Ying Zhou

Tumor Small Extracellular Vesicle‐Transmitted LncRNA CATED Promotes Platinum‐Resistance in High‐Grade Serous Ovarian Cancer

AbstractHigh‐grade serous ovarian cancer (HGSOC) is the most lethal type of gynecological cancer, and platinum‐resistance is a serious challenge in its treatment. Long non‐coding RNAs (lncRNAs) play critical regulatory roles in the occurrence and development of cancers. Here, using RNA sequencing of tumor small extracellular vesicles (sEVs) from HGSOC patients, the lncRNA CATED is identified as significantly upregulated in both tumors and tumor‐derived sEVs in platinum‐resistant HGSOC, and low CATED levels correlate with good prognosis. Functionally, CATED enhances cisplatin resistance by promoting cell proliferation and inhibiting apoptosis in vitro and in vivo. These effects could be transferred via CATED‐overexpressing sEVs from donor cells and HGSOC tumor sEVs. Mechanistically, CATED binds to and upregulates DHX36 via PIAS1‐mediated SUMOylation at the K105 site, and elevated DHX36 levels increase downstream RAP1A protein levels by enhancing RAP1A mRNA translation, consequently activating the MAPK pathway to promote platinum‐resistance in HGSOC. Antisense oligonucleotide mediated knockdown of CATED reverse platinum‐resistance in sEV‐transmitted mouse models via the DHX36‐RAP1A‐MAPK pathway. This study newly identifies a sEV‐transmitted lncRNA CATED in driving HGSOC platinum‐resistance and elucidates the mechanism it regulates the interacting protein through SUMOylation. These findings also provide a novel strategy for improving chemotherapy in HGSOC by targeting CATED.

Is the Homologous Recombination Repair Mutation Defined by a 15-Gene Panel Associated with the Prognosis of Epithelial Ovarian Cancer?

There is no consensus regarding the specific genes included in the homologous recombination repair (HRR) gene panel for identifying the HRR deficiency (HRD) status and predicting the prognosis of epithelial ovarian cancer (EOC) patients. We aimed to explore a 15-gene panel involving the HRR pathway as a predictive prognostic indicator in Chinese patients newly diagnosed with EOC. We reviewed the previously published reports about different HRR gene panels and prespecified the 15-gene panel. The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centers were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) and progression-free survival (PFS) with 15-gene panel HRR mutations (HRRm) status was assessed. 43.2% (133/308) of patients were determined to carry 144 deleterious HRRm, among which 68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2 gene lethal mutations. The hazard ratio (HR) (95% confidence interval, CI) for PFS (HRRm v HRR wild type, HRRwt) using the 15-gene panel HRRm was 0.42 (0.28-0.64) at all stages and 0.42 (0.27-0.65) at stages IIIC-IV. However, a prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. For the subgroups of patients not using PARPis, the HR (95% CI) was 0.41 (0.24-0.68) at stages IIIC-IV. This study provides evidence that 15-gene panel HRRm can predict the prognosis of EOC, of these only the BRCA1/2 mutations, not non-BRCA HRRm, contribute to prognosis prediction. Among patients without PARPis, the HRRm group presented a better PFS. This is the first study of this kind in the Chinese population.

Ascites exosomal lncRNA PLADE enhances platinum sensitivity by inducing R-loops in ovarian cancer

sB7-H4 is a diagnostic biomarker in epithelial ovarian cancer and correlates to platinum resistance

Abstract Ovarian cancer (OC), with its high mortality rate among gynecological cancers, is often diagnosed late due to the lack of early diagnostic symptoms and biomarkers. The tumor immune microenvironment has become a focal point in cancer diagnostic and therapeutic research. Among these, B7-H4, a checkpoint protein, plays a crucial role in immune regulation and tumor suppression, contributing to immune evasion within the tumor microenvironment. This study aims to identify the concentration of soluble B7-H4(sB7-H4) in the plasma of patients with OC and to evaluate its clinical significance. Through a comprehensive analysis involving enzyme-linked immunosorbent assay, immunohistochemistry, and multicolor immunofluorescence, we quantified sB7-H4 levels in patient plasma and ascites, correlating these findings with tissue expression and clinical outcomes. Results indicated a strong association between high sB7-H4 levels and advanced disease, surgical outcomes, lymphatic metastasis, and platinum resistance. When compared with traditional biomarkers CA125 and HE4, sB7-H4, especially in conjunction with these markers, enhances the diagnostic accuracy for epithelial ovarian cancer (EOC), offering insights into disease progression and therapeutic efficacy. This comprehensive analysis suggests that sB7-H4 is a promising biomarker for EOC, providing valuable insights into diagnosis, stage differentiation, treatment effectiveness, and prognosis.

