LncRNA loc285194 is a p53-regulated tumor suppressor

Abstract

Protein-coding genes account for only a small part of the human genome, whereas the vast majority of transcripts make up the non-coding RNAs including long non-coding RNAs (lncRNAs). Accumulating evidence indicates that lncRNAs could play a critical role in regulation of cellular processes such as cell growth and apoptosis as well as cancer progression and metastasis. LncRNA loc285194 was previously shown to be within a tumor suppressor unit in osteosarcoma and to suppress tumor cell growth. However, it is unknown regarding the regulation of loc285194. Moreover, the underlying mechanism by which loc285194 functions as a potential tumor suppressor is elusive. In this study, we show that loc285194 is a p53 transcription target; ectopic expression of loc285194 inhibits tumor cell growth both in vitro and in vivo. Through deletion analysis, we identify an active region responsible for tumor cell growth inhibition within exon 4, which harbors two miR-211 binding sites. Importantly, this loc285194-mediated growth inhibition is in part due to specific suppression of miR-211. We further demonstrate a reciprocal repression between loc285194 and miR-211; in contrast to loc285194, miR-211 promotes cell growth. Finally, we detect downregulation of loc285194 in colon cancer specimens by quantitative PCR arrays and in situ hybridization of tissue microarrays. Together, these results suggest that loc285194 is a p53-regulated tumor suppressor, which acts in part through repression of miR-211.

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

“…Moreover, in vivo studies confirmed that LOC285194 can bind to and downregulate MIR211. 64 Thus LOC285194 may modulate the cancer phenotype through its function as an endogenous miRNA sponge. Additionally, a reciprocal repression feedback loop exists between LOC285194 and MIR211, suggesting that miRNAs can also modulate lncRNAs.…”

“…Additionally, a reciprocal repression feedback loop exists between LOC285194 and MIR211, suggesting that miRNAs can also modulate lncRNAs. 64 In this scenario, lncRNAs and miRNAs may interact as components of a new genomic regulatory network, thereby greatly expanding the functional genetic information in the human genome.…”

“…Although the underlying mechanism is generally unknown, it has been proposed that the expression of certain lncRNAs in CRC can be initiated or modulated by genetic (eg, SNPs in BA318C17.1, 66 sequence mutation of MALAT-1 67 ), epigenetic (eg, MIR211-dependent regulation of LOC285194, histone deacetylationinduced hypoxia-mediated downregulation of lncRNA-LET/NPTN-IT1 68 ), and transcriptional (eg, TCF7L2-dependent regulation of CCAT2, 58 TP53-dependent regulation of PVT1 69 ) regulatory factors and may allow for the exact execution of malignant transformation to some extent. 58,67,68 Intriguingly, in addition to being affected by MIR211, 64 LOC285194 was also found to be regulated by genetic deletion (copy number variation) and TP53, 64,65 suggesting that the expression of specific lncRNAs may be regulated by several regulatory mechanisms.…”

“…By implanting colon cancer cells into nude mice after transfection with LOC285194 expression vectors, Liu et al 64 successfully demonstrated the tumor-suppressive effects of LOC285194 in vivo; both the tumor growth rate and the final tumor weight were significantly decreased when LOC285194 was overexpressed.…”

Long Noncoding RNA in Digestive Tract Cancers: Function, Mechanism, and Potential Biomarker

“…Liu et al reported that lncRNA loc285194, a known lncRNA in osteosarcoma, is a p53 transcription target with two binding sites of miR-211 in its exon 4. The ectopic expression of loc285194 suppressed tumor cell growth in vitro and in vivo by repressing miR-211-induced cell growth [77]. Recently, Hu et al reported that lincRNA GAPLINC was overexpressed in GC tissues and correlated with poor survival of patients with GC.…”