Human Papillomavirus-associated Cervical Cancer Research Articles

Analysis of Human Papillomavirus-Associated Cervical Cancer Differentially Expressed Genes and Identification of Prognostic Factors using Integrated Bioinformatics Approaches

Background: Human papillomavirus (HPV)-induced cervical cancer progresses through a series of steps. Despite our limited understanding of the mechanisms driving this progression, identifying the key genes involved could significantly improve early detection and treatment. Materials and Methods: Two gene expression profiles of GSE9750 and GSE6791, which included cervical cancer HPV-positive and -negative samples, were evaluated using the R limma package with established cut-off criteria of P value < 0.05 and | fold change| ≥ 1. KEGG pathway enrichment was performed to identify potential pathways. Weighted gene co-expression network analysis (WGCNA) was used to discover co-expressed gene modules and trait–module connections. Results: Considering the defined criteria, 115 differentially expressed genes (DEGs) were identified. The DEG’s KEGG pathway enrichment analysis revealed enrichment in highly relevant pathways to the HPV infection, including cell cycle, viral carcinogenesis, autophagy-animal, Epstein-Barr virus infection, human T-cell leukemia virus 1 infection, and microRNAs in cancer. WGCNA results in 13 co-expression modules, and the magenta module is identified with significant relations to HPV, cervical cancer stage, and metastasis traits. The survival analysis identified BEX1 and CDC45 as potential prognostic factors in HPV-associated cervical cancer. Conclusion: The innovation of our work lies in identifying essential genes associated with the multi-step process of cervical carcinogenesis. In fact, the current study has the potential to give a distinct viewpoint on the molecular pathways linked to cervical cancer. Considering the potential importance of the hub genes, we recommend conducting in-depth wet lab research to determine their impact on the biological mechanisms of cervical cancer.

In vitro study of HPV18-positive cervical cancer HeLa cells based on CRISPR/Cas13a system

The E6 protein is a known oncogene in cervical cancer and plays a key role in the development and progression of cervical cancer by reducing the expression level of the tumor suppressor protein P53 and ultimately leading to enhanced cell proliferation and reduced apoptosis. Therefore, antiviral agents that inhibit the expression of E6 oncoprotein are expected to be potential therapies for human cervical cancer. Here we developed CRISPR/Cas13a: crRNA dual plasmid system and demonstrated that CRISPR/Cas13a could effectively and specifically knock down human papillomavirus 18 E6 mRNA, downregulate the expression level of E6 protein, and restore the expression of the tumor suppressor gene P53 protein, thereby inhibiting the growth of cervical cancer cells and increasing their apoptosis, the E6-2, E6-3, and E6-5 groups resulted in apoptosis rates of 25.4%, 22.4%, and 22.2% in HeLa cells. Moreover, CRISPR/Cas13a enhances the proliferation inhibition and apoptosis induction of cisplatin in cervical cancer HeLa cells. The CRISPR/Cas13a system targeting HPV E6 mRNA may be a promising therapeutic approach for the treatment of human papillomavirus-associated cervical cancer.

Bioinformatics analysis to identify the relationship between human papillomavirus-associated cervical cancer, toll-like receptors and exomes: A genetic epidemiology study.

