Microarray expression profile analysis of long non-coding RNAs in pancreatic ductal adenocarcinoma

  • Authors:
    • Yu Zhou
    • Bo Gong
    • Zhi-Lin Jiang
    • Shan Zhong
    • Xing-Chao Liu
    • Ke Dong
    • He-Shui Wu
    • Hong-Ji Yang
    • Shi-Kai Zhu
  • View Affiliations

  • Published online on: December 15, 2015     https://doi.org/10.3892/ijo.2015.3292
  • Pages: 670-680
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Abstract

Long non-coding RNA (lncRNA) is a variety of the human transcriptome that does not code for proteins and plays an important role in the development and progression of multiple solid malignant tumors. However, the roles of lncRNAs in the development of pancreatic ductal adenocarcinoma (PDAC) remain unknown. In this study, we investigated the expression patterns of lncRNAs in three PDAC tumor samples (T) relative to those of matched adjacent non-tumor tissues (N) via a microarray with 30,586 lncRNA probes and 26,109 mRNA probes. The lncRNA microarray revealed 27,279 lncRNAs in PDAC samples, of which 2,331 were significantly upregulated (P<0.05; T/N>2.0) and 1,641 were downregulated (P<0.05; N/T>2.0) compared with matched adjacent non-tumor samples. In addition, 19,995 mRNAs were detected, of which 1,676 were significantly upregulated (P<0.05; T/N>2.0) and 1,981 were downregulated (P<0.05; N/T>2.0). Pathway analysis indicated that 41 pathways corresponded to upregulated transcripts and 25 pathways corresponded to downregulated transcripts (P-value cut-off is 0.05). Gene ontology (GO) analysis showed that the highest enriched GOs targeted by upregulated and downregulated transcripts were tissue homeostasis. The validation results from quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis and microarray analysis were consistent. Furthermore, the expression level of long intergenic non-coding RNA HOTAIRM1 was upregulated in 12 PDAC tissues samples compared with matched adjacent non-tumor samples by qRT-PCR. The results showed that the lncRNA and mRNA expression profiles differed significantly between the PDAC tissues and their adjacent non-tumor tissues, and the revelation of an association between HOTAIRM1 expression and PDAC is especially noteworthy. These findings may provide new potential molecular markers for diagnosis and treatment of PDAC.

References

1 

Kazanjian KK, Hines OJ, Duffy JP, Yoon DY, Cortina G and Reber HA: Improved survival following pancreaticoduodenectomy to treat adenocarcinoma of the pancreas: The influence of operative blood loss. Arch Surg. 143:1166–1171. 2008. View Article : Google Scholar : PubMed/NCBI

2 

Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, et al: Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial. JAMA. 310:1473–1481. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Yang J, Li J, Zhu R, Zhang H, Zheng Y, Dai W, Wang F, Shen M, Chen K, Cheng P, et al: K-ras mutational status in cytohistological tissue as a molecular marker for the diagnosis of pancreatic cancer: A systematic review and meta-analysis. Dis Markers. 2014:5737832014. View Article : Google Scholar : PubMed/NCBI

4 

Cowan RW and Maitra A: Genetic progression of pancreatic cancer. Cancer J. 20:80–84. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Dempe S, Stroh-Dege AY, Schwarz E, Rommelaere J and Dinsart C: SMAD4: A predictive marker of PDAC cell permissiveness for oncolytic infection with parvovirus H-1PV. Int J Cancer. 126:2914–2927. 2010.

6 

Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, et al: MicroRNA expression profiles classify human cancers. Nature. 435:834–838. 2005. View Article : Google Scholar : PubMed/NCBI

7 

Ho AS, Huang X, Cao H, Christman-Skieller C, Bennewith K, Le QT and Koong AC: Circulating miR-210 as a novel hypoxia marker in pancreatic cancer. Transl Oncol. 3:109–113. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Kawaguchi T, Komatsu S, Ichikawa D, Morimura R, Tsujiura M, Konishi H, Takeshita H, Nagata H, Arita T, Hirajima S, et al: Clinical impact of circulating miR-221 in plasma of patients with pancreatic cancer. Br J Cancer. 108:361–369. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Ponting CP, Oliver PL and Reik W: Evolution and functions of long noncoding RNAs. Cell. 136:629–641. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Tay Y, Karreth FA and Pandolfi PP: Aberrant ceRNA activity drives lung cancer. Cell Res. 24:259–260. 2014. View Article : Google Scholar : PubMed/NCBI

