Cervical Cancer
Cervical cancer is the second most prevalent cancer seen in women worldwide, with about 500,000 cases and over 270,000 deaths estimated annually [1]. This cancer happens when cells change in women’s cervix, which connects uterus with vagina.
Currently, accumulating scientific studies have revealed that cervical cancer is a sexually transmitted disease that results from infection with certain high-risk, oncogenic types of the human papillomavirus (HPV), which is a group of about 100 related virus. Among of them, HPV 16 is the most important HPV-HR-type, and HPV 18 is the second. HPV-HR differs from other HPV types by oncogenic properties of two proteins E6 and E7 that may interfere with cell regulation and differentiation.
In cancer, HPV E6 can take its effects on p53, the cellular tumor suppressor gene. Alterations in the p53 gene usually include deletion, insertion and point mutation. The p53 gene negatively regulates cell cycle and requires "loss of function" mutations for tumor formation [2]. E7 in cancer appears to be owing to its effects on the Rb gene product and its related proteins p107 and p130 [3] [4]. Proliferation of normal cells follows an orderly progression through the cell cycle under the influence of cyclins and cyclin dependent kinases (cdk). These interact, when the cell is released from a quiescent state, and phosphorylate substrates, such as Rb (Figure 1).
Figure 1. Regulators of G1 progression
*this diagram is derived from publication on Cancer [4]
A comprehensive genomic analysis of cervical cancer has revealed several novel gene mutations and amplifications. These mutated genes include SHKBP1, CASP8, HLA-A, TGFBR2 and ERBB3 (about 6% of the tumors), etc. In this article, we list part of these proteins involved in cervical cancer based on the information provided by NCG web resource to analyze duplicability, orthology and network properties of cancer genes).
Here, we display several key targets involved in mechanism of cervical cancer, including:
- FBXW7 (F-box and WD repeat domain containing 7) is a gene that encodes a subunit of Skp1-Cul1-F-box protein (SCF) ubiquitin ligase. SCF FBXW7 targets a set of well-known oncoproteins, involving c-Myc, cyclin E, Notch, c-Jun, and Mcl-1, for ubiquitylation and degradation [5] [6]. FBXW7 has been reported to take part in the regulation of numerous cellular processes, including cell proliferation, cell cycle, apoptosis, and differentiation [7] [8]. It is frequently mutated in cervical squamous cell carcinomas [9].
- HLA-B (major histocompatibility complex, class I, B) is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria. The human leukocyte antigen (HLA) genes are highly polymorphic and have shown to be important risk determinants of HPV infection persistence and disease progression [10].
- NFE2L2 (Nuclear factor, erythroid 2 like 2), a redox-sensitive transcription factor, is ubiquitously expressed in the esophagus, thyroid, and other tissues [11]. NFE2L2-mediated oxidative stress is a prominent feature of cervical cancer, promoting the proliferation, inhibiting the apoptosis, and enhancing the migration and invasion of cervical cancer cells, as well as increasing the tumor chemoresistance [12].
- PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase) is a class I PI 3-kinase catalytic subunit. PIK3CA mutations prevalence in TCGA cervical squamous cell carcinoma study is 27.1%. And PIK3CA mutated cervical cancers display a higher tumor mutation burden (TMB) than non-mutated cancers [13]. Emerging evidence has shown that the expression of gene product (p110α) of PIK3CA was increased, and was subsequently associated with high kinase activity in cervical cancer cell lines harboring amplified PIK3CA.
References
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[9] Faying Liu, Yang Zou, Feng Wang, et al. FBXW7 Mutations Promote Cell Proliferation, Migration, and Invasion in Cervical Cancer [J]. Genet Test Mol Biomarkers. 2019, 23(6):409-417.
[10] Anna Paaso, Anna Jaakola, Stina Syrjänen et al. From HPV Infection to Lesion Progression: The Role of HLA Alleles and Host Immunity [J]. Acta Cytol. 2019, 63(2):148-158.
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[12] Qiang Ju , Xinmei Li, Heng Zhang et al. NFE2L2 Is a Potential Prognostic Biomarker and Is Correlated with Immune Infiltration in Brain Lower Grade Glioma: A Pan-Cancer Analysis [J]. Role of Redox Homeostasis in Cancer Biology and Anticancer Therapy. 2020.
[13] Yen Ying Ma, Sung Jen Wei, Yu Chen Lin et al. PIK3CA as an oncogene in cervical cancer [J]. Oncogene. 2000, 19(23), 2739-2744.
