Skip to main content
Springer Nature Link
Log in

Interaction with CCNH/CDK7 facilitates CtBP2 promoting esophageal squamous cell carcinoma (ESCC) metastasis via upregulating epithelial-mesenchymal transition (EMT) progression

  • Research Article
  • Published:
Tumor Biology

Abstract

See More

CtBP2, as a transcriptional corepressor of epithelial-specific genes, has been reported to promote tumor due to upregulating epithelial-mesenchymal transition (EMT) in cancer cells. CtBP2 was also demonstrated to contribute to the proliferation of esophageal squamous cell carcinoma (ESCC) cells through a negative transcriptional regulation of p16INK4A. In this study, for the first time, we reported that CtBP2 expression, along with CCNH/CDK7, was higher in ESCC tissues with lymph node metastases than in those without lymph node metastases. Moreover, both CtBP2 and CCNH/CDK7 were positively correlated with E-cadherin, tumor grade, and tumor metastasis. However, the concrete mechanism of CtBP2’s role in enhancing ESCC migration remains incompletely understood. We confirmed that CCNH/CDK7 could directly interact with CtBP2 in ESCC cells in vivo and in vitro. Furthermore, our data demonstrate for the first time that CtBP2 enhanced the migration of ESCC cells in a CCNH/CDK7-dependent manner. Our results indicated that CCNH/CDK7-CtBP2 axis may augment ESCC cell migration, and targeting the interaction of both may provide a novel therapeutic target of ESCC.

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

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

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
Fig. 7
Fig. 8

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  1. Li X, Suo J, Shao S, Xue L, Chen W, Dong L, et al. Overexpression of OLC1 promotes tumorigenesis of human esophageal squamous cell carcinoma. PLoS One. 2014;9(3):e90958. doi:10.1371/journal.pone.0090958.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Guan C, Shi H, Wang H, Zhang J, Ni W, Chen B, et al. CtBP2 contributes to malignant development of human esophageal squamous cell carcinoma by regulation of p16INK4A. J Cell Biochem. 2013;114(6):1343–54. doi:10.1002/jcb.24475.

    Article  CAS  PubMed  Google Scholar 

  3. Zhang L, Wu YD, Li P, Tu J, Niu YL, Xu CM, et al. Effects of cyclooxygenase-2 on human esophageal squamous cell carcinoma. World J Gastroenterol: WJG. 2011;17(41):4572–80. doi:10.3748/wjg.v17.i41.4572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349(23):2241–52. doi:10.1056/NEJMra035010.

    Article  CAS  PubMed  Google Scholar 

  5. Li M, Yang X, Shi H, Ren H, Chen X, Zhang S, et al. Downregulated expression of the cyclase-associated protein 1 (CAP1) reduces migration in esophageal squamous cell carcinoma. Jpn J Clin Oncol. 2013;43(9):856–64. doi:10.1093/jjco/hyt093.

    Article  PubMed  Google Scholar 

  6. Shagieva GS, Domnina LV, Chipysheva TA, Ermilova VD, Chaponnier C, Dugina VB. Actin isoforms and reorganization of adhesion junctions in epithelial-to-mesenchymal transition of cervical carcinoma cells. Biochem Biokhim. 2012;77(11):1266–76. doi:10.1134/S0006297912110053.

    Article  CAS  Google Scholar 

  7. Shi J, Wang DM, Wang CM, Hu Y, Liu AH, Zhang YL, et al. Insulin receptor substrate-1 suppresses transforming growth factor-beta1-mediated epithelial-mesenchymal transition. Cancer Res. 2009;69(18):7180–7. doi:10.1158/0008-5472.CAN-08-4470.

    Article  CAS  PubMed  Google Scholar 

  8. Wang Y, Liu F, Mao F, Hang Q, Huang X, He S, et al. Interaction with cyclin H/cyclin-dependent kinase 7 (CCNH/CDK7) stabilizes C-terminal binding protein 2 (CtBP2) and promotes cancer cell migration. J Biol Chem. 2013;288(13):9028–34. doi:10.1074/jbc.M112.432005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Prindull G, Zipori D. Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood. 2004;103(8):2892–9. doi:10.1182/blood-2003-08-2807.

    Article  CAS  PubMed  Google Scholar 

  10. Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172(7):973–81. doi:10.1083/jcb.200601018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Voulgari A, Pintzas A. Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta. 2009;1796(2):75–90. doi:10.1016/j.bbcan.2009.03.002.

    CAS  PubMed  Google Scholar 

  12. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7(2):131–42. doi:10.1038/nrm1835.

    Article  CAS  PubMed  Google Scholar 

  13. Tse JC, Kalluri R. Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J Cell Biochem. 2007;101(4):816–29. doi:10.1002/jcb.21215.

