Cuproptosis-Associated lncRNA Gene Signature Establishes New Prognostic Profile and Predicts Immunotherapy Response in Endometrial Carcinoma.

Uterine corpus endometrial carcinoma (UCEC), a prevalent kind of cancerous tumor in female reproductive system that has a dismal prognosis in women worldwide. Given the very limited studies of cuproptosis-related lncRNAs (CRLs) in UCEC. Our purpose was to construct a prognostic profile based on CRLs and explore its assess prognostic value in UCEC victims and its correlation with the immunological microenvironment. METHODS: 554 UCEC tumor samples and 23 normal samples' RNA-seq statistics and clinical details were compiled from data in the TCGA database. CRLs were obtained using Pearson correlation analysis. Using LASSO Cox regression, multivariate Cox regression, and univariate Cox regression analysis, six CRLs are confirmed to develop a risk prediction model at last.We identified two main molecular subtypes and observed that multilayer CRLs modifications were related to patient clinicopathological features, prognosis, and tumor microenvironment (TME) cell infiltration characteristics, and then we verified the prognostic hallmark of UCEC and examined its immunological landscape.Finally, using qRT-PCR, model hub genes' expression patterns were confirmed. RESULTS: A unique CRL signature was established by the combination of six differently expressed CRLs that were highly linked with the prognosis of UCEC patients. According to their CRLs signatures, the patients were divided into two groups: the low-risk and the high-risk groups. Compared to individuals at high risk, patients at low risk had higher survival rates (p < 0.001). Additionally, Cox regression reveals that the profiles of lncRNAs linked to cuproptosis may independently predict prognosis in UCEC patients. The 1-, 3-, and 5-year risks' respective receiver operating characteristics (ROC) exhibited AUC values of 0.778, 0.810, and 0.854. Likewise, the signature could predict survival in different groups based on factors like stage, age, and grade, among others. Further investigation revealed differences between the different risk score groups in terms of drug sensitivity,immune cell infiltration,tumor mutation burden (TMB) score and microsatellite instability (MSI) score. Compared to the group of high risk, the low-risk group had greater rates of TMB and MSI. Results from qRT-PCR revealed that in UCEC vs normal tissues, AC026202.2, NRAV, AC079466.2, and AC090617.5 were upregulated,while LINC01545 and AL450384.1 were downregulated. CONCLUSIONS: Our research clarified the relationship between CRLs signature and the immunological profile and prognosis of UCEC.This signature will establish the framework for future investigations into the endometrial cancer CRLs mechanism as well as the exploitation of new diagnostic tools and new therapeutic.

Effectiveness and safety of REBACIN as a non-invasive intervention for persistent high-risk human papillomavirus infection: A real-world prospective multicenter cohort study.

BACKGROUND: We previously reported that REBACIN effectively eliminates persistent high-risk human papillomavirus (hrHPV) infection. Here, we conducted a prospective multicenter cohort study to evaluate the safety and effectiveness of REBACIN, taking into account factors such as specific hrHPV subtype and patient's age. METHODS: According to inclusion/exclusion criteria and participant willingness, 3252 patients were divided into REBACIN group while 249 patients into control group. Patients in REBACIN group received one course treatment of intravaginal administration of REBACIN while no treatment in control group. After drug withdrawal, participants in both groups were followed up. RESULTS: The clearance rate of persistent hrHPV infection in REBACIN group was 60.64%, compared to 20.08% in control group. Specifically, the clearance rates for single-type infection of HPV16 or HPV18 were 70.62% and 69.23%, respectively, which was higher than that of HPV52 (59.04%) or HPV58 (62.64%). In addition, the single, double, and triple/triple+ infections had a clearance rate of 65.70%, 53.31%, and 38.30%, respectively. Moreover, 1635 patients under 40 years old had a clearance rate of 65.14%, while it was 55.08% for 1447 patients over 40 years old. No serious adverse effects were found. CONCLUSION: This study confirmed that REBACIN can effectively and safely eliminate persistent hrHPV infection, which the clearance rate of HPV16/18 is higher than that of HPV52/58, the clearance rate of single-type infection is higher than that of multiple-type infections, and the clearance rate in young patients is higher than that in elder patients, providing a guidance for REBACIN application in clearing hrHPV persistent infection in real-world settings. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry Registration Number: ChiCTR1800015617 http://www.chictr.org.cn/showproj.aspx?proj=26529 Date of Registration: 2018-04-11.

