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Open Access 01-12-2019 | Colorectal Cancer | Primary research

Expression profile analysis of two antisense lncRNAs to improve prognosis prediction of colorectal adenocarcinoma

Authors: Milad Shademan, Azam Naseri Salanghuch, Khadijeh Zare, Morteza Zahedi, Mohammad Ali Foroughi, Kambiz Akhavan Rezayat, Hooman Mosannen Mozaffari, Kamran Ghaffarzadegan, Ladan Goshayeshi, Hesam Dehghani

Published in: Cancer Cell International | Issue 1/2019

Abstract

Background

Long noncoding RNAs (lncRNAs) are involved in different pathogenesis pathways including cancer pathogenesis. The adenoma-carcinoma pathway in colorectal cancer may involve the aberrant and variable gene expression of regulatory RNAs. This study was conducted to analyse the expression and prognosis prediction ability of two natural antisense transcripts, protein kinase C theta antisense RNA 1 (PRKCQ-AS1), and special AT-rich sequence binding protein 1 antisense RNA 1 (SATB1-AS1) in colorectal low-grade adenoma, advanced adenoma, and adenocarcinomas.

Methods

In this study, from two RNA-seq analyses of CCAT1-ko cells and colorectal carcinoma biopsies having diminished and increased levels of CCAT1 transcription, respectively, we nominated two antisense lncRNAs of PRKCQ-AS1 and SATB1-AS1. Samples from colorectal low-grade adenomas, advanced adenomas, adenocarcinomas, and adjacent tissue were subjected to RT-qPCR to determine the expression of PRKCQ-AS1, SATB1-AS1 along with colon cancer-associated transcript 1 (CCAT1) and cMYC. In addition, we used different bioinformatics analyses and webservers (including GEPIA 2, TCGA, and CancerMine) to elucidate the prognosis prediction value, the expression correlation of sense–antisense pair of genes, and the expression profile of these antisense transcripts at the presence or absence of mutations in the driver genes, or the corresponding sense genes.

Results

PRKCQ-AS1 showed a wide range of expression levels in colorectal adenoma, advanced adenoma, and adenocarcinoma. Upregulation of PRKCQ-AS1 was related to a significant decrease in survival of colorectal cancer (CRC) patients. The expression levels of PRKCQ-AS1 and PRKCQ were strong and significantly concordant in normal and cancerous colorectal tissues. While SATB1-AS1 showed a wide range of expression in colorectal adenoma, advanced adenoma, and adenocarcinoma as well, its expression was not related to a decrease in survival of CRC patients. The expression levels of SATB1-AS1 and SATB1 (the sense gene) were not strong in normal colorectal tissues. In addition, where SATB1 gene was mutated, the expression of SATB1-AS1 was significantly downregulated.

Conclusions

We found the expression of PRKCQ-AS1 and SATB1-AS1 at a given stage of CRC very variable, and not all biopsy samples showed the increased expression of these antisense transcripts. PRKCQ-AS1 in contrast to SATB1-AS1 showed a significant prognostic value. Since a significantly concordant expression was observed for SATB1-AS1 and SATB1 in only cancerous, and for PRKCQ-AS1 and PRKCQ in both normal and cancerous colorectal tissues, it can be concluded that common mechanisms may regulate the expression of these sense and antisense genes.

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Yao RW, Wang Y, Chen LL. Cellular functions of long noncoding RNAs. Nat Cell Biol. 2019;21(5):542–51. https://doi.org/10.1038/s41556-019-0311-8.CrossRefPubMed

Burnett-Hartman AN, Newcomb PA, Hutter CM, Peters U, Passarelli MN, Schwartz MR, et al. Variation in the association between colorectal cancer susceptibility loci and colorectal polyps by polyp type. Am J Epidemiol. 2014;180(2):223–32. https://doi.org/10.1093/aje/kwu114.CrossRefPubMedPubMedCentral

Wang XQD, Dostie J. Chromosome folding and its regulation in health and disease. Curr Opin Genet Dev. 2017;43:23–30. https://doi.org/10.1016/j.gde.2016.10.006.CrossRefPubMed

