Construction and Validation of a Prognostic Risk Prediction Model for Lactate Metabolism-Related lncRNA in Endometrial Cancer.

Endometrial cancer (EC) is a common group of malignant epithelial tumors that mainly occur in the female endometrium. Lactate is a key regulator of signal pathways in normal and malignant tissues. However, there is still no research on lactate metabolism-related lncRNA in EC. Here, we intended to establish a prognostic risk model for EC based on lactate metabolism-related lncRNA to forecast the prognosis of EC patients. First, we found that 38 lactate metabolism-associated lncRNAs were significantly overall survival through univariate Cox regression analysis. Using minimum absolute contraction and selection operator (LASSO) regression analysis and multivariate Cox regression analysis, six lactate metabolism-related lncRNAs were established as independent predictor in EC patients and were used to establish a prognostic risk signature. We next used multifactorial COX regression analysis and receiver operating characteristic (ROC) curve analysis to confirm that risk score was an independent prognostic factor of overall patient survival. The survival time of patients with EC in different high-risk populations was obviously related to clinicopathological factors. In addition, lactate metabolism-related lncRNA in high-risk population participated in multiple aspects of EC malignant progress through Gene Set Enrichment Analysis, Genomes pathway and Kyoto Encyclopedia of Genes and Gene Ontology. And risk scores were strongly associated with tumor mutation burden, immunotherapy response and microsatellite instability. Finally, we chose a lncRNA SRP14-AS1 to validate the model we have constructed. Interestingly, we observed that the expression degree of SRP14-AS1 was lower in tumor tissues of EC patients than in normal tissues, which was consistent with our findings in the TCGA database. In conclusion, our study constructed a prognostic risk model through lactate metabolism-related lncRNA and validated the model, confirming that the model can be used to predict the prognosis of EC patients and providing a molecular analysis of potential prognostic lncRNA for EC.

Construction and Assessment of a Prognostic Risk Model for Cervical Cancer Based on Lactate Metabolism-Related lncRNAs.

Purpose: Cervical cancer (CC) has the fourth highest incidence and mortality rate among female cancers. Lactate is a key regulator promoting tumor progression. Long non-coding RNAs (lncRNAs) are closely associated with cervical cancer (CC). The study was aimed to develop a prognostic risk model for cervical cancer based on lactate metabolism-associated lncRNAs and to determine their clinical prognostic value. Patients and Methods: In this study, CESC transcriptome data were obtained from the TCGA database. 262 lactate metabolism-associated genes were extracted from MsigDB (Molecular Characterization Database). Then, correlation analysis was used to identify LRLs. Univariate Cox regression analysis was performed afterwards, followed by least absolute shrinkage and selection operator (LASSO) regression analysis and multiple Cox regression analysis. 10 lncRNAs were finally identified to construct a risk score model. They were divided into two groups of high risk and low risk according to the median of risk scores. The predictive performance of the models was assessed by Kaplan-Meier (K-M) analysis, subject work characteristics (ROC) analysis, and univariate and multivariate Cox analyses. To assess the clinical utility of the prognostic model, we performed functional enrichment analysis, immune microenvironment analysis, mutation analysis, and column line graph generation. Results: We constructed a prognostic model consisting of 10 LRLs at CC. We observed that high-risk populations were strongly associated with poor survival outcomes. Risk score was an independent risk factor for CC prognosis and was strongly associated with immune microenvironment analysis and tumor mutational load. Conclusion: We developed a risk model of lncRNAs associated with lactate metabolism and used it to predict prognosis of CC, which could guide and facilitate the progress of new treatment strategies and disease monitoring in CC patients.

Long non-coding RNA SOS1-IT1 promotes endometrial cancer progression by regulating hypoxia signaling pathway.

Endometrial cancer (EC) is one of the most common types of gynecological cancer. Hypoxia is an important clinical feature and regulates various tumor processes. However, the prognostic value of hypoxia-related lncRNA in EC remains to be further elucidated. Here, we aimed to characterize the molecular features of EC by the development of a classification system based on the expression profile of hypoxia-related lncRNA. Based on univariate Cox regression analysis, we identified 17 hypoxia-related lncRNAs significantly associated with overall survival. Next, the least absolute shrinkage and selection operator Cox regression model was utilized to construct a multigene signature in the TCGA EC cohort. The risk score was confirmed as an independent predictor for overall survival in multivariate Cox regression analysis and receiver operating characteristic (ROC) curve analysis. Besides, the survival time of EC patients in different risk group was significantly correlated to clinicopathologic factors, such as age, stage and grade. Furthermore, hypoxia-related lncRNA associated with the high-risk group were involved in various aspects of the malignant progression of EC via Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway, and Gene Set Enrichment Analysis. Moreover, the risk score was closely correlated to immunotherapy response, microsatellite instability and tumor mutation burden. Finally, we select one hypoxia-related lncRNA SOS1-IT1 to validate its role in hypoxia and EC progression. Interestingly, we found SOS1-IT1 was overexpressed in tumor tissues, and closely correlated with clinicopathological parameters of EC. The expression level of SOS1-IT1 was significantly increased under hypoxia condition. Additionally, the important hypoxia regulatory factor HIF-1α can directly bind SOS1-IT1 promoter region, and affect its expression level. In summary, this study established a new EC classification based on the hypoxia-related lncRNA signature, thereby provide a novel sight to understand the potential mechanism of human EC development.

