The mammalian genome contains several hundred microRNAs that regulate gene expression through modulation of target mRNAs. Here, we report a fragile chromosomal region lost in specific hematopoietic malignancies. This 7 Mb region encodes about 12% of all genomic microRNAs, including miR-203. This microRNA is additionally hypermethylated in several hematopoietic tumors, including chronic myelogenous leukemias and some acute lymphoblastic leukemias. A putative miR-203 target, ABL1, is specifically activated in these hematopoietic malignancies in some cases as a BCR-ABL1 fusion protein (Philadelphia chromosome). Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels and inhibits tumor cell proliferation in an ABL1-dependent manner. Thus, miR-203 functions as a tumor suppressor, and re-expression of this microRNA might have therapeutic benefits in specific hematopoietic malignancies.

The alterations in carbohydrate metabolism that fuel tumor growth have been extensively studied. However, other metabolic pathways involved in malignant progression, demand further understanding. Here we describe a metabolic acyl-CoA synthetase/stearoyl-CoA desaturase ACSL/SCD network causing an epithelial-mesenchymal transition (EMT) program that promotes migration and invasion of colon cancer cells. The mesenchymal phenotype produced upon overexpression of these enzymes is reverted through reactivation of AMPK signaling. Furthermore, this network expression correlates with poorer clinical outcome of stage-II colon cancer patients. Finally, combined treatment with chemical inhibitors of ACSL/SCD selectively decreases cancer cell viability without reducing normal cells viability. Thus, ACSL/SCD network stimulates colon cancer progression through conferring increased energetic capacity and invasive and migratory properties to cancer cells, and might represent a new therapeutic opportunity for colon cancer treatment.

Semliki Forest virus replicase protein nsP2 shares sequence homology with several putative NTPases and RNA helicases. NsP2 has RNA-dependent NTPase activity. Here we expressed polyhistidine-tagged nsP2 in Escherichia coli, purified it by metal-affinity chromatography, and used it in RNA helicase assays. RNA helicase CI of plum pox potyvirus was used as a positive control. Unwinding of alpha-32P-labelled partially double-stranded RNA required nsP2, Mg2+ and NTPs. NsP2 with a mutation, K192N, in the NTP-binding sequence GVPGSGK192SA could not unwind dsRNA and had no NTPase activity. This is the first demonstration of RNA helicase activity within the large alphavirus superfamily.

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Transcription of microRNAs (miRNAs) is thought to be regulated similarly to that of protein-coding genes. However, how miRNAs are regulated during the cell division cycle is not well understood. We have analyzed the transcription profiles of miRNAs in response to mitogenic stimulation in primary fibroblasts. About 33% of the miRNAs expressed in these cells are induced upon exit from quiescence. Many of these miRNAs are specifically induced by E2F1 or E2F3 during the G 1 /S transition and are repressed in E2F1/3-knockout cells. At least four miRNA clusters, let-7a-d, let-7i, mir-15b-16-2, and mir-106b-25, are direct targets of E2F1 and E2F3 during G 1 /S and are repressed in E2F1/3-null cells. Interestingly, these miRNAs do not contribute to E2F-dependent entry into S phase but rather inhibit the G 1 /S transition by targeting multiple cell cycle regulators and E2F targets. In fact, E2F1 expression results in a significant increase in S-phase entry and DNA damage in the absence of these microRNAs. Thus, E2F-induced miRNAs contribute to limiting the cellular responses to E2F activation, thus preventing replicative stress. Given the known function of E2F of inducing other oncogenic miRNAs, control of miRNAs by E2F is likely to play multiple roles in cell proliferation and in proliferative diseases such as cancer.MicroRNAs (miRNAs) are small (ϳ23-nucleotide [nt]) regulatory RNA molecules that exert posttranscriptional control of specific target mRNAs (3). More than half of the human protein-coding genes appear to have been under selective pressure to maintain pairing of their 3Ј untranslated regions (3Ј-UTRs) to miRNAs (5). This interaction is known to induce mRNA degradation or inhibition of translation through specific albeit imperfect base pairing (22,24). Several target genes have been validated, indicating that each individual miRNA can target a few or, possibly, multiple genes. These small miRNAs therefore regulate fundamental cellular processes such as proliferation, differentiation, or apoptosis during development (65). In addition, deregulation of miRNAs is frequently observed in a wide range of diseases, including cancer (19,21). The analysis of miRNA function and regulation in specific cellular processes has proven to be required for a full understanding of malignant transformation and to envision new therapeutic possibilities.Tumor development is accompanied by a variety of genetic and epigenetic alterations in protein-coding genes and small, noncoding RNA genes. By regulating specific oncogenes or tumor suppressor molecules, miRNAs may have profound effects on tumor development. The first report linking miRNAs and cancer showed a frequent deletion of miR-15a and miR-16-1 in patients with B-cell chronic lymphocytic leukemia (13). Further analysis of miRNA expression signatures has suggested a frequent involvement of miRNAs in the initiation and progression of human tumors (12). Although the critical targets for most cancer-associated miRNAs are unknown, some relevant targets have been characterized in sp...

Mitochondrial metabolism has emerged as a promising target against the mechanisms of tumor growth. Herein, we have screened an FDA-approved library to identify drugs that inhibit mitochondrial respiration. The β1-blocker nebivolol specifically hinders oxidative phosphorylation in cancer cells by concertedly inhibiting Complex I and ATP synthase activities. Complex I inhibition is mediated by interfering the phosphorylation of NDUFS7. Inhibition of the ATP synthase is exerted by the overexpression and binding of the ATPase Inhibitory Factor 1 (IF1) to the enzyme. Remarkably, nebivolol also arrests tumor angiogenesis by arresting endothelial cell proliferation. Altogether, targeting mitochondria and angiogenesis triggers a metabolic and oxidative stress crisis that restricts the growth of colon and breast carcinomas. Nebivolol holds great promise to be repurposed for the treatment of cancer patients.

In the original Figure 8B, the authors failed to indicate that the four lanes showing the expression of miR-203 (top part of the panel) were rearranged to correspond with the samples shown in the lower part of the panel. All four lanes come from the same agarose gel, and this reorganization does not affect the data or the conclusions. The authors regret this error and apologize for any confusion that it may have caused. This has now been corrected in the figure below.

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