Invasive Cervical Carcinoma Research Articles

REST/NRSF Silencing Modifies Neuronal Gene Expression in siRNA-Treated HeLa Cells: A Preliminary Exploration in the Search for Neuronal Biomarkers of Cervical Cancer

Background and Objectives: REST (RE1-silencing transcription factor) diminution is associated with transcriptional relaxation, neuropeptide overexpression, and phenotype redefinition in neuroendocrine cancers, but this effect has barely been studied in cervical cancer (CC). We previously reported reduced expressions of REST in samples with premalignant lesions and CC; however, the transcriptional consequences for neural genes associated with reduced REST expression in CC are unknown. Therefore, the objective of this work was to evaluate the expression of neuronal genes in cancerous cells with reduced expression levels of REST. Materials and Methods: Here, we monitored levels of REST by immunostaining along the premalignant lesions and in invasive cervical squamous cell carcinoma (SCC) and endocervical adenocarcinoma (ADC) in tissue samples from female patients from southern Mexico and the derivative cell lines SiHa and HeLa, respectively. Next, we selected REST target genes in silico and explored the effect of REST silencing by RT-PCR in siRNA-treated HeLa cells. Results: The results show a REST diminution in premalignant lesions, SCC, ADC, and cancerous cell lines. Further REST silencing in HeLa cells altered the expression of genes containing the RE1 (Restrictive Element 1) sequence, including CgA (chromogranin A), CHRNβ2 (cholinergic receptor nicotinic β 2 subunit), BDNF (brain-derived neurotrophic factor), CRF (corticotropin-releasing factor), and RASSF1A (Ras association domain family 1). Conclusions: This work provides preliminary evidence of the role of REST loss in the transcriptional regulation of its target genes in HeLa cells, which could have positive implications for the search for new biomarkers of cervical cancer.

HPV genotypes in high-grade cervical lesions and invasive cervical carcinoma detected in Gabonese women

BackgroundCervical cancer is the third most common cancer among women worldwide, but particularly affects women living in sub-Saharan Africa. Screening and vaccination programs are two prevention approaches that can reduce cervical cancer incidence. However, effective vaccination campaigns require better knowledge of the prevalence of the main human papillomavirus (HPV) genotypes reported in high-grade neoplastic lesions and invasive carcinomas in women.MethodsAll samples collected in this study were processed using standard histopathological methods with haematoxylin and eosin staining of the sections. Areas with abnormal cells were then identified. The HPV genotype was determined on the DNA extracted from the same sections using nested PCR followed by amplicon sequencing and real-time PCR specific to five different HPV genotypes (16, 18, 33, 45 and 58).ResultsA total of 132 Gabonese patients with high-grade neoplastic lesions were included in this study; 81% were squamous cell carcinomas (SCC). At least one HPV was detected in 92.4% patients; HPV16 (75.4%) was the most frequent genotype, followed by HPV18, 58, 45, 33 and 35. Moreover, histological analysis showed that SCC samples had 50% and 58.2% stage III and IV tumor cells, respectively, according to the FIGO classification. Finally, 36.9% of these stage III and IV patients were less than 50 years old.ConclusionsOur results confirm the high prevalence of HPV16 and 18 genotypes among high-grade lesions in Gabonese women. This study confirms the need for a national strategy for early screening of precancerous lesions associated with a broad national vaccination program among non-sexually active women to significantly reduce the long-term cancer burden.

An Immunohistochemical Study on Ki-67 Expression in Squamous Cell Carcinomas of Cervix With Clinicopathological Correlation.

Background Cervical carcinoma is one of the most prevalent cancers affecting women worldwide. Studies on Ki-67 expression in cervical lesions had focused mainly on the intraepithelial lesions of the cervix and not much on invasive carcinomas. The few studies published so far on Ki-67 expression in invasive cervical carcinomas have shown inconsistent results on the association of Ki-67 with various clinicopathological prognostic factors. Aims and objectives To assess Ki-67 expression in cervical carcinomas and to compare it with various clinicopathological prognostic factors. Materials and methods Fifty cases of invasive squamous cell carcinoma (SCC) were included in the study. Histological patterns and grades were identified and noted in these cases after microscopic examination of the histological sections. Immunohistochemical (IHC) staining with anti-Ki-67 was done and scored from 1+ to 3+. This score was compared with clinicopathological prognostic factors like clinical stage, histological pattern, and grade. Result Among the 50 cases of SCC, 41 showed keratinizing pattern (82%) and nine showed non-keratinizing pattern (18%). Four were in stage I, 25 were in stage II, and 21 were in stage III. Overall, 34 (68%) cases had Ki-67 score 3+, 11 (22%) had Ki-67 score 2+, and five (10%) had Ki-67 score 1+. Ki-67 score of 3+ was the most common score in keratinizing SCC (75.6%), poorly differentiated carcinomas (76.2%), and stage III cases (81%). Conclusion We observed statistically significant correlation of Ki-67 expression with higher clinical stage, keratinizing tumours, and poorly differentiated tumours (p<0.05) indirectly implying the poor prognostic significance of this marker.

