Diabetic patients treated with metformin have a reduced incidence of cancer and cancerrelated mortality. Here we show that metformin affects engraftment and growth of breast cancer tumours in mice. This correlates with the induction of metabolic changes compatible with clear anticancer effects. We demonstrate that microRnA modulation underlies the anticancer metabolic actions of metformin. In fact, metformin induces DICER expression and its effects are severely impaired in DICER knocked down cells. Conversely, ectopic expression of DICER recapitulates the effects of metformin in vivo and in vitro. The microRnAs upregulated by metformin belong mainly to energy metabolism pathways. Among the messenger RnAs downregulated by metformin, we found c-mYC, IRs-2 and HIF1alpha. Downregulation of c-mYC requires AmP-activated protein kinase-signalling and mir33a upregulation by metformin. Ectopic expression of c-mYC attenuates the anticancer metabolic effects of metformin. We suggest that DICER modulation, mir33a upregulation and c-mYC targeting have an important role in the anticancer metabolic effects of metformin.

Micro RNAs (miRs) are small non-coding RNAs aberrantly expressed in human tumors. Here, we aim to identify miRs whose deregulated expression leads to the activation of oncogenic pathways in human gastric cancers (GCs). Thirty nine out of 123 tumoral and matched uninvolved peritumoral gastric specimens from three independent European subsets of patients were analyzed for the expression of 851 human miRs using Agilent Platform. The remaining 84 samples were used to validate miRs differentially expressed between tumoral and matched peritumoral specimens by qPCR. miR-204 falls into a group of eight miRs differentially expressed between tumoral and peritumoral samples. Downregulation of miR-204 has prognostic value and correlates with increased staining of Bcl-2 protein in tumoral specimens. Ectopic expression of miR-204 inhibited colony forming ability, migration and tumor engraftment of GC cells. miR-204 targeted Bcl-2 messenger RNA and increased responsiveness of GC cells to 5-fluorouracil and oxaliplatin treatment. Ectopic expression of Bcl-2 protein counteracted miR-204 pro-apoptotic activity in response to 5-fluorouracil. Altogether, these findings suggest that modulation of aberrant expression of miR-204, which in turn releases oncogenic Bcl-2 protein activity might hold promise for preventive and therapeutic strategies of GC.

p53 mutations have profound effects on non-small-cell lung cancer (NSCLC) resistance to chemotherapeutic treatments. Mutant p53 proteins are usually expressed at high levels in tumors, where they exert oncogenic functions. Here we show that p53R175H, a hotspot p53 mutant, induces microRNA (miRNA)-128-2 expression. Mutant p53 binds to the putative promoter of miR128-2 host gene, ARPP21, determining a concomitant induction of ARPP21 mRNA and miR-128-2. miR-128-2 expression in lung cancer cells inhibits apoptosis and confers increased resistance to cisplatin, doxorubicin and 5-fluorouracyl treatments. At the molecular level, miR-128-2 post-transcriptionally targets E2F5 and leads to the abrogation of its repressive activity on p21 waf1 transcription. p21 waf1 protein localizes to the cytoplasmic compartment, where it exerts an anti-apoptotic effect by preventing pro-caspase-3 cleavage. This study emphasizes miRNA-128-2 role as a master regulator in NSCLC chemoresistance. Cell Death and Differentiation (2012) 19, 1038-1048 doi:10.1038/cdd.2011 published online 23 December 2011 Mutations in the TP53 gene are the most frequent type of gene-specific alterations in human cancers. 1 The majority of cancer-associated mutations in TP53 gene are missense mutations that reside mainly in the exons encoding for p53 DNA-binding domain. 2 These mutations frequently result in full-length mutant p53 proteins incapable of activating p53 target genes and suppressing tumorigenesis. 3 Most TP53 mutations can be classified into two main categories according to their effect on the thermodynamic stability of the p53 protein. 4 These two mutation categories are commonly referred to as DNA-contact and conformational mutations. The first group includes mutations in residues directly involved in DNA binding, such as R248Q and R273H. The second group comprises mutations that cause local (such as R249S and G245S) or global (such as R175H and R282W) conformational distortions.Besides losing their wild-type (wt) activities, mutant p53 proteins have also dominant-negative effects that inactivate wt p53 protein expressed from the remaining wt allele. Moreover, some mutant p53 forms also acquire new oncogenic properties -'gain of function' -that overrule those due to loss of wt p53 activity by gene deletion. 5-7 These properties range from enhanced proliferation in culture and resistance to a variety of anticancer drugs commonly used in the clinical practice, to increased tumorigenicity in vivo. [8][9][10] Recent work indicates that mutant p53 protein can augment in vitro and in vivo cell migration and invasion. 11 Fontemaggi et al. 12 showed that mutant p53 increases also the angiogenic potential of cancer cells by modulating, at the transcriptional level, Id4 expression.The existing knowledge regarding the molecular mechanisms whereby mutant p53 regulates gene expression is still lacking. To date, we can depict the three following molecular scenarios to explain gain-of-function of mutant p53 proteins: (i) mutant p53 binds to the promoter of ...

Epidermal growth factor (EGF) stimulates cells by launching gene expression programs that are frequently deregulated in cancer. MicroRNAs, which attenuate gene expression by binding complementary regions in messenger RNAs, are broadly implicated in cancer. Using genome-wide approaches, we showed that EGF stimulation initiates a coordinated transcriptional program of microRNAs and transcription factors. The earliest event involved a decrease in the abundance of a subset of 23 microRNAs. This step permitted rapid induction of oncogenic transcription factors, such as c-FOS, encoded by immediate early genes. In line with roles as suppressors of EGF receptor (EGFR) signaling, we report that the abundance of this early subset of microRNAs is decreased in breast and in brain tumors driven by the EGFR or the closely related HER2. These findings identify specific microRNAs as attenuators of growth factor signaling and oncogenesis.

Mammalian cells must integrate environmental cues to determine coherent physiological responses. The transcription factors Myc and YAP-TEAD act downstream from mitogenic signals, with the latter responding also to mechanical cues. Here, we show that these factors coordinately regulate genes required for cell proliferation. Activation of Myc led to extensive association with its genomic targets, most of which were prebound by TEAD. At these loci, recruitment of YAP was Myc-dependent and led to full transcriptional activation. This cooperation was critical for cell cycle entry, organ growth, and tumorigenesis. Thus, Myc and YAP-TEAD integrate mitogenic and mechanical cues at the transcriptional level to provide multifactorial control of cell proliferation.