Ways to improve the diagnostics and detection of cervical cancer development and recurrence risk

th and the third most common female cancer worldwide. The purpose of the study was to determine risk factors and time to progression and recurrence in patients with cervical cancer after complex treatment (neoadjuvant chemotherapy + radical hysterectomy + combined radiation therapy). Methods: This retrospective study involved female patients with stage IB-IIA cervical cancer registered at Shymkent city oncological dispensary in 2011- 2021 (n=883). All patients underwent (n=883) radical hysterectomy with pelvic lymph node dissection. The patients were selected who underwent radiation therapy of the lower pelvis at a dose of ≥40 g. The age-, stage-, and tumor morphological structure-dependent survival factors and recurrence risk were analyzed during the research decade. Results: Direct correlation of the disease stage and the recurrence period was established. The progression was most often 5 to 6 months after treatment. 68.7% of progression and 63.1% of recurrences occurred in the first year and a half after the end of treatment, so this period is considered the most “dangerous” regarding the recurrence risk. 5.3% of patients had a recurrence 19 to 24 months after treatment, 31.5% – after more than two years. Conclusions: In this research, cervical cancer progressed in 74 (10.6%) out of 883 women and recurred in 19 (3.0%). The recurrence was most frequent in women aged 45-50 years (28.4%) and 50-60 years (26.3%).

Successfully Pregnancy Outcome After LLETZ in Women with Cervical Intraepithelial Neoplasia: A Case Series

BACKGROUND: Human papillomavirus (HPV) has an important role in cervical cancer development and the incidence of cervical intraepithelial neoplasia (CIN) was 1.3–2.7/1000 pregnancies. The HPV and its treatments such as loop electrosurgical excisional procedure (LEEP) or large loop electrosurgical excisional procedure (LLETZ) have an association with poor obstetric outcomes. CASE REPORT: Here, we present four case studies of successful live birth after treatment of CIN. We reported that four patients had been performed LLETZ, with abnormal colposcopy results and liquidbased cytology results were one ASCUS, one ASCH, and two HSIL. The histopathology results were one CIN 1, one CIN 2, and two CIN 3. There was a higher rate of pregnancy for treated women than untreated women. The higher the CIN grades, the more prevalence of cesarean section rate. CONCLUSION: The HPV testing or cotesting at 3-year intervals is recommended after treatment due to the sensitivity of HPV testing. Although pregnancy could delay the progression of precancerous lesions, it is recommended to follow the individualized algorithm in the ASCCP guideline to reduce the risk of cervical cancer progression.

Cervical Cancer Development: Implications of HPV16 E6E7-NFX1-123 Regulated Genes

High-risk human papillomavirus (HR HPV) causes nearly all cervical cancers, half of which are due to HPV type 16 (HPV16). HPV16 oncoprotein E6 (16E6) binds to NFX1-123, and dysregulates gene expression, but their clinical implications are unknown. Additionally, HPV16 E7’s role has not been studied in concert with NFX1-123 and 16E6. HR HPVs express both oncogenes, and transformation requires their expression, so we sought to investigate the effect of E7 on gene expression. This study’s goal was to define gene expression profiles across cervical precancer and cancer stages, identify genes correlating with disease progression, assess patient survival, and validate findings in cell models. We analyzed NCBI GEO datasets containing transcriptomic data linked with cervical cancer stage and utilized LASSO analysis to identify cancer-driving genes. Keratinocytes expressing 16E6 and 16E7 (16E6E7) and exogenous NFX1-123 were tested for LASSO-identified gene expression. Ten out of nineteen genes correlated with disease progression, including CEBPD, NOTCH1, and KRT16, and affected survival. 16E6E7 in keratinocytes increased CEBPD, KRT16, and SLPI, and decreased NOTCH1. Exogenous NFX1-123 in 16E6E7 keratinocytes resulted in significantly increased CEBPD and NOTCH1, and reduced SLPI. This work demonstrates the clinical relevance of CEBPD, NOTCH1, KRT16, and SLPI, and shows the regulatory effects of 16E6E7 and NFX1-123.

From Microbiome to Inflammation: The Key Drivers of Cervical Cancer

Cervical cancer is the third leading cause of cancer-related death worldwide. Microbes and hosts form a mutually beneficial symbiosis relationship, and various parts of the host body are microbial habitats. Microbes can trigger inflammation in certain parts of the host body, contributing to cervical cancer development. This article reviews the relationship between cervicovaginal microbes, inflammation and cervical cancer, and discusses the effect of some key cervical microbes on cervical cancer. Finally, probiotic therapy and immunotherapy are summarized.

