Shijie Yao

BAG2 Inhibits Cervical Cancer Progression by Modulating Type I Interferon Signaling through Stabilizing STING

Abstract Cervical cancer possesses high morbidity and mortality rates, and a comprehensive understanding of its molecular underpinnings is essential for advancing clinical management strategies. The innate immune sensor STING, which activates type I interferon signaling, plays a pivotal role in enhancing anti‐tumor activity. Despite increased attention to STING's involvement in cervical cancer, the regulatory mechanisms governing its protein homeostasis remain poorly understood. In this study, it is found that the BAG2‐STUB1 complex regulates ubiquitin proteasomal degradation of STING, which affects the development of cervical cancer. Mechanistically, BAG2 inhibits ubiquitination of STING and stabilizes it by interacting with STING. Specifically, BAG2 inhibits STUB1 from attaching the K48‐linked ubiquitin chains at K338 and K370 of STING by forming a complex with STUB1. Functionally, enhanced BAG2 expression suppresses cervical cancer progression by activating the type I interferon pathway in a STING‐dependent manner. Notably, clinical cervical cancer samples revealed a positive correlation between BAG2 and STING levels, with low BAG2 expression is strongly linked to advanced disease and poor prognosis in cervical cancer. Collectively, these findings elucidate the molecular mechanism by which the BAG2‐STUB1 complex regulates STING homeostasis, underscoring BAG2's potential as a diagnostic biomarker and therapeutic target in cervical cancer.

Cytoreductive Surgery (CRS) Combined With Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Platinum-Sensitive Recurrence Epithelial Ovarian Cancer With HRR Mutation: A Phase III Randomized Clinical Trial

Background: Epithelial ovarian cancer (EOC) remains the leading cause of gynecologic cancer death worldwide due to the high recurrence rate. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is an alternative modality for platinum-sensitive recurrent EOC. The latest studies demonstrate homologous recombination-related (HRR) mutation status increases the sensitivity to platinum-based chemotherapy drugs in EOC. However, the molecular analysis of recurrent EOC patient benefits from HIPEC is unknown. Thus, we aimed to evaluate the efficacy and safety of CRS combined with HIPEC for platinum-sensitive in recurrent EOC with HRR mutation. Methods: This is a phase III randomized controlled clinical trial in patients with platinum-sensitive recurrent EOC. Participants were divided into 2 groups based on the HRR mutation status and randomized to receive CRS + HIPEC. The patients then received periodic chemotherapy and follow-up. Results: The primary objective of this study was to evaluate the effect of CRS + HIPEC compared to CRS alone in patients with a platinum-sensitive recurrent EOC stratified for HRD status. We hypothesize that the addition of HIPEC to CRS improves the progression-free survival (PFS) of platinum-sensitive recurrent EOC patients with HRR mutation compared with patients without HRR mutation. Conclusion: Recurrent EOC has a poor prognosis due to implantation and metastasis in the abdominal cavity. Intraperitoneal chemotherapy reduced seeding by removing free tumor cells. HIPEC utilizes physical and biological properties to significantly increase the clearance rate of tumors. Van Driel WJ et al proposed that HIPEC using platinum-based chemotherapy improves the survival of patients with ovarian cancer. HRR mutation, as a common pathogenic mutation in ovarian cancer, has a predictive effect on the platinum sensitivity of ovarian cancer patients. Whether lobaplatin-based HIPEC will play a greater role in ovarian cancer patients with HRR mutations is currently unknown.

Alternative Splicing: A New Therapeutic Target for Ovarian Cancer

Background: Increasing evidences have shown that abnormal alternative splicing (AS) events are closely related to the prognosis of various tumors. However, the role of AS in ovarian cancer (OV) is poorly understood. This study aims to explore the correlation between AS and the prognosis of OV and establish a prognostic model for OV. Methods: We downloaded the RNA-seq data of OV from The Cancer Genome Atlas databases and assessed cancer-specific AS through the SpliceSeq software. Then systemically investigated the overall survival (OS)-related AS and splicing factors (SFs) by bioinformatics analysis. The nomogram was established based on the clinical information, and the clinical practicability of the nomogram was verified through the calibration curve. Finally, a splicing correlation network was constructed to reveal the relationship between OS-related AS and SFs. Results: A total of 48,049 AS events were detected from 10,582 genes, of which 1523 were significantly associated with OS. The area under the curve of the final prediction model was 0.785, 0.681, and 0.781 in 1, 3, and 5 years, respectively. Moreover, the nomogram showed high calibration and discrimination in OV patients. Spearman correlation analysis was used to determine 8 SFs significantly related to survival, including major facilitator superfamily domain containing 11, synaptotagmin binding cytoplasmic RNA interacting protein, DEAH-box helicase 35, CWC15, integrator complex subunit 1, LUC7 like 2, cell cycle and apoptosis regulator 1, and heterogeneous nuclear ribonucleoprotein A2/B1. Conclusion: This study provides a prognostic model related to AS in OV, and constructs an AS-clinicopathological nomogram, which provides the possibility to predict the long-term prognosis of OV patients. We have explored the wealth of RNA splicing networks and regulation patterns related to the prognosis of OV, which provides a large number of biomarkers and potential targets for the treatment of OV. Put forward the potential possibility of interfering with the AS of OV in the comprehensive treatment of OV.