Proteomic analysis reveals CAAP1 negatively correlates with platinum resistance in ovarian cancer.

The present study sought to investigate the correlation between CAAP1 and platinum resistance in ovarian cancer and to preliminarily explore the potential biological function of CAAP1. Proteomic analysis was used to analyze differentially expressed proteins in platinum-sensitive and -resistant tissue samples of ovarian cancer. The Kaplan-Meier plotter was used for prognostic analysis. Immunohistochemistry assay and chi-square test were employed to explore the relationship between CAAP1 and platinum resistance in tissue samples. Lentivirus transfection, immunoprecipitation-mass spectrometry, and bioinformatics analysis were used to determine the potential biological function of CAAP1. Based on results, the expression level of CAAP1 was significantly higher in platinum-sensitive tissues compared to that in resistant tissues. Chi-square test demonstrated that there is a negative correlation between high expression of CAAP1 and platinum resistance. Overexpression of CAAP1 increased cis­platinum sensitivity of the A2780/DDP cell line likely via the mRNA splicing pathway by interacting with the splicing factor AKAP17A. In summary, there is a negative correlation between high expression of CAAP1 and platinum resistance. CAAP1 might be a potential biomarker for platinum resistance in ovarian cancer. SIGNIFICANCE: Platinum resistance is a key factor affecting the survival of ovarian cancer patients. Understanding the mechanisms of platinum resistance is highly important for ovarian cancer management. Here, we performed the DIA- and DDA-based proteomics to analyze differentially expressed proteins in tissue and cell samples of ovarian cancer. We found that the protein identified as CAAP1, which was first reported to be involved in the regulation of apoptosis, may be negatively correlates with platinum resistance in ovarian cancer. In addition, we also found that CAAP1 enhanced the sensitivity of platinum-resistant cells to cis­platinum via the mRNA splicing pathway by interacting with the splicing factor AKAP17A. Our data would be useful to reveal novel molecular mechanisms of platinum resistance in ovarian cancer.

Shikonin and cisplatin synergistically overcome cisplatin resistance of ovarian cancer by inducing ferroptosis via upregulation of HMOX1 to promote Fe2+ accumulation.

BACKGROUND: Cisplatin-based chemotherapy often results in ovarian cancer (OC) chemical resistance and treatment failure. The combination of natural compounds with platinum-based agents is a new strategy for overcoming cisplatin resistance. At present, the synergistic effects and mechanism of combination of shikonin and cisplatin to overcome cisplatin resistance in OC are still unknown. PURPOSE: This study was to evaluate the synergistic effects of shikonin and cisplatin on cisplatin-resistant OC cells and to assess the underlying molecular basis for these effects. METHODS: Cell counting kit-8 assay, colony-formation assay, proteomic analysis, reactive oxygen species (ROS) detection, lipid peroxidation (LPO) detection, Fe2+ detection, western blot, and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to evaluate the effects of shikonin and cisplatin on cisplatin-resistant OC cells. Underlying mechanisms of action were investigated in vitro using small molecule inhibitors and siRNA. In vivo, the effect of shikonin and cisplatin combination on tumor growth in BALB/c nude mice was evaluated, with tumor immunohistochemical (IHC) staining performed to detect ferroptosis-related proteins. RESULTS: In vitro, shikonin and cisplatin were shown to synergistically reduce the viability of cisplatin-resistant OC cells. Proteomic results demonstrated that the combination of the two drugs induced a ferroptotic process, as evidenced by increased levels of ROS, LPO, and Fe2+, with downregulation of glutathione peroxidase 4 (GPX4). Heme oxygenase 1 (HMOX1) inhibition and siRNA interference attenuated the combined effect of the two drugs on cell viability. Accumulation of Fe2+ was attenuated by siRNA interference of HMOX1. In vivo, combination treatment significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice and increased the expression of ferroptosis-related proteins in tumor tissue. CONCLUSION: We report for the first time that the co-treatment of shikonin and cisplatin overcomes cisplatin resistance in OC through ferroptosis. Mechanistic analysis reveals the co-treatment induces ferroptosis through upregulation of HMOX1 that promotes Fe2+ accumulation.

Comparison of adenocarcinoma and adenosquamous carcinoma prognoses in Chinese patients with FIGO stage IB-IIA cervical cancer following radical surgery.

BACKGROUND: To compare adenocarcinoma (AC) and adenosquamous carcinoma (ASC) prognoses in patients with FIGO stage IB-IIA cervical cancer who underwent radical hysterectomy. METHODS: We performed a retrospective analysis of 240 patients with AC and 130 patients with ASC. Kaplan-Meier curves, Cox regression models, and log-rank tests were used for statistical analysis. RESULTS: Patients with ASC had higher frequencies of lymphovascular space invasion (LVSI) and serum squamous cell carcinoma antigen (SCC-Ag) > 5 ng/ml (p = 0.049 and p = 0.013, respectively); moreover, they were much older (P = 0.029) than patients with AC. There were no clinically significant differences in overall survival (OS) between the groups. When stratified into three risk groups based on clinicopathological features, survival outcomes did not differ between patients with AC and those with ASC in any risk group. Multivariate analysis showed that lymph node metastasis (LNM) was an independent risk factor for recurrence-free survival (RFS) and OS in patients with AC and in patients with ASC. Carcinoembryonic antigen (CEA) > 5 ng/ml and SCC-Ag > 5 ng/ml were independent predictors of RFS and OS in patients with AC. In addition, among those stratified as intermediate-risk, patients with ASC who received concurrent chemoradiotherapy (CCRT) had significantly better RFS and OS (P = 0.036 and P = 0.047, respectively). CONCLUSIONS: We did not find evidence to suggest that AC and ASC subtypes of cervical cancer were associated with different survival outcomes. CCRT is beneficial for survival in intermediate-risk patients with ASC, but not in those with AC. Serum tumour markers can assist in evaluating prognosis and in providing additional information for patient-tailored therapy for cervical AC.

