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Long non-coding (lnc)RNA PAPAS overexpression inhibits tumor growth in papillary thyroid carcinoma by downregulating lncRNA HOTTIP.

ABSTRACT: The long non-coding (lnc)RNA pre-ribosomal RNA antisense transcripts (PAPAS) can repress ribosomal RNA synthesis, although its role in human disease is currently unknown. The present study aimed to investigate the function of PAPAS in papillary thyroid carcinoma (PTC). PAPAS was downregulated, while the lncRNA HOXA transcript at the distal tip (HOTTIP) was upregulated in patients with PTC. PAPAS and HOTTIP were inversely associated in PTC. PAPAS overexpression led to the downregulation of HOTTIP in PTC cells, while PAPAS expression was not significantly affected by HOTTIP overexpression, suggesting that PAPAS was upstream of HOTTIP. PAPAS expression level decreased, while HOTTIP expression level increased with the increase of clinical staging. PAPAS overexpression led to the inhibition of cell proliferation, while HOTTIP overexpression increased proliferation of PTC cells, and HOTTIP overexpression decreased the effects of PAPAS overexpression. lncRNA PAPAS overexpression may inhibit tumor growth in papillary thyroid carcinoma by downregulating lncRNA HOTTIP.

SUBMITTER: Xiao J

PROVIDER: S-EPMC7039133 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Long non-coding (lnc)RNA PAPAS overexpression inhibits tumor growth in papillary thyroid carcinoma by downregulating lncRNA HOTTIP.

Xiao Juan J Bing Zhaowei Z Xiao Ge G Guan Yang Y Luan Jian J

Oncology letters 20200121 3

The long non-coding (lnc)RNA pre-ribosomal RNA antisense transcripts (PAPAS) can repress ribosomal RNA synthesis, although its role in human disease is currently unknown. The present study aimed to investigate the function of PAPAS in papillary thyroid carcinoma (PTC). PAPAS was downregulated, while the lncRNA HOXA transcript at the distal tip (HOTTIP) was upregulated in patients with PTC. PAPAS and HOTTIP were inversely associated in PTC. PAPAS overexpression led to the downregulation of HOTTIP ...[more]

PMID: 32194727

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Project description:IntroductionMicroRNAs (miRNAs) are small noncoding RNA molecules that regulate genetic expression and are also vital for tumor initiation and development. MiR-29b-3p was found to be involved in regulating various biological processes of tumors, including tumor cell proliferation, metastasis, and apoptosis inhibition; however, the biofunction and molecule-level mechanisms of miR-29b-3p inpapillary thyroid carcinoma (PTC) remain unclear.MethodsThe expression of miR-29b-3p in PTC samples was tested via qRT-PCR. Cellular proliferation was analyzed by CCK-8 and EdU assays, and cellular migratory and invasive abilities were assessed utilizing wound-healing and Transwell assays. In addition, protein expressions of COL1A1, COL5A1, E-cadherin, N-cadherin, Snail, and Vimentin were identified via Western blot (WB) assay. Bioinformatics, qRT-PCR, WB, and dual luciferase reporter assays were completed to identify whether miR-29b-3p targeted COL1A1 and COL5A1. In addition, our team explored the treatment effects of miR-29b-3p on a murine heterograft model.ResultsOur findings revealed that miR-29b-3p proved much more regulated downward in PTC tissue specimens than in adjacent non-cancerous tissues. Meanwhile, decreased expression of miR-29b-3p was strongly related to the TNM stage of PTC patients (p<0.001), while overexpression of miR-29b-3p in PTC cells suppressed cellular migration, invasion, proliferation, and EMT. Conversely, silencing miR-29b-3p yielded the opposite effect. COL1A1 and COL5A1 were affirmed as the target of miR-29b-3p. Additionally, the COL1A1 and COL5A1 were highly expressed in PTC tumor samples than in contrast to neighboring healthy samples. Functional assays revealed that overexpression of COL1A1 or COL5A1 reversed the suppressive role of miR-29b-3p in migration, invasion, and EMT of PTC cells. Finally, miR-29b-3p agomir treatment dramatically inhibited Xenograft tumor growth in the animal model.ConclusionsThese findings document that miR-29b-3p inhibited PTC cells invasion and metastasis by targeting COL1A1 and COL5A1; this study also sparks new ideas for risk assessment and miRNA replacement therapy in PTC.

Project description:It has been revealed from microarray data analysis that long intergenic non‑coding RNA 02454 (LINC02454) is highly expressed in papillary thyroid cancer (PTC). The aim of the present study was to explore the potential role of LINC02454 in the tumorigenesis of PTC. The mRNA expression levels of LINC02454 were assessed using data from The Cancer Genome Atlas (TCGA) and the GSE66783 cohort in thyroid cancer, and were validated using reverse transcription‑quantitative PCR in 104 patients with PTC recruited in the present study. The association between the LINC02454 mRNA expression levels and the clinicopathological features of the 104 patients with PTC were also analyzed. Functional enrichment analyses were conducted on the differentially expressed genes in the high and low LINC02454 expression groups that were identified from the TCGA cohort. RNA interference, using short interfering (si)RNA against LINC02454, was used to investigate the role of LINC02454 in the biological functions of PTC cells in vitro. The expression level of LINC02454 was significantly increased in PTC tissues (P=0.0011) and was significantly associated with a larger tumor size, T stage, an advanced TNM stage and an increased lymph node metastasis (P<0.05), which was consistent with that in the TCGA and GSE66783 cohort. High expression levels of LINC02454 were observed in patients with PTC that also had BRAF mutations (P<0.001), and were significantly associated with a poorer disease‑free survival in the TCGA cohort (P<0.05). Functional enrichment analysis indicated that LINC02454‑related genes were significantly enriched in Gene Ontology terms, such as 'positive regulation of cell proliferation', 'positive regulation of cell division' and 'cell adhesion', and the following Kyoto Encyclopedia of Genes and Genomes pathways: 'Pathways in cancer' 'proteoglycans in cancer' and 'ECM‑receptor interaction'. In vitro, the knockdown of LINC02454 markedly arrested the cells in the G0/G1 phase of the cell cycle, and also led to an overall increase in apoptosis, as well as to an unexpected decrease in cell proliferation. LINC02454 may thus potentially function as an oncogene, which inhibits the apoptosis and enhances proliferation of PTC cells. Thus, as suggested by the findings of the present study, LINC02454 may be used as a diagnostic and prognostic biomarker for PTC in the future.

Dataset Information

Long non-coding (lnc)RNA PAPAS overexpression inhibits tumor growth in papillary thyroid carcinoma by downregulating lncRNA HOTTIP.

Publications

Long non-coding (lnc)RNA PAPAS overexpression inhibits tumor growth in papillary thyroid carcinoma by downregulating lncRNA HOTTIP.

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