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Long noncoding RNA PVT1-214 promotes proliferation and invasion of colorectal cancer by stabilizing Lin28 and interacting with miR-128

A Correction to this article was published on 09 November 2021

This article has been updated


Long noncoding RNAs (lncRNAs) are implicated in human cancer, but their mechanisms of action are largely unknown. In this study, we investigated lncRNA alterations that contribute to colorectal cancer (CRC) through microarray expression profiling in CRC patient samples. Here, we report that the CRC-associated lncRNA PVT1-214 is a key regulator of CRC development and progression; patients with high PVT1-214 expression had a shorter survival and poorer prognosis. In vitro and in vivo investigation of the role of PVT1-214 revealed a complex integrated phenotype affecting cell growth, stem-like properties, migration, and invasion. Furthermore, using RNA pull-down and mass spectrometry, we found that Lin28 (also known as Lin28A), a highly conserved RNA-binding protein, is associated with PVT1-214. Strikingly, we found that PVT1-214 not only upregulated Lin28 protein expression in CRC cells by stabilizing Lin28, but also participated in crosstalk with Lin28 mRNA through competition for miR-128 binding, imposing an additional level of post-transcriptional regulation. In addition, we further show that PVT1-214 repressed expression of let-7 family miRNAs, which was abrogated by Lin28 knockdown. Taken together, our findings support a model in which the PVT1-214/Lin28/let-7 axis serves as a critical regulator of CRC pathogenesis, which may simulate a new direction for CRC therapeutic development.

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Change history


  1. 1.

    Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, et al. Landscape of transcription in human cells. Nature. 2012;489:101–8.

    CAS  Article  Google Scholar 

  2. 2.

    Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014;505:344–52.

    CAS  Article  Google Scholar 

  3. 3.

    Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and otherdiseases. Nat Rev Drug Discov. 2017;16:203–22.

    CAS  Article  Google Scholar 

  4. 4.

    Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013;152:1298–307.

    CAS  Article  Google Scholar 

  5. 5.

    Dhamija S, Diederichs S. From junk to master regulators of invasion: lncRNA functions in migration, EMTand metastasis. Int J Cancer. 2016;139:269–80.

    CAS  Article  Google Scholar 

  6. 6.

    Malone CD, Hannon GJ. Small RNAs as guardians of the genome. Cell. 2009;136:656–68.

    CAS  Article  Google Scholar 

  7. 7.

    Volders PJ, Helsens K, Wang X, Menten B, Martens L, Gevaert K, et al. LNCipedia: a database for annotated human lncRNA transcript sequences and structures. Nucl Acids Res. 2013;41:D246–51.

    CAS  Article  Google Scholar 

  8. 8.

    Chen FC, Pan CL, Lin HY. Functional implications of RNA splicing for human long intergenic noncoding RNAs. Evol Bioinform Online. 2014;10:219–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Cao C, Zhang T, Zhang D, Xie L, Zou X, Lei L, et al. The long non-coding RNA, SNHG6-003, functions as a competing endogenous RNA to promote the progression of hepatocellular carcinoma. Oncogene. 2017;36:1112–22.

    CAS  Article  Google Scholar 

  10. 10.

    Xu MD, Wang Y, Weng W, Wei P, Qi P, Zhang Q, et al. A Positive feedback loop of lncRNA-PVT1 and FOXM1 facilitates gastric cancergrowth and invasion. Clin Cancer Res. 2017;23:2071–80.

    CAS  Article  Google Scholar 

  11. 11.

    Kong R, Zhang EB, Yin DD, You LH, Xu TP, Chen WM, et al. Long noncoding RNA PVT1 indicates a poor prognosis of gastric cancer and promotes cell proliferation through epigenetically regulating p15 and p16. Mol Cancer. 2015;14:82–96.

    Article  Google Scholar 

  12. 12.

    Wang F, Yuan JH, Wang SB, Yang F, Yuan SX, Ye C, et al. Oncofetal long noncoding RNA PVT1 promotes proliferation and stem cell-likeproperty of hepatocellular carcinoma cells by stabilizing NOP2. Hepatology. 2014;60:1278–90.

    CAS  Article  Google Scholar 

  13. 13.

    Wan L, Sun M, Liu GJ, Wei CC, Zhang EB, Kong R, et al. Long Noncoding RNA PVT1 promotes non-small cell lung cancer cell proliferation through epigenetically regulating LATS2 expression. Mol Cancer Ther. 2016;15:1082–94.

    CAS  Article  Google Scholar 

  14. 14.

    Li PD, Hu JL, Ma C, Ma H, Yao J, Chen LL, et al. Upregulation of the long non-coding RNA PVT1 promotes esophageal squamous cellcarcinoma progression by acting as a molecular sponge of miR-203 and LASP1. Oncotarget. 2017;8:34164–176.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Takahashi Y, Sawada G, Kurashige J, Uchi R, Matsumura T, Ueo H, et al. Amplification of PVT-1 is involved in poor prognosis via apoptosis inhibition in colorectal cancers. Br J Cancer. 2014;110:164–171.

    CAS  Article  Google Scholar 

  16. 16.

    Zhou Q, Chen F, Zhao J, Li B, Liang Y, Pan W, et al. Long non-coding RNA PVT1 promotes osteosarcoma development by acting as a molecular sponge to regulate miR-195. Oncotarget. 2016;7:82620–633.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Tseng YY, Moriarity BS, Gong W, Akiyama R, Tiwari A, Kawakami H, et al. PVT1 dependence in cancer with MYC copy-number increase. Nature. 2014;512:82–96.

    CAS  Article  Google Scholar 

  18. 18.

