Heart failure in patients is associated with downregulation of mitochondrial quality control genes.

BACKGROUND: Mitochondrial dysfunction is one of key factors causing heart failure. We performed a comprehensive analysis of expression of mitochondrial quality control (MQC) genes in heart failure. METHODS: Myocardial samples were obtained from patients with ischemic and dilated cardiomyopathy in a terminal stage of heart failure and donors without heart disease. Using quantitative real-time PCR, we analysed a total of 45 MQC genes belonging to mitochondrial biogenesis, fusion-fission balance, mitochondrial unfolded protein response (UPRmt), translocase of the inner membrane (TIM) and mitophagy. Protein expression was analysed by ELISA and immunohistochemistry. RESULTS: The following genes were downregulated in ischemic and dilated cardiomyopathy: COX1, NRF1, TFAM, SIRT1, MTOR, MFF, DNM1L, DDIT3, UBL5, HSPA9, HSPE1, YME1L, LONP1, SPG7, HTRA2, OMA1, TIMM23, TIMM17A, TIMM17B, TIMM44, PAM16, TIMM22, TIMM9, TIMM10, PINK1, PARK2, ROTH1, PARL, FUNDC1, BNIP3, BNIP3L, TPCN2, LAMP2, MAP1LC3A and BECN1. Moreover, MT-ATP8, MFN2, EIF2AK4 and ULK1 were downregulated in heart failure from dilated, but not ischemic cardiomyopathy. VDAC1 and JUN were only genes that exhibited significantly different expression between ischemic and dilated cardiomyopathy. Expression of PPARGC1, OPA1, JUN, CEBPB, EIF2A, HSPD1, TIMM50 and TPCN1 was not significantly different between control and any form of heart failure. TOMM20 and COX proteins were downregulated in ICM and DCM. CONCLUSIONS: Heart failure in patients with ischemic and dilated cardiomyopathy is associated with downregulation of large number of UPRmt, mitophagy, TIM and fusion-fission balance genes. This indicates multiple defects in MQC and represents one of potential mechanisms underlying mitochondrial dysfunction in patients with heart failure.

Single nucleotide polymorphism in the interleukin 12B gene is associated with risk for breast cancer development.

We analysed the association of a single nucleotide polymorphism (SNP) in the gene encoding the IL-12 subunit p40 (IL12B, rs3212227, A>C) with breast cancer. The SNPs allelic and genotypic frequencies were compared between patients (n = 191) and healthy (n = 194) women in a case-control study from Croatia. The major allele (A) was associated with susceptibility to breast cancer (P = 0.003; OR = 1.67; 95% CI: 1.17-2.38). Likewise, the minor allele (C) was significantly correlated with protection (P = 0.003; OR = 0.60; 95% CI: 0.42-0.86). At the genotype level, AA homozygosity was significantly associated with predisposition to disease (P = 0.013; OR = 1.68, 95% CI: 1.09-2.59), whereas the minor allele homozygosity (CC) was correlated with protection to disease (P = 0.020, OR = 0.28, 95% CI: 0.09-0.91). The heterozygous genotype showed no significant correlation with disease. The product of the IL12B gene (IL-12 p40) can either form a homodimeric cytokine or be part of two pro-inflammatory (IL-12 and IL-23) cytokines. It is presently unclear whether the major allele is associated with higher or lower protein levels of IL-12 p40 and IL-12 p70, which are critical in inflammation and adaptive immune responses. However, as the A allele is high producer of IL12B (p40) mRNA, these results might imply that higher levels of IL-12 p40 (either as homodimers or joined with one or both of the other two subunits) predispose to breast cancer.

Low serum MMP-1 in breast cancer: a negative prognostic factor?

In this study we investigated the prognostic significance of serum matrix metalloproteinase (MMP)-1 levels in early-stage breast cancer patients and correlated these levels with various clinicopathologic parameters. MMP-1 levels were determined by enzyme-linked immunosorbent assay. MMP-1 serum levels in patients (n = 60) were significantly lower than in healthy subjects (n = 20, p < 0.0001). We found significant negative correlation between serum levels of MMP-1 and several negative prognostic factors of breast cancer. Kaplan-Meier analysis showed significantly shorter 5-year survival in patients with lower values of MMP-1 compared to those with high levels of MMP-1 (p = 0.0147). Our results suggest a negative prognostic role of low serum MMP-1.

Anti-p53 antibodies in serum: relationship to tumor biology and prognosis of breast cancer patients.

The aim of this study was to analyze the concentration of anti-p53 antibodies in the serum of breast cancer patients and to correlate these results with various clinical, pathological and biochemical parameters. We also wanted to assess the prognostic significance of these antibodies in our patients. Sera from 61 patients with breast cancer and 20 individuals without malignancies were analyzed using enzyme-linked immunoadsorbent assay. High levels of anti-p53 antibodies were detected in twenty-one (35%) breast cancer patients and one control (5%). The difference was statistically significant. We observed an inverse relationship between the anti-p53 antibodies and the age of the patients. We found significant association of anti-p53 antibodies with tumor size, histological grade of the tumors and the number of axillary lymph nodes involved. The levels of anti-p53 antibodies were higher in patients with negative estrogen and progesterone receptors in comparison with patients with positive steroid receptors, but the difference was not statistically significant. No relation was observed between anti-p53 antibodies neither with the Cathepsin D levels in the cytosol nor with the HER-2/neu extracellular domain in the serum. Patients with primary tumors and higher levels of anti-p53 antibodies had shorter 5-year survival than patients with lower levels of anti-p53 antibodies. Our results support the role of anti-p53 antibodies as a biomarker of less favorable phenotype as well as a prognostic factor for patients with breast cancer.