Genetic variants may influence Toll-like receptor (TLR) signaling in the immune response to human papillomavirus (HPV) infection and lead to cervical cancer. In this study, we investigated the pattern of TLR expression in the transcriptome of HPV-positive and HPV-negative cervical cancer samples and looked for variants potentially related to TLR gene alterations in exomes from different populations. A cervical tissue sample from 28 women, which was obtained from the Gene Expression Omnibus database, was used to examine TLR gene expression. Subsequently, the transcripts related to the TLRs that showed significant gene expression were queried in the Genome Aggregation Database to search for variants in more than 5,728 exomes from different ethnicities. Cancer and HPV were found to be associated (p<0.0001). TLR1(p = 0.001), TLR3(p = 0.004), TLR4(221060_s_at)(p = 0.001), TLR7(p = 0.001;p = 0.047), TLR8(p = 0.002) and TLR10(p = 0.008) were negatively regulated, while TLR4(1552798_at)(p<0.0001) and TLR6(p = 0.019) were positively regulated in HPV-positive patients (p<0.05). The clinical significance of the variants was statistically significant for TLR1, TLR3, TLR6 and TLR8 in association with ethnicity. Genetic variants in different TLRs have been found in various ethnic populations. Variants of the TLR gene were of the following types: TLR1(5_prime_UTR), TLR4(start_lost), TLR8(synonymous;missense) and TLR10(3_prime_UTR). The "missense" variant was found to have a risk of its clinical significance being pathogenic in South Asian populations (OR = 56,820[95%CI:40,206,80,299]). The results of this study suggest that the variants found in the transcriptomes of different populations may lead to impairment of the functional aspect of TLRs that show significant gene expression in cervical cancer samples caused by HPV.

Novel computational and drug design strategies for inhibition of human papillomavirus-associated cervical cancer and DNA polymerase theta receptor by Apigenin derivatives

The present study deals with the advanced in-silico analyses of several Apigenin derivatives to explore human papillomavirus-associated cervical cancer and DNA polymerase theta inhibitor properties by molecular docking, molecular dynamics, QSAR, drug-likeness, PCA, a dynamic cross-correlation matrix and quantum calculation properties. The initial literature study revealed the potent antimicrobial and anticancer properties of Apigenin, prompting the selection of its potential derivatives to investigate their abilities as inhibitors of human papillomavirus-associated cervical cancer and DNA polymerase theta. In silico molecular docking was employed to streamline the findings, revealing promising energy-binding interactions between all Apigenin derivatives and the targeted proteins. Notably, Apigenin 4′-O-Rhamnoside and Apigenin-4′-Alpha-l-Rhamnoside demonstrated higher potency against the HPV45 oncoprotein E7 (PDB ID 2EWL), while Apigenin and Apigenin 5-O-Beta-d-Glucopyranoside exhibited significant binding energy against the L1 protein in humans. Similarly, a binding affinity range of − 7.5 kcal/mol to − 8.8 kcal/mol was achieved against DNA polymerase theta, indicating the potential of Apigenin derivatives to inhibit this enzyme (PDB ID 8E23). This finding was further validated through molecular dynamic simulation for 100 ns, analyzing parameters such as RMSD, RMSF, SASA, H-bond, and RoG profiles. The results demonstrated the stability of the selected compounds during the simulation. After passing the stability testing, the compounds underwent screening for ADMET, pharmacokinetics, and drug-likeness properties, fulfilling all the necessary criteria. QSAR, PCA, dynamic cross-correlation matrix, and quantum calculations were conducted, yielding satisfactory outcomes. Since this study utilized in silico computational approaches and obtained outstanding results, further validation is crucial. Therefore, additional wet-lab experiments should be conducted under in vivo and in vitro conditions to confirm the findings.

Role of extracellular vesicle in human papillomavirus-associated cervical cancer.

Cervical cancer is a gynecological malignant tumor and a serious threat to women's health. Although human papillomavirus (HPV) infection and the occurrence of cervical cancer are known to be closely related, the underlying carcinogenic mechanism of HPV is not fully understood. Extracellular vesicles (EVs) are found in a variety of body fluids and play an important role in both intercellular communication and cancer progression. Furthermore, the presence of EVs makes liquid biopsy of cervical cancer possible. The study of EVs in cervical cancer can provide clinical ideas for the diagnosis and treatment of the disease. The purpose of this article is to summarizes the role of EV contents in HPV-associated cervical cancer and discusses the possible clinical application of EVs in cervical cancer treatment. The search terms included the following: HPV with cervical cancer and extracellular vesicles. The initial literature search ended on March 1, 2023. In HPV-positive cervical cancer, EV contents are changed due to the presence of HPV. HPV-positive cervical cancer affects the cell microenvironment and other surrounding cells through the secretion of EVs.

