Haoran Li

BNIP3 as a potential target of esculetin for treating ovarian cancer and prognostic biomarker in ovarian cancer patients

Among gynecological tumors, ovarian cancer has the highest mortality rate and worst prognosis. Therefore, it is crucial to identify and develop novel methods and targets for treating ovarian cancer. Previous studies have shown that esculetin exerts antitumor effects in a variety of cancers, however, its anti-ovarian cancer effects and mechanisms of action remain unclear. In the present study, we investigated the anti-ovarian cancer effects and mechanisms of esculetin in A2780 and OVCAR3 ovarian cancer cells and established an xenograft ovarian cancer mouse model. Esculetin significantly inhibited ovarian cancer cell proliferation, blocked cell cycle progression, and promoted apoptosis and DNA damage in a concentration-dependent manner. Furthermore, esculetin inhibited tumor growth in an xenograft ovarian cancer mouse model. Moreover, RNA-seq showed that 2114 genes were significantly altered in A2780 cells after esculetin treatment. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that these differentially expressed genes were mainly enriched in the calcium, HIF-1, and Rap1 signaling pathways. Interestingly, BNIP3 expression was notably upregulated in ovarian cancer cells after esculetin treatment. Finally, we found that low BNIP3 expression was correlated with poor prognosis in patients with ovarian cancer. These results prove that esculetin may be a valuable anti-ovarian cancer drug, and that BNIP3 is a potential treatment target for esculetin and a potential prognostic biomarker for ovarian cancer.

Significant prognostic value of cell-cycle proteins in early-stage small cell carcinoma of cervix

Small cell carcinoma of cervix (SCCC) was a highly aggressive tumor with dismal prognosis. Current treatment strategies manifested poor survival outcomes and novel treatment options were needed exploration. We aimed to investigate several prognostic biomarkers for SCCC and conducted a novel risk-score system to predict cancer specific survival (CSS) in early-stage SCCC. Seven cell-cycle proteins were detected by immunohistochemistry in 88 SCCCs. Univariate and multivariate analysis were performed to identify prognostic proteins and establish a predicting model. Total patients were divided into two groups by the median risk-score: the high-risk group and the low-risk group. Logistic regression and Wilcoxon test were used to investigate the association between clinical variables and the risk-score system. Seven cell cycle proteins were overexpressed in SCCC. The expression of CDC20, MAD2L1, MCM2 and BUBR1 were correlated to survival outcomes with P < 0.05. A novel risk-score system consisting of CDC20, MAD2L1 and BUBR1 was significantly an independent prognostic factor for CSS and the high-risk group possessed worse survival (P < 0.001). The c-indexes for clinical model, risk-score system and the combined model were 0.668, 0.718 and 0.727, respectively. The AUCs for these three models were 0.730, 0.775 and 0.823, respectively. Furthermore, we discovered that patients with high-risk scores were inclined to possessing older age, parametrial invasion and higher FIGO stage (IIA vs IA/IB) with P < 0.05. This risk-score system consisting of CDC20, MAD2L1 and BUBR1 presented good discrimination and predictability for SCCC. Novel biomarkers in this study might have some merits in providing guidance of novel treatment strategies for SCCC.

Different surgical methods for FIGO stage IVB cervical cancer patients receiving chemotherapy: a population-based study

To assess survival differences between non-extensive surgery (NES) and extensive surgery (ES) in International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer patients receiving chemotherapy from a population-based database, the Surveillance, Epidemiology and End Results. Propensity matching was conducted to minimize heterogeneity. Survival analysis was performed by the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. A total of 154 patients met screening criteria, among whom 84 patients (84/154) underwent NES while 70 patients (70/154) underwent ES. After matching, no survival advantage was observed in ES group compared with NES group (p=0.066; hazard ratio [HR]=1.54; 95% confidence interval [CI]=0.97-2.42). Stratified analyses suggested ES prolonged overall survival in patients with histology other than squamous cell carcinoma and adenocarcinoma (p=0.028; HR=0.36; 95% CI=0.15-0.89) and American Joint Committee on Cancer (AJCC) T stage T1 (p=0.009; HR=0.18; 95% CI=0.05-0.66). Despite no survival benefit after regional lymph node surgery (p=0.629; HR=0.88; 95% CI=0.53-1.47), subgroup analyses demonstrated that patients younger than 50 (p=0.006; HR=0.21; 95% CI=0.07-0.64), with AJCC T stage T1 (p=0.002; HR=0.09; 95% CI=0.02-0.42), T3 (p=0.001; HR=0.02; 95% CI=0.00-0.21), hematogenous metastasis (p=0.036; HR=0.27; 95% CI=0.08-0.92) and without surgery of other sites (p In conclusion, ES or regional lymph node surgery may provide survival advantage for certain subgroup of FIGO IVB cervical cancer patients receiving chemotherapy. However, it deserves large scale prospective clinical trials to confirm.

Surgery of primary sites for stage IVB cervical cancer patients receiving chemoradiotherapy: a population-based study

The purpose of this study was to analyze the impact of surgery of primary sites on stage IVB cervical cancer patients from a population-based database, the Surveillance, Epidemiology and End Results (SEER). Propensity score matching was performed to minimize heterogeneity in patient between with-surgery group and without-surgery group. Clinicopathological characteristics were compared using the χ² or Fisher's exact test. Survival analysis included the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. Between 2010-2015, a total of 1,139 International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer patients receiving chemoradiotherapy (CRT) were included in this retrospective study. Within post-matching cohort, the median duration of overall survival (OS) in stage IVB cervical cancer patients receiving CRT was 22 months. The overall 5-year survival rate was 25.7%. The increasing American Joint Committee on Cancer T stage (T1 vs. T2, p=0.033, hazard ratio [HR]=1.79, 95% confidence interval [CI]=1.05-3.05; T1 vs. T3, p=0.003, HR=2.20, 95% CI=1.31-3.67; T1 vs. T4, p=0.037, HR=2.75, 95% CI=1.06-7.12) and visceral metastasis (with vs. without, p=0.038, HR=1.60, 95% CI=1.03-2.49) was reported as independent risk factors of OS. Surgery of primary sites combined with CRT tended to prolong the survival of stage IVB cervical cancer patients (p<0.001, HR=0.36, 95% CI=0.21-0.61) compared with CRT, especially for patients without visceral metastasis (p=0.005, HR=0.31, 95% CI=0.14-0.70). In conclusion, patients with stage IVB cervical cancer may achieve their best outcomes through CRT combined with surgery of primary sites. However, it deserves large scale prospective clinical trials to confirm.