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Molecular Cancer
Published in: Molecular Cancer 1/2019

Open Access 01-12-2019 | Colorectal Cancer | Research

m6A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1

Authors: Yingmin Wu, Xiangling Yang, Zhuojia Chen, Lin Tian, Guanmin Jiang, Feng Chen, Jiexin Li, Panpan An, Linlin Lu, Nan Luo, Jun Du, Hong Shan, Huanliang Liu, Hongsheng Wang

Published in: Molecular Cancer | Issue 1/2019

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Abstract

Background

Long noncoding RNAs (lncRNAs) have emerged as critical players in cancer progression, but their functions in colorectal cancer (CRC) metastasis have not been systematically clarified.

Methods

lncRNA expression profiles in matched normal and CRC tissue were checked using microarray analysis. The biological roles of a novel lncRNA, namely RP11-138 J23.1 (RP11), in development of CRC were checked both in vitro and in vivo. Its association with clinical progression of CRC was further analyzed.

Results

RP11 was highly expressed in CRC tissues, and its expression increased with CRC stage in patients. RP11 positively regulated the migration, invasion and epithelial mesenchymal transition (EMT) of CRC cells in vitro and enhanced liver metastasis in vivo. Post-translational upregulation of Zeb1, an EMT-related transcription factor, was essential for RP11-induced cell dissemination. Mechanistically, the RP11/hnRNPA2B1/mRNA complex accelerated the mRNA degradation of two E3 ligases, Siah1 and Fbxo45, and subsequently prevented the proteasomal degradation of Zeb1. m6A methylation was involved in the upregulation of RP11 by increasing its nuclear accumulation. Clinical analysis showed that m6A can regulate the expression of RP11, further, RP11 regulated Siah1-Fbxo45/Zeb1 was involved in the development of CRC.

