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A cancer-testis non-coding RNA LIN28B-AS1 activates driver gene LIN28B by interacting with IGF2BP1 in lung adenocarcinoma

Oncogene volume 38, pages 1611–1624 (2019)Cite this article

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Abstract

Our previous work found cancer-testis (CT) genes as a new source of epi-driver candidates of cancer. LIN28B was a CT gene, but the “driver” ability and the activation mechanism in lung adenocarcinoma (LUAD) remain unclear. We observed that LIN28B expression was restricted in testis. It was re-activated in LUAD patients without known genomic alterations in oncogenes and was related to poorer survival. In vitro and In vivo experiments confirmed that the activation of LIN28B could promote the proliferation and metastasis of LUAD cells and can influence cell cycle, DNA damage repair, and genome instability. In addition to the known let-7-LIN28B regulation loop, our results further revealed a let-7-independent Cis-regulator of LIN28B: LIN28B-AS1. LIN28B-AS1 is a CT long non-coding RNA (CT-lncRNA). It altered the messenger RNA stability of LIN28B by directly interacting with another CT protein IGF2BP1 but not with LIN28B and constituted a novel regulation network. In sum, we identify that LIN28B is an “epi-driver” of LUAD and clarify a new lncRNA-activated mechanism of LIN28B, which provide new candidate targets for precise anticancer therapy in the future.

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References

  1. Drilon A, Wang L, Hasanovic A, Suehara Y, Lipson D, Stephens P, et al. Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013;3:630–5.

    Article  CAS  Google Scholar 

  2. Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30:863–70.

    Article  CAS  Google Scholar 

  3. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–703.

    Article  CAS  Google Scholar 

  4. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–1500.

    Article  CAS  Google Scholar 

  5. The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–550.

  6. Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012;150:1107–20.

    Article  CAS  Google Scholar 

  7. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr., Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58.

    Article  CAS  Google Scholar 

  8. Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer. 2005;5:615–25.

    Article  CAS  Google Scholar 

  9. Pineda CT, Ramanathan S, Fon Tacer K, Weon JL, Potts MB, Ou YH, et al. Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell. 2015;160:715–28.

    Article  CAS  Google Scholar 

  10. Watkins J, Weekes D, Shah V, Gazinska P, Joshi S, Sidhu B, et al. Genomic complexity profiling reveals that HORMAD1 overexpression contributes to homologous recombination deficiency in triple-negative breast cancers. Cancer Discov. 2015;5:488–505.

    Article  CAS  Google Scholar 

  11. Wang C, Gu Y, Zhang K, Xie K, Zhu M, Dai N, et al. Systematic identification of genes with a cancer-testis expression pattern in 19 cancer types. Nat Commun. 2016;7:10499.

    Article  CAS  Google Scholar 

  12. Ali PS, Ghoshdastider U, Hoffmann J, Brutschy B, Filipek S. Recognition of the let-7g miRNA precursor by human Lin28B. FEBS Lett. 2012;586:3986–90.

    Article  Google Scholar 

  13. Viswanathan SR, Daley GQ, Gregory RI. Selective blockade of microRNA processing by Lin28. Science. 2008;320:97–100.

    Article  CAS  Google Scholar 

  14. Beachy SH, Onozawa M, Chung YJ, Slape C, Bilke S, Francis P, et al. Enforced expression of Lin28b leads to impaired T-cell development, release of inflammatory cytokines, and peripheral T-cell lymphoma. Blood. 2012;120:1048–59.

    Article  CAS  Google Scholar 

  15. Molenaar JJ, Domingo-Fernandez R, Ebus ME, Lindner S, Koster J, Drabek K, et al. LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nat Genet. 2012;44:1199–206.

    Article  CAS  Google Scholar 

  16. Nguyen LH, Robinton DA, Seligson MT, Wu L, Li L, Rakheja D, et al. Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models. Cancer Cell. 2014;26:248–61.

    Article  CAS  Google Scholar 

  17. Shyh-Chang N, Daley GQ. Lin28: primal regulator of growth and metabolism in stem cells. Cell Stem Cell. 2013;12:395–406.

    Article  Google Scholar 

  18. Busch B, Bley N, Muller S, Glass M, Misiak D, Lederer M, et al. The oncogenic triangle of HMGA2, LIN28B and IGF2BP1 antagonizes tumor-suppressive actions of the let-7 family. Nucleic Acids Res. 2016;44:3845–64.

