In the last decades, the role of the microenvironment in tumor progression and therapeutic outcome has gained increasing attention. Cancer-associated fibroblasts (CAFs) have emerged as key players among stromal cells, owing to their abundance in most solid tumors and their diverse tumor-restraining/promoting roles. The interplay between tumor cells and neighboring CAFs takes place by both paracrine signals (cytokines, exosomes and metabolites) or by the multifaceted functions of the surrounding extracellular matrix. Here, we dissect the most recent identified mechanisms underlying CAF-mediated control of tumor progression and therapy resistance, which include induction of the epithelial-to-mesenchymal transition (EMT), activation of survival pathways or stemness-related programs and metabolic reprogramming in tumor cells. Importantly, the recently unveiled heterogeneity in CAFs claims tailored therapeutic efforts aimed at eradicating the specific subset facilitating tumor progression, therapy resistance and relapse. However, despite the large amount of pre-clinical data, much effort is still needed to translate CAF-directed anti-cancer strategies from the bench to the clinic.

We identified a key oncogenic pathway underlying neuroblastoma progression: specifically, MYCN, expressed at elevated level, transactivates the miRNA 17-5p-92 cluster, which inhibits p21 and BIM translation by interaction with their mRNA 3′ UTRs. Overexpression of miRNA 17-5p-92 cluster in MYCN-not-amplified neuroblastoma cells strongly augments their in vitro and in vivo tumorigenesis. In vitro or in vivo treatment with antagomir-17-5p abolishes the growth of MYCN-amplified and therapy-resistant neuroblastoma through p21 and BIM upmodulation, leading to cell cycling blockade and activation of apoptosis, respectively. In primary neuroblastoma, the majority of cases show a rise of miR-17-5p level leading to p21 downmodulation, which is particularly severe in patients with MYCN amplification and poor prognosis. Altogether, our studies demonstrate for the first time that antagomir treatment can abolish tumor growth in vivo, specifically in therapy-resistant neuroblastoma.

MicroRNAs (miRNAs) are tiny noncoding RNAs whose function as modulators of gene expression is crucial for the proper control of cell growth and differentiation. Although the profile of miRNA expression has been defined for many different cellular systems, the elucidation of the regulatory networks in which they are involved is only just emerging. In this work, we identify a crucial role for three neuronal miRNAs (9, 125a, and 125b) in controlling human neuroblastoma cell proliferation. We show that these molecules act in an additive manner by repressing a common target, the truncated isoform of the neurotrophin receptor tropomyosin-related kinase C, and we demonstrate that the down-regulation of this isoform is critical for regulating neuroblastoma cell growth. Consistently with their function, these miRNAs were found to be down-modulated in primary neuroblastoma tumors.miR-9 ͉ miR-125a ͉ miR125b ͉ tyrosine kinase receptor

Here we report the purification, from Xenopus laevis oocyte nuclear extracts, of a new endoribonuclease, XendoU, that is involved in the processing of the intronencoded box C/D U16 small nucleolar RNA (snoRNA) from its host pre-mRNA. Such an activity has never been reported before and has several uncommon features that make it quite a novel enzyme: it is poly(U)-specific, it requires Mn 2؉ ions, and it produces molecules with 2-3-cyclic phosphate termini. Even if XendoU cleaves U-stretches, it displays some preferential cleavage on snoRNA precursor molecules. XendoU also participates in the biosynthesis of another intron-encoded snoRNA, U86, which is contained in the NOP56 gene of Xenopus laevis. A common feature of these snoRNAs is that their production is alternative to that of the mRNA, suggesting an important regulatory role for all the factors involved in the processing reaction.Endoribonucleases play essential roles in RNA metabolism participating both in degradative pathways, such as mRNA decay, and in maturative pathways, to generate functional RNA molecules (1, 2). Despite the plethora of functions played by processing enzymes in RNA metabolism, in eukaryotes only a few endoribonucleases have been isolated to date. Most of these activities are involved in the biosynthesis of translation components. In particular, RNase P and RNase mitochondrial RNA processing are ribonucleoprotein enzymes, functioning as site-specific endoribonucleases (3, 4). Other well characterized endonucleolytic activities, such as the 3Ј-tRNase, the tRNA splicing endonuclease, and members of the RNase III-like family are protein-only enzymes (5-7). Although the majority of these activities participate in the biosynthesis of a specific class of RNA molecules, RNase III was shown to be required for a large number of different maturative pathways. Saccharomyces cerevisiae RNase III (Rnt1p) was shown to be involved in pre-rRNA, small nuclear RNA (snRNA), 1 and small nucleolar RNA (snoRNA) processing (8 -12). Recently, Rnt1p was also shown to participate in processing the intron-encoded snoRNAs U18 and snR38 from their host pre-mRNA (13). Furthermore, a new member of the metazoan RNase III family has been identified to be involved in the RNA interference process (14).Another process in which the participation of endoribonucleases was expected to play an important role is the biosynthesis of snoRNAs. These RNAs are part of a complex class of molecules that are localized in the nucleolus where they participate, as small ribonucleoprotein particles (snoRNPs), in different rRNA maturative events such as processing and nucleotide modifications (15,16). Most snoRNAs in vertebrates are encoded in introns of protein-coding genes and are released from the host primary transcript either by debranching and exotrimming of the spliced lariat (splicing-dependent pathway) or by endonucleolytic cleavage of the pre-mRNA (splicing-independent pathway) (15, 16). There are only a few cases of intronencoded snoRNAs in vertebrates, which are released throug...

Functionally relevant markers of glioblastoma stem-like cells (GSCs) have potential for therapeutic targeting to treat this aggressive disease. Here we used generation and screening of thousands of monoclonal antibodies to search for receptors and signaling pathways preferentially enriched in GSCs. We identified integrin α7 (ITGA7) as a major laminin receptor in GSCs and in primary high-grade glioma specimens. Analyses of mRNA profiles in comprehensive datasets revealed that high ITGA7 expression negatively correlated with survival of patients with both low- and high-grade glioma. In vitro and in vivo analyses showed that ITGA7 plays a key functional role in growth and invasiveness of GSCs. We also found that targeting of ITGA7 by RNAi or blocking mAbs impaired laminin-induced signaling, and it led to a significant delay in tumor engraftment plus a strong reduction in tumor size and invasion. Our data, therefore, highlight ITGA7 as a glioblastoma biomarker and candidate therapeutic target.