Conclusions

m6A-induced lncRNA RP11 can trigger the dissemination of CRC cells via post-translational upregulation of Zeb1. Considering the high and specific levels of RP11 in CRC tissues, our present study paves the way for further investigations of RP11 as a predictive biomarker or therapeutic target for CRC.
Appendix
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Literature
1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.CrossRef
2.
Van Cutsem E, Cervantes A, Nordlinger B, Arnold D. Metastatic colorectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii1–9.CrossRef
3.
Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology. 2010;138:2088–100.CrossRef
4.
Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013;152:1298–307.CrossRef
5.
Kopp F, Mendell JT. Functional classification and experimental dissection of long noncoding RNAs. Cell. 2018;172:393–407.CrossRef
6.
Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.CrossRef
7.
Ma Y, Yang Y, Wang F, Moyer MP, Wei Q, Zhang P, Yang Z, Liu W, Zhang H, Chen N, et al. Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/beta-catenin signalling pathway via suppression of activator protein 2alpha. Gut. 2016;65:1494–504.CrossRef
8.
Ling H, Spizzo R, Atlasi Y, Nicoloso M, Shimizu M, Redis RS, Nishida N, Gafa R, Song J, Guo Z, et al. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res. 2013;23:1446–61.CrossRef
9.
Xiang JF, Yin QF, Chen T, Zhang Y, Zhang XO, Wu Z, Zhang S, Wang HB, Ge J, Lu X, et al. Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res. 2014;24:513–31.CrossRef
10.
Taniue K, Kurimoto A, Takeda Y, Nagashima T, Okada-Hatakeyama M, Katou Y, Shirahige K, Akiyama T. ASBEL-TCF3 complex is required for the tumorigenicity of colorectal cancer cells. Proc Natl Acad Sci U S A. 2016;113:12739–44.CrossRef
11.
Punt CJ, Koopman M, Vermeulen L. From tumour heterogeneity to advances in precision treatment of colorectal cancer. Nat Rev Clin Oncol. 2017;14:235–46.CrossRef
12.
Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.CrossRef
13.
Craene BD, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97–110.CrossRef
14.
Varga J, Greten FR. Cell plasticity in epithelial homeostasis and tumorigenesis. Nat Cell Biol. 2017;19:1133–41.CrossRef
15.
Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014;16:488–94.CrossRef
16.
Wang YH, Bu F, Royer C, Serres S, Larkin JR, Soto MS, Sibson NR, Salter V, Fritzsche F, Turnquist C, et al. ASPP2 controls epithelial plasticity and inhibits metastasis through beta-catenin-dependent regulation of ZEB1. Nat Cell Biol. 2014;16:1092–104.CrossRef
17.
Krebs AM, Mitschke J, Lasierra Losada M, Schmalhofer O, Boerries M, Busch H, Boettcher M, Mougiakakos D, Reichardt W, Bronsert P, et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol. 2017;19:518–29.CrossRef
18.
Mitra R, Chen X, Greenawalt EJ, Maulik U, Jiang W, Zhao ZM, Eischen CM. Decoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition. Nat Commun. 2017;8:1604.
19.
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98–W102.CrossRef
20.
Hong Y, Downey T, Eu KW, Koh PK, Cheah PY. A 'metastasis-prone' signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Clin Exp Metastasis. 2010;27:83–90.CrossRef
21.
Skrzypczak M, Goryca K, Rubel T, Paziewska A, Mikula M, Jarosz D, Pachlewski J, Oledzki J, Ostrowski J. Modeling oncogenic signaling in colon tumors by multidirectional analyses of microarray data directed for maximization of analytical reliability. PLoS One. 2010;5:e13091.CrossRef
22.
Vasaikar SV, Straub P, Wang J, Zhang B. LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res. 2018;46:D956–63.CrossRef
23.
Huang JF, Guo YJ, Zhao CX, Yuan SX, Wang Y, Tang GN, Zhou WP, Sun SH. Hepatitis B virus X protein (HBx)-related long noncoding RNA (lncRNA) down-regulated expression by HBx (Dreh) inhibits hepatocellular carcinoma metastasis by targeting the intermediate filament protein vimentin. Hepatology. 2013;57:1882–92.CrossRef
24.
Kvaratskhelia M, Grice SF. Structural analysis of protein-RNA interactions with mass spectrometry. Methods Mol Biol. 2008;488:213–9.CrossRef
25.
Huarte M. The emerging role of lncRNAs in cancer. Nat Med. 2015;21:1253–61.CrossRef
26.
Joung J, Engreitz JM, Konermann S, Abudayyeh OO, Verdine VK, Aguet F, Gootenberg JS, Sanjana NE, Wright JB, Fulco CP, et al. Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood. Nature. 2017;548:343–6.CrossRef
27.
Davis FM, Stewart TA, Thompson EW, Monteith GR. Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol Sci. 2014;35:479–88.CrossRef
28.
Singh AB, Sharma A, Smith JJ, Krishnan M, Chen X, Eschrich S, Washington MK, Yeatman TJ, Beauchamp RD, Dhawan P. Claudin-1 up-regulates the repressor ZEB-1 to inhibit E-cadherin expression in colon cancer cells. Gastroenterology. 2011;141:2140–53.CrossRef
29.
