circDENND4C, a novel serum marker for epithelial ovarian cancer, acts as a tumor suppressor by downregulating miR-200b/c.

RESEARCH OBJECTIVE: To explore the diagnostic value of circ-DENN domain containing 4 C (circDENND4C) in epithelial ovarian cancer (EOC) and the corresponding mechanism. METHODS: We determined the expression of circDENND4C and miR-200b/c in tissues and serum specimens as well as EOC cell lines using qRT-PCR. Basic clinical data, and serum HE4 and CAl25 levels were acquired from patients' clinical records. Expression-related correlations and the diagnostic value of serum circDENND4C in EOC were also estimated. CCK-8 and flow cytometry were performed to detect the effect of circDENND4C on cell proliferation and apoptosis. RESULTS: circDENND4C level was lowest while miR-200b/c was highest in EOC tissues, followed by benign and normal tissues. Similarly, serum circDENND4C was lowest while miR-200b/c was highest in EOC patients. Moreover, serum circDENND4C was lower in patients with benign ovarian tumors than in healthy women, while miR-200b/c expression was higher. circDENND4C was negatively associated with miR-200b/c in EOC tissues and serum specimens, and serum circDENND4C was also negatively correlated with serum HE4 and CAl25 in EOC patients. circDENND4C expression in both tissue and serum was negatively related to FIGO and TNM stage, and tumor size in EOC. Serum circDENND4C could distinguish healthy persons from patients with benign ovarian tumors and EOC, and they showed a higher specificity and accuracy than serum CA125 or HE4 in EOC diagnosis. circDENND4C upregulation significantly suppressed EOC cell proliferation and facilitated apoptosis by downregulating miR-200b/c in vitro. CONCLUSIONS: Summarily, circDENND4C acts as a tumor inhibitor by downregulating miR-200b/c in EOC and could be a possible tumor marker for EOC diagnosis.KEY MESSAGEScircDENND4C expression was lowest while miR-200b/c was highest in EOC tissues or serums, followed by benign and normal tissues or serums.circDENND4C was involved in malignant progression of EOC, concretely, overexpression of circDENND4C suppressed EOC cell proliferation and stimulated apoptosis via downregulating miR-200b/c, and circDENND4C expression in both tissue and serum was closely related to FIGO and TNM stages and tumor size in EOC.Serum circDENND4C showed a higher specificity and accuracy than serum CA125 or HE4 in EOC diagnosis.HIGHLIGHTScircDENND4C expression was lowest while miR-200b/c was highest in EOC tissues, followed by benign and normal tissues.Serum circDENND4C was lowest while miR-200b/c was highest in EOC patients, followed by benign patients and healthy women.Overexpression of circDENND4C suppresses EOC cell proliferation and stimulates apoptosis via downregulating miR-200b/c.circDENND4C expression in both tissue and serum was closely related to FIGO and TNM stage and tumor size in EOC.Serum circDENND4C showed a higher specificity and accuracy than serum CA125 or HE4 in EOC diagnosis.

Involvement of retinoblastoma-associated protein 48 during photodynamic therapy of cervical cancer cells.

5-Aminolevulinic acid-mediated photodynamic therapy (ALA­PDT) is an effective treatment option for cervical intraepithelial neoplasia, the precancerous lesion of cervical cancer, and early cervical cancer, particularly for young or nulliparous women who want to remain fertile. A previous report described the involvement of histone deacetylases (HDAC) during ALA­PDT mediated apoptosis in the cerebral cortex of a mouse model. Retinoblastoma­associated protein 48 (RbAp48), a highly abundant component of HDACs, is a critical mediator that controls the transforming activity of human papillomavirus 16 in cervical cancer cells. The aim of the present study was to investigate the involvement of RbAp48 in ALA­PDT­induced cell death in cervical cancer cells. RbAp48 was significantly upregulated in cervical cancer cell lines treated with ALA­PDT, including SiHa and HeLa cells. To establish the relevance of RbAp48 and the efficacy of ALA­PDT in cervical cancer cells, the effect of ALA­PDT was investigated in SiHa or HeLa cells following the depletion of RbAp48 by small interfering RNA (siRNA). Reduction of RbAp48 led to the reduced suppression of proliferation and apoptosis induced by ALA­PDT in cervical cancer cells, which was associated with a reduction in tumor suppressor protein 53 (p53), retinoblastoma (Rb), apoptosis­related enzyme caspase­3, and increased levels of the oncogenic genes, human papillomavirus E6 and E7. These results provide evidence that RbAp48 is an important contributor to the efficacy of ALA­PDT in cervical cancer cells. RbAp48 may be a therapeutic target that may help to improve the treatment of cervical cancer.

Efficacy and safety of acetylcysteine in "non-acetaminophen" acute liver failure: A meta-analysis of prospective clinical trials.

BACKGROUND: Acute liver failure (ALF) is a rare but highly mortal condition without liver transplantation (LT). N-acetylcysteine (NAC), a glutathione precursor that detoxifies the reactive metabolite of acetaminophen and replenishes hepatic glutathione stores, is a highly effective drug for the prevention of ALF caused by acetaminophen. However, therapeutic use of NAC in non-acetaminophen-induced ALF (NAI-ALF) including alcohol intoxication, hepatitis virus infection, or drug and toxin-related hepatotoxicity is still inconclusive. The aim of this article is using meta-analysis method to analyze recent prospective clinical trials for the safety and efficacy of NAC in patients with ALF not caused by acetaminophen poisoning. METHODS: Prospective clinical trials comparing efficacy and safety between NAC and control in the treatment of NAI-ALF were identified by searching Pubmed (2000-2014) and EMBASE (2000-2014) using the search terms acetylcysteine or NAC and NAI-ALF. The primary outcome was overall survival. Secondary outcomes included liver transplantation-free survival, post transplantation survival, length of ICU and hospital stays, and the relationship with coma grade. The safety profiles were also analyzed. RESULTS: Four clinical trials were selected for meta-analysis. A total of 331 patients receiving treatment with NAC (oral or intravenously) and 285 patients in control group were included for meta-analysis. No statistical difference was identified between NAC group and control group for overall survival [236/331 (71%) vs 191/285 (67%); 95% CI 1.16 (0.81-1.67); P=0.42]. However, there were significant differences between NAC group and control group regarding the survival with native liver [112/273 (41%) vs 68/226 (30%); 95% CI 1.61 (1.11-2.34); P=0.01] and post-transplantation survival [78/91 (85.7%) vs 50/70 (71.4%); 95% CI 2.44 (1.11-5.37); P=0.03]. The identified side effects of NAC included nausea, vomiting, and diarrhea or constipation. Rarely, it could cause rashes, fever, headache, drowsiness, low blood pressure, and elevated serum transaminase levels in a patient with cystic fibrosis. At the dose used for acetaminophen toxicity, acetylcysteine does not have hepatotoxic effects. CONCLUSION: NAC is safe for NAI-ALF. It can prolong patients' survival with native liver without transplantation and survival after transplantation, but it cannot improve the overall survival.