Qing Li

The Dual Role of DNA Methylation Test Can Optimize the Clinical Application of High‐Risk Human Papillomavirus Testing in Detecting Cervical Intraepithelial Neoplasia Grade 3 or Worse

ABSTRACT With the rapid development and maturation of high‐risk human papillomavirus (hrHPV) genotyping kits, it is crucial to understand the specific patterns of methylation in different hrHPV statuses, rather than simply categorizing them as hrHPV positive or negative. To achieve this goal, we first assessed the prevalence and CIN3+ risk of specific hrHPV genotypes in 184 cervical scrapings and then evaluated the performance of five host genes methylation to distinguish CIN3+ from <CIN3 not only among hrHPV‐positive and hrHPV‐negative women, but also among women positive for HPV16, HPV18, HPV52, and HPV58. The results showed that women with HPV16 infections had a higher risk of developing CIN3+ than women with other hrHPV infections. More importantly, we found that hrHPV testing caused a high false‐positive rate (43.54%) and leading to over‐referral of <CIN3 cases. Triage of patients with HPV 52/58 positive using ZIC1 m could accurately identify all CIN3+ cases to avoid over‐referral of false‐positive cases. In addition, implementing primary hrHPV testing resulted in 5.7% of CIN3+ patients being missed in our study. Our exploratory analysis found that DNA methylation of specific genes, including ZIC1 m , ZNF582 m , PAX1 m , and MIR129‐2 m , could lower the high false‐positive rate and find 80% (4/5) missed CIN3+ cases caused by hrHPV testing. This study substantiates the dual role of DNA methylation detection in cervical cancer screening. By incorporating methylation detection, the existing HPV‐based screening strategy can be further optimized to achieve precise risk stratification and facilitate the shift from cervical cancer screening to personalized and precise management.

Serinc2 Drives the Progression of Cervical Cancer Through Regulating Myc Pathway

ABSTRACTBackgroundAs one of the most common malignancies, cervical cancer (CC) seriously affects women's health. This study aimed to investigate the biological function of Serinc2 in CC.MethodsSerinc2 expression was surveyed utilizing immunohistochemistry, western blot, and qRT‐PCR. CC cell viability, invasion, proliferation, migration, and apoptosis, were detected via CCK‐8, Transwell assay, colony formation, wound healing assay, and flow cytometry. Glucose consumption, lactate production, and ATP levels were determined by the corresponding kit. The protein expression of c‐Myc, PDK1, HK2, PFKP, LDHA, Snail, Vimentin, N‐cadherin, and E‐cadherin was detected via western blot. The interaction between the promoter of PFKP and Myc was confirmed through luciferase reporter assay and Chip assay. In vivo, to evaluate the function of Serinc2 on tumor growth, a xenograft mouse model was used.ResultsIn CC tissues and cells, Serinc2 was upregulated. In CC cells, knockdown of Serinc2 suppressed cell invasion, proliferation, migration, decreased the expression of Snail, Vimentin, N‐cadherin, HK2, PFKP, LDHA, and PDK1, increased E‐cadherin expression, reduced glucose consumption and the production of lactate and ATP, and induced cell apoptosis; Serinc2 overexpression led to the opposite results. Mechanically, Serinc2 promoted Myc expression, and Myc induced PFKP expression. Furthermore, overexpressed Myc abolished the inhibitive influences of Serinc2 knockdown on the malignant behaviors of CC cells. Additionally, knockdown of Serinc2 inhibited tumor growth and reduced the protein expression of c‐Myc, PFKP, LDHA, and PDK1 in vivo.ConclusionsKnockdown of Serinc2 inhibited the malignant progression of CC, which was achieved via Myc pathway. Our study provides novel insight into CC pathogenesis.

Correlation Analysis of Prognostic Gene Expression, Tumor Microenvironment, and Tumor-Infiltrating Immune Cells in Ovarian Cancer

Objective. Tumor microenvironment (TME) research can provide a crucial direction for the innovation and continuous improvement of novel biologic therapies for cancer. This study examined the relationship between the TME, expression profiles of the tumor-infiltrating immune cell, and prognostic gene expression in ovarian cancer (OC). Materials and Methods. Screening of CD3E, CD3G, CD2, CD3D, CCL19, and IL2RG was performed using the bioinformatics methods. Results. All six genes were found to participate in immune-related molecular mechanisms and could regulate the expression of tumor-infiltrating cells. A Kaplan–Meier survival analysis results demonstrated a strong association between overall survival and all gene expressions in patients with OC. CIBERSORT analysis results showed that the expression level of all genes was positively correlated with γδ T cell proportions. Conclusion. Therefore, in the OC microenvironment, CD3E, CD3G, CD2, CD3D, CCL19, and IL2RG can be potential immunotherapy targets and prognostic markers.

Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT

Abstract Background Metastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is overexpressed in cervical cancer. However, the biological role and mechanism of APE1 in cervical cancer metastasis have rarely been studied. Methods We used gene set enrichment analysis (GSEA) to determine the APE1-related signaling pathways in cervical cancer. To investigate the role and mechanism of APE1 in cervical cancer metastasis and invasion, immunohistochemistry, immunofluorescence, western blotting, secondary structure prediction, coimmunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were performed. The inhibitory effects of the APE1 redox function inhibitor APX3330 on cervical cancer metastasis were evaluated using animal models. Results Clinical data showed that high expression of APE1 was associated with lymph node metastasis in cervical cancer patients. GSEA results showed that APE1 was associated with epithelial to mesenchymal transition (EMT) in cervical cancer. Ectopic expression of APE1 promoted EMT and invasion of cervical cancer cells, whereas inhibition of APE1 suppressed EMT and invasion of cervical cancer cells in a redox function-dependent manner. Notably, APE1 redox function inhibitor APX3330 treatment dramatically suppressed cervical cancer cell lymph node and distant metastasis in vivo. Furthermore, we found that APE1 enhanced the interaction between ZEB1 and the E-cadherin promoter by binding to ZEB1, thereby suppressing the expression of E-cadherin, a negative regulator of EMT. Conclusion Our findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis.

Chromatin modified protein 4C (CHMP4C) facilitates the malignant development of cervical cancer cells

Despite improvements in prevention and treatment, cervical cancer (CC) still poses a serious threat to women’s health. CHMP4C (chromatin modified protein 4C) is a subunit of the endosomal sorting complex required for transport, which is expressed in both nucleus and cytoplasm. Here, we examined the effect of CHMP4C on the biological behavior of CC cells and the underlying mechanisms. We report that CHMP4C expression is higher in CC tissues, and high CHMP4C expression is associated with lower survival. Up‐regulation of CHMP4C in C‐33A cells accelerates cell proliferation, migration and invasion, whereas down‐regulation of CHMP4C in Ca Ski cells had the opposite effect. Moreover, overexpression of CHMP4C induced activation of the epithelial–mesenchymal transition pathway, whereas depletion of CHMP4C inhibited activation. Our results suggest that CHMP4C contributes to the viability and motility of CC cells by modulating epithelial–mesenchymal transition and may facilitate the identification of novel biomarkers for CC therapy.

ZNF671 methylation test in cervical scrapings for cervical intraepithelial neoplasia grade 3 and cervical cancer detection

Effective triage of high-risk human papillomavirus (hrHPV)+ women is warranted to avoid unnecessary referral and overtreatment. Molecular triage tests have recently begun to impact cervical intraepithelial neoplasia grade 3 (CIN3) or cervical cancer (CC), termed CIN3+, detection. We find that zinc finger protein 671 methylation (ZNF671