Systematic Construction and Validation of a Novel Ferroptosis-Related Gene Model for Predicting Prognosis in Cervical Cancer.

Methods: Datasets containing RNA sequencing and corresponding clinical data of cervical cancer patients were obtained from searching publicly accessible databases. The "NMF" R package was conducted to calculate the matrix of the screened prognosis gene expression. Ferroptosis-related differential genes in cervical cancer were detected using the "limma" R function and WGCNA. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression analysis were conducted to develop a novel prognostic signature. The prediction model was verified by the nomogram integrating clinical characteristics; the GSE44001 dataset was used as an external verification. Then, the immune status and tumor mutation load were explored. Finally, immunohistochemistry as well as quantitative polymerase chain reaction (RT-qPCR) was utilized to ascertain the expression of FRGs. Results: Two molecular subgroups (cluster 1 and cluster 2) with different FRG expression patterns were recognized. A ferroptosis-related model based on 4 genes (VEGFA, CA9, DERL3, and RNF130) was developed through TCGA database to identify the unfavorable prognosis cases. Patients in cluster 1 showed significantly decreased overall survival in contrast with those in cluster 2 (P < 0.05). The LASSO technique and Cox regression analysis were both utilized to establish the independence of the prognostic model. The validity of nomogram prognostic predictions has been well demonstrated for 3- and 5-year survival in both internal and external data validation cohorts. These two subgroups showed striking differences in tumor-infiltrating leukocytes and tumor mutation burden. The low-risk subgroup showed a longer overall survival time with a higher immune cell score and higher tumor mutation rate. Gene functional enrichment analyses revealed predominant enrichment in various tumor-associated signaling pathways. Finally, the expression of each gene was confirmed by immunohistochemistry and RT-qPCR. Conclusion: A novel and comprehensive ferroptosis-related gene model was proposed for cervical cancer which was capable of distinguishing the patients independently with high risk for poor survival, and targeting ferroptosis may represent a promising approach for the treatment of CC.

[Corrigendum] miR­135 regulated breast cancer proliferation and epithelial­mesenchymal transition acts by the Wnt/ß­catenin signaling pathway.

After the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 2A on p. 1626, the data panels showing the results for the 'Bright/Blank control' and 'Bright/mi­135 inhibitors' experiments appeared to be identical; furthermore, in Fig. 8 on p. 1632, Figs. 8B and D appeared to contain identical data, even though the contrast settings for the two sets of panels were a little different. The authors have re­examined their original data, and regret that Figs. 2 and 8 were inadvertently both assembled incorrectly, as identified by the external reader. However, the authors retained their original data, and were able to reassemble both these figures correctly. The revised versions of Figs. 2 and 8 are shown on the next two pages, now including the correct data for the 'Bright/Blank control' experiment in Fig. 2A and the correct immunofluorescence data in Fig. 8B. Note that the revised data shown for these figures do not affect the overall conclusions reported in the paper. The authors express their gratitude to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [Journal of Molecular Medicine 43: 1623­1634, 2019; DOI: 10.3892/ijmm.2019.4081].

miR-135 regulated breast cancer proliferation and epithelial-mesenchymal transition acts by the Wnt/ß-catenin signaling pathway.

Breast cancer (BC) is the most common cancer in women around the world. microRNAs (miRNAs/miRs) have been proved to be associated with the development and progression of breast cancer. In the present study, to elucidate the effects of dysregulated miR­135 on cells and underlying mechanisms in BC, in vitro and in vivo experiments were conducted. The biological functions of miR­135 were studied using MTT, colony formation, wound healing, transwell assays as well as tumorigenicity analysis. Gain­ and loss­ of function of miR­135 studies revealed that ectopic expression of miR­135 in MDA­MB­468 and MCF­7 cells significantly inhibited cell growth, migration, invasion and EMT, at least in part through inhibiting the activation of the Wnt/ß­catenin pathway. Moreover, this was reversed in cells which were transfected with miR­135 inhibitors. Taken together, the results of the present study provided evidence that miR­135 acted as a tumor suppressor in BC, which may represent a novel therapeutic strategy for the diagnosis and prognosis of BC.

miR-183 modulated cell proliferation and apoptosis in ovarian cancer through the TGF-ß/Smad4 signaling pathway.

