Deregulation of a Cis-Acting lncRNA in Non-small Cell Lung Cancer May Control HMGA1 Expression

Abstract

BackgroundLong non-coding RNAs (lncRNAs) have long been implicated in cancer-associated phenotypes. Recently, a class of lncRNAs, known as cis-acting, have been shown to regulate the expression of neighboring protein-coding genes and may represent undiscovered therapeutic action points. The chromatin architecture modification gene HMGA1 has recently been described to be aberrantly expressed in lung adenocarcinoma (LUAD). However, the mechanisms mediating the expression of HMGA1 in LUAD remain unknown. Here we investigate the deregulation of a putative cis-acting lncRNA in LUAD, and its effect on the oncogene HMGA1.MethodsLncRNA expression was determined from RNA-sequencing data of tumor and matched non-malignant tissues from 36 LUAD patients. Transcripts with significantly deregulated expression were identified and validated in a secondary LUAD RNA-seq dataset (TCGA). SiRNA-mediated knockdown of a candidate cis-acting lncRNA was performed in BEAS-2B cells. Quantitative real-time PCR was used to observe the effects of lncRNA knockdown on the expression of HMGA1.ResultsWe identified the lncRNA RP11.513I15.6, which we refer to as HMGA1-lnc, neighboring HMGA1 to be significantly downregulated in both LUAD cohorts. Conversely, we found HMGA1 significantly overexpressed in LUAD and anticorrelated with HMGA1-lnc. In vitro experiments demonstrated siRNA-mediated inhibition of HMGA1-lnc in immortalized non-malignant lung epithelial cells resulted in a significant increase in HMGA1 gene expression.ConclusionOur results suggest that HMGA1-lnc is a novel cis-acting lncRNA that negatively regulates HMGA1 gene expression in lung cells. Further characterization of this regulatory mechanism may advance our understanding of the maintenance of lung cancer phenotypes and uncover a novel therapeutic intervention point for tumors driven by HMGA1.

A genome-wide integrated analysis of lncRNA-mRNA in melanocytes from white and brown skin hair boer goats (Capra aegagrus hircus)

“…Homology analysis showed that there were nine DELs with the same amino acid sequences as miRNA precursors and may correspond to miRNA precursors ( Supplementary Table S3 ). lncRNA also has a potential cis -regulatory capacity for adjacent coding genes ( 34 , 35 ). After the prediction of DEL cis -target genes ( Supplementary Table S4 ), statistics from KEGG annotation found that the top potential target gene-enriched terms were involved in GABAergic synapse ( Figure 5C ), which may promote the expression and secretion of gonadotropin signaling molecules ( 36 ).…”

“…The cis -regulatory effects of lncRNAs on neighboring genes have been well-examined ( 30 , 35 ). In this study, 136 cis -genes of DELs overlapped with DEMs, and 139 paired DELs and cis -genes had the same expression trends.…”

Circular RNA‐mediated ceRNA network was identified in human lung adenocarcinoma by high‐throughput sequencing

“…In the study by Stewart et al, high mobility group A1 (HMGA1) was implicated in tumorigenesis. HMGA1 has recently been described as an chromatin architecture modification gene and was found to be aberrantly expressed in LUAD 30 . The oncogenic role of high mobility group A (HMGA) proteins stems from chromatin‐mediated activation of cancer‐driving genes such as E2F transcription factor 1 (E2F1), Activator protein‐1 (AP1), and Cyclin A1 (CCNA1), as well as the repression of tumor suppressive genes such as TP53 31 .…”

“…HMGA1 has recently been described as an chromatin architecture modification gene and was found to be aberrantly expressed in LUAD. 30 The oncogenic role of high mobility group A (HMGA) proteins stems from chromatin-mediated activation of cancer-driving genes such as E2F transcription factor 1 (E2F1), Activator protein-1 (AP1), and Cyclin A1 (CCNA1), as well as the repression of tumor suppressive genes such as 31 Moreover, the expression of noncoding genes, such as miRNAs, has been proved to be affected by the overexpression of HMGA proteins, leading to lung development through dysregulation of the cell cycle. 32 In summary, these mRNAs are closely related to the regulation of inflammatory and hypoxia responses, regulation of artery smooth muscle cell proliferation and apoptosis, the response to the redox state, and the Bone morphogenetic protein (BMP) signaling pathway.…”

Antioxidant stress and anticancer activity of peptide‑chelated selenium in vitro

“…To investigate the function of lncRNAs, the cis-target genes of lncRNAs were predicted. lncRNAs may serve a cis role acting on neighboring target genes ( 49 , 50 ). A total of 100,000 up- and downstream coding genes were selected by Python Script ( ccb.jhu.edu/software/stringtie/ ) ( 51 ).…”