Carcinogenesis and management of human papillomavirus-associated cervical cancer.

Approximately 95% of cervical cancer are caused by human papillomavirus (HPV) infection. Although it is estimated that HPV-associated cervical cancer will decrease with the widespread use of HPV vaccine, it may take time for HPV-associated cervical cancer to be eliminated. For the appropriate management of HPV-associated cervical cancer, it is important to understand the detailed mechanisms of cervical cancer development. First, the cellular origin of most cervical cancers is thought to be cells in the squamocolumnar junction (SCJ) of the uterine cervix. Therefore, it is important to understand the characteristics of SCJ for cervical cancer screening and treatment. Second, cervical cancer is caused by high risk HPV (HR-HPV) infection, however, the manner of progression to cervical cancer differs depending on the type of HR-HPV: HPV16 is characterized by a stepwise carcinogenesis, HPV18 is difficult to detect in precancerous lesions, and HPV52, 58 tends to remain in the state of cervical intraepithelial neoplasia (CIN). Third, in addition to the type of HPV, the involvement of the human immune response is also important in the progression and regression of cervical cancer. In this review, we demonstrate the carcinogenesis mechanism of HPV-associated cervical cancer, management of CIN, and the current treatment of CIN and cervical cancer.

Human Papilloma Virus-Associated Cervical Cancer and Health Disparities.

Cervical cancer develops through persistent infection with high-risk human papilloma virus (hrHPV) and is a leading cause of death among women worldwide and in the United States. Periodic surveillance through hrHPV and Pap smear-based testing has remarkably reduced cervical cancer incidence worldwide and in the USA. However, considerable discordance in the occurrence and outcome of cervical cancer in various populations exists. Lack of adequate health insurance appears to act as a major socioeconomic burden for obtaining cervical cancer preventive screening in a timely manner, which results in disparate cervical cancer incidence. On the other hand, cervical cancer is aggressive and often detected in advanced stages, including African American and Hispanic/Latina women. In this context, our knowledge of the underlying molecular mechanism and genetic basis behind the disparate cervical cancer outcome is limited. In this review, we shed light on our current understanding and knowledge of racially disparate outcomes in cervical cancer.

ТР53 Codon 72 Polymorphism and Human Papilloma Virus-Associated Cervical Cancer in Kyrgyz Women

Background:The aim of this study was to ascertain the magnitude of association of gene ТР53 Arg72Pro polymorphic marker with cervical cancer (CC) in Kyrgyz women. Methods:We identified and included 205 women of Kyrgyz ethnicity for this case-control study, of whom N=103 were women (mean age 53.5 ± 10.0 years) with histologically confirmed CC and N=102 controls (mean age 46.5 ± 8.5 years). We detected human papilloma virus (HPV) DNA types 16 and 18 using polymerase chain reaction (PCR) with hybridization/fluorescent detection. Genotypes of ТР53 gene Arg72Pro polymorphism were identified using PCR-RFLP assay.Results:Eighty-eight percent (90/103) women with CC had HPV, of whom 43.4% (39/90) had HPV type 16, 24.4% (22/90) had HPV type 18, whereas 32.2% (29/90) carried both types. The univariate analysis of allele and genotype distribution of Arg72Pro polymorphic marker of ТР53 gene showed no difference between CC and control groups (χ2=1.24, р=0.54). However, when CC cases associated with HPV were tested against controls, Arg72 allele and Arg72Arg genotype prevalence were greater compared to controls (χ²=7.25; р=0.027 for genotypes and χ²=6.83; р=0.009 for alleles). In HPV-positive women, Arg72Arg genotype of ТР53 gene was associated with a 1.85-fold increase in the likelihood of CC (OR=1.85 [95% confidence interval (CI) 1.03-3.32]), whereas Arg72 allele increased this likelihood 1.94-fold (OR=1.94 [95% CI 1.20-3.15]). Conclusions:Arg72Arg genotype and Arg72 allele of ТР53 gene in Kyrgyz women increase the risk of HPV-associated CC.

