Abstract
Although multiple factors are known to contribute to pancreatic ductal adenocarcinoma (PDAC) progression, the role of long non-coding RNAs (lncRNAs) in PDAC remains largely unknown. In this study, we present data that long intergenic non-coding RNA 346 (LINC00346) functions as a promoting factor for PDAC development. We first show that LINC00346 is highly expressed in pancreatic tumor specimens as compared to normal pancreatic tissue based on interrogation of The Cancer Genome Atlas (TCGA) pancreatic adenocarcinoma dataset. Of significance, this upregulation of LINC00346 is associated with overall survival (OS) and disease-free survival (DFS), respectively. We further show that knockout (KO) of LINC00346 impairs pancreatic cancer cell proliferation, tumorigenesis, migration, and invasion ability. Importantly, these phenotypes can be restored by LINC00346 re-expression in KO cells (i.e., rescue experiment). RNA precipitation assays combined with mass spectrometry analysis indicate that LINC00346 interacts with CCCTC-binding factor (CTCF), a known transcriptional repressor of c-Myc. This interaction between LINC00346 and CTCF prevents the binding of CTCF to c-Myc promoter, relieving the CTCF-mediated repression of c-Myc. Thus, LINC00346 functions as a positive transcriptional regulator of c-Myc. Together, these results suggest that LINC00346 contributes to PDAC pathogenesis by activating c-Myc, and as such, LINC00346 may serve as a potential biomarker and therapeutic target for PDAC.
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References
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
Global Burden of Disease Cancer C, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3:524–48.
Khan MA, Azim S, Zubair H, Bhardwaj A, Patel GK, Khushman M, et al. Molecular drivers of pancreatic cancer pathogenesis: looking inward to move forward. Int J Mol Sci. 2017;18:E779.
Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007;447:799–816.
Kung JT, Colognori D, Lee JT. Long noncoding RNAs: past, present, and future. Genetics. 2013;193:651–69.
Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10:155–9.
Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43:904–14.
Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154:26–46.
Hu W, Alvarez-Dominguez JR, Lodish HF. Regulation of mammalian cell differentiation by long non-coding RNAs. EMBO Rep. 2012;13:971–83.
Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.
Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, et al. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature. 2011;477:295–300.
Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet. 2011;43:621–9.
Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci USA. 2009;106:11667–72.
Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689–93.
Schmitt AM, Garcia JT, Hung T, Flynn RA, Shen Y, Qu K, et al. An inducible long noncoding RNA amplifies DNA damage signaling. Nat Genet. 2016;48:1370–6.
Kim J, Piao HL, Kim BJ, Yao F, Han Z, Wang Y, et al. Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nat Genet. 2018;50:1705–15.
Zetsche B, Gootenberg JS, Abudayyeh OO, Slaymaker IM, Makarova KS, Essletzbichler P, et al. Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Cell. 2015;163:759–71.
Hessmann E, Schneider G, Ellenrieder V, Siveke JT. MYC in pancreatic cancer: novel mechanistic insights and their translation into therapeutic strategies. Oncogene. 2016;35:1609–18.
Huang J, Zhang A, Ho TT, Zhang Z, Zhou N, Ding X, et al. Linc-RoR promotes c-Myc expression through hnRNP I and AUF1. Nucleic Acids Res. 2016;44:3059–69.
Dunn KL, Davie JR. The many roles of the transcriptional regulator CTCF. Biochem Cell Biol. 2003;81:161–7.
Lobanenkov VV, Nicolas RH, Adler VV, Paterson H, Klenova EM, Polotskaja AV, et al. A novel sequence-specific DNA binding protein which interacts with three regularly spaced direct repeats of the CCCTC-motif in the 5’-flanking sequence of the chicken c-myc gene. Oncogene. 1990;5:1743–53.
Filippova GN, Fagerlie S, Klenova EM, Myers C, Dehner Y, Goodwin G, et al. An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes. Mol Cell Biol. 1996;16:2802–13.
Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014;15:7–21.
Li M, Izpisua Belmonte JC. Roles for noncoding RNAs in cell-fate determination and regeneration. Nat Struct Mol Biol. 2015;22:2–4.
Peng WX, Koirala P, Mo YY. LncRNA-mediated regulation of cell signaling in cancer. Oncogene. 2017;36:5661–7.
