Deng Y, et al. J Gynecol Oncol. 2024 Mar;35:e79. https://doi.org/10.3802/jgo.2024.35.e79

Mounting evidence has highlighted the immune environment as a critical feature in the development of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). However, the relationship between the clinical characteristics of the immune environment and CESC remain unclear. Therefore, the aim of this study was to further characterize the relationship between the tumor and immune microenvironment and the clinical features of CESC using a variety of bioinformatic methods. Expression profiles (303 CESCs and three control samples) and relevant clinical data were obtained from The Cancer Genome Atlas. We divided CESC cases into different subtypes and performed a differential gene expression analysis. In addition, gene ontology (GO) and gene set enrichment analysis (GSEA) were performed to identify potential molecular mechanisms. Furthermore, data from 115 CESC patients from East Hospital were used to help identify the relationship between the protein expressions of key genes and disease-free survival using tissue microarray technology. Cases of CESC (n = 303) were divided into five subtypes (C1–C5) based on their expression profiles. A total of 69 cross-validated differentially expressed immune-related genes were identified. Subtype C4 demonstrated a downregulation of the immune profile, lower tumor immune/stroma scores, and worse prognosis. In contrast, the C1 subtype showed an upregulation of the immune profile, higher tumor immune/stroma scores, and better prognosis. A GO analysis suggested that changes in CESC were primarily enriched nuclear division, chromatin binding, and condensed chromosomes. In addition, GSEA demonstrated that cellular senescence, the p53 signaling pathway, and viral carcinogenesis are critical features of CESC. Moreover, high FOXO3 and low IGF-1 protein expression were closely correlated with decreased clinical prognosis. In summary, our findings provide novel insight into the relationship between the immune microenvironment and CESC. As such, our results may provide guidance for developing potential immunotherapeutic targets and biomarkers for CESC.

Metastasis and chemoresistance are the leading causes of death in high-grade serous ovarian carcinoma (HGSOC). Our previous studies revealed that the membrane protein cytochrome b reductase 1 (CYBRD1) is a critical prognostic marker for HGSOC, but its role in HGSOC progression and molecular mechanisms remain unclear. Here, we reveal that CYBRD1 is a druggable factor that drives chemoresistance and tumor progression in HGSOC. Importantly, compared with that in their cisplatin-sensitive counterparts, CYBRD1 expression is elevated in cisplatin-resistant cells. Through genetic manipulation, we showed that CYBRD1 inhibition effectively re‑sensitizes cells to cisplatin and suppresses proliferation, migration, and invasion. Targeted gene expression profiling indicated that CYBRD1 inhibition markedly attenuated JAK2/STAT3 signaling. Using point mutants, we confirmed that phosphorylation of CYBRD1 at Tyr252 is essential for the interaction with JAK2, subsequent activation of JAK2/STAT3 signaling and mediating HGSOC progression. CYBRD1 inhibition significantly restored cisplatin sensitivity and exerted a synergistic tumoricidal effect. In vivo, combined CYBRD1 inhibition and cisplatin markedly reduced tumor metastasis. Furthermore, we found that RUNX1 regulates CYBRD1 transcription. These findings highlight that the combination of CYBRD1 inhibitors and conventional chemotherapy is a promising therapeutic strategy for HGSOC, especially in chemoresistant patients.