Tong Wang

Cryptotanshinone suppresses ovarian cancer via simultaneous inhibition of glycolysis and oxidative phosphorylation

Ovarian cancer is one of the most lethal cancers in female reproductive system due to heterogeneity and lack of effective treatment. Targeting aerobic glycolysis, a predominant energy metabolism of cancer cells has been recognized a novel strategy to overcome cancer cell growth. However, the capability of cancer cells to undergo metabolic reprogramming guarantees their survival even when glycolysis is inhibited. Here in this study, we have shown that Cryptotanshinone (CT), a lipid-soluble bioactive anticancer molecule of Salvia miltiorrhiza, inhibits both glycolysis and oxidative phosphorylation (OXPHOS) in ovarian cancer cells leading to growth suppression and apoptosis induction. Our mechanistic study revealed that CT decreased glucose uptake and lactate production, and inhibited the kinase activity of LDHA and HK2. The molecular docking study showed that CT could directly bind with GLUT1, LDHA, HK2, PKM2 and complex-1. The immunoblotting data showed that CT decreased the expression of aberrantly activated glycolytic proteins includingGLUT1, LDHA, HK2, and PKM2. Besides, we found that CT inhibited mitochondrial ComplexⅠ activity, decreased the ratio of NAD

Engrailed-2 (EN2) protein in cervical mucus: a novel biomarker for endometrial carcinoma

Abstract Objective This study aims to demonstrate that the EN2 protein in cervical mucus may serve as a novel biomarker for screening endometrial cancer. Materials and Methods This study included 133 patients who were treated at Beijing Obstetrics and Gynecology Hospital. According to the pathological results of hysteroscopy endometrial biopsy, the patients were divided into endometrial cancer group (n = 55), endometrial atypical hyperplasia group (n = 16), benign lesion group (n = 28), and control group (n = 34). All patients collected cervical mucus before hysteroscopy, and the level of EN2 protein in cervical mucus was detected by ELISA in the four groups of patients. Nine patients who underwent surgical treatment for endometrial cancer were included, and endometrial cancer lesions and adjacent tissues without endometrial cancer infiltration were taken from the endometrial cancer lesions and cervical tissues. Fifteen patients who underwent hysterectomy for benign lesions were included, and endometrial and cervical tissues were taken from the endometrial cancer lesions and adjacent tissues without endometrial cancer infiltration. PT-PCR, immunohistochemistry, and WB were used to verify the expression differences of EN2 protein in cancerous lesions and endometrial tissues without endometrial infiltration, cervical tissues, and endometrial tissues without endometrial lesions. In addition, HEC1B, KLE, and HeLa cell lines were used to characterize EN2 overexpression in endometrial cancer cells. Immunohistochemistry, RT-PCR, and confocal analysis were used to detect the expression of EN2 protein in different cell lines. Results In different groups, the average concentration of EN2 protein in cervical mucus in the EC group was significantly higher than that in the benign group and the normal control group (573.9 ± 123.4 ng/mL vs 153.5 ± 106.2 ng/mL and 153.0 ± 107.5 ng/mL, P < 0.001). The concentration of EN2 protein in EIN3 case specimens was significantly higher than that in the normal control group (P < 0.001). ROC analysis showed that the optimal threshold for diagnosing endometrial cancer in cervical mucus was 321.1 ng/ml, with a sensitivity of 92.6% and specificity of 95.4% for distinguishing EINIII, EC, and non-cancerous cases. In clinical specimens, the expression level of EN2 protein in endometrial cancer tissues was significantly higher than that in endometrial tissues and cervical tissues without endometrial cancer infiltration. In addition, PT-PCR, immunohistochemistry, suggest that EN2 protein is overexpressed in endometrial cancer cell lines compared to cervical adenocarcinoma cells (P < 0.01). Conclusion The concentration of EN2 protein in cervical mucus can effectively identify endometrial cancer and precancerous lesions. The increased expression of EN2 protein in endometrial cancer lesions leads to an increase in the concentration of EN2 protein in the cervical mucus of endometrial cancer patients.This is a small single-center study, and larger studies are needed to determine the role of EN2 protein in the diagnosis of endometrial cancer.

Associated analysis of PER1/TUBB2B with endometrial cancer development caused by circadian rhythm disorders

Endometrial cancer (EC) is one of the most common gynecologic malignancies, and the incidence rate of night shift among women workers is higher than that in the general population. Circadian rhythm disorder, mainly rhythm gene, is related to various tumor onset, including EC. This study described the sleep/night-shift features of EC patients, explored the mechanism of the circadian clock gene PER and investigated prognostic and functional values of Per1 caused by night shift. A total of 619 subjects were enrolled and divided into two groups according to night-shift duties (rhythm group and control group), analyzed for clinical risk factors and night shift features of endometrial carcinoma. Then samples were randomly selected for sequencing and western blot were performed, and the function of overexpressed PER1 in ishikawa cells was explored. We noticed that severer EC patients experienced night-shift more frequently and with longer durations. A total of 58,174 differentially expressed genes were discovered, mainly rhythm genes and related to up and downstream regulatory genes. Western blot showed that the rhythm group had elevated protein expression of BCAS4, TUBB2B and RSPO4, and decreased expression of PER1 and PER2 in night-shift. In TCGA-EC datasets, PER1 was decreased in the EC patients with a significantly positive correlation with PER2, and higher PER1 expression indicated longer survival, opposite to TUBB2B. The research of overexpressing PER1 gene in EC ishikawa cells found that PER1 can promote apoptosis, expression of TNF-a, IL-6 and PD-1/PD-L1, inhibit the tumor invasion and expression of TUBB2B gene. Together, EC severity was associated with night-shift and rhythm disorders. The rhythm relating factors PER1, TUBB2B and tumor immune factors may regulate the mechanisms of EC onset and progression.