Expression of p16 in cervical intraepithelial neoplasm and invasive cervical carcinoma: An immunohistochemical study

Background: According to WHO-Cervical Cancer is the fourth most common cancer in women. This study evaluated expression of P16 in cervical intraepithelial lesion and cervical carcinoma and its correlation with tumour grade, age, etc.Material and Methods: 106 histopathologically proven Cervical Intraepithelial lesions (CIN) and invasive cervical carcinoma cases were subjected to IHC for p16. Result: Most common age group involved was 51-60years. Bleeding per vaginum was most frequent complaint in Invasive Cervical carcinoma and discharge per vaginum was most frequent complaint in cervical carcinoma patients. P16 showed positivity in only 7.10% of CIN I cases, 30% of CIN II cases, 57.10% of CIN III cases and majority (81.30%) of invasive cervical carcinoma.Conclusion: The expression of P16 positivity increases with increasing grades of dysplasia (Carcinoma>CIN III> CIN II> CIN I).

"I am not a Good Woman?" Exploring the Views and Challenges of Nurses When Discussing HPV Testing and Associated Cervical Screening with Women in Iraq.

Cervical cancer is mostly caused by high-risk Human papillomavirus HPV, with an estimation prevalence of HPV of 99.7% worldwide. The US Food and Drug Administration (FDA) approved an HPV test for primary cervical screening in 2014. An HPV-DNA test, which provides higher protection against invasive cervical carcinomas, is replacing the long-standing Pap smear as the primary method of cervical cancer screening. To explore nurses' experience and knowledge of HPV DNA testing and how screening impacts on women's health through increasing awareness and proposing actions for health education strategies. A qualitative exploratory study was conducted on a purposeful sample of 25 qualified nurses, who were all employed in regional hospitals within a gynecological department in Kirkuk, Iraq. The nurses were interviewed with a semi-structured topic guide between November 2021 and February 2022. Responses were transcribed verbatim, translated into English and analysed using a content thematic analysis approach. Four themes with associated sub-themes emerged following coding and peer review. Participants had lack of experience and fragmented knowledge of HPV DNA testing/screening. Culturally sensitive resources for patients and training for nurses was identified key requirements. Currently, there are no facilities for a HPV testing/screening services available in Iraq. The role of nurses undertaking HPV screening is not established and yet nurses represent the largest sector of health professionals. The dissemination of a collaborative HPV screening training programme to include clinical competence and knowledge for nurses and gynaecologists may improve knowledge, and could also be effective in improving patient awareness and engagement with cervical health.

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

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. 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. 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. 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.

Network modeling suggests HIV infection phenocopies PI3K-AKT pathway mutations to enhance HPV-associated cervical cancer.