    Article  CAS  Google Scholar 

  19. Morris KV, Mattick JS. The rise of regulatory RNA. Nat Rev Genet. 2014;15:423–37.

    Article  CAS  Google Scholar 

  20. Darbre PD, Harvey PW. Parabens can enable hallmarks and characteristics of cancer in human breast epithelial cells: a review of the literature with reference to new exposure data and regulatory status. J Appl Toxicol. 2014;34:925–38.

    Article  CAS  Google Scholar 

  21. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9.

    Article  CAS  Google Scholar 

  22. Fuentes-Mattei E, Velazquez-Torres G, Phan L, Zhang F, Chou PC, Shin JH, et al. Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer. J Natl Cancer Inst. (dju158) 2014; 106.

  23. Cuddihy AR, O’Connell MJ. Cell-cycle responses to DNA damage in G2. Int Rev Cytol. 2003;222:99–140.

    Article  Google Scholar 

  24. Kalb R, Neveling K, Nanda I, Schindler D, Hoehn H. Fanconi anemia: causes and consequences of genetic instability. Genome Dyn. 2006;1:218–42.

    Article  CAS  Google Scholar 

  25. Gong X, Litchfield LM, Webster Y, Chio LC, Wong SS, Stewart TR, et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor abemaciclib. Cancer Cell. 2017;32:761–776 e766.

    Article  CAS  Google Scholar 

  26. Araujo AN, Moraes L, Franca MI, Hakonarson H, Li J, Pellegrino R, et al. Genome-wide copy number analysis in a family with p.G533C RET mutation and medullary thyroid carcinoma identified regions potentially associated with a higher predisposition to lymph node metastasis. J Clin Endocrinol Metab. 2014;99:E1104–E1112.

    Article  CAS  Google Scholar 

  27. Enright AJ, John B, Gaul U, Tuschl T, Sander C, Marks DS. MicroRNA targets in Drosophila. Genome Biol. 2003;5:R1.

    Article  Google Scholar 

  28. Kertesz M, Iovino N, Unnerstall U, Gaul U, Segal E. The role of site accessibility in microRNA target recognition. Nat Genet. 2007;39:1278–84.

    Article  CAS  Google Scholar 

  29. Li JH, Liu S, Zhou H, Qu LH, Yang JH. star Basev2.0: decoding miRNA–ceRNA, miRNA–ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2014;42:D92–D97.

    Article  CAS  Google Scholar 

  30. Yeap BB, Voon DC, Vivian JP, McCulloch RK, Thomson AM, Giles KM, et al. Novel binding of HuR and poly(C)-binding protein to a conserved UC-rich motif within the 3′-untranslated region of the androgen receptor messenger RNA. J Biol Chem. 2002;277:27183–92.

    Article  CAS  Google Scholar 

  31. Khanam T, Muddashetty RS, Kahvejian A, Sonenberg N, Brosius J. Poly(A)-binding protein binds to A-rich sequences via RNA-binding domains 1+2 and 3+4. RNA Biol. 2006;3:170–7.

    Article  CAS  Google Scholar 

  32. Alajez NM, Shi W, Wong D, Lenarduzzi M, Waldron J, Weinreb I, et al. Lin28b promotes head and neck cancer progression via modulation of the insulin-like growth factor survival pathway. Oncotarget. 2012;3:1641–52.

    Article  Google Scholar 

  33. Yamada K, Ono M, Perkins ND, Rocha S, Lamond AI. Identification and functional characterization of FMN2, a regulator of the cyclin-dependent kinase inhibitor p21. Mol Cell. 2013;49:922–33.

    Article  CAS  Google Scholar 

  34. Thornton JE, Gregory RI. How does Lin28 let-7 control development and disease? Trends Cell Biol. 2012;22:474–82.

    Article  CAS  Google Scholar 

  35. Battistelli C, Cicchini C, Santangelo L, Tramontano A, Grassi L, Gonzalez FJ, et al. The Snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition. Oncogene. 2017;36:942–55.

    Article  CAS  Google Scholar 

  36. Hu X, Feng Y, Zhang D, Zhao SD, Hu Z, Greshock J, et al. A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell. 2014;26:344–57.