Recurrence of Cervical Cancer in Mice after Selective Estrogen Receptor Modulator Therapy

Estrogen and its nuclear receptor, estrogen receptor α, are necessary cofactors in the initiation and multistage progression of carcinogenesis in the K14E6/E7 transgenic mouse model of human papillomavirus-associated cervical cancer. Recently, our laboratory reported that raloxifene, a selective estrogen receptor modulator, promoted regression of high-grade dysplasia and cancer that arose in the cervix of K14E6/E7 transgenic mice treated long-term with estrogen. Herein, we evaluated the recurrence of cervical cancer after raloxifene therapy in our preclinical model of human papillomavirus-associated cervical carcinogenesis. We observed recurrence of cervical cancer in mice re-exposed to estrogen after raloxifene treatment, despite evidence suggesting the antagonistic effects of raloxifene persisted in the reproductive tract after treatment had ceased. We also observed recurrence of neoplastic disease in mice that were not retreated with exogenous estrogen, although the severity of disease was less. Recurrent neoplastic disease and cancers retained functional estrogen receptor α and responded to retreatment with raloxifene. Moreover, continuous treatment of mice with raloxifene prevented the emergence of recurrent disease seen in mice in which raloxifene was discontinued. These data suggest that cervical cancer cells are not completely eradicated by raloxifene and rapidly expand if raloxifene treatment is ceased. These findings indicate that a prolonged treatment period with raloxifene might be required to prevent recurrence of neoplastic disease and lower reproductive tract cancers.

Expression and characterization of transforming protein E7 from cervical cancer-associated human papillomavirus type 31

E7 protein is a major oncogenic factor of human papillomaviruses (HPVs) that plays a key role in virus-associated human cervical carcinogenesis. To determine the biochemical properties of the E7 protein of high-risk HPV type 31, the gene encoding the protein was cloned into a bacterial vector, pET-32a (+), to allow expression of HPV-31E7 as a thioredoxin (Trx) fusion protein in Escherichia coli BL21 (DE3). The resulting expression level of the fusion protein reached 15 ∼ 20% of the total cell protein and more than 60% of the target proteins were in soluble form upon cultivation for 6 h at 30°C in the presence of 0.5 mM IPTG. The fusion protein Trx-HPV-31E7 was effectively purified by Ni2+-chelating chromatography and analyzed by SDS-PAGE and Western blotting. After release from the fusion protein by enterokinase cleavage and purification to homogeneity, the recombinant HPV-31E7 (rHPV-31E7) was investigated for in vitro interaction with the pocket protein p107, which is known to interact with the amino-terminal portion of the protein. The immunoprecipitation studies revealed strong interactions of rHPV-31E7 protein with p107, suggesting it had binding activities and retained its conformational properties.

Cervical Cancer-Associated Human Papillomavirus 16 E7 Oncoprotein Inhibits Induction of Anti-Cancer Immunity by a CD4+ T Cell Dependent Mechanism

AbstractAttempts to develop therapeutic vaccines against cervical cancer have been proven difficult. One of the major causes of the failure is due to the use of the wrong mouse models based on transplantable tumours in testing the efficacy of vaccines. Now that a transgenic epithelial mouse model has been developed to closely mimic cervical cancer, the mechanisms needed to eliminate this type of cancer could be studied. The E7 oncoprotein of Human Papillomavirus (HPV) is the most expressed HPV protein in cervical cancers and its continuous production is essential to maintain the cancerous state and therefore the obvious target in the development of vaccines. Skin grafts expressing the HPV 16 E7 protein (E7 autografts) are not spontaneously rejected from an MHC matched immunocompetent host. Interestingly, simultaneous placement of an MHC mismatched skin (allograft) next to an E7 autograft results in the E7 autograft rejection. However when the allograft also expresses E7, the E7 autograft is rejected more slowly. Autograft rejection requires CD8+ T cells, and is accelerated by removal of CD4+ T cells after placement of the E7 expressing allograft, suggesting induction of an E7 specific CD4+ regulatory T cell population by the E7 expressing allograft. This observation may have implications in designing effective vaccines and immunotherapy against cervical cancers in women.

