Skip to main content

Advertisement

SpringerLink
Log in

The long noncoding RNA HOXA transcript at the distal tip promotes colorectal cancer growth partially via silencing of p21 expression

  • Original Article
  • Published:
Tumor Biology

Abstract

Accumulating evidence strongly suggests that dysregulation of long noncoding RNAs (lncRNAs) is associated with human carcinogenesis. The lncRNA HOXA transcript at the distal tip (HOTTIP) is involved in the development of several cancers. However, the biological role of HOTTIP in colorectal cancer (CRC) has not yet been discussed. Here, we report that HOTTIP acts as a functional oncogene in the pathogenesis of CRC. In this study, quantitative polymerase chain reaction (qPCR) was performed to detect the expression of HOTTIP in 48 pairs of colorectal cancer samples. We found that overexpression of HOTTIP is correlated with an advanced pathological stage and a larger tumor size. Moreover, functional analyses revealed that the knockdown of HOTTIP expression by small interfering RNA (siRNA) or small hairpin RNA (shRNA) could inhibit cell proliferation and induce cell apoptosis. More importantly, we observed that HOTTIP knockdown induced a marked increase in the number of cells in the G0/G1 phase and a reduction in the number of cells in the S phase in both DLD-1 cells and SW480 cells. An in vivo experiment also revealed that the knockdown of HOTTIP inhibited tumor growth. Western blot and immunohistochemistry analyses indicated that HOTTIP potentially contributed to CRC cell growth partially through the silencing of p21 expression. Collectively, our results suggest that HOTTIP is involved in the progression of CRC and may provide evidence for HOTTIP being a target for therapy of this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383:1490–502.

    Article  PubMed  Google Scholar 

  2. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.

    Article  PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.

    Article  PubMed  Google Scholar 

  4. Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012;81:145–66.

    Article  CAS  PubMed  Google Scholar 

  5. Li L, Feng T, Lian Y, Zhang G, Garen A, Song X. Role of human noncoding RNAs in the control of tumorigenesis. Proc Natl Acad Sci U S A. 2009;106:12956–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Malek E, Jagannathan S, Driscoll JJ. Correlation of long non-coding RNA expression with metastasis, drug resistance and clinical outcome in cancer. Oncotarget. 2014;5:8027–38.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ling H, Vincent K, Pichler M, Fodde R, Berindan-Neagoe I, Slack FJ, et al. Junk DNA and the long non-coding RNA twist in cancer genetics. Oncogene. 2015;34(39):5003–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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. Nucleic Acids Res. 2013;41:D246–51.

    Article  CAS  PubMed  Google Scholar 

  9. Han D, Wang M, Ma N, Xu Y, Jiang Y, Gao X. Long noncoding RNAs: novel players in colorectal cancer. Cancer lett. 2015;361:13–21.

    Article  CAS  PubMed  Google Scholar 

  10. Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T, et al. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 2011;71:6320–6.

    Article  CAS  PubMed  Google Scholar 

  11. Ling H, Spizzo R, Atlasi Y, Nicoloso M, Shimizu M, Redis RS, et al. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res. 2013;23:1446–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yan B, Gu W, Yang Z, Gu Z, Yue X, Gu Q, et al. Downregulation of a long noncoding RNA-ncRuPAR contributes to tumor inhibition in colorectal cancer. Tumour Biol. 2014;35:11329–35.

    Article  CAS  PubMed  Google Scholar 

  13. Madamanchi NR, Hu ZY, Li F, Horaist C, Moon SK, Patterson C, et al. A noncoding RNA regulates human protease-activated receptor-1 gene during embryogenesis. Biochim Biophys Acta. 2002;1576:237–45.

    Article  CAS  PubMed  Google Scholar 

  14. Abbas T, Dutta A. P21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9:400–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Warfel NA, El-Deiry WS. p21WAF1 and tumourigenesis: 20 years after. Curr Opin Oncol. 2013;25:52–8.

    Article  CAS  PubMed  Google Scholar 

  16. Nie FQ, Sun M, Yang JS, Xie M, Xu TP, Xia R, et al. Long noncoding RNA ANRIL promotes non-small cell lung cancer cell proliferation and inhibits apoptosis by silencing KLF2 and P21 expression. Mol Cancer Ther. 2015;14:268–77.