MicroRNA-411-3p motivates methotrexate's cellular uptake and cytotoxicity via targeting Yin-yang 1 in leukemia cells.

This study aimed to figure out how microRNA (miR)-411-3p's impacts on methotrexate (MTX)'s cellular uptake and cytotoxicity in acute lymphoblastic leukaemia (ALL) CEM-C1 cells by targeting Yin-yang 1 (YY1). miR-411-3p and YY1 were detected by RT-qPCR or Western blot. Intracellular MTX concentration was measured by enzyme-linked immunosorbent assay. Cell viability and apoptosis were evaluated by CCK-8, clonal formation assay, and flow cytometry. Verification of miR-411-3p and YY1's targeting link was manifested. It came out that miR-411-3p mimic or si-YY1 elevated intracellular MTX, MTX-induced cytotoxicity and apoptosis rate in CEM-C1. However, the inverse results were noticed in cells introduced with miR-411-3p inhibitor or oe-YY1. Meanwhile, it was found that cell relative luciferase activity was reduced after co-transfection of miR-411-3p mimic with YY1-WT, indicating that miR-411-3p targeted YY1. Elevation of YY1 could turn around elevating miR-411-3p's impacts on MTX's cellular uptake and cytotoxicity in CEM-C1 cells. These findings convey that miR-411-3p motivated MTX's cellular uptake and cytotoxic impacts via targeting YY1 in leukemia cells. This study is helpful for learning about the mechanisms underlying MTX responses in ALL patients.

Identification and validation of a novel anoikis-related signature for predicting prognosis and immune landscape in ovarian serous cystadenocarcinoma.

Background: Ovarian serous cystadenocarcinoma (OSC) is the most prevalent histological subtype of ovarian cancer (OV) and presents a serious threat to women's health. Anoikis is an essential component of metastasis, and tumor cells can get beyond it to become viable. The impact of anoikis on OSC, however, has only been the topic of a few studies. Methods: The mRNA sequencing and clinical information of OSC came from The Cancer Genome Atlas Target Genotype-Tissue Expression (TCGA TARGET GTEx) dataset. Anoikis-related genes (ARGs) were collected by Harmonizome and GeneCards websites. Centered on these ARGs, we used unsupervised consensus clustering to explore potential tumor typing and filtered hub ARGs to create a model of predictive signature for OSC patients. Furthermore, we presented clinical specialists with a novel nomogram based on ARGs, revealing the underlying clinical relevance of this signature. Finally, we explored the immune microenvironment among various risk groups. Results: We identified 24 ARGs associated with the prognosis of OSC and classified OSC patients into three subtypes, and the subtype with the best prognosis was more enriched in immune-related pathways. Seven ARGs (ARHGEF7, NOTCH4, CASP2, SKP2, PAK4, LCK, CCDC80) were chosen to establish a risk model and a nomogram that can provide practical clinical decision support. Risk scores were found to be an independent and significant prognostic factor in OSC patients. The CIBERSORTx result revealed an inflammatory microenvironment is different for risk groups, and the proportion of immune infiltrates of Macrophages M1 is negatively correlated with risk score (rs = -0.21, P < 0.05). Ultimately, quantitative reverse transcription polymerase chain reaction (RT-PCR) was utilized to validate the expression of the seven pivotal ARGs. Conclusion: In this study, based on seven ARGs, a risk model and nomogram established can be used for risk stratification and prediction of survival outcomes in patients with OSC, providing a reliable reference for individualized therapy of OSC patients.

Identification and Validation of the Anoikis-Related Gene Signature as a Novel Prognostic Model for Cervical Squamous Cell Carcinoma, Endocervical Adenocarcinoma, and Revelation Immune Infiltration.