11 

Salmena L, Poliseno L, Tay Y, Kats L and Pandolfi PP: A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language? Cell. 146:353–358. 2011. View Article : Google Scholar : PubMed/NCBI

12 

Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, et al: The landscape of somatic copy-number alteration across human cancers. Nature. 463:899–905. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N and Stratton MR: A census of human cancer genes. Nat Rev Cancer. 4:177–183. 2004. View Article : Google Scholar : PubMed/NCBI

14 

Stratton MR, Campbell PJ and Futreal PA: The cancer genome. Nature. 458:719–724. 2009. View Article : Google Scholar : PubMed/NCBI

15 

Nagano T and Fraser P: No-nonsense functions for long noncoding RNAs. Cell. 145:178–181. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Flynn RA and Chang HY: Active chromatin and noncoding RNAs: An intimate relationship. Curr Opin Genet Dev. 22:172–178. 2012. View Article : Google Scholar :

17 

Kung JT, Colognori D and Lee JT: Long noncoding RNAs: Past, present, and future. Genetics. 193:651–669. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Hung T and Chang HY: Long noncoding RNA in genome regulation: Prospects and mechanisms. RNA Biol. 7:582–585. 2010. View Article : Google Scholar : PubMed/NCBI

19 

Mercer TR, Dinger ME and Mattick JS: Long non-coding RNAs: Insights into functions. Nat Rev Genet. 10:155–159. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Jiang J, Jing Y, Cost GJ, Chiang JC, Kolpa HJ, Cotton AM, Carone DM, Carone BR, Shivak DA, Guschin DY, et al: Translating dosage compensation to trisomy 21. Nature. 500:296–300. 2013. View Article : Google Scholar : PubMed/NCBI

21 

Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT and Lee JT: Xist RNA is a potent suppressor of hematologic cancer in mice. Cell. 152:727–742. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Hajjari M and Salavaty A: HOTAIR: An oncogenic long non-coding RNA in different cancers. Cancer Biol Med. 12:1–9. 2015.PubMed/NCBI

23 

Pang EJ, Yang R, Fu XB and Liu YF: Overexpression of long non-coding RNA MALAT1 is correlated with clinical progression and unfavorable prognosis in pancreatic cancer. Tumour Biol. 36:2403–2407. 2015. View Article : Google Scholar

24 

Ding C, Yang Z, Lv Z, Du C, Xiao H, Peng C, Cheng S, Xie H, Zhou L, Wu J, et al: Long non-coding RNA PVT1 is associated with tumor progression and predicts recurrence in hepatocellular carcinoma patients. Oncol Lett. 9:955–963. 2015.PubMed/NCBI

25 

Yu M, Ting DT, Stott SL, Wittner BS, Ozsolak F, Paul S, Ciciliano JC, Smas ME, Winokur D, Gilman AJ, et al: RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature. 487:510–513. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Miyabayashi K, Ijichi H, Mohri D, Tada M, Yamamoto K, Asaoka Y, Ikenoue T, Tateishi K, Nakai Y, Isayama H, et al: Erlotinib prolongs survival in pancreatic cancer by blocking gemcitabine-induced MAPK signals. Cancer Res. 73:2221–2234. 2013. View Article : Google Scholar : PubMed/NCBI

27 

Jun S, Lee S, Kim HC, Ng C, Schneider AM, Ji H, Ying H, Wang H, DePinho RA and Park JI: PAF-mediated MAPK signaling hyperactivation via LAMTOR3 induces pancreatic tumorigenesis. Cell Rep. 5:314–322. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Zhang Y, Yan W, Collins MA, Bednar F, Rakshit S, Zetter BR, Stanger BZ, Chung I, Rhim AD and di Magliano MP: Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance. Cancer Res. 73:6359–6374. 2013. View Article : Google Scholar : PubMed/NCBI