Women coinfected with human immunodeficiency virus type 1 (HIV-1) and human papillomavirus (HPV) are six times as likely to develop invasive cervical carcinoma compared to those without HIV. Unlike other HIV-associated cancers, the risk of cervical cancer development does not change when HPV/HIV coinfected women begin antiretroviral therapy, suggesting HIV-associated immune suppression is not a key driver of cervical cancer development in coinfected women. Here, we investigated whether the persistent secretion of inflammatory factors in HIV-positive patients on antiretroviral therapy could enhance cancer signaling in HPV-infected cervical cells via endocrine mechanisms. We integrated previously reported HIV-induced secreted inflammatory factors (Hi-SIFs), HIV and HPV virus-human protein interactions, and cervical cancer patient genomic data using network propagation to understand the pathways underlying disease development in HPV/HIV coinfection. Our results pinpointed the PI3K-AKT signaling pathway to be enriched at the interface between Hi-SIFs and HPV-host molecular networks, in alignment with PI3K pathway mutations being prominent drivers of HPV-associated, but HIV independent, cervical cancer development. Furthermore, we experimentally stimulated cervical cells with 14 Hi-SIFs to assess their ability to activate PI3K-AKT signaling. Strikingly, we found 8 factors (CD14, CXCL11, CXCL9, CXCL13, CXCL17, AHSG, CCL18, and MMP-1) to significantly upregulate AKT phosphorylation (pAKT-S473) relative to a phosphate buffered saline control. Our findings suggest that Hi-SIFs cooperate with HPV infection in cervical cells to over-activate PI3K-AKT signaling, effectively phenocopying PI3K-AKT pathway mutations, resulting in enhanced cervical cancer development in coinfected women. Our insights could support the design of therapeutic interventions targeting the PI3K-AKT pathway or neutralizing Hi-SIFs in HPV/HIV coinfected cervical cancer patients.

P16 and EGFR analyses in cervical carcinoma on paraffin material in Egyptian females: the NCI experience

Abstract Introduction Cervical cancer is considered the fourth most prevalent malignant tumor in women worldwide. In Egypt, it ranks as the 14th most frequent cancer among women. Epidermal growth factor receptor has been an attractive target for anticancer therapy. Although EGFR mutations are less commonly seen in cervical cancer, there is a potential correlation between EGFR expression level and clinical response. Overexpression of p16INK4a is associated with increased overall and disease-free survival in cervical cancer, thus denoting a better prognosis. Aim of the work To investigate the expression of EGFR and p16 by immunohistochemistry as well as amplification of EGFR by FISH technique in cervical carcinoma among Egyptian females. Material and methods Seventy-seven cases of invasive cervical carcinomas were retrieved from paraffin blocks. EGFR and p16 expression were assessed by immunohistochemistry. EGFR gene amplification was assessed by FISH analysis. Results p 16 Positivity was detected in 62.3% of cases. Positive reaction to EGFR (score 3+) was detected in 20.8% of cases. The EGFR gene was not amplified in 77.9% of cases. Statistical significance was found between histological type, p16, and EGFR expression. A fair agreement was detected between EGFR expression and EGFR amplification. Poor agreement was detected between p16, EGFR expression, and EGFR amplification. Conclusion EGFR and p16 have an independent role in the development of cervical cancer in Egyptian females. EGFR overexpression and EGFR amplification represent two different genetic events; in other words, an increase in gene copy number does not mean that there will be an increase in the function of the gene as expressed by an increase in protein expression.

Performance of Aptima HPV E6/E7 mRNA Test for Detection of Cervical Lesions in a Large Chinese Population.

We aimed to examine the effectiveness of Aptima HPV E6/E7 mRNA test for detection of cervical lesions in a large Chinese population. Overall, 4,350 women, who received simultaneously Aptima HPV E6/E7 mRNA test and HPV DNA test, followed by cervical biopsy in the Department of Gynecology of the Second Affiliated Hospital of Soochow University, Jiangsu Province, China from 2016-2020, were recruited. The detection of cervical lesions was compared between Aptima HPV E6/E7 mRNA test and HPV DNA test. Overall, HPV DNA test exhibited a higher detection of all cervical lesions than Aptima HPV E6/E7 mRNA test (P<0.05), and showed a higher efficacy for detection of normal tissues and chronic cervicitis (P<0.05) and low-grade squamous intraepithelial lesions (LSILs) (P<0.05) than Aptima HPV E6/E7 mRNA test; while Aptima HPV E6/E7 mRNA test showed a greater detection of high-grade squamous intraepithelial lesions (HSILs) (P<0.05) and invasive cervical carcinoma than HPV DNA test. Aptima HPV E6/E7 mRNA test exhibited a higher specificity P<0.05), positive and negative prediction rates than HPV DNA test for detection of cervical lesions, and the sensitivity was comparable between the two tests (P>0.05). Aptima HPV E6/E7 mRNA test gradually improves the detection of cervical lesions with disease severity, and shows a higher specificity, positive and negative prediction rates and comparable sensitivity for detection of clinical cervical lesions as compared with HPV DNA test.

