Coenzyme Q10 in association with metabolism-related AMPK/PFKFB3 and angiogenic VEGF/VEGFR2 genes in breast cancer patients.

Low levels of coenzyme Q10 (CoQ10) have been reported in the circulation of patients with breast cancer, particularly in metastatic features. Our objective was to study the correlation between plasma levels of CoQ10 and the tumoral expression levels of AMPK, PFKFB3, VEGF, and VEGFR2. This study was a part of consecutive case series conducted on 100 women with newly diagnosed invasive ductal breast carcinoma, with an age range of 30-60 years. Plasma levels of CoQ10 were measured using HPLC coupled to an UV detector. The expression levels were quantified using quantitative real-time PCR. Structural equation modeling (SEM) was applied to generate pathways describing gene-to-gene inter-correlations. Using SEM identified AMPK expression to contribute positively to VEGF-A/VEGFR2 ratio (coefficient b = 0.64, P < 0.001). The VEGFR2 expression positively correlated with tumor size (coefficient b = 0.31, P < 0.001). A linear correlation between expression levels of AMPK and PFKFB3 was observed (rAdj = - 0.273, P = 0.02). Similarly, VEGF-A was correlated with VEGFR2 (rAdj = 0.698, P < 0.001). There were inverse significant correlations between CoQ10 and the fold changes of AMPK (rAdj = - 0.276, P = 0.030), VEGF-A (rAdj = - 0.319, P = 0.011) and VEGFR2 (rAdj = - 0.262, P = 0.045). The correlation between CoQ10 and the fold changes of PFKFB3 was significantly progesterone receptor (PR) dependent (rAdj = - 0.284, P = 0.041). Plasma CoQ10 was correlated with VEGF-A in hormone receptor-dependent mode (ER + : rAdj = - 0.286, P = 0.032 and PR + : rAdj = - 0.313, P = 0.025). Our findings could provide new insights suggesting CoQ10 can inversely correlate to the expression levels of VEGF-A/VEGFR2 as angiogenic factors and AMPK/PFKFB3 as biomarkers for tumoral glycolysis, especially in a hormone receptor-dependent manner to possibly prevent the progression of breast carcinogenesis.

Expression patterns of three regulation enzymes in glycolysis in esophageal squamous cell carcinoma: association with survival.

Enhanced glycolysis is a common trait of many types of human cancers. This study was to detect the expression pattern of three regulatory enzymes during glycolysis in esophageal squamous cell carcinoma (ESCC) and to investigate their correlation with patients' outcome based on banked pathology material. A total of 141 surgically resected specimens of primary ESCC patients without prior treatments were retrospectively recruited from the First Affiliated Hospital of Wenzhou Medical College Hospital from 2007 to 2009. Expression of HK1, PFKB, and PKM2 in ESCC specimens was analyzed by immunohistochemical staining and Western blotting analysis. HK1-shRNA was used to knock down HK1 expression in ESCC cells, and the functional significance was assessed by CCK8 assay. It was found that the expression of two glycolytic enzymes, HK1 and PKM2, was associated with disease progression, invasion, and poor survival of patients with ESCC. Silence of HK1-inhibited cell proliferation in vitro and suppressed phospho-S6 kinase expression. Our findings suggest that activation of key enzymes in glycolysis might serve as potential therapeutic targets and/or prognostic factors for patients with ESCC.

PFKFB4 as a prognostic marker in non-muscle-invasive bladder cancer.

OBJECTIVES: PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4) is induced by hypoxia and is strongly associated with glycolysis. Previously, we reported that PFKFB4 expression level may serve as a predictor of progression in non-muscle-invasive bladder cancer (NMIBC). Here, the role of PFKFB4 in NMIBC and the relationship between PFKFB4 expression and biological behavior in bladder cancer was investigated. METHODS: One hundred ninety-three primary NMIBC tissue specimens were analyzed by real-time PCR. Immunohistochemical staining was performed on 77 subsets of tumor samples. The results were compared with clinicopathologic parameters, and the Kaplan-Meier method and a multivariate Cox regression model were used to identify the prognostic value of PFKFB4 for recurrence and progression. RESULTS: The mRNA expression levels of PFKFB4 were significantly higher in patients with high stage carcinoma and multiple tumors as compared to low stage and single tumors (P < 0.05 for each). Kaplan-Meier estimates revealed significant differences in time to recurrence and progression between low- and high-mRNA expression groups (log-rank test, P = 0.015 and 0.003, respectively). Multivariate Cox regression analysis revealed that the level of PFKFB4 expression is an independent predictor of bladder tumor progression (HR, 2.026; 95% CI, 1.177-3.488; P = 0.011). Immunohistochemical findings were generally concordant with mRNA expression levels. CONCLUSIONS: PFKFB4 has an important role in the progression of NMIBC, and may serve as a useful prognostic indicator for bladder cancer progression.

Insulin-independent promotion of chemically induced hepatocellular tumor development in genetically diabetic mice.

Diabetes mellitus has been proposed as an epidemiological risk factor for human liver cancer development. One reasonable possibility is that this is attributable to hyperinsulinemia compensatory for obesity-related insulin resistance. However, diabetes mellitus is a complex disease with multiple abnormal conditions essentially caused by hyperglycemia. Therefore, it is not evident whether hyperinsulinemia is prerequisite for the elevated cancer risk. To gain a clue to answer this question, we characterized chemically induced hepatocarcinogenesis in diabetic model mice genetically deficient for insulin. Akita inbred mice originating from the C57BL/6 strain carry a heterozygous germline mutation of the insulin II gene and suffer from inherited insulin deficiency and diabetes in an autosomal dominant manner. They were mated with normal C3H/HeJ mice with high sensitivity to liver carcinogenesis and the resultant F(1) littermates, which were either normal or insulin deficient, were exposed to diethylnitrosamine and induced hepatocellular tumors were evaluated for number, size, proliferative activity, and apoptosis. Unexpectedly, both mean and total volumes of hepatocellular tumors in the insulin-deficient animals were more than twofold larger than those in the normal controls, with no significant difference in tumor number. The tumors in insulin-deficient mice showed a significantly lower frequency of apoptosis but no alteration in cell proliferation. In conclusion, our results indicate that insulin-independent liver tumor promotion occurred in diabetic mice. Clearly, insulin-independent mechanisms for the human case also deserve consideration.