29 

Boreddy SR, Pramanik KC and Srivastava SK: Pancreatic tumor suppression by benzyl isothiocyanate is associated with inhibition of PI3K/AKT/FOXO pathway. Clin Cancer Res. 17:1784–1795. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Roy SK, Chen Q, Fu J, Shankar S and Srivastava RK: Resveratrol inhibits growth of orthotopic pancreatic tumors through activation of FOXO transcription factors. PLoS One. 6:e251662011. View Article : Google Scholar : PubMed/NCBI

31 

Ma Y, Gu Y, Zhang Q, Han Y, Yu S, Lu Z and Chen J: Targeted degradation of KRAS by an engineered ubiquitin ligase suppresses pancreatic cancer cell growth in vitro and in vivo. Mol Cancer Ther. 12:286–294. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Hajjari M and Khoshnevisan A: Potential long non-coding RNAs to be considered as biomarkers or therapeutic targets in gastric cancer. Front Genet. 4:2102013. View Article : Google Scholar : PubMed/NCBI

33 

Huang L, Liao LM, Liu AW, Wu JB, Cheng XL, Lin JX and Zheng M: Overexpression of long noncoding RNA HOTAIR predicts a poor prognosis in patients with cervical cancer. Arch Gynecol Obstet. 290:717–723. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Panzitt K, Tschernatsch MM, Guelly C, Moustafa T, Stradner M, Strohmaier HM, Buck CR, Denk H, Schroeder R, Trauner M, et al: Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology. 132:330–342. 2007. View Article : Google Scholar : PubMed/NCBI

35 

Matouk IJ, Abbasi I, Hochberg A, Galun E, Dweik H and Akkawi M: Highly upregulated in liver cancer noncoding RNA is overexpressed in hepatic colorectal metastasis. Eur J Gastroenterol Hepatol. 21:688–692. 2009. View Article : Google Scholar : PubMed/NCBI

36 

Liu Y, Pan S, Liu L, Zhai X, Liu J, Wen J, Zhang Y, Chen J, Shen H and Hu Z: A genetic variant in long non-coding RNA HULC contributes to risk of HBV-related hepatocellular carcinoma in a Chinese population. PLoS One. 7:e351452012. View Article : Google Scholar : PubMed/NCBI

37 

Sun M, Jin FY, Xia R, Kong R, Li JH, Xu TP, Liu YW, Zhang EB, Liu XH and De W: Decreased expression of long noncoding RNA GAS5 indicates a poor prognosis and promotes cell proliferation in gastric cancer. BMC Cancer. 14:3192014. View Article : Google Scholar : PubMed/NCBI

38 

Renganathan A, Kresoja-Rakic J, Echeverry N, Ziltener G, Vrugt B, Opitz I, Stahel RA and Felley-Bosco E: GAS5 long non-coding RNA in malignant pleural mesothelioma. Mol Cancer. 13:1192014. View Article : Google Scholar : PubMed/NCBI

39 

Arita T, Ichikawa D, Konishi H, Komatsu S, Shiozaki A, Shoda K, Kawaguchi T, Hirajima S, Nagata H, Kubota T, et al: Circulating long non-coding RNAs in plasma of patients with gastric cancer. Anticancer Res. 33:3185–3193. 2013.PubMed/NCBI

40 

Xie H, Ma H and Zhou D: Plasma HULC as a promising novel biomarker for the detection of hepatocellular carcinoma. BioMed Res Int. 2013:1361062013. View Article : Google Scholar : PubMed/NCBI

41 

Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, et al: Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 129:1311–1323. 2007. View Article : Google Scholar : PubMed/NCBI

42 

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. 464:1071–1076. 2010. View Article : Google Scholar : PubMed/NCBI

43 

Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E and Chang HY: Long noncoding RNA as modular scaffold of histone modification complexes. Science. 329:689–693. 2010. View Article : Google Scholar : PubMed/NCBI

44 

Yang Z, Zhou L, Wu LM, Lai MC, Xie HY, Zhang F and Zheng SS: Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol. 18:1243–1250. 2011. View Article : Google Scholar : PubMed/NCBI

