Background Emerging evidence has identified miR-138 as a tumor suppressor that can suppress the proliferation of various cancers. Meanwhile, the cause of abnormal miR-138 expression in cervical cancer remains uncertain. This study clarified the mechanism by which miR-138 regulates proliferation, invasion, metastasis, and EMT in cervical cancer cells. Results miR-138 expression in human cervical cancer and adjacent normal tissue was measured using qPCR. SiHa and C33A cells were used to determine the function of miR-138 via miR-138 mimic or inhibitor transfection, followed by wound healing, Cell Counting Kit-8, flow cytometry, and Transwell assays. Epithelial and mesenchymal marker expression was analyzed using Western blotting. DNA methylation in the miR-138 promoter was examined using bisulfite sequencing PCR. The downstream target genes of miR-138 were identified via bioinformatics analysis and luciferase reporter assays. A tumor xenograft model was employed to validate DNA methylation-induced miR-138 downregulation and tumor growth inhibition in cervical cancer in vivo. miR-138 levels were significantly lower in cervical cancer tissues than in adjacent control tissues. Furthermore, lower miR-138 expression and higher CpG methylation in the miR-138 promoter were identified in lymph node-positive metastatic cervical cancer tumors versus that in non-metastatic tumor tissues. Upon miR-138 overexpression, cell proliferation, metastasis, invasion, and EMT were suppressed. miR-138 agomir transfection and demethylating drug treatment significantly inhibited cervical tumor growth and EMT in tumor xenograft models. DNA methylation inhibited miR-138 transcription, and enhancer of zeste homolog 2 (EZH2) downregulation mediated the tumor suppressor function of miR-138 in cervical cancer. Conclusion We demonstrated that miR-138 suppresses tumor progression by targeting EZH2 in cervical cancer and uncovered the role of DNA methylation in the miR-138 promoter in its downregulation. These findings demonstrated the potential of miR-138 to predict disease metastasis and/or function as a therapeutic target in cervical cancer.
Purpose: Small-cell carcinoma of the cervix (SCCC) is a rare type of cervical cancer. This study aimed to investigate the clinicopathological characteristics and survival as well as the optimal local treatment modalities for SCCC. Patients and Methods: We retrospectively evaluated the data of patients diagnosed with SCCC between 1988 and 2015 in our institutionthose included in the Surveillance, Epidemiology, and End Results (SEER) database and those in the Periodical Database. Kaplan-Meier method and Cox regression proportional hazard methods were used to evaluate overall survival (OS). A nomogram that could predict OS was constructed based on the Cox proportional hazard model. Results: In total, 695 patients were included in this study. The 5-year overall survival in FIGO stage I-IIA and IIB-IV patients was 45.7% and 14.4%, respectively (P <0.01). Univariate and multivariate analyses showed that lymph node status (P <0.01) and cancerdirected surgery (P <0.01) were independent prognostic factors for FIGO I-IIA stage patients, and age (P <0.05), tumor size (P <0.01), chemotherapy (P <0.01) and radiation (P <0.01) were independent prognostic factors for FIGO stage IIB-IV patients. Conclusion: Better prognosis was associated with negative lymph node status, no lymphatic vasculature, surgery, and early-stage patients. Furthermore, our data showed that the prognosis and treatment pattern varied depending on the FIGO stage, and that optimal treatment modalities included radical surgery for early-stage SCCC and chemoradiotherapy for advanced-stage SCCC. It is helpful to assess the individual prognosis of SCCC patients and choose personalized treatment modalities.
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Mounting evidence has highlighted the immune environment as a critical feature in the development of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). However, the relationship between the clinical characteristics of the immune environment and CESC remain unclear. Therefore, the aim of this study was to further characterize the relationship between the tumor and immune microenvironment and the clinical features of CESC using a variety of bioinformatic methods. Expression profiles (303 CESCs and three control samples) and relevant clinical data were obtained from The Cancer Genome Atlas. We divided CESC cases into different subtypes and performed a differential gene expression analysis. In addition, gene ontology (GO) and gene set enrichment analysis (GSEA) were performed to identify potential molecular mechanisms. Furthermore, data from 115 CESC patients from East Hospital were used to help identify the relationship between the protein expressions of key genes and disease-free survival using tissue microarray technology. Cases of CESC (n = 303) were divided into five subtypes (C1–C5) based on their expression profiles. A total of 69 cross-validated differentially expressed immune-related genes were identified. Subtype C4 demonstrated a downregulation of the immune profile, lower tumor immune/stroma scores, and worse prognosis. In contrast, the C1 subtype showed an upregulation of the immune profile, higher tumor immune/stroma scores, and better prognosis. A GO analysis suggested that changes in CESC were primarily enriched nuclear division, chromatin binding, and condensed chromosomes. In addition, GSEA demonstrated that cellular senescence, the p53 signaling pathway, and viral carcinogenesis are critical features of CESC. Moreover, high FOXO3 and low IGF-1 protein expression were closely correlated with decreased clinical prognosis. In summary, our findings provide novel insight into the relationship between the immune microenvironment and CESC. As such, our results may provide guidance for developing potential immunotherapeutic targets and biomarkers for CESC.
Backgroud Endometrial Carcinoma (EC) is the most common gynecological malignancy among women. Even with a favorable prognosis, cure is still elusive with recurrence, chemotherapy resistance and poor outcome. Poly ADP-ribose polymerase inhibitors (PARPi) have been emerged as promising cancer therapeutics, especially for tumors with deficient homologous recombination (HR) repair. Niraparib for example is well established for ovarian cancer. Metformin, an antidiabetic drug, has been reported to be a new adjunctive strategy for different cancer types, including endometrial cancer. While the effect of Niraparib for EC as monotherapy or in combination with Metformin is still unknown. Method Here we used two types of endometrial cancer cell lines Ishikawa and HEC-1B to detect the effect of Niraparib as monotherapy or in combination with Metformin on cell proliferation, apoptosis, invasion and metastasis. The 50% Inhibitory concentration (IC50) was assessed, and transwell, Annexin V staining, clonogenic assay were applied. Also, western blotting was performed to determine the expression of proteins involved, such as Bax, Caspase-3, Bcl-2, p-AKT, RAD51, γ-H2AX and so on. Results Our study demonstrated that Niraparib inhibited endometrial cell growth in both Ishikawa and HEC-1B cell lines with IC50 0.024umol/L and 0.127umol/L separately. The invasion and metastasis were also suppressed. Annexin V staining showed that Niraparib could significantly promoted apoptosis, which was largely enhanced by Metformin combination therapy (p<0.01). Accordingly, the apoptosis-related proteins Bax, Caspase-3, and DNA damage-related protein RAD51, γ-H2AX were increased, while proliferation-related protein p-AKT, anti-apoptosis-related protein Bcl-2, invasion and metastasis-related protein E-cadherin were decreased, as confirmed by western blotting. Conclusion Niraparib shows the anticancer effect on endometrial cancer cell through inhibiting the cell viability, metastasis and inducing apoptosis, which is significantly enhanced by the combination with Metformin. Our results provide preclinical evidence that the combination of these well-establised drugs may warrant further clinical investigation for endometrial cancer treatment. Citation Format: Qiyu Gan, Jingxin Cheng, Rui Chen, Yachun Bie, Guozeng Wang, Linlin Chang. Combination Niraparib and Metformin synergistically inhibits endometrial cancer cell growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1009.
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