Ioana Berindan-Neagoe

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.

MicroRNAome genome: A treasure for cancer diagnosis and therapy

The interplay between abnormalities in genes coding for proteins and noncoding microRNAs (miRNAs) has been among the most exciting yet unexpected discoveries in oncology over the last decade. The complexity of this network has redefined cancer research as miRNAs, produced from what was once considered “genomic trash,” have shown to be crucial for cancer initiation, progression, and dissemination. Naturally occurring miRNAs are very short transcripts that never produce a protein or amino acid chain, but act by regulating protein expression during cellular processes such as growth, development, and differentiation at the transcriptional, posttranscriptional, and/or translational level. In this review article, miRNAs are presented as ubiquitous players involved in all cancer hallmarks. The authors also describe the most used methods to detect their expression, which have revealed the identity of hundreds of miRNAs dysregulated in cancer cells or tumor microenvironment cells. Furthermore, the role of miRNAs as hormones and as reliable cancer biomarkers and predictors of treatment response is discussed. Along with this, the authors explore current strategies in designing miRNA‐targeting therapeutics, as well as the associated challenges that research envisions to overcome. Finally, a new wave in molecular oncology translational research is introduced: the study of long noncoding RNAs. CA Cancer J Clin 2014;64:311–336.

Apoptosis in cancer: Key molecular signaling pathways and therapy targets

Apoptosis is a physiological process vital for embryologic development and the maintenance of homeostasis in multicellular organisms, but it is also involved in a wide range of pathological processes, including cancer. In mammalian cells, apoptosis has been divided into two major pathways: the extrinsic pathway, activated by proapoptotic receptor signals at the cellular surface, and the intrinsic pathway, which involves the disruption of mitochondrial membrane integrity. Although many of the proteins vital for apoptosis have been identified, the molecular pathways of cellular death still remain to be elucidated. This review provides references concerning the apoptotic molecules, their interactions, the mechanisms involved in apoptosis resistance, and also the modulation of apoptosis for the treatment of cancer.

Junk DNA and the long non-coding RNA twist in cancer genetics.

The central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs (lncRNAs) have attracted much attention due to their large number and biological significance. Many lncRNAs have been identified as mapping to regulatory elements including gene promoters and enhancers, ultraconserved regions and intergenic regions of protein-coding genes. Yet, the biological function and molecular mechanisms of lncRNA in human diseases in general and cancer in particular remain largely unknown. Data from the literature suggest that lncRNA, often via interaction with proteins, functions in specific genomic loci or use their own transcription loci for regulatory activity. In this review, we summarize recent findings supporting the importance of DNA loci in lncRNA function and the underlying molecular mechanisms via cis or trans regulation, and discuss their implications in cancer. In addition, we use the 8q24 genomic locus, a region containing interactive SNPs, DNA regulatory elements and lncRNAs, as an example to illustrate how single-nucleotide polymorphism (SNP) located within lncRNAs may be functionally associated with the individual’s susceptibility to cancer.

The relationship between the structure and biological actions of green tea catechins.

Catechins and their gallate esters are a class of polyphenolic compounds. The catechin subclass known as flavan-3-ols have recently attracted much attention with regards to their beneficial effect on human health. Their biological actions are dependent on the structure of the compounds and vary according to cell type. They are best known as powerful antioxidants; however depending on the doses they also exhibit prooxidant effects. The anti- or prooxidant effects of green tea catechins have been implicated in the modulation of several cellular functions often associated with strong chemoprotective properties. This review summarises the benefit catechins to human health, the main molecular pathways modulated by catechins. The relationship between the structure and activity of the catechins needs to be studied further. In the future, the structure of catechins could be modified so as to synthesise novel compounds with more specific beneficial properties and higher bioavailability.

Allele-specific reprogramming of cancer metabolism by the long non-coding RNA, CCAT2

Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the major nutrients that fuel cellular metabolism, and the pathways utilizing these nutrients are often altered in cancer. Here, we show that the long ncRNA CCAT2, located at the 8q24 amplicon on cancer risk-associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo in an allele-specific manner by binding the Cleavage Factor I (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68). The CCAT2 interaction with the CFIm complex fine-tunes the alternative splicing of Glutaminase (GLS) by selecting the poly(A) site in intron 14 of the precursor mRNA. These findings uncover a complex, allele-specific regulatory mechanism of cancer metabolism orchestrated by the two alleles of a long ncRNA.