Background and Objectives: Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) are malignant disorders with adverse prognoses for advanced patients. Anoikis, which is involved in tumor metastasis, facilitates the survival and separation of tumor cells from their initial site. Unfortunately, it is rarely studied, and in the literature, studies have only addressed the prognosis character of anoikis for patients with CESC. Materials and Methods: We utilized anoikis-related genes (ANRGs) to construct a prognostic signature in CESC patients that were selected from the Genecards and Harmonizome portals. Furthermore, we revealed the underlying clinical value of this signature for clinical maneuvers by providing clinical specialists with an innovative nomogram on the basis of ANRGs. Finally, we investigated the immune microenvironment and drug sensitivity in different risk groups. Results: We screened six genes from fifty-eight anoikis-related differentially expressed genes in the TCGA-CESC cohort, and we constructed a prognostic signature. Then, we built a nomogram combined with CESC clinicopathological traits and risk scores, which demonstrated that this model may improve the prognosis of CESC patients in clinical therapy. Next, the prognostic risk scores were confirmed to be an independent prognostic indicator. Additionally, we programmed a series of analyses, which included immune infiltration analysis, therapy-related analysis, and GSVA enrichment analysis, to identify the functions and mechanisms of the prognostic models during the progression of cancer in CESC patients. Finally, we performed quantitative reverse transcription polymerase chain reaction (qRT-PCR) to verify the six ANRGs. Conclusions: The present discovery verified that the predictive 6-anoikis-related gene (6-ANRG) signature and nomogram serve as imperative factors that might notably impact a CESC patient's prognosis, and they may be able to provide new clinical evidence to assume the role of underlying biological biomarkers and thus become indispensable indicators for prospective diagnoses and advancing therapy.

Pain-Related Gene Solute Carrier Family 24 Member 3 Is a Prognostic Biomarker and Correlated with Immune Infiltrates in Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma: A Study via Integrated Bioinformatics Analyses and Experimental Verification.

The aim of this study was to explore cervical carcinoma and screen a suitable gene as the biomarker used for prognosis evaluation as well as pain therapy. Low expression levels of solute carrier family 24 member 3 (SLC24A3) was involved in the appearance and development of numerous malignancies. Nevertheless, the prognostic value of SLC24A3 expression with cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) patients remains uncertain. During the present study, SLC24A3 expression in CESC was retrieved from TCGA, GEO, and MSigDB databases. Based on TCGA and GEO profiles, we performed survival and difference analyses about SLC24A3 both in two GEO (GSE44001 and GSE63514) and TCGA-CESC cohorts (all p < 0.05), indicating that SLC24A3 was low expressed in tumors and associated with higher overall survival in CESC patients. Additionally, we programmed a series of analyses, including genomic profiling, enrichment analysis, immune infiltration analysis, and therapy-related analysis to identify the mechanism of the SLC24A3 in the process of cancer in CESC. Meanwhile, qRT-PCR was used to validate that the expression of SLC24A3 mRNA in Hela and SiHa cell lines was significantly lower than in PANC-1 and HUCEC cell lines. Our finding elucidated that the SLC24A3, a sodium-calcium regulator of cells, is an indispensable factor which can significantly influence the prognosis of patients with CESC and could provide novel clinical evidence to serve as a potential biological indicator for future diagnosis and pain therapy.

Synchronous mucinous metaplasia and neoplasia of the female genital tract (SMMN­FGT): A case report and literature review.

The present study reported a case of Synchronous Mucinous Metaplasia and Neoplasia of the Female Genital Tract (SMMN-FGT), which occurred in a 47-year-old woman. The patient complained of pelvic mass during a physical examination a month ago. Ultrasound examination found an anechoic spot in the left ovary and several anechoic spots were detected in the cervix. The patient underwent left adnexectomy and the left ovarian frozen section revealed a mucinous borderline tumor. Total abdominal hysterectomy and right salpingo-oophorectomy were subsequently performed. Microscopically, multifocal mucinous lesions were involved in the female genital tract, including bilateral ovarian mucinous borderline tumor, cervical and endometrial mucinous adenocarcinoma and the bilateral fallopian tube epithelium showed mucinous metaplasia. Immunohistochemistry revealed that the tumor cells of the ovary, cervix and endometrium expressed MUC6, exhibiting features of gastric-type differentiation. The Ki-67 proliferative index was ~10-70%. Cumulative evidence established SMMN-FGT as the final histopathological diagnosis with International Federation of Gynecology and Obstetrics stage I. Following surgery, the patient received a course of pelvic radiotherapy and survived for 16 months.

Polo-like kinase 1 as a biomarker predicts the prognosis and immunotherapy of breast invasive carcinoma patients.

