Cervical cancer in low and middle-income countries

Abstract

Cervical cancer is a malignant tumour that occurs in the cervix and is classified into two histological types, adenocarcinoma and squamous cell carcinoma (SCC); SCC is more common and accounts for 70% of all cases. In 2018 there were ~569,000 new cases of cervical cancer diagnosed worldwide and ~311,000 deaths were attributed to cervical cancer. Of these, between 84 and 90% occurred in low- and middle-income countries (LMICs) such as South Africa, India, China and Brazil. The most common cause of cervical cancer is persistent infection caused by the sexually transmitted human papilloma virus. Other factors that contribute to the incidence of cervical cancer include geography, traditional practices and beliefs, the screening levels, socioeconomic status, healthcare access, public awareness, use of oral contraceptives, smoking and co-infection with HIV. An estimated 11 million women from LMICs will be diagnosed with cervical cancer in the next 10-20 years. The aim of this review was to explore various types of genetic and epigenetic factors that influence the development, progression or suppression of cervical cancer.

Keywords: Brazil; India; South Africa; Tanzania; cervical cancer; miRNA.

Figure 1.

Incidence of cervical cancer. (A) Worldwide incidence by country. (B) The difference in incidence and mortality rates based on economic development compared with the global average. (C) Incidence and mortality rates based on geographic location.

Figure 2.

Risk factors associated with the development of cervical cancer. HPV infection is the most important risk factor associated with the development of cervical cancer. The risk of infection with HPV is associated with various sexual and reproductive factors, which further increase the risk of developing cervical cancer. HPV, human papilloma virus; CIN, cervical intraepithelial neoplasia; TLR, toll-like receptor.

Figure 3.

Long non-coding RNA LINC00673 serves an anti-tumour function by controlling PTPN11 degradation. The figure demonstrates how mutations due to SNPs in LINC00673 can promote the development of squamous cell carcinoma. An SNP at position rs11655237 in LINC00673 can increase the risk of developing cervical cancer. A decrease in the level of the normal wild type and an increase in the level of a variant known as LINC00673A that contains a G-to-A nucleotide substitution at rs11655237 may cause dysregulated transcription and result in an increase in the risk of developing cervical cancer. PTPN11, tyrosine-protein phosphatase non-receptor type 11; SRC-ERF, proto-oncogene tyrosine protein kinase-ETS domain-containing transcription factor; STAT, signal transducer and activation of transcription.

Figure 4.

Pathways of aberrant alternative splicing resulting in diseases such as cervical cancer. The flow chart depicts the causes, mechanisms and results of aberrant alternative splicing. Aberrant alternative splicing is caused by genomic point mutations in splicing factors or elements. These lead to changes in splicing and different populations of splice variants, such as exon alteration, intron retention, alteration in 3′ and 5′ splicing, mutually exclusive introns, alteration in polyA tail length or occurrence of multiple promoters. Aberrant alternative splicing can contribute to a variety of pathologies. SR protein, serine arginine domain splicing factors; hnRNP, Heterogeneous nuclear ribonucleoproteins.

Figure 5.

Aberrant alternative splicing of the IL1RAP gene leads to immune evasion and development of cervical cancer. The synthesis of mIL1RAP is controlled by the SRSF10 splicing factor. This allows the alternative splicing of the iLIl1rap exon 13 to form the mRNA corresponding to the membrane-bound isoform. This stimulates the IL-1β-induced NF-κB-mediated transcription of CD47, allowing the tumour cells to avoid phagocytosis by macrophages. CD47, CD antigen 47; E2F1, E2 Transcription factor 1; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; IL1RAP, interleukin-1-receptor accessory protein; mIL1RAP, membrane form of interleukin-1-receptor accessory protein; p65, transcription factor 65; SRSF10, serine- and arginine-rich splicing factor 10.

Figure 6.

TLR4 signaling pathways in cervical cancer. (A) Binding of LPS to TLR4 leads to the transmission of signals via MyD88, At the same time the activation of TLR5 leads to increased Nox1 signaling. The primary role of NOX1 is to generate ROS. NOX1 signaling also leads to the inhibition of HIF-1α degradation, which increases the possibly of developing cervical cancer MyD88 signaling in conjunction with NOX1 leads to the activation of transcription factors and Interfrons (IFN), leading to a pro-inflammatory and antiviral response. This pathway demonstrates how inflammation can lead to cancer progression. CD1, cluster differentiation 1; HIF-1α, hypoxia inducible factor 1α; IL-6, interleukin 6; IFN, interferon; IRAK, interleukin-1 receptor-associated kinase; IRF3, interferon regulatory factor 3; LPS, lipopolysaccharides; MyD8, myeloid differentiation primary response 8; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nox1, NADPH oxidase 1; PHDs, propyl hydroxylases; Rac1, ras-related C3 botulinum toxin substrate 1; TAK1, transforming growth factor beta-activated kinase 1; TLR, toll-like receptor; Traf6, tumor necrosis factor receptor (TNFR)-associated factor 6; NADH, nicotinamide adenine dinucleotide hydrogen.

Figure 6.

TLR4 signaling pathways in cervical cancer. (A) Binding of LPS to TLR4 leads to the transmission of signals via MyD88, At the same time the activation of TLR5 leads to increased Nox1 signaling. The primary role of NOX1 is to generate ROS. NOX1 signaling also leads to the inhibition of HIF-1α degradation, which increases the possibly of developing cervical cancer MyD88 signaling in conjunction with NOX1 leads to the activation of transcription factors and Interfrons (IFN), leading to a pro-inflammatory and antiviral response. This pathway demonstrates how inflammation can lead to cancer progression. CD1, cluster differentiation 1; HIF-1α, hypoxia inducible factor 1α; IL-6, interleukin 6; IFN, interferon; IRAK, interleukin-1 receptor-associated kinase; IRF3, interferon regulatory factor 3; LPS, lipopolysaccharides; MyD8, myeloid differentiation primary response 8; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nox1, NADPH oxidase 1; PHDs, propyl hydroxylases; Rac1, ras-related C3 botulinum toxin substrate 1; TAK1, transforming growth factor beta-activated kinase 1; TLR, toll-like receptor; Traf6, tumor necrosis factor receptor (TNFR)-associated factor 6; NADH, nicotinamide adenine dinucleotide hydrogen.

Figure 7.

Increased expression of ROCK1 in cancer may be due to decreased levels of miR-217. ROCK1 expression is regulated by miR-217. Lower transcript levels of this miRNA are associated with metastatic and non-metastatic cervical cancer. Overexpression of miR-217 significantly inhibits cell growth. ROCK1 leads to increased invasion and metastasis. ERK, extracellular signal-regulated kinases; ERM, ezrin, radixin and moesin; LIM kinase, Lin11, Isl-1 and Mec-3 kinase; miR, microRNA; MLC phosphatase, myosin light-chain phosphatase; ROCK1, rho-associated coiled-coil containing protein kinase 1.