Electrochemical immunosensors in breast and ovarian cancer.

During the last decades the incidence of cancer increased dramatically especially in developed countries. In spite of the fact that the immunochemical methods allowed the diagnosis in early stages, the biopsies are generally invasive methods that create discomfort to patients. The need for fast, sensitive, easy to use and noninvasive diagnosis tools is actually of great interest for many research groups all over the world. Immunosensors (ISs) are miniaturized measuring devices, which selectively detect their targets by means of antibodies (Abs) and provide concentration-dependent signals. Ab binding leads to a variation in electric charge, mass, heat or optical properties, which can be detected directly or indirectly by a variety of transducers. A great number of proteins could be considered as recognition element. In this review the attention was focused on main cancer biomarkers, currently used by immunological methods (immunohistochemistry, ELISA, flow cytometry, Western blot, immunofluorescence etc) and in the development of electrochemical immunoassays that could be used in cancer diagnosis, prognosis and therapy monitoring.

The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis

Objective MicroRNA (miRNA) expression profile can be used as prognostic marker for human cancers. We aim to explore the significance of miRNAs in colorectal cancer (CRC) metastasis. Design We performed miRNA microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by quantitative real-time PCR (qRT-PCR). We tested metastatic activity of selected miRNAs and identified miRNA targets by prediction algorithms, qRT-PCR, western blot and luciferase assays. Clinical outcomes were analysed in six sets of CRC cases (n=449), including The Cancer Genome Atlas (TCGA) consortium and correlated with miR-224 status. We used the Kaplan–Meier method and log-rank test to assess the difference in survival between patients with low or high levels of miR-224 expression. Results MiR-224 expression increases consistently with tumour burden and microsatellite stable status, and miR-224 enhances CRC metastasis in vitro and in vivo. We identified SMAD4 as a miR-224 target and observed negative correlation (Spearman Rs=−0.44, p<0.0001) between SMAD4 and miR-224 expression in clinical samples. Patients with high miR-224 levels display shorter overall survival in multiple CRC cohorts (p=0.0259, 0.0137, 0.0207, 0.0181, 0.0331 and 0.0037, respectively), and shorter metastasis-free survival (HR 6.51, 95% CI 1.97 to 21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (HR 4.12, 95% CI 1.1 to 15.41, p=0.0175). Conclusions MiR-224 promotes CRC metastasis, at least in part, through the regulation of SMAD4. MiR-224 expression in primary CRC, alone or combined with its targets, may have prognostic value for survival of patients with CRC.

Molecular Pathways: microRNAs, Cancer Cells, and Microenvironment

One of the most unexpected discoveries in molecular oncology over the last decade is the interplay between abnormalities in protein-coding genes and short noncoding microRNAs (miRNA) that are causally involved in cancer initiation, progression, and dissemination. This phenomenon was initially defined in malignant cells; however, in recent years, more data have accumulated describing the active participation of miRNAs produced by microenvironment cells. As hormones, miRNAs can be released by a donor cell in various forms of vesicles or as “free” molecules secreted by active mechanisms. These miRNAs spread as signaling molecules that are uptaken either as exosomes or as “free” RNAs, by cells located in other parts of the organism. Here, we discuss the communication between cancer cells and the microenvironment through miRNAs. We further expand this in a more translational context and present miRNAs as predictors of treatment response, as crucial agents in targeted therapeutics, and as significant molecules to target. Clin Cancer Res; 20(24); 6247–53. ©2014 AACR.

Non-coding RNAs as theranostics in human cancers

Theranostics was coined originally as a term used to describe a system that combines diagnosis and therapy, aiming to provide the tools for personalized medicine. This review reasserts the grounds for regarding non‐coding RNAs (ncRNA) as theranostics in human cancers. The microRNAs (miRNAs) are the most well studied ncRNAs in recent years; their pivotal role in orchestrating tumor initiation and progression has been confirmed in all types of cancers. Hence, these small ncRNAs have emerged as attractive therapeutic targets and diagnostic tool. Various approaches to use their therapeutic potential have been taken, here we summarize the most important ones. In the near future, the focus of theranostics will be shifted towards longer and mechanistically more versatile ncRNAs, and we included some recent advances supporting this view. J. Cell. Biochem. 113: 1451–1459, 2012.