The HPV-TP53-MALAT1 Axis: Unravelling interactions in cervical cancer development.

INTRODUCTION: Cervical cancer, primarily driven by Human Papillomavirus (HPV) infection, stands as a substantial global health challenge. The TP53 gene's, Arg72Pro polymorphism has emerged as a noteworthy player in cervical cancer development, particularly among individuals harboring high-risk (HR) HPV types. Additionally, long non-coding RNAs (lncRNAs), exemplified by metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), exert critical roles in cancer biology. This study delves into unravelling the intricate connections linking HPV infection, TP53 Arg72Pro polymorphism, and MALAT1 expression in the context of cervical cancer. MATERIALS AND METHODS: Within a cohort of cervical cancer patients, we discerned HPV infection statuses, executed genotyping for the TP53 Arg72Pro polymorphism, and quantified MALAT1 expression through quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Statistical analyses meticulously probed relationships intertwining HPV infection, TP53 polymorphism, and MALAT1 expression. FINDINGS: Our investigation revealed a striking prevalence of the TP53 Arg72Pro polymorphism among HPV-positive subjects, accompanied by a robust and statistically significant correlation linking MALAT1 overexpression (p<0.01) and HR-HPV positivity (p<0.03). Importantly, a subset of MALAT1 overexpression cases unveiled a concomitant TP53 Pro72Pro polymorphism. In contrast, HPV-negative invasive cervical carcinoma samples exhibited no discernible shifts in MALAT1 expression. CONCLUSION: The contours of our findings sketch a compelling landscape wherein HR-HPV infection, TP53 polymorphism, and MALAT1 expression intertwine significantly in cervical cancer. The voyage ahead entails delving deeper into molecular underpinnings to decipher MALAT1's nuanced role and its dance with TP53 within HPV-associated cervical carcinogenesis. This expedition promises insights that may engender targeted therapeutic interventions and bespoke prognostic markers, tailored to the realm of HR-HPV-related cervical cancer.

Competing Endogenous RNA (ceRNA) Networks and Splicing Switches in Cervical Cancer: HPV Oncogenesis, Clinical Significance and Therapeutic Opportunities.

Cervical cancer (CC) is the primary cause of female cancer fatalities in low-middle-income countries (LMICs). Persistent infections from the human papillomavirus (HPV) can result in cervical cancer. However, numerous different factors influence the development and progression of cervical cancer. Transcriptomic knowledge of the mechanisms with which HPV causes cervical cancer pathogenesis is growing. Nonetheless, there is an existing gap hindering the development of therapeutic approaches and the improvement of patient outcomes. Alternative splicing allows for the production of numerous RNA transcripts and protein isoforms from a single gene, increasing the transcriptome and protein diversity in eukaryotes. Cancer cells exhibit astounding transcriptome modifications by expressing cancer-specific splicing isoforms. High-risk HPV uses cellular alternative splicing events to produce viral and host splice variants and proteins that drive cancer progression or contribute to distinct cancer hallmarks. Understanding how viruses utilize alternative splicing to drive pathogenesis and tumorigenesis is essential. Although research into the role of miRNAs in tumorigenesis is advancing, the function of other non-coding RNAs, including lncRNA and circRNA, has been understudied. Through their interaction with mRNA, non-coding RNAs form a network of competing endogenous RNAs (ceRNAs), which regulate gene expression and promote cervical cancer development and advancement. The dysregulated expression of non-coding RNAs is an understudied and tangled process that promotes cervical cancer development. This review will present the role of aberrant alternative splicing and immunosuppression events in HPV-mediated cervical tumorigenesis, and ceRNA network regulation in cervical cancer pathogenesis will also be discussed. Furthermore, the therapeutic potential of splicing disruptor drugs in cervical cancer will be deliberated.

The Catastrophic HPV/HIV Dual Viral Oncogenomics in Concert with Dysregulated Alternative Splicing in Cervical Cancer.

Cervical cancer is a public health problem and has devastating effects in low-to-middle-income countries (LTMICs) such as the sub-Saharan African (SSA) countries. Infection by the human papillomavirus (HPV) is the main cause of cervical cancer. HIV positive women have higher HPV prevalence and cervical cancer incidence than their HIV negative counterparts do. Concurrent HPV/HIV infection is catastrophic, particularly to African women due to the high prevalence of HIV infections. Although various studies show a relationship between HPV, HIV and cervical cancer, there is still a gap in the knowledge concerning the precise nature of this tripartite association. Firstly, most studies show the relationship between HPV and cervical cancer at genomic and epigenetic levels, while the transcriptomic landscape of this relationship remains to be elucidated. Even though many studies have shown HPV/HIV dual viral pathogenesis, the dual molecular oncoviral effects on the development of cervical cancer remains largely uncertain. Furthermore, the effect of highly active antiretroviral therapy (HAART) on the cellular splicing machinery is unclear. Emerging evidence indicates the vital role played by host splicing events in both HPV and HIV infection in the development and progression to cervical cancer. Therefore, decoding the transcriptome landscape of this tripartite relationship holds promising therapeutic potential. This review will focus on the link between cellular splicing machinery, HPV, HIV infection and the aberrant alternative splicing events that take place in HIV/HPV-associated cervical cancer. Finally, we will investigate how these aberrant splicing events can be targeted for the development of new therapeutic strategies against HPV/HIV-associated cervical cancer.

Splicing Genomics Events in Cervical Cancer: Insights for Phenotypic Stratification and Biomarker Potency.

Gynaecological cancers are attributed to the second most diagnosed cancers in women after breast cancer. On a global scale, cervical cancer is the fourth most common cancer and the most common cancer in developing countries with rapidly increasing mortality rates. Human papillomavirus (HPV) infection is a major contributor to the disease. HPV infections cause prominent cellular changes including alternative splicing to drive malignant transformation. A fundamental characteristic attributed to cancer is the dysregulation of cellular transcription. Alternative splicing is regulated by several splicing factors and molecular changes in these factors lead to cancer mechanisms such as tumour development and progression and drug resistance. The serine/arginine-rich (SR) proteins and heterogeneous ribonucleoproteins (hnRNPs) have prominent roles in modulating alternative splicing. Evidence shows molecular alteration and expression levels in these splicing factors in cervical cancer. Furthermore, aberrant splicing events in cancer-related genes lead to chemo- and radioresistance. Identifying clinically relevant modifications in alternative splicing events and splicing variants, in cervical cancer, as potential biomarkers for their role in cancer progression and therapy resistance is scrutinised. This review will focus on the molecular mechanisms underlying the aberrant splicing events in cervical cancer that may serve as potential biomarkers for diagnosis, prognosis, and novel drug targets.