Clinical characteristics and prognosis of ovarian clear cell carcinoma: a 10-year retrospective study

Abstract Background Ovarian clear cell carcinoma (OCCC) is a special pathological type of epithelial ovarian carcinoma (EOC). We conducted this research to investigate the clinical characteristics and outcomes of OCCC and to provide additional supporting evidence to aid in the clinical diagnosis and management. Methods This was a retrospective study investigating the clinical characteristics and survival outcomes of 86 patients with OCCC treated at our center between January 2010 and March 2020. Survival analysis was also performed on 179 patients with OCCC obtained from the Surveillance, Epidemiology and End Results (SEER) cancer registry database. Results The median age of participants was 49.21 ± 9.91 years old, and 74.42% of them were diagnosed at early stage. The median CA125 level was 601.48 IU/mL, while 19.77% of the patients had normal CA125 levels. Sixteen patients (18.60%) had co-existing endometriosis and 8 patients (9.3%) developed venous thromboembolism (VTE). There were 5 patients received suboptimal cytoreduction. Sixty-six patients (76.74%) underwent lymphadenectomy, and only 3 (4.55%) patients had positive lymph nodes. Patients diagnosed at an early stage had higher 3-year overall survival (OS) and progression-free survival (PFS) rates than those with advanced stage OCCC. CA19–9 ( P  = 0.025) and ascites ( P  = 0.001) were significantly associated with OS, while HE4 ( P  = 0.027) and ascites ( P  = 0.001) were significantly associated with PFS. Analysis of data from the SEER database showed that positive lymph nodes is also an independent prognostic factor for OS ( P  = 0.001). Conclusions OCCC often presents at an early stage and young age with a mildly elevated CA125. CA19–9, HE4, massive ascites, and positive lymph node are independent prognostic factors.

[Retracted] Investigation of the Clinical Application Value of HR‐HPV DNA Combined with Liquid Based Cytology in Colposcopy of Cervical Cancer

In order to investigate the clinical application value of HR‐HPV DNA combined with liquid‐based cytology in colposcopy of cervical cancer, a retrospective analysis is performed on 428 patients who underwent a cervical pathological examination in our hospital from May 2020 to December 2021. The pathological biopsy results are used as the gold standard to determine whether cervical lesions occurred in patients, and patients with positive gold standard results are included in the study group. The positive rates of liquid‐based cytology and HR‐HPV DNA are observed and recorded, and the patients with negative gold standard results are used as the control group. The positive rate of HR‐HPV DNA and liquid‐based cytology will increase with the aggravation of pathological results. The ROC curve shows that HR‐HPV DNA combined with liquid‐based cytology has high diagnostic efficiency in colposcopy of cervical lesions. It is clearly evident that both liquid‐based cytology and HR‐HPV DNA tests have certain advantages in the screening of cervical lesions, and the combined detection can further improve the screening value of cervical lesions.

Landscape of extrachromosomal DNA characteristics in high-grade serous ovarian cancer via long-read sequencing

The non-Mendelian inheritance of extrachromosomal DNA (ecDNA) exacerbates tumor genomic heterogeneity and evolution. Due to short-read sequencing's reconstruction deficiencies, ecDNA abundance in clinical tumor tissues requires further estimation, and the mechanisms driving tumor evolution remain underexplored. Here, we perform long-read whole-genome sequencing on primary and paired metastatic tumor tissues from 12 patients with high-grade serous ovarian cancer (HGSOC) and 6 normal tubal tissues, constructing a comprehensive ecDNA profile. In HGSOC, ecDNA exhibits significantly greater genomic instability and lower methylation than chromosomal DNA. Beyond oncogene and immunomodulatory gene amplification, ecDNA amplifies extensive enhancers to promote gene expression via mechanisms including enhancer hijacking and mobile enhancers. Notably, we observe activation of transposable elements on hypomethylated ecDNA, which is strongly correlated with epithelial-mesenchymal transition gene expression and poor clinical outcomes. These findings reveal ecDNA as a multifunctional driver of genomic variations and tumor progression in HGSOC, highlighting its therapeutic potential.