Integrating ferroptosis-related genes (FRGs) and prognostic models to enhance UCEC outcome prediction and therapeutic insights.

Ferroptosis is closely associated with uterine corpus endometrial carcinoma (UCEC) development. This project aimed to identify new potential biomarkers to predict the prognosis of UCEC. In this work, UCEC transcriptome data along with clinical information was retrieved from the TCGA database including a total of 382 FRGs. We performed univariate Cox regression analysis to evaluate ferroptosis-related genes (FRGs) for prognostic significance. The genes with prognostic significance were then analyzed using LASSO-Cox to construct a prognosis model. The model genes were further characterized through various proteomic analyses and expression detection in clinical samples. A multivariate Cox regression model was constructed containing four FRGs (CDKN1A, CDKN2A, CEBPG, NOS2). Among four FRGs, higher expressions of CDKN2A, CEBPG, and NOS2 were associated with poorer overall survival probability, while higher expression of CDKN1A was associated with better overall survival probability. The area under the receiver operating characteristic curve of the risk model was 0.617, 0.688, and 0.693 for 1 year, 3 years, and 5 years, respectively. Moreover, proteomic analysis showed that the protein expression of CDKN1A, CDKN2A, and CEBPG was higher in tumor tissues than that in normal tissues. Higher protein expression of CDKN1A and CDKN2A predicted poorer survival probability. Besides, CDKN1A protein had an interaction relationship with CDKN2A protein or NOS2 protein. In clinical samples, all four FRGs were upregulated in UCEC tissues, regardless of gene expression or protein expression. Our four FRGs risk model provides new insights for predicting the prognosis of UCEC patients.

Glycoprotein α-Subunit of Glucosidase II (GIIα) is a novel prognostic biomarker correlated with unfavorable outcome of urothelial carcinoma.

BACKGROUND: Urothelial carcinoma (UC) is among the most prevalent malignancies. The muscle-invasive bladder cancer (MIBC) shows an invasive feature and has poor prognosis, while the non-muscle invasive bladder cancer (NMIBC) shows a better prognosis as compared with the MIBC. However, a significant proportion (10%-30%) of NMIBC cases progress to MIBC. Identification of efficient biomarkers for the prediction of the course of UC remains challenging nowadays. Recently, there is an emerging study showed that post-translational modifications (PTMs) by glycosylation is an important process correlated with tumor angiogenesis, invasion and metastasis. Herein, we reported a data-driven discovery and experimental validation of GANAB, a key regulator of glycosylation, as a novel prognostic marker in UC. METHODS: In the present study, we conducted immunohistochemistry (IHC) assay to evaluate the correlation between the expression levels of GANAB protein and the prognosis of UC in our cohort of 107 samples using whole slide image (WSI) analysis. In vitro experiments using RNAi were also conducted to investigate the biological functions of GANAB in UC cell lines. RESULTS: We observed that positive GANAB protein expression was significantly correlated with poor prognosis of UC in our cohort, with p-value of 0.0017 in Log-rank test. Notably, tumor cells at the invasive front of the tumor margin showed stronger GANAB expression than the tumor cells inside the tumor body in UCs. We further validated that the elevated expression levels of GANAB were significantly correlated with high grade tumors (p-values of 1.72 × 10-10), advanced stages (6.47 × 10-6), and elevated in luminal molecular subtypes. Moreover, knocking-down GANAB using RNAi in UM-UC-3 and T24 cells inhibited cell proliferation and migration in vitro. Knockdown of GANAB resulted in cell cycle arrest at G1 phase. We demonstrated that GANAB mediated HIF1A and ATF6 transcriptional activation in the ER stress signaling, and regulated the gene expression of cell cycle-related transcriptional factors E2F7 and FOXM1. CONCLUSIONS: The elevated expression of GANAB is a novel indicator of poorer prognosis of UC. Our data suggests that GANAB is not only a new and promising prognostic biomarker for UC, but also may provide important cues for the development of PTM-based therapeutics for UC treatment.

Identification of leucine-rich repeat-containing protein 59 (LRRC59) located in the endoplasmic reticulum as a novel prognostic factor for urothelial carcinoma.