    Article  CAS  PubMed  Google Scholar 

  17. Liu Y, Zhao J, Zhang W, Gan J, Hu C, Huang G, et al. LncRNA GAS5 enhances G1 cell cycle arrest via binding to YBX1 to regulate p21 expression in stomach cancer. Sci Rep. 2015;5:10159.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Xu TP, Liu XX, Xia R, Yin L, Kong R, Chen WM, et al. SP1-induced upregulation of the long noncoding RNA TINCR regulates cell proliferation and apoptosis by affecting KLF2 mRNA stability in gastric cancer. Oncogene. 2015;34(45):5648–61.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang H, Zhao L, Wang YX, Xi M, Liu SL, Luo LL. Long non-coding RNA HOTTIP is correlated with progression and prognosis in tongue squamous cell carcinoma. Tumour Biol. 2015;36(11):8805–9.

    Article  CAS  PubMed  Google Scholar 

  20. Cheng Y, Jutooru I, Chadalapaka G, Corton JC, Safe S. The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration. Oncotarget. 2015;6:10840–52.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Quagliata L, Matter MS, Piscuoglio S, Arabi L, Ruiz C, Procino A, et al. Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients. Hepatology. 2014;59:911–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011;472:120–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tsang FH, Au SL, Wei L, Fan DN, Lee JM, Wong CC, et al. Long non-coding RNA HOTTIP is frequently up-regulated in hepatocellular carcinoma and is targeted by tumour suppressive miR-125b. Liver Int. 2015;35:1597–606.

    Article  CAS  PubMed  Google Scholar 

  24. Xu MD, Qi P, Du X. Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application. Mod Pathol. 2014;27:1310–20.

    Article  CAS  PubMed  Google Scholar 

  25. Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer Discov. 2011;1:391–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tsang WP, Ng EKO, Ng SSM, Jin H, Yu J, Sung JJY, et al. Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer. Carcinogenesis. 2010;31:350–8.

    Article  CAS  PubMed  Google Scholar 

  27. Li Y, Li Y, Chen W, He F, Tan Z, Zheng J, et al. NEAT expression is associated with tumor recurrence and unfavorable prognosis in colorectal cancer. Oncotarget. 2015;6(29):27641–50.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 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. Brit J Cancer. 2013;110:164–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Qiu J, Yan J. Long non-coding RNA LINC01296 is a potential prognostic biomarker in patients with colorectal cancer. Tumor Biol. 2015;36(9):7175–83.

    Article  CAS  Google Scholar 

  30. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993;366:701–4.

    Article  CAS  PubMed  Google Scholar 

  31. Gartel AL, Radhakrishnan SK. Lost in transcription: p21 repression, mechanisms, and consequences. Cancer Res. 2005;65:3980–5.

    Article  CAS  PubMed  Google Scholar 

  32. Shi Y, Liu Y, Wang J, Jie D, Yun T, Li W, et al. Downregulated long noncoding RNA BANCR promotes the proliferation of colorectal cancer cells via downregulation of p21 expression. PLoS ONE. 2015;10:e122679.

    Google Scholar 

  33. Xie M, Sun M, Zhu YN, Xia R, Liu YW, Ding J, et al. Long noncoding RNA HOXA-AS2 promotes gastric cancer proliferation by epigenetically silencing P21/PLK3/DDIT3 expression. Oncotarget. 2015;6:33587–601.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the Medical Science and Technology Development Foundation, the Jiangsu Province Department of Health (H201407), the Six Talents Peak Project of Jiangsu province (WSN-050), and the Natural Science Foundation of Jiangsu Province of China (BK20151578).

Author information

Author notes

    Authors and Affiliations

    1. Department of Oncology, Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210000, Jiangsu, China

      Yifan Lian, Jie Ding, Ya Zhu, Juan Li, Peng Peng, Jirong Wang, Yingrui Fan & Keming Wang

    2. Departments of Pathology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu, China

      Zhihong Zhang

    3. Department of Oncology, Taixing People’s Hospital, Taixing, 225400, Jiangsu, China

      Yongguo Shi

    4. Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210000, Jiangsu, China

      Wei De

    Authors
    1. Yifan Lian
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jie Ding
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Zhihong Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yongguo Shi
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ya Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Juan Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Peng Peng
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Jirong Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Yingrui Fan
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Wei De
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Keming Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Keming Wang.

    Ethics declarations

    Informed consent was obtained from all patients. Our study was approved by the Research Ethics Committee of Nanjing Medical University, China.

    Conflicts of interest

    None

    Additional information

    Yifan Lian, Jie Ding and Zhihong Zhang contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Lian, Y., Ding, J., Zhang, Z. et al. The long noncoding RNA HOXA transcript at the distal tip promotes colorectal cancer growth partially via silencing of p21 expression. Tumor Biol. 37, 7431–7440 (2016). https://doi.org/10.1007/s13277-015-4617-2

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s13277-015-4617-2

    Keywords

    Search

    Navigation