Yu Chen

Correlation of cell cycle–related kinase and SII with FIGO stage, lymph node metastasis, and prognosis of serous ovarian cancer

Abstract Background: Ovarian cancer has no specific manifestations in the early stage, and most patients have advanced to the advanced stage when diagnosed for the first time. The 5-year survival rate for patients receiving standardized treatment is still low. The systemic immune inflammation index (SII) can comprehensively reflect host inflammation and immune balance status, and has good application value in evaluating the condition and prognosis of various malignant tumors. Cell cycle related kinase (CCRK) can regulate cell cycle, promote cell proliferation and division, and is closely related to the occurrence and development of various malignant tumors. Therefore, to detect the positive expression of CCRK and the level of SII index in serous ovarian cancer tissue, and to explore the relationship between CCRK and SII with the pathological characteristics and prognosis of serous ovarian cancer, analyze the possible mechanisms of CCRK and SII in the occurrence and development of serous ovarian cancer, and provide reference for clinical diagnosis and treatment of ovarian cancer. Methods: The malignant group included 315 patients with serous ovarian cancer who were hospitalized by us from January 2018 to January 2019, and 158 patients with ovarian serous cystadenoma were enrolled in the benign group. During the operation, the cancerous foci and lesion tissues of the two groups were collected. The expression of CCRK in pathological tissues was detected by immunohistochemistry. CCRK expression and SII levels in the benign and malignant groups, and patients with different clinicopathologic features of serous ovarian cancer were compared. Taking the average SII level of the malignant group as the grouping standard, the invalids were divided into SII high- and low-expression groups and observed until January 2022. To analyze the correlation between CCRK expression, SII, FIGO stage, lymph node metastasis, and prognosis of serous ovarian cancer. The survival of patients with CCRK-positive and -negative expression of this disease, and SII high and low expressions were statistically analyzed. Results: Positive CCRK expression was more prevalent in serous ovarian cancer tissues than in serous cystadenoma tissues, and the CCRK-positive grade in serous ovarian cancer was higher than that of cystadenoma. SII of patients with this disease was greater than that of those with serous cystadenoma and the difference was statistically significant (P < 0.05). FIGO stage and lymph node metastases were associated with positive expression of CCRK in serous ovarian cancer (P < 0.05). SII was correlated with FIGO stage, differentiation degree, lymph node metastasis, and serum CA125 level (P < 0.05). Spearman correlation analysis showed that the expression of CCRK in invalids with serous ovarian cancer was positively correlated with FIGO stage and lymph node metastasis of serous ovarian cancer (r = 0.538, r = 0.605, P < 0.001). SII was positively correlated with FIGO stage and lymph node metastasis of serous ovarian cancer (r = 0.689, r = 0.622, P < 0.001). The Kaplan–Meier survival curve and the log-rank test demonstrated that the CCRK-positive expression group had an lower survival rate than the CCRK-negative expression group, and that the SII high-expression group had an lower survival rate than the SII low-expression group (rank = 19.504, 16.184, P < 0.05). Conclusion: Positive CCRK expression and an elevated SII have a role in the development of serous ovarian cancer and have the potential to predict the prognosis of patients.

MiR‐326 regulates the proliferation and apoptosis of endometrial cancer by targeting Bcl‐2

AbstractAimMiR‐326 has been investigated to be correlated with multiple types of malignancies; however, the role of miR‐326 in endometrial cancer (EC) remains rarely reported. The aim of our research is to investigate the functions of miR‐326 in EC and the potential molecular mechanism.MethodsRT‐qPCR was performed to compare the expression of miR‐326 and Bcl‐2 in normal endometrial epithelial cell line (End1/e6e7) and EC cells lines (HEC‐1A, Ishikawa), respectively. Bioinformatic analysis and luciferase assay verified the relationship between miR‐326 and the 3’‐UTR of Bcl‐2. 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide (MTT) assay, soft agar colony formation assay and the flow cytometry were performed to investigate the functions of miR‐326 and Bcl‐2 on proliferation and apoptosis in EC. Western blotting was employed to explore the expression of Bcl‐2, Bcl2‐associated X (Bax) and caspase‐3.ResultsThe expression of miR‐326 decreased in EC cell lines compared to normal endometrial epithelial cell line, while Bcl‐2 expression was increased in EC cells. Results of MTT and soft agar colony formation assays showed that miR‐326 suppressed proliferation in EC cells. In addition, flow cytometry revealed that miR‐326 promoted apoptosis in EC cells. Western blotting showed that silencing miR‐326 promoted the expression of Bcl‐2. Bioinformatics analysis and luciferase assay verified the 3’‐UTR of Bcl‐2 was a target of miR‐326. Furthermore, MTT assay, soft agar colony formation assay and the flow cytometry proved that miR‐326 acts as tumor suppressor via inhibiting the expression of Bcl‐2.ConclusionMiR‐326 acts as a cancer suppressor to inhibit proliferation and promote apoptosis via targeting Bcl‐2 axis in EC.

