Missing Links in Epithelial-Mesenchymal Transition: Long Non-Coding RNAs Enter the Arena

131

Background/Aims: HOX transcript antisense RNA (HOTAIR) plays a vital role in carcinogenesis. However, its functional and regulatory roles remain unclear. In this study, we aimed to investigate its biological function and clinical significance in human colorectal cancer (CRC). Methods: We examined the expression levels of lncRNA HOTAIR and miR-203a-3p in CRC tissues and CRC cell lines by qRT-PCR. Gain and loss-of-function assays were performed to examine the effects of HOTAIR and miR-203a-3p on the proliferation and chemoresistance of CRC cells. The possible mechanisms of HOTAIR were also explored by fluorescence reporter assay and Western blot. Results: The expressions of HOTAIR were upregulated in CRC tissue tissues compared to adjacent control tissues. We also found HOTAIR was downregulated by miR-203a-3p in CRC cell lines. Both HOTAIR knockdown and miR-203a-3p overexpression in CRC cell lines led to inhibited cell proliferation and reduced chemoresistance. We also determined that β-catenin and GRG5 were inhibitory targets of miR-203a-3p, and that Wnt/β-catenin signaling was inhibited by both HOTAIR knockdown and miR-203a-3p overexpression. Significantly, we found that increased expression of miR-203a-3p is essential for cell proliferation repression, chemoresistance reduction, and Wnt/β-catenin signaling inhibition induced by HOTAIR knockdown. Conclusions: Our study demonstrated that the lncRNA HOTAIR could regulate the progression and chemoresistance of CRC via modulating the expression levels of miR-203a-3p and the activity of Wnt/β-catenin signaling pathway.

Section: Introductionmentioning

confidence: 99%

LncRNA HOTAIR is a Prognostic Biomarker for the Proliferation and Chemoresistance of Colorectal Cancer via MiR-203a-3p-Mediated Wnt/ß-Catenin Signaling Pathway

Xiao

Chen

et al. 2018

131

“…A lot of such noncoding transcripts are processed to produce small noncoding RNAs including lncRNAs or miRNAs. As a family of small (18-22 nucleotide, nt) and endogenous noncoding RNA molecules, miRNAs target specific messenger RNAs and hence play a negative regulatory role in gene expression by triggering the translational repression or degradation of their target genes [13,14].In contrary, lncRNAs belong to a big family of transcribed RNA molecules (over 200 nt) with little potential to code proteins [15,16]. Recent studies have focused on the effects of lncRNAs in atherosclerosis [17].…”

Section: Introductionmentioning

confidence: 99%

Association Between the Deletion Allele of Ins/Del Polymorphism (Rs145204276) in the Promoter Region of GAS5 with the Risk of Atherosclerosis

Shen

Qiang

2018

Background/Aims: LncRNA is a growth arrest-specific transcript 5 (GAS5) with tumor suppressor activities in some cancers, but its role in atherosclerosis is unclear. Methods: Bioinformatics algorithm analysis was utilized to search the target of GAS5 and miR-21, followed by luciferase assay to confirm these targets. Real-time PCR and western-blot were utilized to verify the connection among GAS5, miR-21 and Programmed cell death 4 (PDCD4). MTT assay and flow cytometry analysis were performed to explore the mechanism of GAS5 in the regulation of atherosclerosis. Results: GAS5 directly targets miR-21 and functions as a competing endogenous RNA to suppress miR-21 expression. We also observed that rs145204276 polymorphism, including INS/INS and DEL/DEL, on GAS5 promoter increased transcription activity of GAS5, but the presence of rs145204276 DEL/DEL allele significantly promoted the transcription of GAS5 promoter compared with rs145204276 INS/INS allele. PDCD4 was predicted as a direct target gene of miR-21 with a binding site on PDCD4 3’UTR. It was further confirmed by luciferase assay that miR-21 significantly reduced the luciferase activity of wild-type PDCD4 3’UTR but not that of mutant PDCD4 3’UTR. In addition, high glucose significantly inhibited the growth rate of EC genotyped as DEL/DEL or INS/ INS, and apparently promoted the apoptotic rate of either DEL/DEL or INS/INS genotype ECs. Furthermore, the effect of high glucose was stronger in the INS/INS group, while the expression of GAS5 was dramatically upregulated with the presence of GAS5 DEL/DEL, while GAS5 positively regulated PDCD4 expression via inhibiting miR-21 expression. GAS5 siRNA and miR-21 mimics significantly decreased GAS5 and PDCD4 expressions, and the inhibitory effects of GAS5 siRNA or miR-21 mimics on GAS5 and PDCD4 expressions in the INS/INS group was stronger. Moreover, GAS5 siRNA and miR-21 mimics remarkably triggered cells proliferation and suppressed cell apoptosis, and the inhibition effects of GAS5 siRNA or miR-21 mimics on either cell viability and apoptosis in the INS/INS group was stronger. In this study, we enrolled 1,306 subjects with or without atherosclerosis and found that the INS/DEL or DEL/DEL genotypes significantly decreased the risk of atherosclerosis compared with the ins/ins genotype (adjusted odds ratio: 0.74 and 0.40, respectively). Conclusion: In summary, rs145204276 was associated with the risk of atherosclerosis by affecting the proliferation and apoptosis of endothelial cells via regulating the GAS5/miR-21/PDCD4 signaling pathway.

“…Recently, lncRNAs have emerged as new regulators of cancer progression [14,35]. MALAT1 is overexpressed and has been …”

Section: Discussionmentioning

confidence: 99%

“…Currently, highthroughput microarray profiles and RNA sequencing (RNA-seq) experiments have identified a large number of abnormally expressed lncRNAs in various cancers [9][10][11][12][13][14]. The expression of lncRNAs is generally tissue-specific [15,16].…”

Section: Introductionmentioning

confidence: 99%

Circulating Long Noncoding RNAs as Biomarkers for Predicting Head and Neck Squamous Cell Carcinoma

Yao

Chen

Lü

et al. 2018

Background/Aims: The anatomical complexity of the head and neck region and the lack of sufficiently specific and sensitive biomarkers often lead to the diagnosis of head and neck squamous cell carcinoma (HNSCC) at advanced stages. To identify novel biomarkers for early diagnosis of primary HNSCC through a minimally invasive method, we investigated circulating long noncoding RNA (lncRNA) levels in plasma of HNSCC patients. Methods: The global lncRNA expression profiles of HNSCC patients were measured using microarray and next-generation RNA-sequencing (RNA-seq) data from both circulating and tissue samples. The diagnosis prediction model based on the lncRNA signatures and clinical features was evaluated by multi-stage validation and risk score analysis. Results: The data showed that 432 lncRNA transcripts were differentially expressed by fold changes of > 4 in circulating samples and 333 in tissues samples, respectively. Only 12 lncRNAs consistently emerged in these two kinds of samples. After the risk score analysis including a multistage validation, we identified three lncRNAs, namely, HOXA11-AS, LINC00964 and MALAT1, which were up-regulated in the plasma of HNSCC patients compared with those in healthy controls with merged areas under the curve (AUCs) in training and validation sets of 0.925 and 0.839, respectively. Conclusion: HOXA11-AS, LINC00964 and MALAT1 might be potential circulating biomarkers for the early detection of HNSCC in the future.