Frequency of Abnormal Pap Smear Cytology in Women with Post-Coital Bleeding

Risk of development of cervical carcinoma has been identified in patients with abnormal cytology on Pap smear. A long duration of prior to development of invasive cervical carcinoma is governed by a precancerous lesion. Consequently, screening and proper treatment reduces the overall risk of cervical carcinoma. Objective: Aim of study was to identify the frequency of abnormal cervical cytology detected by Papanicolaou smear in married child bearing female presenting with bleeding following coitus. Methods: A Descriptive, Cross-sectional study was carried from 15th November 2021 to 31st May 2022 in the Department of Obstetrics and Gynecology, Jinnah Post graduate Medical Centre, Karachi. A total of 218 females of reproductive age group (18-50 years) presenting with post-coital bleeding were included. Patients with previously histo pathological diagnosis, ablative or excisional treatment modalities of cervix and trauma to genital tract were excluded. All cases underwent Pap smear testing with standard technique by utilization of Ayre's spatula and were fixated with 95% ethanol on microscopic slides. Two specimens were prepared for each patient and were assessed for abnormalities. Results: Patients encountered were between 18 to 50 years with mean of 32.20 ± 7.80 years. Majority (139; 67.43%) of the patients were between 18 to 35 years. Mean parity was 3.53 ± 1.51. Mean BMI was 29.12 ± 2.37 kg/m2. Frequency of abnormal cervical cytology was found in 37 (16.97%). Conclusions: This study concluded that Pap smear is an easy, effective and a cheap method for detecting women with cervical pathology.

PAX1 Methylation Status in Cervical Scrapes as Novel Diagnostic Biomarker in CIN 2/3 and Invasive Squamous Cell Carcinoma.

DNA methylation of paired box-1 (PAX-1) gene has been shown to be a potential biomarker for the detection of high-grade cervical intra-epithelial neoplasia (CIN) and invasive cervical cancer. The objective of this pilot study was to quantify and compare methylation percentage of PAX1 gene in benign cervical lesion, pre-invasive and invasive cervical cancer. A total of 200 screen positive women (VIA, VILI and Pap test) underwent colposcopy. Cervical scrapes taken were taken and stored for DNA analysis and PAX 1 methylation status. Women with Swede score of 5 or more (n = 98) were biopsied. Cervical scrapes and biopsy were taken from women with obvious cervical growth (n = 14), without prior colposcopy. Sixty women were recruited to the study and allocated into three groups on the basis of histopathology, i.e., benign cervix (Group 1; n = 20), CIN 2/3 (Group 2; n = 20) and invasive cervical carcinoma (Group; n = 20). PAX 1 methylation percentage was calculated from the DNA extracted from the cervical scrapes of the women recruited. The mean PAX1 methylation percentage in benign lesions, CIN 2/3 and invasive cancer was 9.58% (SD ± 2.37%), 18.21% (SD ± 2.67%) and 24.34% (SD ± 4.09%), respectively, with p-value of < 0.001. PAX 1 gene methylation has a promising role in identifying high-grade lesions and invasive cancer.

Alteration of Na/H exchange regulatory factor-1 protein levels in anogenital lesions positive for mucosal high-risk human papillomavirus type 16

Mucosal high-risk (HR) human papillomaviruses (HPV) are associated with anogenital carcinogenesis. The products of two early genes, E6 and E7, act as major viral oncoproteins. Functional studies in experimental models showed that HPV16 E6 induces degradation of the PDZ protein, the Na+/H+ exchanger regulatory factor-1 (NHERF-1). Here, we determined NHERF-1 protein levels by immunohistochemistry (IHC) in (i) benign anogenital warts (n = 8) (ii) premalignant lesions (L-SIL and H-SIL) (n = 43) and (iii) invasive cervical squamous cell carcinomas (SCC) (n = 17). A decrease of NHERF-1 protein level was not observed in genital warts in comparison to healthy epithelium. Conversely, a clearly decrease in NHERF-1 protein levels was observed in HPV16-positive pre-malignant and malignant lesions, while the phenomenon was much attenuated in lesions induced by other HR HPV types. In conclusion, these findings show that mucosal HPV types differently impact on NHERF-1 protein level in benign and malignant anogenital lesions.

A Review on the Use of the HPV Vaccine in the Prevention of Cervical Cancer.