    Wang Y, Zhou J, Wang Z, Wang P, Li S. Upregulation of SOX2 activated LncRNA PVT1 expression promotes breast cancer cell growth and invasion. Biochem Biophys Res Commun. 2017;493:429–36.

    CAS  Article  Google Scholar 

  19. 19.

    Guo K, Yao J, Yu Q, Li Z, Huang H, Cheng J, et al. The expression pattern of long non-coding RNA PVT1 in tumor tissues and inextracellular vesicles of colorectal cancer correlates with cancer progression. Tumour Biol. 2017;39:9122–32.

    Google Scholar 

  20. 20.

    Zheng J, Yu F, Dong P, Wu L, Zhang Y, Hu Y, et al. Long non-coding RNA PVT1 activates hepatic stellate cells through competitivelybinding microRNA-152. Oncotarget. 2016;7:62886–897.

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Izaurralde E. Elucidating the temporal order of silencing. EMBO Rep. 2012;13:662–73.

    CAS  Article  Google Scholar 

  22. 22.

    Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers insight. Nat Rev Genet. 2008;9:102–14.

    CAS  Article  Google Scholar 

  23. 23.

    Heo I, Joo C, Cho J, Ha M, Han J, Kim VN. Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell. 2008;32:276–84.

    CAS  Article  Google Scholar 

  24. 24.

    Newman MA, Thomson JM, Hammond SM. Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNAprocessing. RNA. 2008;14:1539–49.

    CAS  Article  Google Scholar 

  25. 25.

    Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet. 2006;15:R17–29.

    CAS  Article  Google Scholar 

  26. 26.

    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;41:843–58.

    CAS  Article  Google Scholar 

  27. 27.

    Cao D, Allan RW, Cheng L, Peng Y, Guo CC, Dahiya N, et al. RNA-binding protein LIN28 is a marker for testicular germ cell tumors. Hum Pathol. 2011;42:710–18.

    CAS  Article  Google Scholar 

  28. 28.

    Wang T, He Y, Zhu Y, Chen M, Weng M, Yang C, et al. Comparison of the expression and function of Lin28A and Lin28B in colon cancer. Oncotarget. 2016;7:79605–16.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language. Cell. 2011;146:353–68.

    CAS  Article  Google Scholar 

  30. 30.

    Song YX, Sun JX, Zhao JH, Yang YC, Shi JX, Wu ZH, et al. Non-coding RNAs participate in the regulatory network of CLDN4 via ceRNA mediatedmiRNA evasion. Nat Commun. 2017;8:289–302.

    Article  Google Scholar 

  31. 31.

    Ma MZ, Zhang Y, Weng MZ, Wang SH, Hu Y, Hou ZY, et al. Long noncoding RNA GCASPC, a target of miR-17-3p, negatively regulates pyruvate carboxylase-dependent cell proliferation in gallbladder cancer. Cancer Res. 2016;76:5361–71.

    CAS  Article  Google Scholar 

  32. 32.

    Lu W, Wang J, Yang G, Yu N, Huang Z, Xu H, et al. Posttranscriptional regulation of Galectin-3 by miR-128 contributes to colorectal cancer progression. Oncotarget. 2017;8:15242–351.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Powers JT, Tsanov KM, Pearson DS, Roels F, Spina CS, Ebright R, et al. Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma. Nature. 2016;535:246–51.

    CAS  Article  Google Scholar 

  34. 34.

    Gokbuget D, Pereira JA, Bachofner S, Marchais A, Ciaudo C, Stoffel M, et al. The Lin28/let-7 axis is critical for myelination in the peripheral nervoussystem. Nat Commun. 2015;6:8584–93.

    CAS  Article  Google Scholar 

  35. 35.

    Cho SW, Xu J, Sun R, Mumbach MR, Carter AC, Chen YG, et al. Promoter of lncRNA gene PVT1 is a tumor-suppressor dna boundary element. Cell. 2018;173:1398–412.

    CAS  Article  Google Scholar 

  36. 36.

    Di CS, Zhang F, Sancho A, Li S, Aguilo F, Sun Y, et al. RBM5-AS1 is critical for self-renewal of colon cancer stem-like cells. Cancer Res. 2016;76:5615–27.

    Article  Google Scholar 

  37. 37.

    He F, Chen H, Yang P, Wu Q, Zhang T, Wang C, et al. Gankyrin sustains PI3K/GSK-3beta/beta-catenin signal activation and promotescolorectal cancer aggressiveness and progression. Oncotarget. 2016;7:81156–71.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    He F, Peng F, Xia X, Zhao C, Luo Q, Guan W, et al. MiR-135a promotes renal fibrosis in diabetic nephropathy by regulating TRPC1. Diabetologia. 2014;57:1726–36.

    CAS  Article  Google Scholar 

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This work was supported by grants from the National Natural Science Foundation of China (Grant no. 8187101464, 81600654 and 81600862); the Guangdong Natural Science Foundation (Grant no. 2017A030311035, 2016A030313490 and 2016A030310227); the Fundamental Research Funds for the Central Universities (Grant no. XZYXD2175080); and the Guangdong Provincial Department of Science and Technology (Grant no. 2017A020215146); Guangzhou Science Technology and Innovation Commission (Grant no. 201805010003); and US National Institutes of Health (NIH) grant R01 HL136507.

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Correspondence to Jie Cao.

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The authors declare that they have no conflict of interest.

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Accession numbers: Microarray data have been deposited in the Gene Expression Omnibus database (accession number GSE109454).

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He, F., Song, Z., Chen, H. et al. Long noncoding RNA PVT1-214 promotes proliferation and invasion of colorectal cancer by stabilizing Lin28 and interacting with miR-128. Oncogene 38, 164–179 (2019).

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