Hongyan Guo

Construction and validation of a prognostic model for overall survival time of patients with ovarian cancer by metabolism‐related genes

Abstract Background Ovarian cancer is a female‐specific malignancy with high morbidity and mortality. The metabolic reprogramming of tumor cells is closely related to the biological behavior of tumors. Methods The prognostic signature of the metabolism‐related gene (MRGs) was established by LASSO‐Cox regression analysis. The prognostic signature of MRGs was also prognosticated in each clinical subgroup. These genes were subjected to functional enrichment analysis and tissue expression exploration. Analysis of the MRG prognostic signature in terms of immune cell infiltration and antitumor drug susceptibility was also performed. Results A MRG prognostic signature including 21 genes was established and validated. Most of the 21 MRGs were expressed at different levels in ovarian cancer than in normal ovarian tissue. The enrichment analysis suggested that MRGs were involved in lipid metabolism, membrane organization, and molecular binding. The MRG prognostic signature demonstrated the predictive value of overall survival time in various clinical subgroups. The monocyte, NKT, Tgd and Tex cell scores showed differences between the groups with high‐ and low‐risk score. The antineoplastic drug analysis we performed provided information on ovarian cancer drug therapy and drug resistance. In vitro experiments verified that PLCH1 in 21 MRGs can regulate the apoptosis and proliferation of ovarian cancer cells. Conclusion This metabolism‐related prognostic signature was a potential prognostic factor in patients with ovarian cancer, demonstrating high stability and accuracy.

A novel BRCA mutation classification system reveals differential responses to PARP inhibition and prognostic outcomes in epithelial ovarian cancer: a multicenter study

Although poly (ADP-ribose) polymerase inhibitors (PARPis) have transformed the treatment landscape for the BReast CAncer susceptibility gene (BRCA)-mutated ovarian cancer, emerging evidence suggests significant heterogeneity in treatment efficacy. However, findings regarding the impact of mutation location and type remain debated, underscoring the necessity for more data and better subclassification. This study aimed to evaluate the association between novel BRCA mutation subgroups and PARPi response in epithelial ovarian cancer. This is a multicenter retrospective study conducted in China which enrolled BRCA1/2-mutated epithelial ovarian cancer patients between 2015 and 2024. Patients who achieved complete or partial response after surgery and platinum-based chemotherapy were included. Progression-free survival (PFS) was assessed with Kaplan-Meier curves (log-rank test) and Cox models to estimate hazard ratios with 95% confidence intervals. A total of 465 patients were included, of whom 319 (68.6%) received PARPi as maintenance therapy. We introduced a novel classification system that continuously segments the entire BRCA1 gene. Patients with mutations in the DNA-binding domain (DBD) and adjacent region [between DBD and C-terminal domain of BRCA1 (BRCT) (DB)] had poor prognosis without PARPi treatment but showed substantial benefit with PARPi (P = 0.0097 and P = 0.0016, respectively). Conversely, mutations in the Really Interesting New Gene (RING) domain and its downstream region (between RING and DBD) showed limited therapeutic benefit from PARPi and were associated with poorer overall outcomes. Patients with mutations located in the BRCT domain exhibited favorable prognosis regardless of PARPi treatment, diminishing the relative benefit of PARPi in this subgroup. According to the mutation type, patients with frameshift or nonsense mutations experienced significant improvement with PARPi (both P < 0.05). Our novel classification revealed that PARPi efficacy and prognosis varied significantly by mutation location, with the central region linked to superior outcomes compared with the N- and C-terminal regions. Comprehensive mutation profiling should guide treatment decisions to optimize outcomes in patients with BRCA-mutated ovarian cancer.

Ferroptosis promotes 5-aminolevulinate acid-based photodynamic therapy in cervical cancer

Cervical cancer has the highest incidence rate among all gynecologic malignancies. Photodynamic therapy (PDT) is a minimal invasive treatment widely used in various tumors. Intracellular generation of reactive oxygen species (ROS) is the essential effect in PDT, which also plays a pivotal role in ferroptosis. We hypothesize that ferroptosis inducer could enhance 5-Aminolevulinic acid (5-ALA) based PDT in cervical cancer. In vitro efficacy of 5-ALA-based photodynamic therapy was assessed via viability and apoptosis of cervical cancer cell line SiHa. Ferroptosis related markers were detected in SiHa cells received 5-ALA-PDT treatment. Anti-tumor effects of ferroptosis inducer sorafenib on 5-ALA-based photodynamic therapy were evaluated in both cell line and mouse model. Efficacy of 5-ALA-based photodynamic therapy was validated in SiHa cervical cancer cells. Increased intracellular generation of ROS and lipid ROS, accompanied by decreased GPX4 expression was observed after 5-ALA-PDT treatment, indicating ferroptosis triggered by photodynamic therapy. Ferroptosis inducer sorafenib, a clinical approved cancer drug, promotes 5-ALA-based photodynamic therapy in SiHa cells. In vivo combined anti-tumor effect of sorafenib and 5-ALA-based photodynamic therapy was confirmed in cervical cancer xenografts. We identified that 5-ALA-PDT inhibited cell viability and induced ferroptosis in cervical cancer. Ferroptosis inducer sorafenib promotes 5-ALA-based photodynamic therapy. These findings may provide new insights into mechanisms of photodynamic therapy and cervical cancer treatment in the future.

MAP4K4 mediates the SOX6-induced autophagy and reduces the chemosensitivity of cervical cancer

AbstractThere are nearly 40% of cervical cancer patients showing poor response to neoadjuvant chemotherapy that can be induced by autophagy, however, the underlying mechanism has not yet been fully clarified. We previously found thatSex-determining region of Y-related high-mobility-group box 6(SOX6), a tumor suppressor gene or oncogene in several cancers, could induce autophagy in cervical cancer. Accordingly, this study aims to investigate the mechanism of SOX6-induced autophagy and its potential significance in the platinum-based chemotherapy of cervical cancer. Firstly, we found that SOX6 could promote autophagy in cervical cancer cells depending on its HMG domain.Mitogen-activated protein kinase kinase kinase kinase-4(MAP4K4) gene was identified as the direct target gene of SOX6, which was transcriptionally upregulated by binding the HMG domain of SOX6 protein to its double-binding sites withinMAP4K4gene promoter. MAP4K4 mediated the SOX6-induced autophagy through inhibiting PI3K-Akt-mTOR pathway and activating MAPK/ERK pathway. Further, the sensitivity of cervical cancer cells to cisplatin chemotherapy could be reduced by the SOX6-induced autophagy in vitro and in vivo, while such a phenomenon could be turned over by autophagy-specific inhibitor and MAP4K4 inhibitor, respectively. Moreover, cisplatin itself could promote the expression of endogenous SOX6 and subsequently the MAP4K4-mediated autophagy in cervical cancer cells, which might in turn reduce the sensitivity of these cells to cisplatin treatment. These findings uncovered the underlying mechanism and potential significance of SOX6-induced autophagy, and shed new light on the usage of MAP4K4 inhibitor or autophagy-specific inhibitor for sensitizing cervical cancer cells to the platinum-based chemotherapy.