Promoter Hypomethylation and Increased Expression of the Long Non-coding RNA LINC00152 Support Colorectal Carcinogenesis
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ORIGINAL ARTICLE
Promoter Hypomethylation and Increased Expression of the Long Non-coding RNA LINC00152 Support Colorectal Carcinogenesis Orsolya Galamb 1,2 & Alexandra Kalmár 1,2 & Anna Sebestyén 3 & Titanilla Dankó 3 & Csilla Kriston 3 & István Fűri 1 & Péter Hollósi 3 & István Csabai 4 & Barnabás Wichmann 1,2 & Tibor Krenács 3 & Barbara Kinga Barták 1 & Zsófia Brigitta Nagy 1 & Sára Zsigrai 1 & Gábor Barna 3 & Zsolt Tulassay 2 & Péter Igaz 1,2 & Béla Molnár 1,2 Received: 18 September 2019 / Accepted: 27 February 2020 # The Author(s) 2020
Abstract Up-regulation of the long non-coding RNA LINC00152 can contribute to cancer development, proliferation and invasion, including colorectal cancer, however, its mechanism of action in colorectal carcinogenesis and progression is only insufficiently understood. In this work we correlated LINC00152 expression with promoter DNA methylation changes in colorectal tissues along the normal-adenoma-carcinoma sequence and studied the effects of LINC00152 silencing on the cell cycle regulation and on the whole transcriptome in colon carcinoma cells using cell and molecular biology techniques. LINC00152 was significantly up-regulated in adenoma and colorectal cancer (p < 0.001) compared to normal samples, which was confirmed by real-time PCR and in situ hybridization. LINC00152 promoter hypomethylation detected in colorectal cancer (p < 0.01) was strongly correlated with increased LINC00152 expression (r=-0.90). Silencing of LINC00152 significantly suppressed cell growth, induced apoptosis and decreased cyclin D1 expression (p < 0.05). Whole transcriptome analysis of LINC00152-silenced cells revealed significant down-regulation of oncogenic and metastasis promoting genes (e.g. YES proto-oncogene 1, PORCN porcupine Oacyltransferase), and up-regulation of tumour suppressor genes (e.g. DKK1 dickkopf WNT signalling pathway inhibitor 1, PERP p53 apoptosis effector) (adjusted p < 0.05). Pathway analysis confirmed the LINC00152-related activation of oncogenic molecular pathways including those driven by PI3K/Akt, Ras, WNT, TP53, Notch and ErbB. Our results suggest that promoter hypomethylation related overexpression of LINC00152 can contribute to the pathogenesis of colorectal cancer by facilitating cell progression through the up-regulation of several oncogenic and metastasis promoting pathway elements. Keywords LINC00152 . CYTOR . Long non-coding RNA . Colorectal cancer . Colorectal adenoma
Orsolya Galamb and Alexandra Kalmár contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12253-020-00800-8) contains supplementary material, which is available to authorized users. * Orsolya Galamb [email protected] 1
2nd Department of Internal Medicine, Semmelweis University, Szentkirályi str 46, 1088 Budapest, Hungary
2
MTA-SE Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
3
1st Department of Pathology and Experimental Cancer Res
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