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:

Targeting LIN28B reprograms tumor glucose metabolism and acidic microenvironment to suppress cancer stemness and metastasis

Oncogene volume 38, pages 4527–4539 (2019)Cite this article

Subjects

Abstract

The altered metabolism and acidic microenvironment plays an important role in promoting tumor malignant characteristics. A small population of cancer stem cells (CSCs) were considered as a therapy target to reserve tumor relapse, resistance, and metastasis. However, the molecular mechanism that regulates CSCs metabolism remains poorly understood. In this study, we demonstrate a fundamental role of stemness gene LIN28B in maintaining CSCs glycolysis metabolism. Using LIN28B-expressing cancer cell lines, we found that the rate of extracellular acidification, glucose uptake, and lactate secretion are all suppressed by LIN28B knockdown in vitro and in vivo. Importantly, metabolic analyses reveal that CSCs have enhanced aerobic glycolysis metabolic characteristics and the glycolytic product lactate further promotes cancer associated stemness properties. LIN28B silencing suppresses MYC expression that further increases miR-34a-5p level. Furthermore, the glycolysis metabolism of human breast cancer cell line MDA-MB-231 is suppressed by either MYC siRNA or miR-34a-5p mimic. Clinically, high MYC and low miR-34a-5p level are correlated with high LIN28B expression and poor prognosis in human breast cancer patients. Notably, blocking LIN28B/MYC/miR-34a-5p signaling pathway by LIN28B-specific inhibitor causes dramatic inhibition of tumor growth and metastasis in immunodeficient orthotopic mouse models of human breast cancer cell MDA-MB-231. Taken together, our findings offer a preclinical investigation of targeting LIN28B to suppress CSCs glycolysis metabolism and tumor progression that may improve the therapeutic benefit for cancer patients.

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
Fig. 7

Similar content being viewed by others

References

  1. Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.

    Article  CAS  Google Scholar 

  2. Spinelli JB, Yoon H, Ringel AE, Jeanfavre S, Clish CB, Haigis MC. Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass. Science. 2017;358:941–6.

    Article  CAS  Google Scholar 

  3. Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, et al. Lactate metabolism in human lung tumors. Cell. 2017;171:358–71.

    Article  CAS  Google Scholar 

  4. Ciavardelli D, Rossi C, Barcaroli D, Volpe S, Consalvo A, Zucchelli M, et al. Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment. Cell Death Dis. 2014;5:e1336.

    Article  CAS  Google Scholar 

  5. Lee KM, Giltnane JM, Balko JM, Schwarz LJ, Guerrero-Zotano AL, Hutchinson KE, et al. MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab. 2017;26:633–47.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NFkappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell. 2009;139:693–706.

    Article  CAS  Google Scholar 

  8. Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S, et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet. 2009; 41: 843–8.

    Article  CAS  Google Scholar 

  9. Chen C, Cao F, Bai L, Liu Y, Xie J, Wang W, et al. IKKβ enforces a LIN28B/TCF7L2 positive feedback loop that promotes cancer Cell stemness and metastasis. Cancer Res. 2015;75:1725–35.

    Article  CAS  Google Scholar 

  10. Feng C, Neumeister V, Ma W, Xu J, Lu L, Bordeaux J, et al. Lin28 regulates HER2 and promotes malignancy through multiple mechanisms. Cell Cycle. 2012;11:2486–94.

    Article  CAS  Google Scholar 

  11. Piskounova E, Polytarchou C, Thornton JE, LaPierre RJ, Pothoulakis C, Hagan JP, et al. Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell. 2011;147:1066–79.

    Article  CAS  Google Scholar 

  12. 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 

  13. Zhu H, Shah S, Shyh-Chang N, Shinoda G, Einhorn WS, Viswanathan SR, et al. Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nat Genet. 2010;42:626–30.

    Article  CAS  Google Scholar 

  14. Zhang J, Ratanasirintrawoot S, Chandrasekaran S, Wu Z, Ficarro SB, Yu C, et al. LIN28 regulates stem cell metabolism and Conversion to primed pluripotency. Cell Stem Cell. 2016;19:66–80.

    Article  CAS  Google Scholar 

  15. Wu L, Nguyen LH, Zhou K, de Soysa TY, Li L, Miller JB, et al. Precise let-7 expression levels balance organ regeneration against tumor suppression. Elife. 2015;4:e09431.

    Article  Google Scholar 

  16. Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, metabolism, and cancer. Cancer Discov. 2015;5:1024–39.