An increasing body of evidence has revealed that the aberrant expression of microRNAs (miRNAs/miRs) is involved in the development and progression of ovarian cancer (OC). miR­183 has been demonstrated to act as a tumor suppressor and oncogene in various types of human cancers. However, the biological role of miR­183 in OC still remains unclear. The aim of the present study was to investigate the role of miR­183 and evaluate its underlying mechanism in OC. In the present study, miR­183 was observed to be upregulated in OC tissues and cell lines as determined by reverse transcription­quantitative polymerase chain reaction. The effects of miR­183 on OC were further investigated via western blotting, MTT, wound healing, Transwell and immunofluorescence analyses. Downregulation of miR­183 markedly inhibited cell proliferation, migration and invasion, and promoted apoptosis in OC cells. Furthermore, it was initially confirmed that mothers against decapentaplegic homolog 4 (Smad4) was identified as an efficient target of miR­183 by luciferase activity assay. Finally, the results revealed that miR­183 directly regulated biological function via the transforming growth factor (TGF)­ß/Smad4 signaling pathway in OC cells. In conclusion, the results of the present study suggested that miR­183 exerted tumor­promoting roles in OC, at least partially by regulating Smad4 via the TGF­ß/Smad4 signaling pathway. Therefore, miR­183 may serve as a potential target for the diagnosis and prognosis of OC.

Vaginal cuff length during radical hysterectomy is a prognostic factor for stage IB-IIA cervical cancer: a retrospective study.

PURPOSE: The aim of this study was to investigate the impact of vaginal cuff length (VCL) resected during radical hysterectomy (RH) on the long-term survival outcomes of patients with cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] stage IB-IIA) and to explore whether VCL is a prognostic factor for cervical cancer. METHODS: A total of 435 eligible patients with stage IB and IIA cervical cancer who underwent RH in Zhongnan Hospital of Wuhan University (Wuhan, People's Republic of China) from January 2007 to February 2017 were retrospectively analyzed. These patients were divided into two groups (VCL ≤2.0 cm and >2.0 cm) for further analysis according to the VCL during RH. The Kaplan-Meier method was adopted to calculate the survival rates. Univariate and multivariate Cox regression models were used to analyze independent prognosis factors for survival. RESULTS: Of the 435 identified patients, 196 had VCL ≤2.0 cm and 239 had VCL >2.0 cm after RH. The 5-year disease-free survival (DFS) for the group who had VCL ≤2.0 cm vs the group who had VCL >2.0 cm was 68.1% vs 87.5% (P<0.001). Correspondingly, the overall survival (OS) for the two groups was 71.4% vs 89.2% (P<0.001). More interestingly, the VCL was significantly associated with the 5-year local recurrence rate, but not associated with the distant metastasis rate. In addition to the VCL, FIGO stage and lymph node involvement were also identified as significant prognostic factors for cervical cancer. CONCLUSION: Resection of VCL >2.0 cm in RH has a more favorable long-term outcome than VCL ≤2.0 cm among patients with cervical cancer (FIGO stage IB-IIA); shorter VCL resection was significantly associated with local recurrence, DFS, and OS; thus, it can be considered as a prognostic factor for cervical cancer.

Impact of cervical cancer on quality of life of women in Hubei, China.

We aimed to assess the quality of life (QOL) of the patients with cervical cancer after initial treatment, the factors affecting QOL and their clinical relevance. A total of 256 patients with cervical cancer who visited Zhongnan Hospital of Wuhan University from January 2017 to December 2017 were enrolled in this study. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 item (EORTC QLQ-C30) and cervical cancer module (EORTC QLQ-CX24) was used to assess the QOL of patients. More than half of the patients with cervical cancer reported an excellent QOL. Symptoms mostly experienced were insomnia, constipation, financial difficulties, and menopausal symptoms. Global QOL and social functioning were statistically associated with education level, occupation, the area of living, family income and treatment modality. Similarly, role functioning showed significant association with the stage of cancer, treatment modality and time since diagnosis. The rural area of living and poor economic status of the patients with cervical cancer has a negative impact on overall quality of life. Younger and educated patients are more worried about sexuality. Patients treated with multiple therapies had more problems with their QOL scales than patients treated with surgery only.

MiR-142 inhibits the development of cervical cancer by targeting HMGB1.

It has been reported that miRNAs is deregulated in diverse human cancers, involving human cervical cancer. However, the clinical significances and potential mechanisms of miR-142 in the development and progression of cervical cancer were not elucidated completely till now. In this study, we found that the expression of miR- 142 was obviously down-regulated in human cervical cancer tissues and a panel of cell lines. According to statistics, the expression of miR-142 was negatively related to advanced FIGO stage and lymphatic metastasis (p < 0.001). Furthermore, our functional analysis revealed the overexpression of miR-142 affected cell proliferation and invasiveness, and enhanced cell apoptosis in representative SiHa and HeLa cells. Based on the molecular level, our findings showed the 3' untranslated region (3'-UTR) of high-mobility group box 1 protein (HMGB1) was a direct target of miR-142, and determined an inverse correlation with the expression of miR-142. Ectopic expression of HMGB1 could attenuate the inhibitory impact of miR-142 on the proliferation and invasiveness of cervical cancer cells. In conclusion, the present work suggested that miR-142 affects cervical cancer cell proliferation and invasiveness, and enhances cell apoptosis via directly targeting the expression of HMGB1, and these findings may lay a novel foundation for the promising therapy target of cervical cancer.