Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

LINC00346 promotes pancreatic cancer progression through the CTCF-mediated Myc transcription

Oncogene volume 38, pages 6770–6780 (2019)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. 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.

    Article  Google Scholar 

  2. 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.

    Article  Google Scholar 

  3. 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.

    Article  Google Scholar 

  4. 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.

    Article  CAS  Google Scholar 

  5. Kung JT, Colognori D, Lee JT. Long noncoding RNAs: past, present, and future. Genetics. 2013;193:651–69.

    Article  CAS  Google Scholar 

  6. Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10:155–9.

    Article  CAS  Google Scholar 

  7. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43:904–14.

    Article  CAS  Google Scholar 

  8. Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154:26–46.

    Article  CAS  Google Scholar 

  9. Hu W, Alvarez-Dominguez JR, Lodish HF. Regulation of mammalian cell differentiation by long non-coding RNAs. EMBO Rep. 2012;13:971–83.

    Article  CAS  Google Scholar 

  10. 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.

    Article  CAS  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. 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.

    Article  CAS  Google Scholar 

  18. 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.

    Article  CAS  Google Scholar 

  19. 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.

    Article  CAS  Google Scholar 

  20. Dunn KL, Davie JR. The many roles of the transcriptional regulator CTCF. Biochem Cell Biol. 2003;81:161–7.

    Article  CAS  Google Scholar 

  21. 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.

    CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  Google Scholar 

  23. Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014;15:7–21.

    Article  CAS  Google Scholar 

  24. Li M, Izpisua Belmonte JC. Roles for noncoding RNAs in cell-fate determination and regeneration. Nat Struct Mol Biol. 2015;22:2–4.

    Article  CAS  Google Scholar 

  25. Peng WX, Koirala P, Mo YY. LncRNA-mediated regulation of cell signaling in cancer. Oncogene. 2017;36:5661–7.

    Article  CAS  Google Scholar 

  26. McMahon SB. MYC and the control of apoptosis. Cold Spring Harb Perspect Med. 2014;4:a014407.

    Article  Google Scholar 

  27. Dang CV. Web of the extended Myc network captures metabolism for tumorigenesis. Cancer Cell. 2015;27:160–2.

    Article  CAS  Google Scholar 

  28. Chen H, Liu H, Qing G. Targeting oncogenic Myc as a strategy for cancer treatment. Signal Transduct Target Ther. 2018;3:5.

    Article  Google Scholar 

  29. 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.

    Article  CAS  Google Scholar 

  30. 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.

    Article  CAS  Google Scholar 

  31. Sears RC. The life cycle of C-myc: from synthesis to degradation. Cell Cycle. 2004;3:1133–7.

    Article  CAS  Google Scholar 

  32. Conacci-Sorrell M, McFerrin L, Eisenman RN. An overview of MYC and its interactome. Cold Spring Harb Perspect Med. 2014;4:a014357.

    Article  Google Scholar 

  33. Iaccarino I. lncRNAs and MYC: an intricate relationship. Int J Mol Sci. 2017;18:E1497.

    Article  Google Scholar 

  34. 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.

    Article  CAS  Google Scholar 

  35. 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.

    Article  Google Scholar 

  36. 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.

    Article  CAS  Google Scholar 

  37. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43:904–14.

    Article  CAS  Google Scholar 

  38. 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.

    Article  CAS  Google Scholar 

  39. 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.

    Article  CAS  Google Scholar 

  40. 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.

    Article  CAS  Google Scholar 

  41. Herold M, Bartkuhn M, Renkawitz R. CTCF: insights into insulator function during development. Development. 2012;139:1045–57.

    Article  CAS  Google Scholar 

  42. 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.

    Article  Google Scholar 

  43. 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.

    Article  CAS  Google Scholar 

  44. 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.

    PubMed  PubMed Central  Google Scholar 

  45. 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.

    Article  CAS  Google Scholar 

  46. 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.

    Article  CAS  Google Scholar 

  47. 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.

    Article  Google Scholar 

  48. 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.

    Article  Google Scholar 

  49. 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.

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China

    Wan-Xin Peng & Liu Yang

  2. Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA

    Wan-Xin Peng, Rong-Zhang He & Yin-Yuan Mo

  3. Translational Medicine Institute, National and Local Joint Engineering Laboratory for High-through Molecular Diagnosis Technology, the First People’s Hospital of Chenzhou, Chenzhou, 423000, Hunan, China

    Rong-Zhang He

  4. Department of Pulmonary Medicine, Tongji Hospital, Tongji University, Shanghai, 200065, China

    Ziqiang Zhang

  5. Department of Pharmacology/Toxicology, University of Mississippi Medical Center, Jackson, MS, USA

    Yin-Yuan Mo

Authors
  1. Wan-Xin Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rong-Zhang He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ziqiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yin-Yuan Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Liu Yang or Yin-Yuan Mo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0918-z

This article is cited by

Search

Advanced search

Quick links