BACKGROUND: Urothelial carcinoma (UC) is one of the most common cancers worldwide. The biological heterogeneity of UCs causes considerable difficulties in predicting treatment outcomes and usually leads to clinical mismanagement. The identification of more sensitive and efficient predictive biomarkers is important in the diagnosis and classification of UCs. Herein, we report leucine-rich repeat-containing protein 59 (LRRC59) located in the endoplasmic reticulum as a novel predictive factor and potential therapeutic target for UCs. METHODS: Using whole-slide image analysis in our cohort of 107 UC samples, we performed immunohistochemistry to evaluate the prognostic value of LRRC59 expression in UCs. In vitro experiments using RNAi were conducted to explore the role of LRRC59 in promoting UC cell proliferation and migration. RESULTS: A significant correlation between LRRC59 and unfavorable prognosis of UCs in our cohort was demonstrated. Subsequent clinical analysis also revealed that elevated expression levels of LRRC59 were significantly associated with higher pathological grades and advanced stages of UC. Subsequently, knockdown of LRRC59 in UM-UC-3 and T24 cells using small interfering RNA significantly inhibited cell proliferation and migration, resulting in cell cycle arrest at the G1 phase. Conversely, the overexpression of LRRC59 in UC cells enhanced cell proliferation and migration. An integrated bioinformatics analysis revealed a significant functional network of LRRC59 involving protein misfolding, ER stress, and ubiquitination. Finally, in vitro experiments demonstrated that LRRC59 modulates ER stress signaling. CONCLUSIONS: LRRC59 expression was significantly correlated with UC prognosis. LRRC59 might not only serve as a novel prognostic biomarker for risk stratification of patients with UC but also exhibit as a potential therapeutic target in UC that warrants further investigation.

The prevalence, genotype distribution of human papillomavirus and cervical cytology in Wenzhou, China: a retrospective research of 7391 cases.

BACKGROUND: Human papillomavirus (HPV) infection is the main pathogen of precancerous transformation and finally progress to cervical cancer. It associated with cervical squamous and glandular lesions. However, the genotype distribution of HPV and the relationship between HPV infection and cervical disease are still remind unclear. MATERIAL AND METHODS: A total of 7391 abnormal cervical cytology cases with detailed histological reports and HPV genotypes were collected. The prevalence of HPV infection in squamous epithelial lesions and glandular epithelial lesions were statistically analyzed. RESULT: Around 6958 cytological squamous epithelial lesions and 433 glandular epithelial lesions were enrolled. 79.72% of cytological squamous epithelial lesions and 26.56% of glandular epithelial lesions were HPV infected. The HPV infection rates in squamous cell carcinoma, cervical adenocarcinoma and endometrial adenocarcinoma were 66.67%, 54.17% and 19.72%, respectively. HVP16, 18 and 58 are the most common types in squamous and glandular epithelial lesions. Among the squamous epithelial lesions, women less than 25 years old had the highest HPV infection rate, and majority of multiple infections was found in women >55 years old. The total infection rate of HPV in glandular epithelial lesions was the highest in the 35 to 45 group. Multiple infections peaked in women around 55 years old. CONCLUSION: The prevalence of HPV infection is divergent in different types of cervical cancer. The HPV infections in cervical squamous epithelial lesions tended to be younger. HPV detection is one of the necessary tests for cervical disease screening and should be individualized in an age manner.

MiR-206 inhibits epithelial ovarian cancer cells growth and invasion via blocking c-Met/AKT/mTOR signaling pathway.

BACKGROUND: MicroRNAs play important roles in the pathogenesis of various kinds of tumors. However, there are few studies on the expression profile and function of miRNAs in epithelial ovarian cancer. In this study, we performed microRNA array to compare the expression profile of microRNA in ovarian cancer tissues with noncancerous tissues. METHODS: qRT-PCR was used to further confirm the microRNA expression levels in epithelial ovarian cancer tissues and cell lines. The function of microRNA was analyzed by overexpressing microRNA mimics followed by the analysis of cell cycle, proliferation, and metastasis. The downstream target of miR-206 was found and western blot analysis was performed to measure the activation of the downstream signaling pathway. RESULTS: In this study, we found the expression of miR-206 was significantly down-regulated in epithelial ovarian cancer tissues and epithelial ovarian cancer cell lines. In epithelial ovarian cancer patients, downregulation of miR-206 was associated with metastasis and poor prognosis. In epithelial ovarian cancer cell lines, miR-206 contributed to the cell cycle regulation, cell apoptosis, and cancer cell metastasis. MiR-206 mimics inhibited cancer cell proliferation and metastasis, and induced cell apoptosis. Moreover, our results demonstrated that miR-206 directly targeted c-Met and repressed the activation of downstream AKT/mTOR signaling pathway. CONCLUSION: Our results demonstrated that miR-206 was down-regulated in epithelial ovarian cancer tissues and cell lines. MiR-206 inhibits the development of epithelial ovarian cancer cell by directly targeting c-Met and inhibiting the c-Met/AKT/mTOR signaling pathway.