Cervical Cancer-Associated Human Papillomavirus 16 E7 Oncoprotein Inhibits Induction of Anti-Cancer Immunity by a CD4+ T Cell Dependent Mechanism

Cervical Cancer-Associated Human Papillomavirus 16 E7 Oncoprotein Inhibits Induction of Anti-Cancer Immunity by a CD4+ T Cell Dependent Mechanism

Genetic variant of CCND1: Association with HPV-mediated cervical cancer in Indian population

The potential association of single nucleotide polymorphisms (SNPs) (G870A and G1722C) of CCND1 with susceptibility to cervical cancer was investigated. The study included 200 cervical cancer cases along with an equal number of healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and direct sequencing were employed for genotyping. We found that women carrying the 870AA genotype have a 2.49-fold increased risk for the development of cervical cancer (odds ratio (OR) 2.49; 95% confidence interval (CI) 1.51–4.09; p = 0.0004) compared with GG+GA genotypes. For the 1722 locus, the frequency of the polymorphic ‘C’ allele was strongly associated with a reduced risk of cervical cancer (p = 0.019; OR 0.71; 95% CI 0.54–0.94). Our data suggest that CCND1 G870A polymorphism could act as a risk factor for the development of cervical cancer. And G1722C polymorphism may play a protective role against the development of human papillomavirus-associated cervical cancer among Indian women.

Treating Cancer as an Infectious Disease—Viral Antigens as Novel Targets for Treatment and Potential Prevention of Tumors of Viral Etiology

BackgroundNearly 20% of human cancers worldwide have an infectious etiology with the most prominent examples being hepatitis B and C virus-associated hepatocellular carcinoma and human papilloma virus-associated cervical cancer. There is an urgent need to find new approaches to treatment and prevention of virus-associated cancers.Methodology/Principal FindingsViral antigens have not been previously considered as targets for treatment or prevention of virus-associated cancers. We hypothesized that it was possible to treat experimental HPV16-associated cervical cancer (CC) and Hepatitis B-associated hepatocellular carcinoma (HCC) by targeting viral antigens expressed on cancer cells with radiolabeled antibodies to viral antigens. Treatment of experimental CC and HCC tumors with 188Re-labeled mAbs to E6 and HBx viral proteins, respectively, resulted in significant and dose-dependent retardation of tumor growth in comparison with untreated mice or mice treated with unlabeled antibodies.Conclusions/SignificanceThis strategy is fundamentally different from the prior uses of radioimmunotherapy in oncology, which targeted tumor-associated human antigens and promises increased specificity and minimal toxicity of treatment. It also raises an exciting possibility to prevent virus-associated cancers in chronically infected patients by eliminating cells infected with oncogenic viruses before they transform into cancer.

Future of RNAi-Based Therapies for Human Papillomavirus-Associated Cervical Cancer

Over 99% of cervical cancers are associated with infection of high-risk type human papillomaviruses (HPV). These viruses infect epithelial cells lining the cervix and express the early viral genes E6 and E7, which are oncogenes and are primarily responsible for the transformation of the epithelial cells. The continuous expression of those genes is essential for maintenance of the cancer cell phenotype and viability. These viral genes can be silenced using oligonucleotide-based techniques, for example RNAi, antisense RNA and ribozymes. In spite of promising results in vitro and in vivo, in mice, these methods have thus far proved unsuccessful in humans, owing to the lack of an effective delivery system amongst other limitations. In this review we will discuss potential gene-silencing strategies in cervical cancer that would target both viral genes such as E6 and E7, and cellular genes that become deregulated such as E2F, p53, Akt, mTor, NF-κB or Bcl-2. By investigating these approaches we may generate an effective treatment for HPV-induced cervical cancer using gene silencing.