The main risk factor for invasive cervical carcinoma is persistent infection by the high-risk human papillomavirus (HPV). HPV is the most prevalent sexually transmitted infection (STI) and has been linked to 15 different cancers. Cervical cancer is one of the most frequent cancers among women, particularly in resource-limited countries. Cervical cancer is an HPV disease with the highest worldwide burden in resource-limited nations. With improved medical care and nationwide screening programmes, the mortality rate from cervical cancer has decreased in the past 40 years. Many developing nations have been shown to have inadequate knowledge and health-seeking practices, making proper awareness and immunisation programmes necessary. The best strategy to reduce the incidence of cervical cancer is through the administration of HPV vaccines along with routine cervical screening. The HPV vaccine is crucial for public health. Vaccinations against all HPV subtypes, namely, bivalent, quadrivalent, and nonavalent, are available. Financial issues are the main barrier to HPV vaccination. The framework for behavioural and social drivers of vaccination, which includes practical concerns, motivation, social processes, thoughts, and feelings, is widely used to uncover important aspects linked with HPV vaccination. The burden of cervical cancer due to HPV and the advantages of HPV vaccination are summarised in this review article.

The Creation of the Suppressive Cancer Microenvironment in Patients with HPV-Positive Cervical Cancer.

The development of malignancy is closely connected with the process of cancer microenvironment remodeling. As a malignancy develops, it stimulates the creation of the suppressive microenvironment of the tumor through the presence of cells that express membrane proteins. These proteins are secreted into the cancer microenvironment, where they enable tumor growth. In patients with cancer of the cervix, the development of the disease is also linked to high-risk HPV (hr-HPV) infection. Such infections are common, and most clear spontaneously; however, a small percentage of these infections can persist and progress into precancerous cervical intraepithelial neoplasia and invasive cervical carcinoma. Consequently, it is assumed that the presence of hr-HPV infection alone is not sufficient for the development of cancer. However, chronic HPV infection is associated with the induction of the remodeling of the microenvironment of the epithelium. Furthermore, the local microenvironment is recognized as a cofactor that participates in the persistence of the HPV infection and disease progression. This review presents the selected immune evasion mechanisms responsible for the persistence of HPV infection, beginning with the delay in the virus replication process prior to the maturation of keratinocytes, the shift to the suppressive microenvironment by a change in keratinocyte immunomodulating properties, the alteration of the Th1/Th2 polarization of the immune response in the microenvironment, and, finally, the role of HLA-G antigen expression.

Diagnosis of Cervical Intraepithelial Neoplasia and Invasive Cervical Carcinoma by Cervical Biopsy under Colposcopy and Analysis of Factors Influencing.

Objective To explore the diagnosis of cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma (ICC) by cervical biopsy under colposcopy and analyze the factors influencing the detection. Methods The clinical data of 134 CIN confirmed by colposcopy biopsy in our hospital from June 2018 to October 2019 and subsequent LEEP treatment were analyzed retrospectively. All patients were diagnosed pathologically after the operation. The diagnosis of CIN by cervical biopsy under colposcopy was observed. The influencing factors of CIN and ICC detected by colposcopy biopsy were analyzed by the pathological results of loop electrosurgical excision procedure (LEEP) as the gold standard. Results After LEEP, the number of the no intraepithelial or malignant lesions (NILM) or ICC were higher than that of colposcopy biopsy, and CIN-III was lower than that of colposcopy biopsy, the differences were all statistically significant (P < 0.05). Among the 134 patients, the coincidence rate between colposcopy biopsy and LEEP examination results was 79.10% (106/134), and postoperative pathological findings showed that there were 13 cases (9.70%) with the pathological upgrade and 19 cases (14.18%) with pathological decrease. Multivariate logistic analysis showed that the image quality of colposcopy image, atypical blood vessels, biopsy sampling method, and visible lesion area of the cervix were the independent influencing factors for the detection of CIN and ICC by colposcopy biopsy (P < 0.05). Conclusion CIN and ICC can be diagnosed by colposcopy cervical biopsy and postoperative histopathology. However, there are still some missed and misdiagnosed cervical biopsies under colposcopy, and the combined detection of the two can further ensure the diagnosis rate. The clinical registration number is E2018091.

GLUT1, LDHA, and MCT4 Expression Is Deregulated in Cervical Cancer and Precursor Lesions.