Background: Invasive breast carcinoma (BRCA) is associated with poor prognosis and high risk of mortality. Therefore, it is critical to identify novel biomarkers for the prognostic assessment of BRCA. Methods: The expression data of polo-like kinase 1 (PLK1) in BRCA and the corresponding clinical information were extracted from TCGA and GEO databases. PLK1 expression was validated in diverse breast cancer cell lines by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Single sample gene set enrichment analysis (ssGSEA) was performed to evaluate immune infiltration in the BRCA microenvironment, and the random forest (RF) and support vector machine (SVM) algorithms were used to screen for the hub infiltrating cells and calculate the immunophenoscore (IPS). The RF algorithm and COX regression model were applied to calculate survival risk scores based on the PLK1 expression and immune cell infiltration. Finally, a prognostic nomogram was constructed with the risk score and pathological stage, and its clinical potential was evaluated by plotting calibration charts and DCA curves. The application of the nomogram was further validated in an immunotherapy cohort. Results: PLK1 expression was significantly higher in the tumor samples in TCGA-BRCA cohort. Furthermore, PLK1 expression level, age and stage were identified as independent prognostic factors of BRCA. While the IPS was unaffected by PLK1 expression, the TMB and MATH scores were higher in the PLK1-high group, and the TIDE scores were higher for the PLK1-low patients. We also identified 6 immune cell types with high infiltration, along with 11 immune cell types with low infiltration in the PLK1-high tumors. A risk score was devised using PLK1 expression and hub immune cells, which predicted the prognosis of BRCA patients. In addition, a nomogram was constructed based on the risk score and pathological staging, and showed good predictive performance. Conclusions: PLK1 expression and immune cell infiltration can predict post-immunotherapy prognosis of BRCA patients.

REBACIN® inhibits E6/E7 oncogenes in clearance of human papillomavirus infection.

Previous studies have demonstrated that REBACIN® intervention eliminates persistent high-risk human papillomavirus (hrHPV) infection. The initial establishment and subsequent progression of cervical cancer mainly depends on two major oncogenes, E6/E7, and previous studies have proposed E6/E7 oncogenes as a target for therapeutic drug development. The aim of this study was to investigate in vitro and in vivo whether REBACIN® inhibits E6/E7 oncogenes for elucidating the mechanism of REBACIN® in the clearance of persistent hrHPV infection. In vitro, after REBACIN® treatment, the growth of both Ca Ski and HeLa cervical cancer cells containing the E6/E7 oncogenes was prevented. In line with this finding is that E6/E7 expression was inhibited, which can be counteracted by the co-application of anti-REBACIN® antibody. These studies demonstrated that REBACIN® can effectively inhibit the growth of cervical cancer cells via targeting HPV E6/E7 expression. To further verify this finding in clinic, 108 volunteer patients with persistent hrHPV infections were randomly divided into REBACIN®, recombinant human interferon alpha-2b (Immunological drug control), or no-treatment blank control groups, received intravaginal administration of REBACIN®, interferon or no-treatment every other day for three months, and then followed up for E6/E7 mRNA assay. In REBACIN® group, 68.57% of patients showed complete clearance of HPV E6/E7 mRNA, which was significantly higher compared to 25.00% in the interferon immunological drug control group and 20.00% in blank control group, confirming that REBACIN® is potently efficacious on clearing persistent hrHPV infections via inhibition of HPV E6/E7 oncogenes. Clinical trial registration: http://www.chictr.org.cn/historyversionpuben.aspx?regno=ChiCTR2100045911, identifier ChiCTR2100045911.

Development and validation of an autophagy-related long non-coding RNA prognostic signature for cervical squamous cell carcinoma and endocervical adenocarcinoma.

Background: In this study, we aimed to investigate the signature of the autophagy-related lncRNAs (ARLs) and perform integrated analysis with immune infiltration in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Methods and results: The UCSC Xena and HADb databases provided the corresponding data. The ARLs were selected via constructing a co-expression network of autophagy-related genes (ARGs) and lncRNAs. Univariate Cox regression analysis combined with LASSO regression and multivariate Cox regression analysis were utilized to screen lncRNAs. The ARL risk signature was established by Cox regression and tested if it was an independent element bound up with patient prognosis. We used the xCell algorithm and ssGSEA to clarify the pertinence between immune infiltration and the expression of ARLs. Finally, we predicted the sensitivity of drug treatment as well as the immune response. Results indicated that the three prognostic ARLs (SMURF2P1, MIR9-3HG, and AC005332.4) possessed significant diversity and constituted the ARL signature. Risk score was an individual element (HR = 2.82, 95% CI = 1.87-4.30; p < 0.001). Immune infiltration analysis revealed significant increases in central memory CD8+ T cells, endothelial cells, CD8+ naive T cells, and preadipocytes in the high-risk group (p < 0.05). There were 10 therapeutic agents that varied significantly in their estimated half-maximal inhibitory concentrations in the two groups. According to the experimental validation, we found that SMURF2P1 belongs to the co-stimulatory genes and might assume greater importance in the development of cervical adenocarcinoma. MIR9-3HG and AC005332.4 belonged to the tumor-suppressor genes and they may play a more positive role in cervical squamous cell carcinoma. Conclusions: This research explored and validated a novel signature of the ARLs, which can be applied to forecast the prognosis of patients with CESC and is closely associated with immune infiltration.