TLR9 Expression and Function Is Abolished by the Cervical Cancer-Associated Human Papillomavirus Type 16

Cervical cancer development is linked to the persistent infection by high-risk mucosal human papillomaviruses (HPVs) types. The E6 and E7 major oncoproteins from this dsDNA virus play a key role in the deregulation of the cell cycle, apoptosis, and adaptive immune surveillance. In this study, we show for the first time that HPV type 16 (HPV16), the most carcinogenic type among the high-risk subgroup, interferes with innate immunity by affecting the expression of TLRs. Infection of human primary keratinocytes with HPV16 E6 and E7 recombinant retroviruses inhibits TLR9 transcription and hence functional loss of TLR9-regulated pathways. Similar findings were achieved in HPV16-positive cancer-derived cell lines and primary cervical cancers, demonstrating that this event occurs also in an in vivo context. Interestingly, E6 and E7 from the low-risk HPV type 6 are unable to down-regulate the TLR9 promoter. In addition, E6 and E7 from the high-risk HPV type 18, which are known to persist less competently in the host than HPV16, have reduced efficiency compared with HPV16 in inhibiting TLR9 transcription. Furthermore, a CpG motif derived from the HPV16 E6 DNA sequence activated TLR9, indicating this virus is able to initiate innate responses via the receptor it later down-regulates. This study reveals a novel mechanism used by HPV16 to suppress the host immune response by deregulating the TLR9 transcript, providing evidence that abolishing innate responses may be a crucial step involved in the carcinogenic events mediated by HPVs.

Detection of autoantibodies to survivin in cervical mucus from patients with human papillomavirus-associated cervical cancer and precursor lesions

Objectives. To investigate the prevalence of mucosal autoantibodies to survivin in patients with human papillomavirus (HPV)-associated cervical cancer and precursor lesions.Methods. Cervical mucus from 117 HPV-associated cervical cancer, 102 high-grade squamous intraepithelial lesion (HSIL), 107 low-grade SIL (LSIL), and 80 normal controls were tested by ELISA using either full length recombinant survivin or survivin-derived peptides. Survivin expression in cervical tissue biopsies was studied by Western Blotting.Results. Cervical mucus from 33 cervical cancer (28.2%), 17 HSIL (16.6%), and 8 LSIL (7.4%) patients reacted with recombinant survivin. The IgA-class antibody response was significantly higher than that observed in the normal controls. The level of mucosal anti-survivin response was associated to the level and intensity of survivin expression in the different lesions. Finally, reactivity against a survivin Nt-derived peptide was found more frequently than reactivity against a Ct-derived peptide.Conclusions. IgA-class autoantibodies against survivin are present in a substantial proportion of cervical mucus from patients with HPV-associated cervical cancer, and precursor lesions. Mucosal anti-survivin response is positively associated with the level of survivin expression and the grade of cervical lesion.

Cyclin A1 promoter hypermethylation in human papillomavirus-associated cervical cancer