45 

Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T, Tanaka F, Shibata K, Suzuki A, Komune S, et al: Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 71:6320–6326. 2011. View Article : Google Scholar : PubMed/NCBI

46 

Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, Kim S and Safe S: HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene. 32:1616–1625. 2013. View Article : Google Scholar

47 

Lin R, Maeda S, Liu C, Karin M and Edgington TS: A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene. 26:851–858. 2007. View Article : Google Scholar

48 

Ji P, Diederichs S, Wang W, Böing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E, et al: MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 22:8031–8041. 2003. View Article : Google Scholar : PubMed/NCBI

49 

Schorderet P and Duboule D: Structural and functional differences in the long non-coding RNA hotair in mouse and human. PLoS Genet. 7:e10020712011. View Article : Google Scholar : PubMed/NCBI

50 

Liu JH, Chen G, Dang YW, Li CJ and Luo DZ: Expression and prognostic significance of lncRNA MALAT1 in pancreatic cancer tissues. Asian Pac J Cancer Prev. 15:2971–2977. 2014. View Article : Google Scholar : PubMed/NCBI

51 

Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, et al: A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 472:120–124. 2011. View Article : Google Scholar : PubMed/NCBI

52 

Li Z, Zhao X, Zhou Y, Liu Y, Zhou Q, Ye H, Wang Y, Zeng J, Song Y, Gao W, et al: The long non-coding RNA HOTTIP promotes progression and gemcitabine resistance by regulating HOXA13 in pancreatic cancer. J Transl Med. 13:842015. View Article : Google Scholar : PubMed/NCBI

53 

Ma C, Nong K, Zhu H, Wang W, Huang X, Yuan Z and Ai K: H19 promotes pancreatic cancer metastasis by derepressing let-7's suppression on its target HMGA2-mediated EMT. Tumour Biol. 35:9163–9169. 2014. View Article : Google Scholar : PubMed/NCBI

54 

Peng W, Gao W and Feng J: Long noncoding RNA HULC is a novel biomarker of poor prognosis in patients with pancreatic cancer. Med Oncol. 31:3462014. View Article : Google Scholar : PubMed/NCBI

55 

You L, Chang D, Du HZ and Zhao YP: Genome-wide screen identifies PVT1 as a regulator of Gemcitabine sensitivity in human pancreatic cancer cells. Biochem Biophys Res Commun. 407:1–6. 2011. View Article : Google Scholar : PubMed/NCBI

56 

Tahira AC, Kubrusly MS, Faria MF, Dazzani B, Fonseca RS, Maracaja-Coutinho V, Verjovski-Almeida S, Machado MC and Reis EM: Long noncoding intronic RNAs are differentially expressed in primary and metastatic pancreatic cancer. Mol Cancer. 10:1412011. View Article : Google Scholar : PubMed/NCBI

57 

Ding YC, Yu W, Ma C, Wang Q, Huang CS and Huang T: Expression of long non-coding RNA LOC285194 and its prognostic significance in human pancreatic ductal adenocarcinoma. Int J Clin Exp Pathol. 7:8065–8070. 2014.

58 

Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M, Nishida H, Yap CC, Suzuki M, Kawai J, et al: FANTOM Consortium: Antisense transcription in the mammalian transcriptome. Science. 309:1564–1566. 2005. View Article : Google Scholar : PubMed/NCBI

59 

Wang D, Garcia-Bassets I, Benner C, Li W, Su X, Zhou Y, Qiu J, Liu W, Kaikkonen MU, Ohgi KA, et al: Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature. 474:390–394. 2011. View Article : Google Scholar : PubMed/NCBI

60 

Li W, Notani D, Ma Q, Tanasa B, Nunez E, Chen AY, Merkurjev D, Zhang J, Ohgi K, Song X, et al: Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature. 498:516–520. 2013. View Article : Google Scholar : PubMed/NCBI

61 

Hah N, Danko CG, Core L, Waterfall JJ, Siepel A, Lis JT and Kraus WL: A rapid, extensive, and transient transcriptional response to estrogen signaling in breast cancer cells. Cell. 145:622–634. 2011. View Article : Google Scholar : PubMed/NCBI

