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Promoter Hypomethylation and Increased Expression of the Long Non-coding RNA LINC00152 Support Colorectal Carcinogenesis
Pathology & Oncology Research ( IF 2.3 ) Pub Date : 2020-04-20 , DOI: 10.1007/s12253-020-00800-8
Orsolya Galamb , Alexandra Kalmár , Anna Sebestyén , Titanilla Dankó , Csilla Kriston , István Fűri , Péter Hollósi , István Csabai , Barnabás Wichmann , Tibor Krenács , Barbara Kinga Barták , Zsófia Brigitta Nagy , Sára Zsigrai , Gábor Barna , Zsolt Tulassay , Péter Igaz , Béla Molnár

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 O-acyltransferase), 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.



中文翻译:

启动子低甲基化和长非编码RNA LINC00152的表达增加支持大肠癌发生。

长的非编码RNA LINC00152的上调可能有助于癌症的发展,增殖和侵袭,包括结直肠癌,但是,其在结直肠癌发生和发展中的作用机理尚不清楚。在这项工作中,我们将LINC00152的表达与沿正常腺瘤-癌序列的大肠组织中启动子DNA甲基化变化相关联,并使用细胞和分子生物学技术研究了LINC00152沉默对结肠癌细胞的细胞周期调控和整个转录组的影响。与正常样品相比,LINC00152在腺瘤和结直肠癌中显着上调(p <0.001),这通过实时PCR和原位证实杂交。在大肠癌中检测到的LINC00152启动子低甲基化(p <0.01)与LINC00152表达增加密切相关(r = -0.90)。LINC00152的沉默可显着抑制细胞生长,诱导凋亡并降低细胞周期蛋白D1表达(p <0.05)。对LINC00152沉默的细胞进行的整个转录组分析显示,显着下调了致癌和转移促进基因(例如YES原癌基因1,PORCN豪猪O-酰基转移酶),并上调了抑癌基因(例如DKK1 dickkopf WNT信号通路抑制剂1,PERP p53凋亡效应子)(调整后的p <0.05)。途径分析证实了LINC00152相关的致癌分子途径的激活,包括PI3K / Akt,Ras,WNT,TP53,Notch和ErbB驱动的那些。

更新日期:2020-04-22
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