Balbin OA, Malik R, Dhanasekaran SM, Prensner JR, Cao X, Wu YM, et al. The landscape of antisense gene expression in human cancers. Genome Res. 2015;25(7):1068–79. https://doi.org/10.1101/gr.180596.114.CrossRefPubMedPubMedCentral

Feinberg AP. The key role of epigenetics in human disease prevention and mitigation. N Engl J Med. 2018;378(14):1323–34. https://doi.org/10.1056/NEJMra1402513.CrossRefPubMed

Abedini P, Fattahi A, Agah S, Talebi A, Beygi AH, Amini SM, et al. Expression analysis of circulating plasma long noncoding RNAs in colorectal cancer: the relevance of lncRNAs ATB and CCAT1 as potential clinical hallmarks. J Cell Physiol. 2019. https://doi.org/10.1002/jcp.28765.CrossRefPubMed

Li Y, Jing F, Ding Y, He Q, Zhong Y, Fan C. Long noncoding RNA CCAT1 polymorphisms are associated with the risk of colorectal cancer. Cancer Genet. 2018;222–223:13–9. https://doi.org/10.1016/j.cancergen.2018.02.003.CrossRefPubMed

Ozawa T, Matsuyama T, Toiyama Y, Takahashi N, Ishikawa T, Uetake H, et al. CCAT1 and CCAT2 long noncoding RNAs, located within the 8q.24.21 ‘gene desert’, serve as important prognostic biomarkers in colorectal cancer. Ann Oncol. 2017;28(8):1882–8. https://doi.org/10.1093/annonc/mdx248.CrossRefPubMedPubMedCentral

Zhao W, Song M, Zhang J, Kuerban M, Wang H. Combined identification of long non-coding RNA CCAT1 and HOTAIR in serum as an effective screening for colorectal carcinoma. Int J Clin Exp Pathol. 2015;8(11):14131–40.PubMedPubMedCentral

10.

McCleland ML, Mesh K, Lorenzana E, Chopra VS, Segal E, Watanabe C, et al. CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016;126(2):639–52. https://doi.org/10.1172/JCI83265.CrossRefPubMedPubMedCentral

11.

Ye Z, Zhou M, Tian B, Wu B, Li J. Expression of lncRNA-CCAT1, E-cadherin and N-cadherin in colorectal cancer and its clinical significance. Int J Clin Exp Med. 2015;8(3):3707–15.PubMedPubMedCentral

12.

Xiang JF, Yin QF, Chen T, Zhang Y, Zhang XO, Wu Z, et al. Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res. 2014;24(5):513–31. https://doi.org/10.1038/cr.2014.35.CrossRefPubMedPubMedCentral

13.

Ren T, Hou J, Liu C, Shan F, Xiong X, Qin A, et al. The long non-coding RNA HOTAIRM1 suppresses cell progression via sponging endogenous miR-17-5p/ B-cell translocation gene 3 (BTG3) axis in 5-fluorouracil resistant colorectal cancer cells. Biomed Pharmacother. 2019;117:109171. https://doi.org/10.1016/j.biopha.2019.109171.CrossRefPubMed

14.

Wan L, Kong J, Tang J, Wu Y, Xu E, Lai M, et al. HOTAIRM1 as a potential biomarker for diagnosis of colorectal cancer functions the role in the tumour suppressor. J Cell Mol Med. 2016;20(11):2036–44. https://doi.org/10.1111/jcmm.12892.CrossRefPubMedPubMedCentral

15.

Parsons BL. Multiclonal tumor origin: evidence and implications. Mutat Res. 2018;777:1–18. https://doi.org/10.1016/j.mrrev.2018.05.001.CrossRefPubMed

16.

Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):e45. https://doi.org/10.1093/nar/29.9.e45.CrossRefPubMedPubMedCentral

17.

Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47(W1):W556–60. https://doi.org/10.1093/nar/gkz430.CrossRefPubMedPubMedCentral

18.