Zhang P, Wei Y, Wang L, Debeb BG, Yuan Y, Zhang J, Yuan J, Wang M, Chen D, Sun Y, et al. ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1. Nat Cell Biol. 2014;16:864–75.CrossRef
30.
Liu B, Sun L, Liu Q, Gong C, Yao Y, Lv X, Lin L, Yao H, Su F, Li D, et al. A cytoplasmic NF-kappaB interacting long noncoding RNA blocks IkappaB phosphorylation and suppresses breast cancer metastasis. Cancer Cell. 2015;27:370–81.CrossRef
31.
Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.CrossRef
32.
Lan X, Yan J, Ren J, Zhong B, Li J, Li Y, Liu L, Yi J, Sun Q, Yang X, et al. A novel long noncoding RNA Lnc-HC binds hnRNPA2B1 to regulate expressions of Cyp7a1 and Abca1 in hepatocytic cholesterol metabolism. Hepatology. 2016;64:58–72.CrossRef
33.
Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 2017;18:31–42.CrossRef
34.
Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell. 2017;169:1187–200.CrossRef
35.
Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10:93–5.CrossRef
36.
Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014;24:177–89.CrossRef
37.
Alarcon CR, Goodarzi H, Lee H, Liu XH, Tavazoie S, Tavazoie SF. HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell. 2015;162:1299–308.CrossRef
38.
Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, Liu F, Pan W, Wang TT, Zhou CC, et al. A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25:666–81.CrossRef
39.
Prensner JR, Iyer MK, Sahu A, Asangani IA, Cao Q, Patel L, Vergara IA, Davicioni E, Erho N, Ghadessi M, et al. The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet. 2013;45:1392–8.CrossRef
40.
Damas ND, Marcatti M, Come C, Christensen LL, Nielsen MM, Baumgartner R, Gylling HM, Maglieri G, Rundsten CF, Seemann SE, et al. SNHG5 promotes colorectal cancer cell survival by counteracting STAU1-mediated mRNA destabilization. Nat Commun. 2016;7:13875.CrossRef
41.
Wang LH, Bu PC, Ai YW, Srinivasan T, Chen HJ, Xiang K, Lipkin SM, Shen XL. A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division. Elife. 2016;5:e14620.
42.
Grelet S, Link LA, Howley B, Obellianne C, Palanisamy V, Gangaraju VK, Diehl JA, Howe PH. A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression. Nat Cell Biol. 2017;19:1105–15.CrossRef
43.
Su L, Luo YL, Yang Z, Yang J, Yao C, Cheng FF, Shan JJ, Chen J, Li FF, Liu LM, et al. MEF2D transduces microenvironment stimuli to ZEB1 to promote epithelial-mesenchymal transition and metastasis in colorectal Cancer. Cancer Res. 2016;76:5054–67.CrossRef
44.
Xu M, Zhu C, Zhao X, Chen C, Zhang H, Yuan H, Deng R, Dou J, Wang Y, Huang J, et al. Atypical ubiquitin E3 ligase complex Skp1-pam-Fbxo45 controls the core epithelial-to-mesenchymal transition-inducing transcription factors. Oncotarget. 2015;6:979–94.PubMed
45.
Chen A, Wong CSF, Liu MCP, House CM, Sceneay J, Bowtell DD, Thompson EW, Moller A. The ubiquitin ligase Siah is a novel regulator of Zeb1 in breast cancer. Oncotarget. 2015;6:862–73.PubMed
46.
Zhao XY, Li S, Wang GX, Yu Q, Lin JD. A long noncoding RNA transcriptional regulatory circuit drives thermogenic adipocyte differentiation. Mol Cell. 2014;55:372–82.CrossRef
47.
Wang H, Liang L, Dong Q, Huan L, He J, Li B, Yang C, Jin H, Wei L, Yu C, et al. Long noncoding RNA miR503HG, a prognostic indicator, inhibits tumor metastasis by regulating the HNRNPA2B1/NF-kappaB pathway in hepatocellular carcinoma. Theranostics. 2018;8:2814–29.CrossRef
48.
Ng SY, Bogu GK, Soh BS, Stanton LW. The long noncoding RNA RMST interacts with SOX2 to regulate neurogenesis. Mol Cell. 2013;51:349–59.CrossRef
49.
Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bogler O, et al. m6A demethylase ALKBH5 maintains Tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31:591–606 e596.CrossRef
50.
Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, Huang H, Nachtergaele S, Dong L, Hu C, et al. FTO plays an oncogenic role in acute myeloid leukemia as a N6-Methyladenosine RNA demethylase. Cancer Cell. 2017;31:127–41.CrossRef
51.
Yang D, Qiao J, Wang G, Lan Y, Li G, Guo X, Xi J, Ye D, Zhu S, Chen W, et al. N6-Methyladenosine modification of lincRNA 1281 is critically required for mESC differentiation potential. Nucl Acid Res. 2018;46:3906–20.CrossRef
52.
Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015;518:560–4.CrossRef
53.
Mann M, Wright PR, Backofen R. IntaRNA 2.0: enhanced and customizable prediction of RNA-RNA interactions. Nucl Acid Res. 2017;45:W435–9.CrossRef
Metadata
Title
m6A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1
Authors
Yingmin Wu
Xiangling Yang
Zhuojia Chen
Lin Tian
Guanmin Jiang
Feng Chen
Jiexin Li
Panpan An
Linlin Lu
Nan Luo
Jun Du
Hong Shan
Huanliang Liu
Hongsheng Wang
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2019
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-019-1014-2

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