62 

Melo CA, Drost J, Wijchers PJ, van de Werken H, de Wit E, Oude Vrielink JA, Elkon R, Melo SA, Léveillé N, Kalluri R, et al: eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol Cell. 49:524–535. 2013. View Article : Google Scholar : PubMed/NCBI

63 

Huarte M and Rinn JL: Large non-coding RNAs: Missing links in cancer? Hum Mol Genet. 19R:R152–R161. 2010. View Article : Google Scholar

64 

Gibb EA, Brown CJ and Lam WL: The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 10:382011. View Article : Google Scholar : PubMed/NCBI

65 

Tsai MC, Spitale RC and Chang HY: Long intergenic noncoding RNAs: New links in cancer progression. Cancer Res. 71:3–7. 2011. View Article : Google Scholar : PubMed/NCBI

66 

Maruyama R and Suzuki H: Long noncoding RNA involvement in cancer. BMB Rep. 45:604–611. 2012. View Article : Google Scholar : PubMed/NCBI

67 

Spizzo R, Almeida MI, Colombatti A and Calin GA: Long non-coding RNAs and cancer: A new frontier of translational research? Oncogene. 31:4577–4587. 2012. View Article : Google Scholar : PubMed/NCBI

68 

Reference Genome Group of the Gene Ontology Consortium. The Gene Ontology's Reference Genome Project: A unified framework for functional annotation across species. PLoS Comput Biol. 5:e10004312009. View Article : Google Scholar : PubMed/NCBI

69 

Mizuma M, Rasheed ZA, Yabuuchi S, Omura N, Campbell NR, de Wilde RF, De Oliveira E, Zhang Q, Puig O, Matsui W, et al: The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models. Mol Cancer Ther. 11:1999–2009. 2012. View Article : Google Scholar : PubMed/NCBI

70 

Feng J, Ma T, Ge Z, Lin J, Ding W, Chen H, Zhu W, Zhou S and Tan Y: PKM2 gene regulates the behavior of pancreatic cancer cells via mitogen-activated protein kinase pathways. Mol Med Rep. 11:2111–2117. 2015.

71 

Zhang X, Lian Z, Padden C, Gerstein MB, Rozowsky J, Snyder M, Gingeras TR, Kapranov P, Weissman SM and Newburger PE: A myelopoiesis-associated regulatory intergenic noncoding RNA transcript within the human HOXA cluster. Blood. 113:2526–2534. 2009. View Article : Google Scholar : PubMed/NCBI

72 

McCarthy DJ and Smyth GK: Testing significance relative to a fold-change threshold is a TREAT. Bioinformatics. 25:765–771. 2009. View Article : Google Scholar : PubMed/NCBI

73 

Su X, Malouf GG, Chen Y, Zhang J, Yao H, Valero V, Weinstein JN, Spano JP, Meric-Bernstam F, Khayat D, et al: Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes. Oncotarget. 5:9864–9876. 2014. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
APA
Zhou, Y., Gong, B., Jiang, Z., Zhong, S., Liu, X., Dong, K. ... Zhu, S. (2016). Microarray expression profile analysis of long non-coding RNAs in pancreatic ductal adenocarcinoma. International Journal of Oncology, 48, 670-680. https://doi.org/10.3892/ijo.2015.3292
MLA
Zhou, Y., Gong, B., Jiang, Z., Zhong, S., Liu, X., Dong, K., Wu, H., Yang, H., Zhu, S."Microarray expression profile analysis of long non-coding RNAs in pancreatic ductal adenocarcinoma". International Journal of Oncology 48.2 (2016): 670-680.
Chicago
Zhou, Y., Gong, B., Jiang, Z., Zhong, S., Liu, X., Dong, K., Wu, H., Yang, H., Zhu, S."Microarray expression profile analysis of long non-coding RNAs in pancreatic ductal adenocarcinoma". International Journal of Oncology 48, no. 2 (2016): 670-680. https://doi.org/10.3892/ijo.2015.3292