Identification and validation of a novel necroptosis-related prognostic signature in cervical squamous cell carcinoma and endocervical adenocarcinoma.

Background: The purpose of this study was to investigate the prognostic signature of necroptosis-related lncRNAs (NRLs) and explore their association with immune-related functions and sensitivity of the therapeutic drug in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Methods: UCSC Xena provided lncRNA sequencing and clinical data about CESC, and a necroptosis gene list was obtained from the KEGG database. NRLs were selected by structuring a co-expression network of lncRNAs and necroptosis-related genes. To further screen lncRNAs, we used the univariate Cox regression method, Lasso regression, and multivariate Cox regression. Afterward, an NRL signature was established. We used the xCell algorithm and single-sample gene set enrichment analysis (ssGSEA) to clarify the pertinence between immune infiltration and NRL expressions in CESC patients and explored the relationship between the target lncRNAs and immune-related genes. By leveraging the GDSC database, the therapy-sensitive response of the prognostic signature was forecasted and an experimental validation was performed. We performed GSEA with the aim of recognizing the potential pathway related to the individual prognostic signature. Results: The two prognostic NRLs (AC009095.1 and AC005332.4) showed significant diversity and constituted the NRL signature. On the grounds of our signature, risk score was an independent element which was bound up with patient outcome (HR = 4.97 CI: 1.87-13.2, P = 0.001). The CESC patients were classified by the median risk score. Immune infiltration analysis revealed significant increases in CD4 + Tcm, eosinophils, epithelial cells, fibroblasts, NKT, plasma cells, platelets, and smooth muscle in the high-risk group (P< 0.05). Target lncRNAs also showed some correlation with NRGs. The estimated IC50 values of bicalutamide, CHIR.99021, and imatinib were lower in the high-risk group. Through the subsequent experimental validation, both AC009095.1 and AC005332.4 were significantly more highly expressed in SiHa than in Hela. AC009095.1 was expressed more highly in SiHa than in HUCEC, but the expression of AC005332.4 was reversed. Conclusions: This study elucidated that NRLs, as a novel signature, were indispensable factors which can significantly influence the prognosis of patients with CESC and could provide novel clinical evidence to serve as a potential molecular biomarker for future therapeutic targets.

Exploration of the Immune-Related Long Noncoding RNA Prognostic Signature and Inflammatory Microenvironment for Cervical Cancer.

Purpose: Our research developed immune-related long noncoding RNAs (lncRNAs) for risk stratification in cervical cancer (CC) and explored factors of prognosis, inflammatory microenvironment infiltrates, and chemotherapeutic therapies. Methods: The RNA-seq data and clinical information of CC were collected from the TCGA TARGET GTEx database and the TCGA database. lncRNAs and immune-related signatures were obtained from the GENCODE database and the ImPort database, respectively. We screened out immune-related lncRNA signatures through univariate Cox, LASSO, and multivariate Cox regression methods. We established an immune-related risk model of hub immune-related lncRNAs to evaluate whether the risk score was an independent prognostic predictor. The xCell and CIBERSORTx algorithms were employed to appraise the value of risk scores which are in competition with tumor-infiltrating immune cell abundances. The estimation of tumor immunotherapy response through the TIDE algorithm and prediction of innovative recommended medications on the target to immune-related risk model were also performed on the basis of the IC50 predictor. Results: We successfully established six immune-related lncRNAs (AC006126.4, EGFR-AS1, RP4-647J21.1, LINC00925, EMX2OS, and BZRAP1-AS1) to carry out prognostic prediction of CC. The immune-related risk model was constructed in which we observed that high-risk groups were strongly linked with poor survival outcomes. Risk scores varied with clinicopathological parameters and the tumor stage and were an independent hazard factor that affect prognosis of CC. The xCell algorithm revealed that hub immune-related signatures were relevant to immune cells, especially mast cells, DCs, megakaryocytes, memory B cells, NK cells, and Th1 cells. The CIBERSORTx algorithm revealed an inflammatory microenvironment where naive B cells (p < 0.01), activated dendritic cells (p < 0.05), activated mast cells (p < 0.0001), CD8+ T cells (p < 0.001), and regulatory T cells (p < 0.01) were significantly lower in the high-risk group, while macrophages M0 (p < 0.001), macrophages M2 (p < 0.05), resting mast cells (p < 0.0001), and neutrophils (p < 0.01) were highly conferred. The result of TIDE indicated that the number of immunotherapy responders in the low-risk group (124/137) increased significantly (p = 0.00000022) compared to the high-risk group (94/137), suggesting that the immunotherapy response of CC patients was completely negatively correlated with the risk scores. Last, we compared differential IC50 predictive values in high- and low-risk groups, and 12 compounds were identified as future treatments for CC patients. Conclusion: In this study, six immune-related lncRNAs were suggested to predict the outcome of CC, which is beneficial to the formulation of immunotherapy.