McMahon SB. MYC and the control of apoptosis. Cold Spring Harb Perspect Med. 2014;4:a014407.
Dang CV. Web of the extended Myc network captures metabolism for tumorigenesis. Cancer Cell. 2015;27:160–2.
Chen H, Liu H, Qing G. Targeting oncogenic Myc as a strategy for cancer treatment. Signal Transduct Target Ther. 2018;3:5.
Lin CY, Loven J, Rahl PB, Paranal RM, Burge CB, Bradner JE, et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell. 2012;151:56–67.
Lu Y, Hu Z, Mangala LS, Stine ZE, Hu X, Jiang D, et al. MYC targeted long noncoding RNA DANCR promotes cancer in part by reducing p21 levels. Cancer Res. 2018;78:64–74.
Sears RC. The life cycle of C-myc: from synthesis to degradation. Cell Cycle. 2004;3:1133–7.
Conacci-Sorrell M, McFerrin L, Eisenman RN. An overview of MYC and its interactome. Cold Spring Harb Perspect Med. 2014;4:a014357.
Iaccarino I. lncRNAs and MYC: an intricate relationship. Int J Mol Sci. 2017;18:E1497.
Maldotti M, Incarnato D, Neri F, Krepelova A, Rapelli S, Anselmi F, et al. The long intergenic non-coding RNA CCR492 functions as a let-7 competitive endogenous RNA to regulate c-Myc expression. Biochim Biophys Acta. 2016;1859:1322–32.
Xiao ZD, Han L, Lee H, Zhuang L, Zhang Y, Baddour J, et al. Energy stress-induced lncRNA FILNC1 represses c-Myc-mediated energy metabolism and inhibits renal tumor development. Nat Commun. 2017;8:783.
Hung CL, Wang LY, Yu YL, Chen HW, Srivastava S, Petrovics G, et al. A long noncoding RNA connects c-Myc to tumor metabolism. Proc Natl Acad Sci USA. 2014;111:18697–702.
Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43:904–14.
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;24:513–31.
Zhang P, Cao L, Fan P, Mei Y, Wu M. LncRNA-MIF, a c-Myc-activated long non-coding RNA, suppresses glycolysis by promoting Fbxw7-mediated c-Myc degradation. EMBO Rep. 2016;17:1204–20.
Klenova EM, Nicolas RH, Paterson HF, Carne AF, Heath CM, Goodwin GH, et al. CTCF, a conserved nuclear factor required for optimal transcriptional activity of the chicken c-myc gene, is an 11-Zn-finger protein differentially expressed in multiple forms. Mol Cell Biol. 1993;13:7612–24.
Herold M, Bartkuhn M, Renkawitz R. CTCF: insights into insulator function during development. Development. 2012;139:1045–57.
Peng WX, Huang JG, Yang L, Gong AH, Mo YY. Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer. Mol Cancer. 2017;16:161.
Wu F, Chiocca S, Beck WT, Mo YY. Gam1-associated alterations of drug responsiveness through activation of apoptosis. Mol Cancer Ther. 2007;6:1823–30.
Gupta SC, Singh R, Pochampally R, Watabe K, Mo YY. Acidosis promotes invasiveness of breast cancer cells through ROS-AKT-NF-kappaB pathway. Oncotarget. 2014;5:12070–82.
Singh R, Gupta SC, Peng WX, Zhou N, Pochampally R, Atfi A, et al. Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis. Cell Death Dis. 2016;7:e2262.
Sachdeva M, Wu H, Ru P, Hwang L, Trieu V, Mo YY. MicroRNA-101-mediated Akt activation and estrogen-independent growth. Oncogene. 2011;30:822–31.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.
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.
Acknowledgements
This research was supported by grants from National Natural Science Foundation of China, No. 81772575 (LY) and the key project of Health Bureau of Zhejiang Province, No. 2018274734 (LY), and NIH grant R01 CA154989 (YM).
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Peng, WX., He, RZ., Zhang, Z. et al. LINC00346 promotes pancreatic cancer progression through the CTCF-mediated Myc transcription. Oncogene 38, 6770–6780 (2019). https://doi.org/10.1038/s41388-019-0918-z
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DOI: https://doi.org/10.1038/s41388-019-0918-z
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