Classic congenital adrenal hyperplasia with unilateral functional adrenal cortical adenoma: case report.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders related to adrenal steroid biosynthesis, and mainly caused by mutations in the CYP21A2 gene encoding 21-hydroxylase. Adrenal tumors are common in CAH, but functional adrenal tumors are rare. Here, we report a 17-year-old female with virilized external genitalia and primary amenorrhea, accompanied by a right adrenal tumor. Her 17-OHP level was normal, cortisol and androgen levels were significantly elevated, and the tumor pathology showed adrenal cortical adenoma. Gene testing for CYP21A2 showed c.518T > A in exon 4 and c.29313C > G in intron 2. The possibility of untreated classic CAH with 21-OH deficiency causing functional adrenal cortical adenoma should be considered. When clinical diagnosis highly considers CAH and cannot rule out the influence of functional adrenal tumors' secretion function on 17-OHP, gene mutation analysis should be performed.

Exploring tumor microenvironment in molecular subtyping and prognostic signatures in ovarian cancer and identification of SH2D1A as a key regulator of ovarian cancer carcinogenesis.

Introduction: A deadly gynecological cancer, ovarian cancer (OV), has a poor prognosis because of late-stage diagnosis and few targeted therapies. Addressing the tumor microenvironment (TME) in solid tumors has shown promise since it is crucial in promoting cancer progression. Methods: We obtained bulk RNA-seq data from TCGA-OV, GSE26712, GSE102073, and ICGC cohorts, as well as scRNA-seq data from EMTAB8107, GSE118828, GSE130000, and GSE154600 cohorts using the TISCH2 database. The ConsensusClusterPlus package was used to cluster the OV tumor tissues hierarchically to determine two molecularly different groups (C1 and C2). A total of ten different types of machine learning techniques with 101 combinations were used for prognostic model construction. Using eight TME algorithms integrated into the IOBR R package, the bulk RNA-seq dataset was analyzed. For in vitro experiments, OVCAR3 and SKOV3, two OV cell lines, were used. The migratory potential of the ovarian cancer cells was assessed using Transwell assay, while proliferation was assessed using CCK8 assay. Results: Based on TME-related gene set expression, two distinct molecular subgroups (C1 and C2) were identified through consensus clustering, with C1 showing higher TME activity. Further analysis indicated that C1 had increased cancer-associated fibroblasts (CAFs), M1 macrophages, and CD8+ T cells, suggesting a more activated and pro-inflammatory TME. Drug sensitivity analysis revealed that 5-Fluorouracil might be beneficial to C1 patients. Functional differences between C1 and C2 were identified, including cell adhesion, mononuclear cell differentiation, and leukocyte migration. A machine learning model was developed to create a TME-related prognostic signature, demonstrating strong prognostic capabilities across multiple datasets. High-risk patients showed a more immune-suppressive TME and higher tumor stemness. ScRNA-seq disclosed a highly activated TME-related signature in OV. Cancer cell lines had significantly higher SH2D1A mRNA expression than normal ovarian epithelial cells. We observed that SH2D1A knockdown in 2 ovarian cancer cell lines (OVCAR3 and SKOV3) reduced migration and proliferation through a series of in-vitro experiments. Conclusion: TME-associated genes were efficient in ovarian cancer molecular subtyping. A TME-based prognosis model was constructed for vigorous prognostic stratification efficacy across multiple datasets. Moreover, we identified a pivotal role of SH2D1A in promoting proliferation and migration in ovarian cancer.

Development and validation of matrix metalloproteinase for predicting prognosis and tumour microenvironment immune profiles in uterine corpus endometrial carcinoma.