Correction: The pan-cancer analysis of the two types of uterine cancer uncovered clinical and prognostic associations with m6A RNA methylation regulators.

Correction for 'The pan-cancer analysis of the two types of uterine cancer uncovered clinical and prognostic associations with m6A RNA methylation regulators' by Zhilin Zou et al., Mol. Omics, 2021, 17, 438-453, DOI: 10.1039/d0mo00113a.

The pan-cancer analysis of the two types of uterine cancer uncovered clinical and prognostic associations with m6A RNA methylation regulators.

The role of m6A RNA methylation modification in uterine cancer has not been studied until now. We explored the relationship between m6A regulators and clinical characteristics and prognosis in uterine corpus endometrial carcinoma (UCEC) and uterine carcinosarcoma (UCS) with the data from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). We found that several regulators were up-regulated or down-regulated in the two types of cancer, and identified two cluster subgroups with statistically significant differences in pathological grade, age and survival rate. Multivariate Cox regression analysis showed that methyltransferase-like 16 (METTL16) had a low hazard ratio in UCEC. We used several regulators to construct a risk signature and divided tumor patients into high-risk and low-risk groups, and found that the high-risk group had significantly lower survival rates. Independent prognostic analysis showed that the insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) was a pan-prognostic regulator of uterine cancer. This result was further verified in the Gene Expression Omnibus (GEO) database. Based on above results, we conducted gene-ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to further reveal a potential mechanism for m6A RNA methylation regulators. We found that IGF2BP1 was enriched in gene expression (GO:0010467), poly(A) RNA binding (GO:0044822) and RNA binding (GO:0003723) pathways. KEGG analysis showed that IGF2BP1 was enriched in microRNAs in the cancer (hsa05206) pathway. Our study systematically elucidated the relationship between m6A RNA methylation regulators and uterine cancer and constructed the risk signature that can predict the prognosis and clinicopathological characteristics of uterine cancer.

AIB1 predicts tumor response to definitive chemoradiotherapy and prognosis in cervical squamous cell carcinoma.

Amplified in breast cancer 1 (AIB1) gene, has been reported to be associated with biological malignancy in several cancers. However, the molecular status of the AIB1 gene in cervical cancer and the clinicopathological/prognostic significance of AIB1 expression in chemoradiotherapy (CRT) sensitivity have not been determined. In our present study, we found that the high expression of AIB1 was frequent detected in specimens of cervical cancer patients, and this was significantly correlated with CRT response (P = 0.014), clinical stage (P = 0.003), T status (P = 0.027), N status (P = 0.021), M status (P = 0.015) and progression-free survival (P < 0.001). Moreover, the clonogenic survival fraction and cell apoptosis experiments showed that knockdown of AIB1 substantially increased cervical cancer cells sensitivity to ionizing radiation (IR) or cisplatin/5-fluorouracil. Collectively, our results demonstrated that the high expression of AIB1 in cervical cancer cells contributes to the resistance to CRT, which provides the evidence that AIB1 may be a promising predictor of aggressive cervical cancer patients with poor response to CRT.

miR-421 is a diagnostic and prognostic marker in patients with osteosarcoma.