BackgroundThe aim of this study was to evaluate epigenetic status of cyclin A1 in human papillomavirus-associated cervical cancer. Y. Tokumaru et al., Cancer Res 64, 5982-7 (Sep 1, 2004)demonstrated in head and neck squamous-cell cancer an inverse correlation between cyclin A1 promoter hypermethylation and TP53 mutation. Human papillomavirus-associated cervical cancer, however, is deprived of TP53 function by a different mechanism. Therefore, it was of interest to investigate the epigenetic alterations during multistep cervical cancer development.MethodsIn this study, we performed duplex methylation-specific PCR and reverse transcriptase PCR on several cervical cancer cell lines and microdissected cervical cancers. Furthermore, the incidence of cyclin A1 methylation was studied in 43 samples of white blood cells, 25 normal cervices, and 24, 5 and 30 human papillomavirus-associated premalignant, microinvasive and invasive cervical lesions, respectively.ResultsWe demonstrated cyclin A1 methylation to be commonly found in cervical cancer, both in vitro and in vivo, with its physiological role being to decrease gene expression. More important, this study demonstrated that not only is cyclin A1 promoter hypermethylation strikingly common in cervical cancer, but is also specific to the invasive phenotype in comparison with other histopathological stages during multistep carcinogenesis. None of the normal cells and low-grade squamous intraepithelial lesions exhibited methylation. In contrast, 36.6%, 60% and 93.3% of high-grade squamous intraepithelial lesions, microinvasive and invasive cancers, respectively, showed methylation.ConclusionThis methylation study indicated that cyclin A1 is a potential tumor marker for early diagnosis of invasive cervical cancer.

Cell Cycle Regulatory Protein Expression Profiles by Adenovirus p53 Infection in Human Papilloma Virus-associated Cervical Cancer Cells

The tumor suppressor gene, p53, has been established as an essential component for the suppression of tumor cell growth. In this study, we investigated the time-course anticancer effects of adenoviral p53 (Adp53) infection on human ovarian cancer cells to provide insight into the molecular-level understanding of the growth suppression mechanisms involved in Adp53-mediated apoptosis and cell cycle arrest. Three human cervical cancer cell lines (SiHa, CaSki, HeLa and HT3) were used. The effect of Adp53 infection was studied via cell count assay, cell cycle analysis, FACS, Western blot and macroarray assay. Adp53 exerts a significant role in suppressing cervical cancer cell growth. Adp53 also showed growth inhibitory effects in each cell line, and it induced apoptosis and cell cycle arrest. Adp53 differentially regulated the expression of genes and proteins, and the gene expression profiles in the SiHa cells revealed that the p21, p53 and mdm2 expressions were significantly up-regulated at 24 and 48 hr. Western blot shows that the p21 and p53 expression-levels were significantly increased after Adp53 infection. In addition, in all cell lines, both the CDK4 and PCNA protein expression levels were decreased 48 h after Adp53 infection. Cell cycle arrest at the G1 phase was induced only in the SiHa and HeLa cells, suggesting that exogenous infection of Adp53 in cancer cells was significantly different from the other HPV-associated cervical cancer cells. Adp53 can inhibit cervical cancer cell growth through induction of apoptosis and cell cycle arrest, as well as through the regulation of the cell cycle-related proteins. The Adp53-mediated apoptosis can be employed as an advanced strategy for developing preferential tumor cell-specific delivery.

Interleukin-2 (IL-2) receptor-βγ signalling is activated by c-Kit in the absence of IL-2, or by exogenous IL-2 via JAK3/STAT5 in human papillomavirus-associated cervical cancer

Activation of the interleukin-2 receptor (IL-2R) induces signalling cascades promoting T cell proliferation. However, signal transduction pathways triggered in IL-2R-expressing solid tumours are unknown. This report shows that human papillomavirus (HPV)-associated cervical cancer cells express an IL-2R composed of β and γ chains (IL-2Rβγ), and that IL-2-mediated activation increases the phosphorylation of JAK3 and STAT5, stimulating cell proliferation. Interestingly, endogenous IL-2 is not produced by these cells, suggesting the activation of IL-2Rβγ by an alternative mechanism. Accordingly, we found that Stem Cell Factor (SCF)-activated c-Kit induces phosphorylation of the IL-2Rβ chain in the absence of IL-2. Moreover, inhibition of IL-2Rβ phosphorylation by blocking c-Kit tyrosine kinase activity abolishes both, IL-2 and SCF-mediated proliferation. Thus, these results demonstrate that IL-2 triggers a JAK3/STAT5 cascade in HPV-associated cervical cancer cells expressing IL-2Rβγ, and that this receptor can be alternatively activated by SCF-activated c-Kit in the absence of IL-2.