Krüppel-like factor 12 decreases progestin sensitivity in endometrial cancer by inhibiting the progesterone receptor signaling pathway.

OBJECTIVE: This study aimed to clarify the mechanism by which Krüppel-like factor 12 (KLF12) affects progesterone sensitivity in endometrial cancer (EC) through the progesterone receptor PGR signaling pathway. METHODS: The relationship of KLF12 with PGR in EC patients was examined by immunohistochemistry, and the expression of KLF12 and PGR in EC cell lines was detected by real-time PCR and western blotting. Cell proliferation assay, plate clone formation, cell apoptosis assay, and cell cycle analysis were conducted to determine the impact of KLF12 intervention on progesterone therapy. CUT&Tag analysis and the dual-luciferase reporter experiment were used to determine the underlying regulatory effect of KLF12 on the PGR DNA sequence. A subcutaneous xenograft nude mouse model was established to validate the in vivo effect of KLF12 on progesterone sensitivity via PGR expression modulation. RESULTS: KLF12 demonstrated decreased progesterone sensitivity and a negative correlation with PGR expression in EC tissues. Progesterone sensitivity was increased by KLF12 deficiency through PGR overexpression, a result that could be significantly reversed by PGR downregulation. PGR was identified as a target gene of KLF12, which could directly bind to the PGR promotor region and inhibit its expression. CONCLUSION: This study is the first to investigate the effect of KLF12 expression on EC cell resistance to progesterone. Our results offer important mechanistic insight into the direct regulation of the PGR promoter region, demonstrating that KLF12 expression strongly suppressed the PGR signaling pathway and, as a result, reduced progesterone sensitivity in EC patients.

Triglyceride-glucose index (TyG index) and endometrial carcinoma risk: A retrospective cohort study.

OBJECTIVE: We analyzed the association between the triglyceride-glucose index (TyG index) and incident endometrial carcinogenesis, aiming to determine whether the TyG index is a promising predictive biomarker for endometrial carcinoma (EC). METHODS: In this retrospective cohort study, multiple logistic regression analysis was performed to evaluate the relationship between TyG index and EC incidence and progression. The receiver operating characteristic (ROC) curve was used to calculate the area under the curve (AUC), as well as the cut-off value of the TyG index for EC incidence. RESULTS: The TyG index was significantly higher in patients with EC or endometrial atypical hyperplasia (EAH) than in those with normal endometrium (P < 0.001). A continuous rise was observed in the incidence of EC and EAH among the tertiles of the TyG index (P < 0.001). The multiple logistic regression analysis revealed that the TyG index was associated with EC and EAH risk after adjusting for potential confounding factors (EAH: odds ratio [OR] 2.54, 95% confidence interval [CI] 1.33-4.85, P = 0.005; EC: OR 2.65, 95% CI 1.60-4.41, P < 0.001). Moreover, high TyG index was positively associated with advanced pathological stage (OR 2.14, 95% CI 1.32-3.47, P = 0.002) and poorer differentiation (OR 2.53, 95% CI 1.36-4.72, P = 0.004). CONCLUSION: The TyG index might be a promising biomarker for endometrial carcinogenesis. Subjects with a higher TyG index should be aware of the risk of EC incidence and progression.

The relationship between Triglyceride and glycose (TyG) index and the risk of gynaecologic and breast cancers.

BACKGROUND AND PURPOSE: The relationship between triglyceride glucose (TyG) index and gynaecologic and breast cancers is unclear. We hypothesized that an increase in the TyG index is associated with elevated risk of cancers of the uterine, cervix, ovary and breast. METHODS AND RESULTS: For this observational study, we collected data from the National Health and Nutrition Examination Survey (NHANSE, 1999-2018). A total of 11466 individuals were included, involving 586 (5.1%) individuals with a previous cancer diagnosis in female reproductive tissues (i.e., breast, ovarian, cervical or uterine). Logistic regression was performed to evaluate the association between TyG index and incidence of gynaecologic and breast cancers. We observed that higher TyG index is significantly linked to greater prevalence of gynaecologic and breast cancers in US adult population. After adjustment of multi-variates, participants with the highest quartile of TyG index had an OR = 1.516 (95% confidence interval (CI) 1.121, 2.050) (P < 0.05) versus the lowest. In addition, TyG index was associated with the risk of female cancers of the breast OR per one standard deviation increase 2.25,95% confidence interval:1.50 to 3.37], cervix (1.68,0.99 to 2.84), ovary (3.73,1.01 to 13.87), uterine (2.42,1.14 to 5.16). The optimal cut-off value for predicting gynaecologic and breast cancers is 8.70. Kaplan-Meier curves showed that individuals (TyG index≥8.70) had higher cancer mortality (P value < 0.05). CONCLUSIONS: The Elevated TyG index increases the incidence of cancers in female reproductive tissues. In the future studies, more evidence may be warranted to assess the correlation between TyG index and incidence of gynaecologic and breast cancers.