Metabolic reprogramming of the ovarian cancer microenvironment in the development of antiangiogenic resistance

Antiangiogenic therapies, such as treatment with bevacizumab, display modest survival benefits in ovarian cancer (OC) patients. After a transient response, the upregulation of compensatory proangiogenic pathways and the adoption of alternative vascularization processes lead to the development of resistance. Considering the high mortality rate of OC, there is an urgent need to uncover the underlying mechanisms of antiangiogenic resistance for the development of novel and effective treatment strategies. Recent investigations have confirmed that metabolic reprogramming in the tumor microenvironment (TME) exerts an essential effect on tumor aggressiveness and angiogenesis. In this review, we provide an overview of the metabolic crosstalk between OC and the TME, highlighting the regulatory mechanisms underlying the development of antiangiogenic resistance. Metabolic interventions may interrupt this complex and dynamic interactive network, providing a promising therapeutic option to improve clinical outcome in OC patients

OXIDATION AND SULFOMETHYLATION OF ALKALI-EXTRACTED LIGNIN FROM CORN STALK

A lignosulfonate was prepared from alkali-extracted corn stalk lignin (AEL) by oxidation under mild conditions and sulfomethylation. The oxidized AEL exhibited lower molecular weight, narrower molecular weight distribution, and higher phenolic hydroxyl content than AEL, demonstrating that oxidized AEL was more reactive than those before oxidation. The content of sulfonic groups was significantly increased with the increase in sodium sulphite to AEL ratio, while the content slightly decreased when the ratio was above 1:1. During the sulfomethylation, the content of sulfonic groups increased with time and then achieved a constant level with the increase in time. The content of sulfonic groups reached 1.29 mmol/g, the maximum value, at 5 h and a sodium sulphite to AEL ratio of 1:1. The solubility of AEL was obviously improved by sulfomethylation with the increase in the content of sulfonic groups. The surface activity of AEL was improved after sulfomethylation. The sulfomethylation products exhibited good dispersibility and showed potential for use as a dye dispersant

Development and validation of SIRT3-related nomogram predictive of overall survival in patients with serous ovarian cancer

Abstract Objective Our aim is to analyzed the expression pattern of sirtuin(SIRT) superfamily and evaluated their prognostic values in serous ovarian cancer patients. Methods We first analyzed the differential expression of SIRT members among fallopian tube epithelium (FTE), primary serous ovarian cancers/tubal cancers (PSOCs/PSTCs), and omental metastases using GSE10971 and GSE30587 datasets. The prognostic values of SIRT members were evaluated using TCGA and GSE9891 dataset. Results SIRT3 and SIRT5 expression were significantly decreased and increased in PSOCs/PSTCs compared with that in normal counterparts, respectively. SIRT6 and SIRT7 were overexpressed in ometal metastases compared with corresponding primary counterparts. With respect to recurrence free survival, however, SIRT7 overexpression was correlated with better prognosis. A similar trend was observed by multivariable analysis. Regarding overall survival (OS), increased expression of SIRT3, SIRT5, and SIRT7 were associated with better survival by univariable analysis. Subsequent multivariable analysis showed that SIRT3 remained an independent favorable prognostic factor for OS. The SIRT3-related nomogram illustrated age at initial diagnosis as sharing the largest contribution to OS, followed by SIRT3 expression and FIGO stage. The C-index for OS prediction was 0.65 (95%CI, 0.61–0.69) in training cohort (TCGA dataset) and 0.65 (95%CI, 0.59–0.71) in validation cohort (GSE9891 dataset), respectively. The calibration plots showed optimal agreement between the prediction by SIRT3-related nomogram and actual observation for 1-, 3-, and 5-year OS probability. Conclusion In conclusion, SIRT3 was an independent favorable prognostic factor for OS in serous ovarian cancer, and added prognostic value to the traditional clinicopathological factors used to evaluate patients’ prognosis

The epigenetic factor CHD4 contributes to metastasis by regulating the EZH2/β-catenin axis and acts as a therapeutic target in ovarian cancer

Abstract Background The overall survival rate of patients with advanced ovarian cancer (OC) has remained static for several decades. Advanced ovarian cancer is known for its poor prognosis due to extensive metastasis. Epigenetic alterations contribute to tumour progression and therefore are of interest for potential therapeutic strategies. Methods Following our previous study, we identified that CHD4, a chromatin remodelling factor, plays a strong role in ovarian cancer cell metastasis. We investigated the clinical significance of CHD4 through TCGA and GEO database analyses and explored the effect of CHD4 expression modulation and romidepsin treatment on the biological behaviour of ovarian cancer through CCK-8 and transwell assays. Bioluminescence imaging of tumours in xenografted mice was applied to determine the therapeutic effect of romidepsin. GSEA and western blotting were used to screen the regulatory mechanism of CHD4. Results In ovarian cancer patient specimens, high CHD4 expression was associated with a poor prognosis. Loss of function of CHD4 in ovarian cancer cells induced suppression of migration and invasion. Mechanistically, CHD4 knockdown suppressed the expression of EZH2 and the nuclear accumulation of β-catenin. CHD4 also suppressed the metastasis of ovarian cancer cells and prevented disease progression in a mouse model. To inhibit the functions of CHD4 that are mediated by histone deacetylase, we evaluated the effect of the HDAC1/2 selective inhibitor romidepsin. Our findings indicated that treatment with romidepsin suppressed the progression of metastases in vitro and in vivo. Conclusions Collectively, our results uncovered an oncogenic function of CHD4 in ovarian cancer and provide a rationale for clinical trials of romidepsin in ovarian cancer patients