Metabolic reprogramming is typical in cancerous cells and is required for proliferation and cellular survival. In addition, oncoproteins of high-risk human papillomavirus (HR-HPV) are involved in this process. This study evaluated the relationship between glucose transporter I (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter type 4 (MCT4) expression and cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma (ICC) with HR-HPV infection. The protein expression was evaluated in women with CIN I (n=20), CIN II/III (n=16), or ICC (n=24) by immunohistochemistry. The protein expression was analyzed qualitatively by van Zummeren score and quantitatively by Image ProPlus 6 software. LDHA expression increases in HPV-16 infection. In the CIN I group, GLUT1 immunostaining has a 35% protein expression at the membrane level at more than two thirds of the epithelium, which increased by 21.25% more in CIN II/III in more than two thirds of the epithelium. While LDHA and MCT4 in CIN I mostly do not present immunostaining, or this was only limited to the basal stratum, this expression is increased in CIN II/III and ICC cases. The GLUT1, LDHA, and MCT4 expression increased in ICC. The overexpression in high-grade CIN with HR-HPV infection shows a higher risk for cervical carcinoma progression.

AIB1 is a novel target of the high-risk HPV E6 protein and a biomarker of cervical cancer progression.

The high‐risk human papillomaviruses (HPV‐16, ‐18) are critical etiologic agents in human malignancy, most importantly in cervical cancer. These oncogenic viruses encode the E6 and E7 proteins that are uniformly retained and expressed in cervical cancers and required for maintenance of the tumorigenic phenotype. The E6 and E7 proteins were first identified as targeting the p53 and pRB tumor suppressor pathways, respectively, in host cells, thereby leading to disruption of cell cycle controls. In addition to p53 degradation, a number of other functions and critical targets for E6 have been described, including telomerase, Myc, PDZ‐containing proteins, Akt, Wnt, mTORC1, as well as others. In this study, we identified Amplified in Breast Cancer 1 (AIB1) as a new E6 target. We first found that E6 and hTERT altered similar profiling of gene expression in human foreskin keratinocytes (HFK), independent of telomerase activity. Importantly, AIB1 was a common transcriptional target of both E6 and hTERT. We then verified that high‐risk E6 but not low‐risk E6 expression led to increases in AIB1 transcript levels by real‐time RT‐PCR, suggesting that AIB1 upregulation may play an important role in cancer development. Western blots demonstrated that AIB1 expression increased in HPV‐16 E6 and E7 expressing (E6E7) immortalized foreskin and cervical keratinocytes, and in three of four common cervical cancer cell lines as well. Then, we evaluated the expression of AIB1 in human cervical lesions and invasive carcinoma using immunohistochemical staining. Strikingly, AIB1 showed positivity in the nucleus of cells in the immediate suprabasal epithelium, while nuclei of the basal epithelium were negative, as evident in the Cervical Intraepithelial Neoplasia 1 (CIN1) samples. As the pathological grading of cervical lesions increased from CIN1, CIN2, CIN3 carcinoma in situ and invasive carcinoma, AIB1 staining increased progressively, suggesting that AIB1 may serve as a novel histological biomarker for cervical cancer development. For cases of invasive cervical carcinoma, AIB1 staining was specific to cancerous lesions. Increased expression of AIB1 was also observed in transgenic mouse cervical neoplasia and cancer models induced by E6E7 and estrogen. Knockdown of AIB1 expression in E6E7 immortalized human cervical cells significantly abolished cell proliferation. Taken together, these data support AIB1 as a novel target of HPV E6 and a biomarker of cervical cancer progression.

Perceptions and attitude of women of Luderitz, Namibia on Pap smear and cervical cancer prevention

BackgroundCervical cancer is one of the leading malignancies globally and has taken third place in Namibia amongst women aged 15–44 years. Infection with the Human Immunodeficiency Virus (HIV) has been proven to increase women’s susceptibility to developing cervical carcinoma. Sadly, Namibia carries a twin burden of HIV and cervical cancer. Namibians are aware of HIV/AIDS, but remain poorly informed about cervical cancer. Furthermore, among those who are aware of the disease, low utilisation of screening tests have been reported.ObjectiveThe purpose was to explore perceptions and attitudes held by women about cervical cancer, reasons for low uptake of Pap smear testing amongst those who are aware of the malignancy as well as unearth motivation factors that has fuelled women to go for screening.MethodologyA descriptive, cross-sectional study was conducted using convenience sampling as a sampling technique. The survey instrument used was a self-administered questionnaire. It consisted of both closed and open ended questions. A total of 136 women were surveyed.Results and conclusionThe level of awareness for cervical cancer (92.6%) and Pap smear (93.4%) were high. Most were able to identify that Pap smear test is used for screening for pre-cancerous lesions. However, knowledge about the impact of a HIV positive status along with co infection with HPV as the leading causes for progression of invasive cervical carcinoma was not well known. Knowledge about the other risk factors such as multiple sexual partners (39.7%), early sex debut (34.9%) and smoking was poorly demonstrated. This suggests that a high awareness level does not necessarily translate into having a good perception or understanding of a disease. A good attitude towards screening was observed although less than half of the study population reported ever having a test done.

