exogenous co-factors, such as cigarette smoking, alcohol consumption, obesity, gastroesophageal reflux disease (GERD); infection with oncogenic viruses is suspected to be one of the major factors contributing to EC development. Oncogenic viruses, including human papillomavirus (HPV), Epstein Barr virus (EBV), Cytomegalovirus (CMV) and Herpes Simplex Virus (HSV) have been detected in various proportions of EC samples. Nonetheless, their aetiological roles in EC remain debatable. In this review, we garnered previous studies that focus on the association between oncogenic viruses and EC. Among these oncogenic viruses, HPV appears to have a stronger association with EC than the others. In addition, we also discuss the pros and cons of the treatment regimens to treat EC patients, including immunotherapy, chemo- and chemoradiotherapy, and their efficacy.

Temporal-Geographical Dispersion of SARS-CoV-2 Spike Glycoprotein Variant Lineages and Their Functional Prediction Using in Silico Approach.

SARS-CoV-2 is a positive-sense single-stranded RNA virus with emerging mutations, especially on the Spike glycoprotein (S protein). To delineate the genomic diversity in association with geographic dispersion of SARS-CoV-2 variant lineages, we collected 939,591 complete S protein sequences deposited in the Global Initiative on Sharing All Influenza Data (GISAID) from December 2019 to April 2021. An exponential emergence of S protein variants was observed since October 2020 when the four major variants of concern (VOCs), namely, alpha (α) (B.1.1.7), beta (ß) (B.1.351), gamma (γ) (P.1), and delta (δ) (B.1.617), started to circulate in various communities. We found that residues 452, 477, 484, and 501, the 4 key amino acids located in the hACE2 binding domain of S protein, were under positive selection. Through in silico protein structure prediction and immunoinformatics tools, we discovered D614G is the key determinant to S protein conformational change, while variations of N439K, T478I, E484K, and N501Y in S1-RBD also had an impact on S protein binding affinity to hACE2 and antigenicity. Finally, we predicted that the yet-to-be-identified hypothetical N439S, T478S, and N501K mutations could confer an even greater binding affinity to hACE2 and evade host immune surveillance more efficiently than the respective native variants. This study documented the evolution of SARS-CoV-2 S protein over the first 16 months of the pandemic and identified several key amino acid changes that are predicted to confer a substantial impact on transmission and immunological recognition. These findings convey crucial information to sequence-based surveillance programs and the design of next-generation vaccines. IMPORTANCE Our study showed the global distribution of SARS-CoV-2 S protein variants from January 2020 to the end of April 2021. We highlighted the key amino acids of S protein subjected to positive selection. Using computer-aided approaches, we predicted the impact of the amino acid variations in S protein on viral infectivity and antigenicity. We also predicted the potential amino acid mutations that could arise in favor of SARS-CoV-2 virulence. These findings are vital for vaccine designing and anti-SARS-CoV-2 drug discovery in an effort to combat COVID-19.