Impact of sites versus number of metastases on survival of patients with organ metastasis from newly diagnosed cervical cancer.

OBJECTIVE: The aim of this study was to investigate the potential associations of the sites and the number of specific metastases with survival in patients newly diagnosed with cervical cancer. METHODS: Medical records of patients with organ metastases of newly diagnosed cervical cancer at Zhejiang Cancer Hospital from October 2006 to December 2016 were reviewed retrospectively. Survival times were compared using the Kaplan-Meier method. Variables associated with survival were identified using univariate and multivariate Cox proportional hazards models. RESULTS: A total of 99 patients with newly diagnosed organ metastatic cervical cancer were identified. Median follow-up was 11.6 months (range, 0.5-114.7 months). Median overall survival (OS) time was 11.7 months from diagnosis, with 1, 2, and 5-year OS rates of 48.2%, 22.8%, and 12.6%, respectively. The most common site of organ metastasis was bone (36.8%), followed by lung (32.8%) and liver (24%). In univariate analysis, OS rates were better for bone metastasis than visceral metastasis (P=0.013), oligometastasis than non-oligometastasis (P=0.003) and single organ metastasis than multiple organ metastases (P=0.016), while that for liver metastasis was poorer than non-liver metastases (P<0.001). In multivariate analysis, liver metastasis (hazard ratio [HR] =4.02; 95% confidence interval [CI], 1.15-14.05, P=0.029) was significantly and independently related to poor overall survival. CONCLUSION: Our data revealed the site of metastasis is associated with overall survival of patients with newly diagnosed organ metastatic cervical cancer, with liver metastasis signifying particularly poor overall survival. Individualized treatments should be administered to patients depending on the specific metastatic sites.

Increased frequency of regulatory T cells in the peripheral blood of patients with endometrioid adenocarcinoma.

The aim of the present study was to investigate the frequency of cluster of differentiation (CD)4+CD25+CD127- regulatory T cells (Tregs) in the peripheral blood mononuclear cells (PBMCs) of patients with endometrioid adenocarcinoma (EA). A total of 82 female patients with EA were recruited. The PBMCs were flow cytometrically analyzed to determine the percentage of CD4+CD25+CD127- Tregs within the CD4+ T cell population. The associations between the prevalence of Tregs in PBMCs and defined clinical prognostic parameters were evaluated. To study the immunoregulatory capacity of Tregs, the level of specific cytokines were detected by ELISA, and the proliferation of cells was analyzed by incorporation of 3H-thymidine. It was revealed that Treg/CD4+ ratio in the peripheral blood of patients with EA was 4.89±1.42%, significantly higher than Treg/CD4+ ratio in healthy women. No correlation was observed between Treg frequency and stage, grade of differentiation, menopausal status or age. CD4+CD25+CD127- Tregs secreted large amounts of IL-10 but not IFN-γ. The level of IL-10 secreted by Tregs from patients with EA and healthy controls was not significantly different. In addition, there was no significant difference in the suppressive activity of Tregs in patients with EA compared with that of the healthy controls. These findings demonstrate that the increased frequency of immunosuppressive Tregs in patients with EA may be responsible for immune tolerance in endometrial cancer.

Efficacy of radical doses of pelvic radiotherapy for primary tumor treatment in patients with newly diagnosed organ metastatic cervical cancer.

BACKGROUND: The clinical efficacy of definitive pelvic radiotherapy for primary tumors in patients with newly diagnosed organ metastatic cervical cancer is unclear. Therefore, we conducted a retrospective study to evaluate the efficacy of definitive pelvic radiotherapy combined with systemic chemotherapy in patients with organ metastatic cervical cancer. METHODS: We retrospectively analysed medical records from patients with newly diagnosed organ metastatic cervical cancer, all treated with chemotherapy at the Zhejiang Cancer Hospital between October 2006 and December 2016. Survival times were compared using the Kaplan-Meier method. The univariate log-rank method and multivariate Cox proportional hazard models were used to identify associated variables with survival. RESULTS: A total of 48 patients were identified from 11,982 primary cervical cancer patients and divided into two groups according to treatment mode: 36 patients received chemotherapy combined with definitive pelvic radiotherapy (group A), 12 patients underwent chemotherapy with/without palliative pelvic radiotherapy (group B). Median follow-up was 14.4 months (range, 4.6-114.7 months). Median overall survival (OS) for group A and group B was 17.3 and 10 months, respectively. Using the univariate analysis, group A was found to have a better OS than group B (p = 0.002). In multivariate analysis, group A (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.15-0.67, p = 0.003) was associated with lower risk of death compared with group B. The main reason for treatment failure was found to be due to the progression of distant metastatic lesions in 36 patients (75%) from the whole cohort. CONCLUSION: In this cohort of organ metastatic cervical cancer patients in good performance status, chemotherapy combined with definitive pelvic radiotherapy was associated with improved survival outcomes when compared with chemotherapy with/without palliative pelvic radiotherapy. Prospective trials evaluating definitive pelvic radiotherapy for newly diagnosed organ metastatic cervical cancer, therefore, are warranted.