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

Abstract

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.

Identification and Validation of Invasion-Related Molecular Subtypes and Prognostic Features for Cervical Cancer

“…Cervical cancer is usually histologically classified into different subtypes, including squamous cell carcinoma occurring in the outer cervix (accounting for about 75% of invasive cervical cancer cases), adenocarcinoma originating from the cervical canal, and less common adenosquamous, serous papilla, and clear cell carcinoma of the cervix and small cell or neuroendocrine. Cervical cancer is a heterogeneous cancer showing heterogeneity also in other aspects, such as molecular characteristics [ 4 ], metabolism [ 5 ], invasive risk [ 6 ], local microenvironments [ 7 ], and responses to treatment [ 8 ]. Hence, subtype classification related to these factors is critical to the treatment and prognosis of patients.…”

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

“…With some geographical variation, HPV infection causes 70% of cancers of the vulva, 75% of all vaginal cancers, 60% of all penile cancers, 90% of all anal cancers and 70% of all oropharyngeal cancers. In terms of cervical cancer, it is thought that nearly all cervical cancers are caused by persistent HPV infection [ 3 , 26 ].…”

“…Upregulated snRNPs favour alternative splicing, while overexpression of hnRNPs inhibits AS. Evidence of HPV-mediated AS in cervical cancer has been documented [ 3 ].…”

“…SCC is the most common type accounting for over 70% of all cases [ 1 , 2 ]. Cervical cancer can be attributed to various risk factors, and these include smoking, alcohol consumption, multiple sexual partners, unprotected sex, socioeconomic status, a family history of cervical cancer, extended use of oral contraceptives, human immunodeficiency virus (HIV) infection and persistent human papillomavirus (HPV) infection [ 3 , 4 , 5 , 6 ]. However, persistent HPV infection is the key contributor to the development of cervical cancer [ 1 , 7 ].…”

“…As a result of this, the splicing machinery of the host is also compromised upon HPV infection. As an oncovirus, HPV infection will result in the synthesis of splice variants of viral and cellular mRNA that favour cell survival mechanisms such as excessive cell proliferation, immune response evasion and inhibition of tumour suppressor proteins [ 3 , 23 ]. This review focuses 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.…”