[show abstract][hide abstract] ABSTRACT: miRNAs are noncoding RNAs that posttranscriptionally regulate gene expression. Altered expression and function have been observed in bladder cancer. We analyzed the expression profile of a group of miRNAs involved in bladder cancer angiogenesis, tumor cell proliferation, tumor suppressor inhibition, epithelial-mesenchymal transition and metastasis activation. Prognostic and diagnostic value, and validated targets were further examined.
Using quantitative real-time polymerase chain reaction 77 bladder cancer cases and 77 matched tumor associated normal samples were investigated to determine the expression of miR-10b, 19a, 19b, 21, 126, 145, 205, 210, 221, 296-5p and 378. The relationship between miRNA expression, patient survival and tumor pathological features was also examined.
miR-10b, 19a, 126, 145, 221, 296-5p and 378 were significantly down-regulated in bladder cancer compared to adjacent normal urothelium. miR-145 was the most down-regulated microRNA of this group. miR-19b, 21, 205 and 210 showed no significant difference between the 2 tissue types. High miR-21 expression correlated with worse overall patient survival (p = 0.0099). Multivariate analysis revealed that miR-21, 210 and 378 may serve as independent prognostic factors for overall patient survival (p = 0.005, 0.033 and 0.012, respectively). miR-21 and 378 may serve as independent prognostic factors for recurrence (p = 0.030 and 0.031, respectively). miR-145, 221, 296-5p and 378 showed the best combined ROC curves for specificity and sensitivity. miRWalk analysis was used to identify validated miRNA target genes. Further Gene Ontology enrichment revealed the main classes of biological functions of these validated targets.
Most miRNAs analyzed are down-regulated in bladder cancer. They may serve as candidate biomarkers for diagnostic and prognostic purposes in the future.
The Journal of urology 06/2012; 188(2):615-23. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Triple negative breast cancer is deprived of estrogen receptor alpha (ERα), progesterone receptor (PR) and HER-2 protein. It constitutes the most heterogeneous and aggressive group of breast carcinomas, for which identification of novel characteristics and characterization of putative targets becomes very demanding. In the present work we have assayed the expression of ERα36, a recently identified ERα variant of 36kDa, in a series of triple negative breast cancers, in relation to the clinical behavior and other clinico-pathological features of the tumors. While widely expressed within the cytoplasm in almost all tumors, we found that exclusively the membrane/submembrane expression of the receptor exhibits a correlation with patient's survival. Moreover, membrane ERα36 correlates in an inverse manner with the expression of miRNA210, a pro-angiogenic miR, with high prognostic relevance in triple negative carcinomas. A thorough transcriptomic, pharmacological-based approach in breast cancer cell lines, revealed an early (direct) transcriptional signature of the receptor activation, related to immune system processes and T-cell differentiation, RNA biosynthesis, regulation of metabolism, VEGF signaling and regulation of the cell cycle, with a down-regulation of CREB, NFκB and STATs transcription factors. Finally, ERα36 expression is not limited within breast cancer epithelial linen, but is equally identified in tumor vasculature, peritumoral fat tissue, lymphocytic infiltrate and stromal fibroblasts. In light of the above, ERα36 could represent a major counterpart in triple negative breast cancer.
[show abstract][hide abstract] ABSTRACT: Esophageal squamous-cell carcinoma (ESCC) is an invasive neoplastic disease generally associated with poor survival rates. The incidence of ESCC is characterized by marked geographic variation, with highest rates noted in developing Southeastern African, Central and Eastern Asian countries. In the developed Western European and North American regions where there is a low disease incidence, heavy alcohol and cigarette consumption constitute major risk factors. The toxic effects of both these risk factors cause chronic irritation and inflammation of the esophageal mucosa, while at the cellular level they further confer mutagenic effects by the activation of oncogenes (e.g., RAS mutations), inhibition of tumor-suppressor genes, and profound DNA damage. Viral infections, particularly with human papillomavirus, may activate specific antiapoptotic, proliferative and malignant cellular responses that may be intensified in combination with the effects of alcohol and tobacco. In countries with a high ESCC incidence, low socioeconomic status and an inadequate diet of poorly preserved food are combined with basic nutritional deficiencies and inadequate medical treatment. These conditions are favorable to the above-mentioned risk factors implicated in ESCC development, which may be present and/or habitually used in certain populations. New perspectives in epidemiological studies of ESCC development and its risk factors allow genome-wide research involving specific environments and habits. Such research should consist of adequately large and representative samples, should use newly designed informative genetic markers, and apply genomic variation analysis of the functional transcripts involved in malignant cell cycle regulation and neoplastic transformation in the multi-step process of ESCC carcinogenesis.
The International journal of biological markers 10/2011; 27(1):1-12. · 1.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: miRNAs are small, regulatory molecules approximately 21-24 nucleotides in length. They function at the post-transcriptional level by controlling the expression of more than 50% of human protein-coding genes and play an essential role in cell signaling pathways. The objective of the present study was to explore the expression profile of oncomiRs and tumor-suppressor miRs, and to define their possible correlations in triple-negative (ER, PR and Her2/neu) primary breast cancers. Forty-nine primary triple-negative breast cancer cases, along with 34 matched tumor-associated normal samples were investigated for the expression of 9 miRNAs using qPCR. Relationships between the expression of miR-10b, miR-21, miR-122a, miR-145, miR-205, miR-210, miR-221, miR-222 and miR-296 and the pathologic features of the tumors were examined, as were the influences of miR expression on patient overall and cancer-specific survival. miR-21, miR-210 and miR-221 were significantly overexpressed, whereas miR-10b, miR-145, miR-205, miR-122a were significantly underexpressed in the triple-negative primary breast cancers. Significant correlations among all of the studied miRs were scored both in the breast cancer and control tissue. Expression of miR-222 and miR-296 did not exhibit any significant difference between the breast cancer and normal tissue. There was a non-significant trend for high expression levels of the microRNAs, miR-21, miR-210, miR-221 and miR-222, to be associated with worse patient disease-free and overall survival. miR-21, miR-210 and miR-221 expression plays a significant role in triple- negative primary breast cancers.
[show abstract][hide abstract] ABSTRACT: In advanced renal cell carcinoma (RCC), surgery combined with systemic chemotherapy and immunotherapy have had limited effectiveness. Therapeutic modalities targeting VEGF, PDGF, and c-kit using tyrosine kinase inhibitors and m-TOR using specific biologic factors are in development. Therapeutic approaches targeting TNF-alpha have shown limited efficacy, while anti-TRAIL (TNFSF10) antibodies have shown enhanced activity. The presence and potential significance of other members of the TNFSF has not been investigated. Here, we assayed the TNFSF members APRIL, BAFF, TWEAK and their receptors (BCMA, TACI, BAFFR, Fn14) in 86 conventional type clear cell RCC, using immunohistochemistry and correlated our findings with histological data and, in a limited series, follow-up of patients. We observed a differential expression of these TNFSF ligands and receptors in cancerous and non-cancerous structures. BAFF was found in all RCC; APRIL expression is associated with an aggressive phenotype, correlating negatively with patients' disease-free survival, while TWEAK and its receptor Fn14 are heterogeneously expressed, correlating negatively with the grade and survival of RCC patients. This is the first study, presenting together the TNFSF members APRIL, BAFF, TWEAK and their receptors in different areas of normal renal tissue and RCC, suggesting a potential role of these TNFSF members in renal tumor biology.