    Article  CAS  Google Scholar 

  17. Walz S, Lorenzin F, Morton J, Wiese KE, von Eyss B, Herold S, et al. Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature. 2014;511:483–7.

    Article  CAS  Google Scholar 

  18. Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet. 2008;40:43–50.

    Article  CAS  Google Scholar 

  19. Bu P, Chen KY, Chen JH, Wang L, Walters J, Shin YJ, et al. A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. Cell Stem Cell. 2013;12:602–15.

    Article  CAS  Google Scholar 

  20. Park EY, Chang E, Lee EJ, Lee HW, Kang HG, Chun KH, et al. Targeting of miR34a-NOTCH1 axis reduced breast cancer stemness and chemoresistance. Cancer Res. 2014;74:7573–82.

    Article  CAS  Google Scholar 

  21. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011;17:211–5.

    Article  CAS  Google Scholar 

  22. Valton J, Cabaniols JP, Galetto R, Delacote F, Duhamel M, Paris S, et al. Efficient strategies for TALEN-mediated genome editing in mammalian cell lines. Methods. 2014;69:151–70.

    Article  CAS  Google Scholar 

  23. Zhang S, Li L, Kendrick SL, Gerard RD, Zhu H. TALEN-mediated somatic mutagenesis in murine models of cancer. Cancer Res. 2014;74:5311–21.

    Article  CAS  Google Scholar 

  24. Pike Winer LS, Wu M. Rapid analysis of glycolytic and oxidative substrate flux of cancer cells in a microplate. PLoS ONE. 2014;9:e109916.

    Article  Google Scholar 

  25. Wang Y, Yu Y, Tsuyada A, Ren X, Wu X, Stubblefield K, et al. Transforming growth factor-β regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM. Oncogene. 2011;30:1470–80.

    Article  CAS  Google Scholar 

  26. Levi BP, Yilmaz OH, Duester G, Morrison SJ. Aldehyde dehydrogenase 1a1 is dispensable for stem cell function in the mouse hematopoietic and nervous systems. Blood. 2009;113:1670–80.

    Article  CAS  Google Scholar 

  27. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–67.

    Article  CAS  Google Scholar 

  28. Silva AS, Yunes JA, Gillies RJ, Gatenby RA. The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion. Cancer Res. 2009;69:2677–84.

    Article  CAS  Google Scholar 

  29. Moellering RE, Black KC, Krishnamurty C, Baggett BK, Stafford P, Rain M, et al. Acid treatment of melanoma cells selects for invasive phenotypes. Clin Exp Metastas-. 2008;25:411–25.

    Article  CAS  Google Scholar 

  30. Rofstad EK, Mathiesen B, Kindem K, Galappathi K. Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res. 2006;66:6699–707.

    Article  CAS  Google Scholar 

  31. King CE, Cuatrecasas M, Castells A, Sepulveda AR, Lee JS, Rustgi AK. LIN28B promotes colon cancer progression and metastasis. Cancer Res. 2011;71:4260–8.

    Article  CAS  Google Scholar 

  32. 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 

  33. Qiu C, Ma Y, Wang J, Peng S, Huang Y. Lin28-mediated post-transcriptional regulation of OCT4 expression in human embryonic stem cells. Nucleic Acids Res. 2010;38:1240–8.

    Article  CAS  Google Scholar 

  34. Roos M, Pradère 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 

  35. Mayr F, Heinemann U. Mechanisms of Lin28-mediated miRNA and mRNA regulation--a structural and functional perspective. Int J Mol Sci. 2013;14:16532–53.

    Article  Google Scholar 

  36. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem. 2010;31:455–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Xiao Z, Li CH, Chan SL, Xu F, Feng L, Wang Y, et al. A small-molecule modulator of the tumor-suppressor miR34a inhibits the Growth of hepatocellular carcinoma. Cancer Res. 2014;74:6236–47.

    Article  CAS  Google Scholar 

  38. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214-–8.

    Article  CAS  Google Scholar 

  39. Kleppe M, Levine RL. Tumor heterogeneity confounds and illuminates: assessing the implications. Nat Med. 2014;20:342–4.

    Article  CAS  Google Scholar 

  40. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  Google Scholar 

  41. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7:11–20.

    Article  CAS  Google Scholar 

  42. Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E, Kim J, et al. Metabolic heterogeneity in human lung tumors. Cell. 2016;164:681–94.