Background: Matrix metalloproteinases (MMPs) are involved in many processes of tumour progression and invasion. However, few studies have analysed the effects of MMP expression patterns on endometrial cancer (EC) development from the perspective of the tumour microenvironment (TME). we quantified MMP expression in individual by constructing an MMP score and found MMP score effectively predict the prognosis of EC patients. Methods: MMPs expression profiles were determined based on the differential expression of 12 MMP-related regulators. Principal component analysis (PCA) was used to construct an MMP scoring system which can quantify the MMPs expression patterns individually of EC patients. Kaplan-Meier analysis, the log-rank test, and time-dependent receiver operating characteristic (ROC) curve analysis were used to evaluate the value of MMPs expression in predicting prognosis. Single-cell RNA sequencing (scRNA-seq) dataset was used to verify correlation between MMPs and progression of EC. Gene Ontology (GO) analysis was used to investigate the pathways and functions underlying MMPs expression. Tumour immune dysfunction, exclusion prediction, and pharmacotherapy response analyses were performed to assess the potential response to pharmacotherapy based on MMPs patterns. Results: We downloaded the MMPs expression data, somatic mutation data and corresponding clinical information of EC patients from the TCGA website and ICGC portal. Based on the MMP-related differentially expressed genes (DEGs), the MMP score was constructed, and EC patients were divided into high and low MMP score groups. There was a positive correlation between MMP score and prognosis of EC patients. Patients with high MMP scores had better prognosis, more abundant immune cell infiltration and stronger antitumoor immunity. Although prognosis is worse with the lower group than the high, patients with low MMP score had better response to immunotherapy, which means they could prolong the survival time through Immunological checkpoint blockade (ICB) therapy. scRNA-seq analysis identified significant heterogeneity between MMP score and classical pathways in EC. Conclusion: Our work indicates that the MMP score could be a potential tool to evaluate MMP expression patterns, immune cell infiltration, response to pharmacotherapy, clinicopathological features, and survival outcomes in EC. This will provide the more effective guide to select immunotherapeutic strategies of EC in the future.

MYO3B promotes cancer progression in endometrial cancer by mediating the calcium ion-RhoA/ROCK1 signaling pathway.

PURPOSE: This study aimed to investigate the effect of MYO3B on endometrial cancer (EC) proliferation and invasion. METHODS: The expression of MYO3B in EC tissues and cells was analyzed using TCGA database, immunohistochemical staining, real-time PCR, and western blot (WB). Cell proliferation was detected by CCK8, Annexin V-APC/PI flow cytometry was used to detect apoptosis, intracellular calcium ion (Ca2+) was detected by flow cytometry with Fluo-4 AM fluorescent probe, cell migration by scratch assay, and cell invasion by Transwell assay, and the expression of proteins related to Ca2+ homeostasis and RhoA/ROCK1 signaling pathway was detected by WB and immunofluorescence staining. RESULTS: The expression of MYO3B was an influential factor in EC recurrence, and the expression of MYO3B was significantly up-regulated in EC tissues and cells, but down-regulated in KLE cells, and MYO3B knockdown inhibited the proliferation, migration, and invasion ability of EC cells and promoted apoptosis, suggesting that MYO3B plays a tumor-promoting role in EC. Furthermore, MYO3B knockdown decreased Ca2+ concentration in EC cells and the RhoA/ROCK1 signaling pathway was inhibited, and the effect of MYO3B knockdown on RhoA/ROCK1 signaling was reversed by treatment with the Calmodulin agonist CALP-2, and the effects of MYO3B knockdown on cell proliferation, migration, and invasion were reversed after treatment with the RhoA agonist U-46,619. CONCLUSION: MYO3B promotes the proliferation and migration of endometrial cancer cells via Ca2+-RhoA/ROCK1 signaling pathway. High expression of MYO3B may be a biomarker for EC metastasis.

Effects of HOX family regulator-mediated modification patterns and immunity characteristics on tumor-associated cell type in endometrial cancer.