HIF-3α-Induced miR-630 Expression Promotes Cancer Hallmarks in Cervical Cancer Cells by Forming a Positive Feedback Loop

Background Hypoxia has crucial functions in cervical cancer development and metastasis by inducing the level of numerous genes, including microRNA genes. But we know little about how the hypoxia factors and microRNAs orchestrate to regulate hallmarks of cervical cancer cells. Methods We used RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing experiments (ChIP-seq) to investigate the targets of HIF-3α or miR-630. ChIP-qPCR and RT-qPCR were used to validate the sequencing results of ChIP-seq and RNA-seq. Cellular, molecular and radiation experiments were used to explore the functions of miR-630.Results Here, we show that hypoxia-induced overexpression HIF-3α increased the expression of dozens of miRNAs, including miR-630. Further experiment showed the activation of miR-630 was induced by hypoxia treatment. We showed that hypoxia induces expression of HIF-3α to activate miR-630 expression by directly binding to its promoter. Meanwhile, miR-630 positively regulates HIF-1α expression, but represses HIF-1α. Stable overexpression of miR-630 in HeLa cells promotes cancer hallmarks, including radioresistance, inhibition of apoptosis, increased migration and invasion, and EMT-mediated metastasis. Stable inhibition of miR-630 showed opposite features. Conclusion Taken together, our findings implicate a novel hypoxia-induced HIF3a-miR-630 regulatory feedback loop contributing to metastasis and progression of cervical cancer cells, and suggest HIF3a and miR630 might be applied as a potential biomarker and therapeutic target for cervical cancer.

Cervical Squamous Intraepithelial Lesions Are Associated with Differences in the Vaginal Microbiota of Mexican Women

Human papillomavirus (HPV) plays a critical role in cervical carcinogenesis but is not sufficient for cervical cancer development, indicating the involvement of other factors. The vaginal microbiota is an important factor in controlling infections caused by HPV, and, depending on its composition, it can modulate the microenvironment in vaginal mucosa against viral infections.

Association study of relationships of polymorphisms in the miR-21, miR-26b, miR-221/222 and miR-126 genes with cervical intraepithelial neoplasia and cervical cancer

Background miR-21, miR-26b, miR-221/222 and miR-126 play crucial roles in cervical cancer development. Studies have shown that polymorphisms in miRNA genes can affect miRNA expression, which might be associated with cancer development. Methods Ten single-nucleotide polymorphisms (SNPs) in the miR-21, miR-26b, miR-221/222 and miR-126 genes (rs1292037, rs13137 in miR-21; rs2227255, rs2227258 in miR-26b; rs2858061, rs34678647, rs2858060, rs2745709 in miR-221/222; rs2297537, rs2297538 in miR-126) were selected, and genotyped in a total of 2176 individuals, including 435 patients with cervical intraepithelial neoplasia (CIN), 743 patients with cervical cancer (CC) and 998 healthy persons using TaqMan assays, and their associations with CIN and CC were evaluated. Results Our results showed significant differences for the rs2297538 genotypes between the CIN and CC groups (P = 0.001). In addition, our results also showed significant differences for the rs2297537 alleles between the CIN and CC groups (P = 0.003), and the C allele of rs2297537 might be associated with a decreased risk of CC (OR = 0.72, 95%CI: 0.58–0.90). At the inheritance analysis, between the CIN and control groups, the T/T-T/C genotype in rs1292037 and A/A-A/T genotype in rs13137 might be associated with an increased risk of CIN in the recessive model (OR = 1.61, 95% CI: 1.17–2.20 and OR = 1.58, 95% CI: 1.15–2.15). In addition, the C/C-T/T genotype of rs2745709 might be associated with a decreased risk of CIN in the overdominant model (OR = 0.66, 95% CI: 0.52–0.82). Between, CIN and CC group, the T/T-C/C genotype in rs1292037 and A/A-T/T genotype in rs13137 might be associated with an increased risk of CC in the overdominant model (OR = 1.43, 95% CI: 1.12–1.81 and OR = 1.42, 95% CI: 1.12–1.80). The rs2297538 G/G-A/G genotype might be associated with an increased risk of CC in the recessive model (OR = 2.83, 95% CI: 1.52–5.25). The rs2297537 2C/C + C/G genotype might be associated with a decreased risk of CC (OR = 0.71, 95% CI: 0.57–0.89) in the log-additive model. The rs2745709 T/T-C/C genotype might be associated with an increased risk of CC (OR = 1.44, 95% CI: 1.13–1.83) in the overdominant model. Conclusion Our results indicate that rs2297538 and rs2297537 in miR-126, rs1292037 and rs13137 in miR-21, and rs2745709 in miR-221/222, may have important roles in the development of CIN or CC.