    Article  CAS  Google Scholar 

  43. Davidson SM, Papagiannakopoulos T, Olenchock BA, Heyman JE, Keibler MA, Luengo A, et al. Environment impacts the metabolic dependencies of ras-driven non-small cell lung cancer. Cell Metab. 2016;23:517–28.

    Article  CAS  Google Scholar 

  44. Corbet C, Pinto A, Martherus R, Santiago de Jesus JP, Polet F, Feron O. Acidosis drives the reprogramming of fatty acid metabolism in cancer cells through changes in mitochondrial and histone acetylation. Cell Metab. 2016;24:311–23.

    Article  CAS  Google Scholar 

  45. Janiszewska M, Suvà ML, Riggi N, Houtkooper RH, Auwerx J, Clément-Schatlo V, et al. Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells. Genes Dev. 2012;26:1926–44.

    Article  CAS  Google Scholar 

  46. Ye XQ, Li Q, Wang GH, Sun FF, Huang GJ, Bian XW, et al. Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells. Int J Cancer. 2011;129:820–31.

    Article  CAS  Google Scholar 

  47. Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, et al. PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell. 2013;23:287–301.

    Article  CAS  Google Scholar 

  48. Sancho P, Burgos-Ramos E, Tavera A, Bou Kheir T, Jagust P, Schoenhals M, et al. MYC/PGC-1α balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metab. 2015;22:590–605.

    Article  CAS  Google Scholar 

  49. Ito K, Carracedo A, Weiss D, Arai F, Ala U, Avigan DE, et al. A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med. 2012;18:1350–8.

    Article  CAS  Google Scholar 

  50. Ma X, Li C, Sun L, Huang D, Li T, He X, et al. Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1. Nat Commun. 2014;5:5212.

    Article  Google Scholar 

  51. Albright JD, Moran DB, Wright WB Jr, Collins JB, Beer B, Lippa AS, et al. Synthesis and anxiolytic activity of 6-(substituted-phenyl)-1,2,4-triazolo[4,3-b]-pyridazines. J Med Chem. 1981;24:592–600.

    Article  CAS  Google Scholar 

  52. American Type Culture Collection. Cell line verification test recommendations; ATCC recommends cell line verification tests and guidelines for publishing. ATCC Technical Bulletin No. 8. Manassas, VA: ATCC; 2007.

    Google Scholar 

  53. Hu Y, Smyth GK. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009;347:70–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This project was supported by grants from the 973 Program of China (2013CB967202, Yunping Luo); the National Natural Science Foundation of China (91029734 and 81071711, Yunping Luo), the National Natural Science Foundation of China (81502562, Chong Chen); and the Fundamental Research Funds for the Central Universities (33320140173, Chong Chen). We thank Zhigang Wang (Department of Bioengineering, Chinese Academy of Medical Sciences) for the bioinformatics analysis in this study and Cameron R. Mckay (Department of Immunology, Nankai University) for critically reading and polishing this manuscript.

Author information

Authors and Affiliations

  1. Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China

    Chong Chen, Lipeng Bai, Fengqi Cao, Shengnan Wang, Huiwen He, Mingcheng Song, Huilin Chen, Yan Liu, Jian Guo, Qin Si, Yundi Pan, Ruizhe Zhu & Yunping Luo

  2. Collaborative Innovation Center for Biotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China

    Chong Chen, Lipeng Bai, Fengqi Cao, Shengnan Wang, Huiwen He, Mingcheng Song, Huilin Chen, Yan Liu, Jian Guo, Qin Si, Yundi Pan, Ruizhe Zhu & Yunping Luo

  3. Department of Clinical Laboratory, Jiangxi Cancer Hospital, Nanchang, 330029, China

    Lipeng Bai

  4. Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, Taiwan

    Tsung-Hsien Chuang

  5. Department of Immunology, Nankai University, Tianjin, 300071, China

    Rong Xiang

Authors
  1. Chong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lipeng Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fengqi Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shengnan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huiwen He
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mingcheng Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Huilin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jian Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qin Si
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yundi Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ruizhe Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tsung-Hsien Chuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Rong Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yunping Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yunping Luo.

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

Chen, C., Bai, L., Cao, F. et al. Targeting LIN28B reprograms tumor glucose metabolism and acidic microenvironment to suppress cancer stemness and metastasis. Oncogene 38, 4527–4539 (2019). https://doi.org/10.1038/s41388-019-0735-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0735-4

This article is cited by

Search

Advanced search

Quick links