    Article  CAS  Google Scholar 

  37. Roos M, Pradere U, Ngondo RP, Behera A, Allegrini S, Civenni G, et al. A small-molecule inhibitor of Lin28. ACS Chem Biol. 2016;11:2773–81.

    Article  CAS  Google Scholar 

  38. Leung EL, Fiscus RR, Tung JW, Tin VP, Cheng LC, Sihoe AD, et al. Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS ONE. 2010;5:e14062.

    Article  Google Scholar 

  39. Anders S, McCarthy DJ, Chen Y, Okoniewski M, Smyth GK, Huber W, et al. Count-based differential expression analysis of RNA sequencing data using R and Bioconductor. Nat Protoc. 2013;8:1765–86.

    Article  Google Scholar 

  40. Anders S, Pyl PT, Huber W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.

    Article  CAS  Google Scholar 

  41. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    Article  CAS  Google Scholar 

  42. Zhang M, Hong Y, Han Y, Han H, Peng J, Qiu C, et al. Proteomic analysis of tegument-exposed proteins of female and male Schistosoma japonicum worms. J Proteome Res. 2013;12:5260–70.

    Article  CAS  Google Scholar 

  43. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

    Article  CAS  Google Scholar 

  44. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–7.

    Article  CAS  Google Scholar 

  45. Van Loo P, Nordgard SH, Lingjaerde OC, Russnes HG, Rye IH, Sun W, et al. Allele-specific copy number analysis of tumors. Proc Natl Acad Sci USA. 2010;107:16910–5.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the TCGA project for use of the multi-omics data of LUAD samples, and the Genotype-Tissue Expression (GTEx) project for use of the expression abundance of multiple normal tissues. This work was supported by Science Fund for Creative Research Groups of the National Natural Science Foundation of China (81521004), the State Key Program of National Natural Science of China (31530047), National Key Research and Development Program of China (2017YFC0907905), the Young Scientists Fund of the National Natural Science Foundation of China (81703295, 81702266), the National Key Basic Research Program Grant (2015CB943003), the Ten Thousand Talent Program, Jiangsu Specially-Appointed Professor project, Natural Science Foundation of Jiangsu Province (BK20160046), the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine), and Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015A067).

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  1. These authors contributed equally: Cheng Wang, Yayun Gu, Erbao Zhang

Authors and Affiliations

  1. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 211166, Nanjing, China

    Cheng Wang, Yayun Gu, Erbao Zhang, Kai Zhang, Na Qin, Juncheng Dai, Meng Zhu, Jia Liu, Kaipeng Xie, Yue Jiang, Xuejiang Guo, Mingxi Liu, Guangfu Jin, Hongxia Ma, Tao Jiang, Bin Shen, Ran Huo, Jiahao Sha, Hongbing Shen & Zhibin Hu

  2. Department of Epidemiology and Biostatistics, School of Public Health, Center of Global Health, Nanjing Medical University, 211166, Nanjing, China

    Cheng Wang, Yayun Gu, Erbao Zhang, Kai Zhang, Na Qin, Juncheng Dai, Meng Zhu, Jia Liu, Kaipeng Xie, Yue Jiang, Guangfu Jin, Hongxia Ma, Tao Jiang, Hongbing Shen & Zhibin Hu

  3. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, 211166, Nanjing, China

    Cheng Wang, Yayun Gu, Erbao Zhang, Kai Zhang, Na Qin, Juncheng Dai, Meng Zhu, Jia Liu, Kaipeng Xie, Yue Jiang, Guangfu Jin, Hongxia Ma, Tao Jiang, Hongbing Shen & Zhibin Hu

  4. Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, 211166, Nanjing, China

    Cheng Wang

  5. Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University Affiliated Cancer Hospital, 210009, Nanjing, China

    Rong Yin & Lin Xu

  6. Department of Molecular Cell Biology and Toxicology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, 211166, Nanjing, China

    Yankai Xia & Shouyu Wang

  7. Digestive Endoscopy Center, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, China

    Li Liu

  8. Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), School of Medicine, Saarland University, Saarbrücken, Germany

    Bin Qu

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Correspondence to Hongbing Shen or Zhibin Hu.

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Wang, C., Gu, Y., Zhang, E. et al. A cancer-testis non-coding RNA LIN28B-AS1 activates driver gene LIN28B by interacting with IGF2BP1 in lung adenocarcinoma. Oncogene 38, 1611–1624 (2019). https://doi.org/10.1038/s41388-018-0548-x

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