Repression of FBXW7 by HES5 contributes to inactivation of the TGF-ß signaling pathway and alleviation of endometriosis.

Endometriosis (EMS) is a gynecologic disorder associated with infertility and characterized by the endometrial-type mucosa outside the uterine cavity. Currently available treatment modalities are limited to undesirable effects. Thus, in the present study, we sought to study the pathogenesis mechanism of EMS. For this purpose, the ectopic and eutopic endometrial tissues were resected from 86 patients with EMS and 54 infertile patients without EMS, respectively. The regulatory mechanism among HES family bHLH transcription factor 5 (HES5), transforming growth factor-beta (TGF-ß)-induced factor 1 (TGIF1), F-box, and WD repeat domain containing 7 (FBXW7) was studied by performing co-immunoprecipitation, dual-luciferase reporter gene assay, and chromatin immunoprecipitation, respectively. A mouse model of EMS was established to verify the aforementioned regulatory mechanism in vivo. Upregulation of HES5 and TGIF1, as well as downregulation of FBXW7, was observed in EMS endometrial tissues and human endometrial stromal cells (hESCs), respectively. The overexpression of HES5 was found to suppress the FBXW7 transcription and TGIF1 degradation, resulting in the inactivation of the TGF-ß signaling pathway, as well as inhibition of hESC proliferation and invasion, thereby enhancing apoptosis. Results from a mouse model of EMS showed that the presence of HES5 contributed to the alleviation of EMS. Collectively, we attempted to provide a mechanistic insight into the unrecognized roles of the HES5/FBXW7 in EMS progression.

Systematic Analysis of Autophagy-Related Signature Uncovers Prognostic Predictor for Acute Myeloid Leukemia.

Autophagy, a highly conserved cellular protein degradation process, has been involved in acute myeloid leukemia (AML). The present study aims to establish a novel, autophagy-related prognostic signature for prediction of AML prognosis. Differentially expressed autophagy-related genes in AML and healthy samples were screened using GSE1159. Univariate Cox regression analysis was applied to determine survival-associated autophagy-related genes in The Cancer Genome Atlas (TCGA) AML cohort. Lasso regression was performed to develop multiple-gene prognostic signatures. A novel six-gene signature (including CASP3, CHAF1B, KLHL24, OPTN, VEGFA, and VPS37C) DC was established for AML prognosis prediction. The Kaplan-Meier survival analysis revealed that patients in the high-risk score group had poorer overall survival (OS). The receiver operating characteristic (ROC) curve validated its good performance in survival prediction in TCGA AML cohort, and the area under the curve value was 0.817. Moreover, our signature could independently predict OS. A nomogram was constructed, including the six-gene signature and other clinical parameters, and predictive efficiency was confirmed using the ROC curve and calibration curve. Furthermore, gene set enrichment analyses identified several tumor-associated pathways that may contribute to explain the potential molecular mechanisms of our signature. Overall, we developed a new autophagy-associated gene signature and nomogram to predict OS of AML patients, which may help in clinical decision-making for AML treatment.

Comprehensive Characterization of the Prognosis Value of Alternative Splicing Events in Acute Myeloid Leukemia.

Increasing evidence have demonstrated that dysregulated alternative splicing (AS) events promoted tumor development and was correlated with worse prognosis in the context of certain malignancies. Nevertheless, a comprehensive examination of the prognosis role of AS events in acute myeloid leukemia (AML) has not yet been illuminated. In this study, univariate and multivariate Cox regression analysis were used to identify survival-related AS events and independent prognostic predictors. The interaction between splicing factors (SFs) and AS events was visualized by Cytoscape. A total of 3013 survival-associated AS events in 1977 genes were screened in 151 AML patients. Interestingly, the majority (2031 events) were revealed to be protective factors. Furthermore, the prediction models were constructed for each type of AS and all of them displayed good performance in predicting prognosis, considering their area under curve values of the receiver operating characteristic were all above 0.7. Notably, the splicing regulatory network displayed the underlying interaction networks between SFs and AS events. Taken together, our study demonstrated the survival-related AS events in AML and uncovered the possible association between SFs and prognostic AS events, which provide new prognostic biomarkers and aid to develop novel targets for AML therapy.

BAG2-Mediated Inhibition of CHIP Expression and Overexpression of MDM2 Contribute to the Initiation of Endometriosis by Modulating Estrogen Receptor Status.

Endometriosis is an estrogen-dependent gynecological disease primarily affecting women of childbearing age, which gives rise to pelvic pain calling for multiple operations, and sometimes leading to infertility. However, the etiology of endometriosis remains poorly understood. In this study we investigated the roles of two Ubiquitin E3 Ligases, namely hsc70-interacting protein (CHIP) and mouse double minute 2 (MDM2), in the abnormal estrogenic activity in endometriosis. We first collected endometrial tissues from 91 cases of endometriosis and 78 cases of uterine myomas. Next, we established a murine endometriosis model by ectopic endometrial tissue implantation. In other studies, we isolated human endometrial stromal cells (HESCs) were isolated from the endometrial tissues, and performed HA- or FLAG-immunoprecipitation assays and immunoblotting with an anti-ubiquitin antibody to test the interactions among BAG2, CHIP, MDM2, estrogen receptor α (ERα), and ERß. The expression of ERα was downregulated while that of ERß, BAG2, and MDM2 was upregulated in human endometriosis and in the mouse model. CHIP degraded ERß instead of ERα via the ubiquitin-proteasome pathway, while BAG2 impaired the CHIP-mediated degradation of ERß in cultured HESCs derived from human endometriosis. The degradation of ERα by MDM2 in cultured endometriosis-HESCs also occurred through the ubiquitin-proteasome pathway. Knockdown of both BAG2 and MDM2 alleviated the development of endometriosis in mice. Our findings suggest that the interference of BAG2 and MDM2 may have therapeutic effects in endometriosis. Understanding better the molecular mechanisms underlying the regulation of the abnormal estrogenic activity in endometriosis is crucial for the advancement of targeted therapeutic strategies.