Cervical cancer incidence rates considering migration status in mainland China using Bayesian model—Estimation based on 2016 cancer registry data

AbstractIn mainland China, cancer registration relies on household‐registered populations, overlooking migrant populations. Estimating cervical cancer incidence among permanent residents, including migrants, offers a more accurate representation of the true burden. The data from 487 cancer registries across China in 2016 were analyzed using a Bayesian spatial regression model with the integrated nested Laplace approximation‐stochastic partial differential equation method. The study estimated cervical cancer incidence among household‐registered populations and adjusted for migrant populations using a weighting method based on interprovincial distribution and age stratification to derive the incidence of cervical cancer in the permanent residents. Data from the China Population Census, the China Migrants Dynamic Survey, and the Urban Statistical Yearbook were incorporated. The estimated crude incidence rate of cervical cancer among permanent residents was 17.4/100,000 in mainland China, with an age‐standardized incidence rate (ASIR) of 17.2/100,000. The largest disparities in cervical cancer crude incidence rate between permanent residents and household‐registered populations were observed in Guizhou (2.4/100,000, 95% CI 1.9–2.9/100,000), Zhejiang (−1.2/100,000, 95% CI −1.8 to −0.6/100,000) and Tianjin (−1.1/100,000, 95% CI −1.5 to −0.7/100,000). The number of the estimated cervical cancer incident cases was 8948. Guangdong saw an increase of 887 cases, while Henan had a decrease of 1430 cases. Guizhou had the highest ASIR (28.1/100,000), and Beijing had the lowest ASIR (11.0/100,000). The significance of this study is that it improves the accuracy of cervical cancer data in China. These findings provide evidence for developing cervical cancer prevention and control strategies, and offer insights for other countries and regions facing migration challenges.

Predictive models for personalized precision medical intervention in spontaneous regression stages of cervical precancerous lesions

Abstract Background During the prolonged period from Human Papillomavirus (HPV) infection to cervical cancer development, Low-Grade Squamous Intraepithelial Lesion (LSIL) stage provides a critical opportunity for cervical cancer prevention, giving the high potential for reversal in this stage. However, there is few research and a lack of clear guidelines on appropriate intervention strategies at this stage, underscoring the need for real-time prognostic predictions and personalized treatments to promote lesion reversal. Methods We have established a prospective cohort. Since 2018, we have been collecting clinical data and pathological images of HPV-infected patients, followed by tracking the progression of their cervical lesions. In constructing our predictive models, we applied logistic regression and six machine learning models, evaluating each model’s predictive performance using metrics such as the Area Under the Curve (AUC). We also employed the SHAP method for interpretative analysis of the prediction results. Additionally, the model identifies key factors influencing the progression of the lesions. Results Model comparisons highlighted the superior performance of Random Forests (RF) and Support Vector Machines (SVM), both in clinical parameter and pathological image-based predictions. Notably, the RF model, which integrates pathological images and clinical multi-parameters, achieved the highest AUC of 0.866. Another significant finding was the substantial impact of sleep quality on the spontaneous clearance of HPV and regression of LSIL. Conclusions In contrast to current cervical cancer prediction models, our model’s prognostic capabilities extend to the spontaneous regression stage of cervical cancer. This model aids clinicians in real-time monitoring of lesions and in developing personalized treatment or follow-up plans by assessing individual risk factors, thus fostering lesion spontaneous reversal and aiding in cervical cancer prevention and reduction. Graphical Abstract

The circadian rhythm and core gene Period2 regulate the chemotherapy effect and multidrug resistance of ovarian cancer through the PI3K signaling pathway

Abstract Background: Ovarian cancer is the most lethal cancer in the female reproductive system. It has been shown that ‘time chemotherapy’ of ovarian cancer has an important impact on the chemotherapy effect and prognosis of patients, but the specific mechanism is not known. Methods: We designed a case–control study in strict accordance with epidemiological principles. We collected resection samples of ovarian cancer patients who worked night-shifts and those who did not, and analyzed the differences in protein expression. Through construction of a normal/circadian-rhythm disorder model of ovarian cancer in nude mice, we explored the molecular mechanism of a ‘biological clock’ rhythm on treatment of ovarian cancer. Results: Expression of interleukin (IL)-6, programmed cell death receptor-1 (PD-1) and programmed death ligand 1 (PD-L1) increased, and expression of tumor necrosis factor (TNF)-α, Period 1 (Per1) and Period 2 (Per2) decreased in the night-shift group. Methylation of CpG islands in the promoter of Per2 could result in its decreased expression in SKOV3/DDP (Cisplatin) cells. Dysrhythmia of the circadian clock: (i) had a negative effect on the chemotherapy effect against ovarian cancer; (ii) affected expression of immune factors and the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Conclusion: The Per2 gene can affect the drug resistance of ovarian cancer by inhibiting the PI3K/Akt signaling pathway and then acting on its downstream drug-resistance factors, thereby providing a new target for ovarian cancer treatment.