LAUSR

Long non-coding RNAs (lncRNAs) are gradually drawing the attention of the cancer research community due to their pivotal involvement in tumorigenesis and tumor progression [1]. These non-protein coding,[200 nucleotides long transcripts are aberrantly expressed in the majority of human malignancies, including gastric cancer (GC) [1, 2]. The discovery that lncRNAs are severely deregulated across different human malignancies [1] has prompted the pursuit of revealing a possible central involvement of lncRNAs in carcinogenesis. Indeed, it seems that lncRNAs influence, through epigenetic and transcriptional regulation, key events during malignant transformation and tumor progression that include apoptosis, epithelial-to-mesenchymal transition, and metastatic spread. As a result, many lncRNAs are now categorized as oncogenes (e.g., HOTAIR, ANRIL, MALAT1) or tumor suppressor genes (e.g., GAS5, MEG3, TUG1) [1, 2]. But how can lncRNAs affect so many biological processes of such importance? The answer is apparently simple: by interacting with most types of biomolecules (DNA, RNA, and proteins). In GC, in particular, lncRNAs, such as ANRIL, H19, HOTAIR, and MALAT1, recruit molecular complexes that modify histones and at the same time inhibit the transcription of target genes via the formation of DNA–RNA complexes. Furthermore, lncRNAs directly interact and modify the activity (e.g., GAS5, H19, and MEG3) of well-known tumor suppressor (p53) or tumor promoting (c-Myc) proteins. Another central mechanism of action of lncRNAs is the interaction with other RNA types and the resulting modulation of their bioavailability. MALAT1, for example, can form complexes by complementary base pairing with mRNAs, or, interestingly, with microRNAs (miRNAs), another RNA species that also exert a broad range of regulatory functions in human malignancies. By ‘‘sponging’’ miRNA molecules, lncRNAs not only modify the target miRNA levels but also affect the transcriptional profile of the mRNA target of the miRNA [1–3]. One such case has been recently reported for GC, where HOTAIR sponges miR331, alleviating the inhibitory effect of the latter on the oncogene HER2, thus increasing the oncogenic potential of GC cells [3]. All of these interactions give shape to complex competing-endogenous RNA networks. An analogous network of interactions is described in this issue of Digestive Diseases and Sciences by Li et al. [4] for PVT1, a known oncogenic lncRNA for GC [5]. More precisely, they reported that PVT1 sponges miR-152 in vitro, as perhaps expected by the in silico analysis that revealed three binding sites for miR-152 in the PVT1 sequence. As a consequence of the above-mentioned interaction, CD151 and FGF2 mRNA levels are decreased. A significant inverse correlation between miR-152 and PVT1, as well as a positive correlation between PVT1 and both CD151 and FGF2 (targets of miR-152), was detected in GC tissues [4]. The regulatory effect of PVT1 needs to be validated using in vivo models, and, most importantly, the consequences of miR-152 sponging should also be investigated in vivo in terms of GC cell proliferation, migration, and metastatic potential. Nonetheless, the approach described in this work serves as a definite impetus for further research. Starting from a simple targeted analysis of a specific lncRNA, previously & Konstantinos Mavridis [email protected]; [email protected]