M5C-driven stabilization of SERPINB5 promotes cervical cancer progression and chemotherapy resistance

Abstract RNA 5-methylcytosine (m 5 C) plays a critical role in cancer, yet its functional mechanisms and therapeutic relevance in cervical cancer remain unclear. Here, we generate the first base-resolution m 5 C transcriptome maps in cervical cancer, revealing globally elevated m 5 C levels in tumors. By integrating spatial transcriptomics and single-cell RNA-seq, we identify SERPINB5 as a novel m 5 C-regulated oncogenic effector. m 5 C modification enhances SERPINB5 mRNA stability and protein expression, promoting tumor growth, metastasis, and resistance to microtubule-targeting chemotherapeutics. Mechanistically, SERPINB5 upregulates mitotic regulators and microtubule motor proteins, including CENPE, enhancing mitotic progression and counteracting drug-induced mitotic arrest. Loss-of-function experiments demonstrate that SERPINB5 depletion sensitizes cervical cancer cells to paclitaxel and vincristine, while its reintroduction restores chemoresistance even in m 5 C-deficient cells. Our study uncovers a previously unrecognized m 5 C–SERPINB5 axis as a central driver of cervical cancer malignancy and chemoresistance, highlighting SERPINB5 as a clinically actionable target to improve outcomes for patients receiving microtubule-targeting chemotherapy.

NAD+ Metabolism Reprogramming Drives SIRT1‐Dependent Deacetylation Inducing PD‐L1 Nuclear Localization in Cervical Cancer

AbstractCervical cancer (CC) is a major health threat to women, with immunotherapies targeting the programmed death receptor 1/programmed death ligand 1(PD‐1/PD‐L1) axis showing promise but encountering resistance in a significant patient population. This resistance has driven a critical quest to uncover the underlying mechanisms. This study uncovers a novel metabolic axis involving the nicotinamide adenine dinucleotide (NAD+) salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) and the deacetylase Sirtuin 1 (SIRT1), which regulates PD‐L1 expression and nuclear localization in CC. This axis may be a key factor contributing to the resistance observed in immunotherapy. This study reveals that PD‐L1 overexpression in cancers is regulated by both transcriptional and post‐transcriptional processes. Acetyl‐proteomic analysis pinpoints SIRT1 as a central regulator in the deacetylation of histone H3 at lysines 27, which may influence PD‐L1 subcellular distribution. This finding reveals the epigenetic control of immune checkpoint proteins by metabolic pathways, offering a new perspective on the regulation of PD‐L1. The identification of the NAMPT/SIRT1 metabolic axis as a critical factor suggests that targeting this axis may enhance therapeutic responses.

Engineering Chemotherapeutic-Augmented Calcium Phosphate Nanoparticles for Treatment of Intraperitoneal Disseminated Ovarian Cancer

Ovarian cancer is a common gynecologic malignancy with a high fatality rate. Intraperitoneal chemotherapy has been proved as an efficient clinical treatment for disseminated ovarian cancer. However, there are limitations for conventional small molecule drugs to achieve an ideal therapeutic effect. Herein, a synergistic treatment for intraperitoneally disseminated ovarian cancer was achieved by Arg-Gly-Asp (RGD)-modified amorphous calcium phosphate loading with doxorubicin (designated as RGD-CaPO/DOX). The engineered calcium-involved nanomedicine augmented the therapeutic effect of DOX by aggravating endoplasmic reticulum stress, calcium overload, and mitochondrial dysfunction, ultimately triggering mitochondrial apoptosis in the SKOV3 (human ovarian cancer) cell line. In an intraperitoneally disseminated tumor model, RGD modification and the weak negative surface potential of the NPs were beneficial for intraperitoneal retention and tumor targeting. Moreover, intraperitoneal injection of RGD-CaPO/DOX NPs resulted in a favorable antitumor effect. The mean survival time of SKOV3-bearing mice was significantly extended from 29 to 59 days with negligible toxicity. Therefore, this study has been designed to provide an effective chemotherapeutic-augmented treatment for intraperitoneally disseminated ovarian cancer.

Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2)

Abstract Background: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. Methods: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. Results: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09–1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case–control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. Conclusions: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. Impact: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.