A predictive study of metabolism reprogramming in cervical carcinoma

BackgroundMetabolic reprogramming has been identified as a hallmark of cancer, influencing the immunity in the tumor microenvironment. Because of the high-heterogeneity of cervical carcinoma, we aim to figure out the metabolic subtypes of cervical carcinoma indicating the prognosis.MethodsWe profiled the distinct metabolic signatures using data from transcriptomes obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Bioinformatics analyses were conducted to identify the possible biomarkers of overall survival and chemotherapy resistance.ResultsImmune infiltration was closely related to metabolic pathways, especially in the carbohydrate pathway and the lipid and energy pathway. Two distinct clusters of differentially expressed genes were identified. Six genes were selected as possible indicators of prognosis, including ELK3, BIN2, MEI1, CCR7, CYP4F12, and DUOX1, relating to the immune status of tumor microenvironment. Under the risk score model based on metabolic genes, the high-risk group showed significantly lower survival (HR =6.802, with 95% CI: 3.637−12.721, P<0.0001), higher possibility of chemotherapy resistance, and higher infiltration of anti-tumor immune cells compared to the low-risk group.ConclusionsMetabolic reprogramming, especially in the carbohydrate pathway and the lipid and energy metabolic pathway, is associated with the immune cell microenvironment, which is crucial for the prognosis of Invasive cervical carcinoma (ICC), providing potential therapeutic targets in clinic.

Clinical significance of CD34, podoplanin and Ki-67 expression in patients with locally advanced squamous cell cervical carcinoma

The aim of the study was to assess immunohistochemical CD34, podoplanin and Ki-67 expression in cervical tumour of patients with cervical squamous cell carcinoma (SCC) staged IIB and IIIB, a relationship with selected clinical and histological parameters and its prognostic significance. This prospective study included 52 patients. Microvessel density (MVD) by CD34, lymphatic vessel density (LVD) by podoplanin and the Ki-67 index in specimens from paraffin blocks with cervical SCC tissues were examined. The relationship between these data and selected clinical and histological parameters was analysed. Positive correlation of MVD and the Ki-67 index was observed. No correlation was observed for MVD, LVD and the Ki-67 index in the tumour with staging, grading, length of treatment and squamous cell carcinoma antigen (SCC-Ag) concentration before and after treatment. The expression of MVD, LVD and the Ki-67 index in cervical SCC did not contribute to the risk of relapse and cancer-related death. No relationship was found for MVD, LVD and the Ki-67 index in cervical tumour of patients with locally advanced cervical SCC with staging, grading and serum SCC-Ag level. MVD, LVD and the Ki-67 index in the tumour did not contribute to the risk of relapse or cervical SCC-related death. Impact Statement What is already known on this subject? In many patients, invasive cervical squamous cell carcinoma (SCC) is diagnosed in a locally advanced stage, when the prognosis depends on many well-known factors connected with tumour biology, staging and general condition of the patient. Despite numerous studies, the value of immunohistochemical CD34, podoplanin and Ki-67 expression in cervical tumour of these patients is still not well defined. What do the results of this study add? In our prospective study, no relationship for microvessel density (MVD), lymphatic vessel density (LVD) and the Ki-67 index in cervical tumour of patients with locally advanced cervical SCC with staging, grading and serum squamous cell carcinoma antigen (SCC-Ag) level was found. Additionally, MVD, LVD and the Ki-67 index in the tumour did not contribute to the risk of relapse or cervical SCC-related death. What are the implications of these findings for clinical practice and/or further research? Our study underlines the limited value of immunohistochemical CD34, podoplanin and Ki-67 expression in cervical tumour of patients with locally advanced cervical SCC. Further research should be focussed on identifying and validating novel prognostic and predictive factors.