Dual-modal imaging-guided theranostic nanocarriers based on 2-methoxyestradiol and indocyanine green.

Drug toxicity and insufficient drug dosing place a limit on the effect of chemotherapy. Optimal efficacy is achieved by exposing tumor cells to the maximum tolerated dose of a chemotherapeutic drug. In this study, we developed a strategy (graphic summary) for enhancing the therapeutic and diagnostic capabilities of known chemotherapeutics. We used a dual-mode near-infrared (NIR) fluorescence/photoacoustic imaging technology to achieve actively guided tumor targeting of the photothermal therapeutic agent indocyanine green (ICG) and the chemotherapeutic drug 2-methoxyestradiol (2-ME), which were loaded into thermosensitive liposomes (TSLs) with surface-grafted tumor-targeting peptide cRGDyk (cRGDyk-2-ME@ICG-TSLs). In vitro studies demonstrated that cRGDyk-2-ME@ICG-TSLs effectively induced drug accumulation and cytotoxicity in NIR laser-irradiated B16-F10 melanoma cells using dual targeting based on the cRGDyk peptide and temperature sensitivity. An in vivo study showed that 24 h after intravenously injecting cRGDyk-2-ME@ICG-TSLs into melanoma tumor-bearing mice, the dual-mode NIR fluorescence/photoacoustic imaging could accurately identify tumors and normal tissues. In addition, the combination of cRGDyk-2-ME@ICG-TSLs and NIR radiation suppressed tumor growth in tumor-bearing nude mice and was associated with a low risk of side effects on normal organs. Our results indicate that TSLs are a suitable drug delivery system for diagnostic and chemotherapeutic agents guided by dual-mode imaging.

Involvement of DNA methyltransferase 1 (DNMT1) and multidrug resistance-associated proteins in 2-methoxyestradiol-induced cytotoxicity in EC109/Taxol cells.

BACKGROUND: Due to acquired drug resistance, paclitaxel-based chemotherapy has limited clinical effects in the treatment of various tumors including esophageal cancer. This study analyzes the hypothesis that paclitaxel resistance is related to changes in the expression of DNA methyltransferase 1 (DNMT1). The thesis also studies multidrug resistance-related proteins and the mechanism underlying 2-methoxyestradiol (2-ME)-induced cytotoxicity in EC109/Taxol cells was examined. METHODS: In this study, the mechanisms of 2-ME-induced cytotoxicity in EC109/Taxol cells was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, DNA ladder assay, DNMT activity assay, and Western blotting. The result of 2-ME-induced cytotoxicity EC109/Taxol cells is compared with that of EC109 parental cells. RESULTS: The results show that low concentrations of 2-ME (0.5-10 µM) inhibited cell growth, with IC50 values of 2.04 and 5.38 µmol/L in EC109/Taxol cells and EC109 parental cells after 72 hours of treatment, respectively. Exposure to 2-ME could increase G2/M cell cycle arrest and could increase apoptosis more effectively in EC109/Taxol cells than that observed in the EC109 parental cells. Furthermore, it is observed that paclitaxel resistance is associated with decreased DNMT activity. This study shows that 2-ME decreases DNMT1-mediated paclitaxel resistance by simultaneously reducing the expression of ATP-binding cassette (ABC) transporters, including phosphoglycoprotein (P-gp), breast cancer resistance protein (BCRP), and multi-drug resistance protein 1 (MRP1), in EC109/Taxol cells. CONCLUSIONS: In this study, the co-treatment of Taxol and 2-ME to EC109 could significantly induce cytotoxic effects, whose mechanism might be associated with DNMT1 and multidrug resistance-associated proteins.

Progesterone receptor antagonist provides palliative effects for uterine leiomyoma through a Bcl-2/Beclin1-dependent mechanism.

Uterine leiomyoma is the most common benign smooth muscle tumor of uterus in women of reproductive age, with a high lifetime incidence. Nowadays, the exploration on the pharmacotherapies, such as progesterone receptor antagonist (PRA) requires more attention. Hence, the current study aimed to examine whether mifepristone, a PRA, influences the autophagy and apoptosis of uterine leiomyoma cells. Primary uterine leiomyoma cells were collected from 36 patients diagnosed with uterine leiomyoma to establish PR-M-positive (PR-M[+]) cells. The lentiviral vector overexpressing or silencing PR-M was subsequently delivered into one part of PR-M(+) cells in order to evaluate the role of PR-M in PR-M(+) cells. The results obtained revealed that cell viability was increased, while cell autophagy and apoptosis were diminished in the PR-M(+) cells treated with overexpressed PR-M, whereby the Bcl-2 level was elevated and the level of Beclin1 was reduced. An opposite trends were identified following treatment with knockdown of PR-M. Mifepristone at different concentrations (low, moderate, or high) was then applied to treat another part of the PR-M(+) cells. Mifepristone was identified to promote cell autophagy and apoptosis, decrease Bcl-2 level and increase Beclin1 level, accompanied by weakened interaction between Bcl-2 and Beclin1. Moreover, these effects of mifepristone on PR-M(+) cells were enhanced with increasing of the concentration. Taken together, the present study present evidence indicates the ability of PRA to regulate the Bcl-2/Beclin1 axis, ultimately promoting the autophagy and apoptosis of uterine leiomyoma cells, highlighting that PRA serves as a promising therapeutic target for the treatment of uterine leiomyoma.