Endometrial cancer (UCEC) is one of three major malignant tumors in women. The HOX gene regulates tumor development. However, the potential roles of HOX in the expression mechanism of multiple cell types and in the development and progression of tumor microenvironment (TME) cell infiltration in UCEC remain unknown. In this study, we utilized both the The Cancer Genome Atlas (TCGA) database and International Cancer Genome Consortium (ICGC) database to analyze transcriptome data of 529 patients with UCEC based on 39 HOX genes, combing clinical information, we discovered HOX gene were a pivotal factor in the development and progression of UCEC and in the formation of TME diversity and complexity. Here, a new scoring system was developed to quantify individual HOX patterns in UCEC. Our study found that patients in the low HOX score group had abundant anti-tumor immune cell infiltration, good tumor differentiation, and better prognoses. In contrast, a high HOX score was associated with blockade of immune checkpoints, which enhances the response to immunotherapy. The Real-Time quantitative PCR (RT-qPCR) and Immunohistochemistry (IHC) exhibited a higher expression of the HOX gene in the tumor patients. We revealed that the significant upregulation of the HOX gene in the epithelial cells can activate signaling pathway associated with tumour invasion and metastasis through single-cell RNA sequencing (scRNA-seq), such as nucleotide metabolic proce and so on. Finally, a risk prognostic model established by the positive relationship between HOX scores and cancer-associated fibroblasts (CAFs) can predict the prognosis of individual patients by scRNA-seq and transcriptome data sets. In sum, HOX gene may serve as a potential biomarker for the diagnosis and prediction of UCEC and to develop more effective therapeutic strategies.

Up-regulation of MTHFD2 is associated with clinicopathological characteristics and poor survival in ovarian cancer, possibly by regulating MOB1A signaling.

BACKGROUND: MTHFD2 is a folate-coupled metabolic enzyme, which has been proved to participant in the metabolic reprogramming and tumor cell-sustaining proliferative capacity. However, the function of MTHFD2 in the development of ovarian cancer and its potential molecular mechanisms is still unclear. MATERIALS AND METHODS: The expression, various mutations, prognosis, and related network signaling pathways of MTHFD2 were analyzed using bioinformatics-related websites, including Oncomine, GEPIA, UCSC, cBioPortal, KM Plotter, TISIDB and TIMER. The prognostic value of MTHFD2 expression was validated by our own ovarian cancer samples using RT-qPCR. The migration ad invasion of ovarian cancer cells were further analyzed by CCK-8 and transwell assay. The Western-blot assay was performed to explore the protein levels of MTHFD2 and MOB1A. RESULTS: We obtained the following important results. (1) MTHFD2 expression was markedly up-regulated in ovarian cancer than normal samples. (2) Among patients with ovarian cancer, those with higher MTHFD2 expression was associated with lower survival rate. (3) The major mutation type of MTHFD2 in ovarian cancer samples was missense mutation. (4) MTHFD2 knockdown inhibited proliferation, migration, invasion, as well as the expression of MOB1A in vitro. CONCLUSION: MTHFD2, as a NAD + -dependent enzyme, accelerated tumor progression by up-regulating MBO1A, suggesting that this protein may be an independent prognostic factor and a potential therapeutic target for future ovarian cancer treatments.

Endometrial microbiota from endometrial cancer and paired pericancer tissues in postmenopausal women: differences and clinical relevance.

OBJECTIVE: The incidence of postmenopausal endometrial cancer (EC) is rising, and the uterine microbiota has recently been suggested to be an etiology of EC. However, the differences in microbiota profiles in paired EC and the adjacent non-EC endometrium, and the functional microbiota of clinical relevance remain largely unknown. Therefore, we examined the differences in microbiota profiles between EC and non-EC endometrium and investigated their clinical relevance to EC. METHODS: Twenty-eight EC-affected postmenopausal women undergoing hysterectomy were enrolled. Endometrial microbiome from paired EC and adjacent non-EC tissue samples were detected using 16S rRNA sequencing, and the data were analyzed using R language software. RESULTS: The α diversity and evenness of the endometrial bacterial community significantly increased in EC tissues than those in pericancer tissues ( P < 0.05 for all variables). Lactobacillus and Gardnerella were the main bacterial genera present in both EC and adjacent non-EC-invading endometrium, whereas Prevotella , Atopobium , Anaerococcus , Dialister , Porphyromonas , and Peptoniphilus were more commonly enriched in the EC endometrium (corrected P < 0.05 for all variables). Finally, the abundance of some observed endometrial bacteria was associated with clinical aspects, particularly the vaginal pH, vaginal Lactobacillus abundance, and EC clinical stage. CONCLUSIONS: Paired EC and adjacent non-EC endometrium harbor different endometrial microbiota, and the functional bacteria residing in the endometrium are clinically relevant but require further investigation.