Dastsooz H, Cereda M, Donna D, Oliviero S. A comprehensive bioinformatics analysis of UBE2C in Cancers. Int J Mol Sci. 2019. https://doi.org/10.3390/ijms20092228.CrossRefPubMedPubMedCentral

19.

Lever J, Zhao EY, Grewal J, Jones MR, Jones SJM. CancerMine: a literature-mined resource for drivers, oncogenes and tumor suppressors in cancer. Nat Methods. 2019;16(6):505–7. https://doi.org/10.1038/s41592-019-0422-y.CrossRefPubMed

20.

Zare K, Shademan M, Ghahramani Seno MM, Dehghani H. CRISPR/Cas9 knockout strategies to Ablate CCAT1 lncRNA gene in cancer cells. Biol Proced Online. 2018;20:21. https://doi.org/10.1186/s12575-018-0086-5.CrossRefPubMedPubMedCentral

21.

Milevskiy MJ, Al-Ejeh F, Saunus JM, Northwood KS, Bailey PJ, Betts JA, et al. Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer. Hum Mol Genet. 2016;25(15):3269–83. https://doi.org/10.1093/hmg/ddw177.CrossRefPubMedPubMedCentral

22.

Xiao Z, Qu Z, Chen Z, Fang Z, Zhou K, Huang Z, et al. LncRNA HOTAIR is a prognostic biomarker for the proliferation and chemoresistance of colorectal cancer via MiR-203a-3p-mediated Wnt/ss-catenin signaling pathway. Cell Physiol Biochem. 2018;46(3):1275–85. https://doi.org/10.1159/000489110.CrossRefPubMed

23.

Zhang Y, Yu S, Jiang L, Wang X, Song X. HOTAIR is a promising novel biomarker in patients with thyroid cancer. Exp Ther Med. 2017;13(5):2274–8. https://doi.org/10.3892/etm.2017.4231.CrossRefPubMedPubMedCentral

24.

Xie Z, Chen X, Li J, Guo Y, Li H, Pan X, et al. Salivary HOTAIR and PVT1 as novel biomarkers for early pancreatic cancer. Oncotarget. 2016;7(18):25408–19. https://doi.org/10.18632/oncotarget.8323.CrossRefPubMedPubMedCentral

25.

Elsayed ET, Salem PE, Darwish AM, Fayed HM. Plasma long non-coding RNA HOTAIR as a potential biomarker for gastric cancer. Int J Biol Markers. 2018. https://doi.org/10.1177/1724600818760244.CrossRefPubMed

26.

Mimori K, Saito T, Niida A, Miyano S. Cancer evolution and heterogeneity. Ann Gastroenterol Surg. 2018;2(5):332–8. https://doi.org/10.1002/ags3.12182.CrossRefPubMedPubMedCentral

27.

Wanowska E, Kubiak MR, Rosikiewicz W, Makalowska I, Szczesniak MW. Natural antisense transcripts in diseases: From modes of action to targeted therapies. Wiley Interdiscip Rev RNA. 2018. https://doi.org/10.1002/wrna.1461.CrossRefPubMedPubMedCentral

28.

Goyal A, Fiskin E, Gutschner T, Polycarpou-Schwarz M, Gross M, Neugebauer J, et al. A cautionary tale of sense-antisense gene pairs: independent regulation despite inverse correlation of expression. Nucleic Acids Res. 2017;45(21):12496–508. https://doi.org/10.1093/nar/gkx952.CrossRefPubMedPubMedCentral

Title: Expression profile analysis of two antisense lncRNAs to improve prognosis prediction of colorectal adenocarcinoma
Authors: Milad Shademan
Azam Naseri Salanghuch
Khadijeh Zare
Morteza Zahedi
Mohammad Ali Foroughi
Kambiz Akhavan Rezayat
Hooman Mosannen Mozaffari
Kamran Ghaffarzadegan
Ladan Goshayeshi
Hesam Dehghani
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI: https://doi.org/10.1186/s12935-019-1000-1

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