HOXB9 promotes endometrial cancer progression by targeting E2F3.

HOXB9, as a HOX family transcription factor, playing a significant role in embryonic development and cancer progression. However, the function of HOXB9 and its precise mechanism in regulating endometrial cancer progression remains unknown. Here, we demonstrated that the expression of HOXB9 was increased in endometrial cancer, and associated with histological grade and lymph node metastasis. In addition, elevated HOXB9 predicts a poor prognosis in endometrial cancer patients. Interestingly, bioinformatics analysis of TCGA cancer database showed that HOXB9 expression is positively correlated with E2F3 expression. Moreover, HOXB9 promoted E2F3 expression by directly targeting to its promoter. Furthermore, we found that knocking down E2F3 abolished the ability of HOXB9 in enhancing cell migration. Taken together, for the first, we demonstrated the function and mechanism of HOXB9 in regulating endometrial cancer progression, and indicated HOXB9 may be a novel prognostic marker of endometrial cancer.

Expression of a mitochondrial progesterone receptor (PR-M) in leiomyomata and association with increased mitochondrial membrane potential.

CONTEXT: Clinical evidence supports a role for progestins in the growth of leiomyomata (fibroids). The mechanism(s) for this is thought to involve gene regulation via the nuclear progesterone receptors. Recently a mitochondrial progesterone receptor (PR-M) has been identified with evidence of a progesterone/progestin-dependent increase in cellular respiration. This observation raises a possible new mechanism whereby progesterone/progestin may affect the growth of fibroids. OBJECTIVE: The goals of this research were to determine differential expression of PR-M in normal myometrium compared with the edge of a fibroid within the same uterus, to demonstrate a progestin-dependent increase in mitochondria membrane potential using an immortalized human myometrial cell line and to examine mitochondrial membrane potential in transfected cells expressing the complete coding sequence of PR-M. DESIGN: Protein levels of PR-M, PR-B, PR-A, mitochondrial porin, and glyceraldehyde-3-phosphate dehydrogenase were determined in the myometrium and adjacent edge of a fibroid in 10 subjects undergoing hysterectomy for benign indications. Mitochondrial membrane potential was determined by fluorescent emission of 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolecarbocyanide iodine in hTERT-HM cells treated with R5020 and in transfected hTERT-HM cells determined by the fluorescent emission of tetramethylrhodamine methyl ester. RESULTS: Higher levels of PR-M and mitochondrial porin were found in the fibroid edge compared with adjacent myometrium. Progestin increased mitochondrial membrane potential in hTERT-HM cells, which was not affected by a translation inhibitor. This effect was exaggerated in hTERT-HM cells expressing PR-M after transient transfection. CONCLUSION: These studies suggest a mechanism whereby progesterone/progestin may affect the growth of fibroids by altering mitochondrial activity.

[Expression of hSef and FGF-2 in epithelial ovarian tumor].

OBJECTIVE: To detect the expression of human similar expression to FGF gene(hSef) and fibroblast growth factor-2(FGF-2) and their correlation with epithelial ovarian tumor. METHODS: Immunohistochemical SP staining was used to detect the expression of hSef and FGF-2 proteins in 31 cases of epithelial ovarian carcinoma (EOC), 18 cases of benign epithelial tumor (BET), 10 cases of normal ovarian (NO) tissues collected from July 2007 to May 2008. The expression of hSef mRNA in 24 cases of EOC, BET and NO collected from July 2008 to May 2009 were analyzed by RT-PCR. RESULTS: The results of immunohistochemical study showed that the expression of hSef in the EOC tissues were significantly lower than that in the NO and BET (P < 0.001). However, the expression of FGF-2 was higher (P = 0.002). The expression of hSef had a negative correlation with FGF-2 (r(s) = -0.324, P = 0.012). The RT-PCR results showed that there was a gradually declined trend of expression of hSef in NO, BET to EOC (P < 0.001), but the expression of FGF-2 in NO, BET to EOC was gradually increased (P < 0.001), with a significant negative correlation (NO: r(s) = -0.910, P < 0.001; BET: r(s) = -0.859, P < 0.001; EOC: r(s) = -0.888, P < 0.001). CONCLUSIONS: The expression of hSef is decreased in epithelial ovarian carcinoma tissue, but the expression of FGF-2 is increased. It is likely that low hSef expression is related to the the carcinogenesis and development of epithelial ovarian carcinoma by suppressing the promoting effects of FGF-2 to cell proliferation.