MicroRNAs (miRNAs) are a new class of prognostic and diagnostic biomarkers for many cancers. Recent studies have shown that miRNAs are highly stable in plasma/serum. The aim of this study was to investigate the role of miR-421 in osteosarcoma. We found that the serum expression levels of miR-421 were significantly higher in osteosarcoma patients than those in healthy volunteers. Moreover, miR-421 expression was significantly higher in osteosarcoma tissues compared with that in the adjacent normal tissues. Meanwhile, the expression of miR-421 was upregulated in 90 % (36/40) osteosarcoma tissues compared to non-tumor tissues. More importantly, the expression levels of miR-421 in osteosarcoma tissues were correlated with those in patients' serum. In addition, patients with high miR-421 expression had shorter overall survival (OS) than those with low expressions. We also found that overexpression of miR-421 promoted osteosarcoma cell line MG-63 proliferation, migration, and invasion. In conclusion, miR-421 expression levels were upregulated in osteosarcoma tissue and serum and it may be a useful marker for diagnosis of osteosarcoma.

The Downregulation of MiR-182 Is Associated with the Growth and Invasion of Osteosarcoma Cells through the Regulation of TIAM1 Expression.

BACKGROUND: Osteosarcoma is the most common primary bone malignancy in children and young adults. Increasing results suggest that discovery of microRNAs (miRNAs) might provide a novel therapeutical target for osteosarcoma. METHODS: MiR-182 expression level in osteosarcoma cell lines and tissues were assayed by qRT-PCR. MiRNA mimics or inhibitor were transfected for up-regulation or down-regulation of miR-182 expression. Cell function was assayed by CCK8, migration assay and invasion assay. The target genes of miR-182 were predicated by bioinformatics algorithm (TargetScan Human). RESULTS: MiR-182 was down-regulated in osteosarcoma tissues and cell lines. Overexpression of miR-182 inhibited tumor growth, migration and invasion. Subsequent investigation revealed that TIAM1 was a direct and functional target of miR-182 in osteosarcoma cells. Overexpression of miR-182 impaired TIAM1-induced inhibition of proliferation and invasion in osteosarcoma cells. CONCLUSIONS: Down-expression of miR-182 in osteosarcoma promoted tumor growth, migration and invasion by targeting TIAM1. MiR-182 might act as a tumor suppressor gene whose down-regulation contributes to the progression and metastasis of osteosarcoma, providing a potential therapy target for osteosarcoma patients.

Alterations in gene expression during sexual differentiation in androgen receptor knockout mice induced by environmental endocrine disruptors.

In the present study, we aimed to explore the effect of environmental endocrine disruptors (EEDs) on sexual differentiation in androgen receptor (AR)-/-, AR+/- and AR+/+ male mice. By using a Cre-loxP conditional knockout strategy, we generated AR knockout mice. By mating flox-AR female mice with AR-Cre male mice, the offspring male mice which were produced were examined. Mice not subjected to any type of intervention were used as the controls. Furthermore, male mice of different genotypes were selected and further divided into subgroups as follows: the control group, bisphenol A (BPA) group and the dibutyl phthalate [corrected] (DBP) group. The expression of the Wilms tumor 1 (WT1), lutropin/choriogonadotropin receptor (LHR), 17-ß-hydroxysteroid dehydrogenase type 3 (17ßHSD3) and steroid-5-alpha-reductase, alpha polypeptide 2 (SRD5A2) genes was determined by RT-qPCR and western blot analysis. There was no statistically significant difference in the weight of the mice between the control group and the knockout group (P>0.05). The results revealed that, compared with the control group, in the knockout group, anogenital distance was shortened, and testicular weight and testosterone levels were decreased; estradiol levels were elevated; the differences were statistically significant (P<0.05). In the group of AR+/- male mice exposed to 100 mg/l EEDs, hypospadias was successfully induced, suggesting that EEDs are involved in the embryonic stage of sexual development in male mice. The quantitative detection of WT1, LHR, 17ßHSD3 and SRD5A2 gene expression by RT-qPCR and western blot analysis indicated that these genes were significantly downregulated in the mice in the BPA group. In conclusion, exposure to EEDs induces hypospadias in heterozygous and wild-type male mice offspring during sexual differentiation, but has no effect on homozygous offspring. Therefore, EEDs play an important role during the third stage of sexual differentiation.