Identification of a novel circ_0018289/miR-183-5p/TMED5 regulatory network in cervical cancer development

Background Circular RNAs (circRNAs) are increasingly implicated in regulating human carcinogenesis. Previous work showed the oncogenic activity of circ_0018289 in cervical cancer. However, the molecular basis underlying the modulation of circ_0018289 in cervical carcinogenesis is still not fully understood. Methods The levels of circ_0018289, microRNA (miR)-183-5p, and transmembrane p24 trafficking protein 5 (TMED5) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Ribonuclease (RNase) R and subcellular localization assays were used to characterize circ_0018289. Cell proliferation was detected by the Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (Edu) assays. Cell apoptosis and tube formation were assessed by flow cytometry and tube formation assays, respectively. A dual-luciferase reporter assay was performed to confirm the direct relationship between miR-183-5p and circ_0018289 or TMED5. The role of circ_0018289 in tumor growth was gauged by mouse xenograft experiments. Results Circ_0018289 was overexpressed in cervical cancer tissues and cells. Circ_0018289 silencing impeded cell proliferation, enhanced cell apoptosis, and suppressed angiogenesis in vitro, as well as diminished tumor growth in vivo. Mechanistically, circ_0018289 targeted and regulated miR-183-5p by binding to miR-183-5p, and circ_0018289 regulated cervical cancer development and angiogenesis partially through miR-183-5p. Moreover, TMED5 was directly targeted and inhibited by miR-183-5p through the perfect complementary sites in TMED5 3′UTR, and TMED5 knockdown phenocopied miR-183-5p overexpression in suppressing cervical cancer development and angiogenesis. Furthermore, circ_0018289 induced TMED5 expression by competitively binding to shared miR-183-5p. Conclusion Our observations identified the circ_0018289/miR-183-5p/TMED5 regulatory network as a novel molecular basis underlying the modulation of cervical carcinogenesis.

TPP1 Regulates hTERT Expression and Predicts Early Malignant Event and Prognosis of Cervical Cancer

Background: Cervical cancer is one of the most common deadly cancer in women worldwide. However, identifying specific biomarkers is still needed. Telomere-binding protein 1 (TPP1) is vital to telomerase activity. However, the role of TPP1 in cervical cancer and its association with human telomerase reverse transcriptase (hTERT) is unclear.This study aimed at exploring the role of telomere-binding protein 1 (TPP1) in cervical cancer development and progression, and potential mechanisms.Methods: Tissue samples from a total of 274 participants were enrolled for the evaluation of protein expression,156 of whom diagnosed withcervical cancers, 102 with cervical intraepithelial neoplasia (CIN) and 16 with normal cervix. In addition, in vitro cellular models with cervical cancer cell lines Hela, Siha, and C33a were transfected by TPP1-siRNAand protein expression of TPP1 and hTERT were assessed. Results: Compared with normal cervix, TPP1 expression was significantly higher in CIN-III and cervical cancers (P<0.001 for both). High expression of TPP1alone (Plog-rank=0.047)andhigh co-expression of TPP1/hTERT (Plog-rank=0.005)weresignificantly associated with worse survival of cervical cancer patients.After adjusting for well-known prognosis factors, hazard ratio was 2.03(95% confidence interval [CI] 0.99-4.16)for high expression of TPP1 and 2.01(95% CI 1.10-3.67) for high co-expression of TPP1/hTERT. TPP1 and hTERT expressions were positively correlated atall levels of cervical lesions (r=0.524, P<0.001). Knockdown of TPP1 decreased hTERT mRNA and protein expression.Conclusions: High expression of TPP1 might be an early event during cervical cancer development and could be served as apotential prognosis biomarker, especially when used together with hTERT. TPP1 might regulate hTERT expression with detailed underlying mechanisms warrant further investigation.