    Article  CAS  PubMed  Google Scholar 

  14. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, et al. Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol. 2007;213(2):374–83. doi:10.1002/jcp.21223.

    Article  CAS  PubMed  Google Scholar 

  15. Boyd JM, Subramanian T, Schaeper U, La Regina M, Bayley S, Chinnadurai G. A region in the C-terminus of adenovirus 2/5 E1a protein is required for association with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation, tumorigenesis and metastasis. EMBO J. 1993;12(2):469–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Schaeper U, Boyd JM, Verma S, Uhlmann E, Subramanian T, Chinnadurai G. Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation. Proc Natl Acad Sci U S A. 1995;92(23):10467–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang Q, Wang SY, Nottke AC, Rocheleau JV, Piston DW, Goodman RH. Redox sensor CtBP mediates hypoxia-induced tumor cell migration. Proc Natl Acad Sci U S A. 2006;103(24):9029–33. doi:10.1073/pnas.0603269103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Grooteclaes ML, Frisch SM. Evidence for a function of CtBP in epithelial gene regulation and anoikis. Oncogene. 2000;19(33):3823–8. doi:10.1038/sj.onc.1203721.

    Article  CAS  PubMed  Google Scholar 

  19. Tang L, Yang J, Ng SK, Rodriguez N, Choi PW, Vitonis A, et al. Autoantibody profiling to identify biomarkers of key pathogenic pathways in mucinous ovarian cancer. Eur J Cancer. 2010;46(1):170–9. doi:10.1016/j.ejca.2009.10.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Barroilhet L, Yang J, Hasselblatt K, Paranal RM, Ng SK, Rauh-Hain JA, et al. C-terminal binding protein-2 regulates response of epithelial ovarian cancer cells to histone deacetylase inhibitors. Oncogene. 2013;32(33):3896–903. doi:10.1038/onc.2012.380.

    Article  CAS  PubMed  Google Scholar 

  21. Birts CN, Harding R, Soosaipillai G, Halder T, Azim-Araghi A, Darley M, et al. Expression of CtBP family protein isoforms in breast cancer and their role in chemoresistance. Biol Cell Under Auspices Eur Cell Biol Organ. 2010;103(1):1–19. doi:10.1042/BC20100067.

    Article  Google Scholar 

  22. Fujii W, Nishimura T, Kano K, Sugiura K, Naito K. CDK7 and CCNH are components of CDK-activating kinase and are required for meiotic progression of pig oocytes. Biol Reprod. 2011;85(6):1124–32. doi:10.1095/biolreprod.111.091801.

    Article  CAS  PubMed  Google Scholar 

  23. Bartkova J, Zemanova M, Bartek J. Expression of CDK7/CAK in normal and tumor cells of diverse histogenesis, cell-cycle position and differentiation. Int J Cancer. 1996;66(6):732–7. doi:10.1002/(SICI)1097-0215(19960611)66:6<732::AID-IJC4>3.0.CO;2-0.

    Article  CAS  PubMed  Google Scholar 

  24. Fei M, Lu M, Wang Y, Zhao Y, He S, Gao S, et al. Arsenic trioxide-induced growth arrest of human hepatocellular carcinoma cells involving FOXO3a expression and localization. Med Oncol. 2009;26(2):178–85. doi:10.1007/s12032-008-9105-8.

    Article  CAS  PubMed  Google Scholar 

  25. Mouriaux F, Casagrande F, Pillaire MJ, Manenti S, Malecaze F, Darbon JM. Differential expression of G1 cyclins and cyclin-dependent kinase inhibitors in normal and transformed melanocytes. Invest Ophthalmol Vis Sci. 1998;39(6):876–84.

    CAS  PubMed  Google Scholar 

  26. Collins CS, Hong J, Sapinoso L, Zhou Y, Liu Z, Micklash K, et al. A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase. Proc Natl Acad Sci U S A. 2006;103(10):3775–80. doi:10.1073/pnas.0600040103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sobin LH, Fleming ID. TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997;80(9):1803–4.

    Article  CAS  PubMed  Google Scholar 

  28. Wang Y, Yang S, Ni Q, He S, Zhao Y, Yuan Q, et al. Overexpression of forkhead box J2 can decrease the migration of breast cancer cells. J Cell Biochem. 2012;113(8):2729–37. doi:10.1002/jcb.24146.

    Article  CAS  PubMed  Google Scholar 

  29. Scheel C, Weinberg RA. Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells? Int J Cancer. 2011;129(10):2310–4. doi:10.1002/ijc.26311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang J, Yang X, Wang Y, Shi H, Guan C, Yao L, et al. Low expression of cyclinH and cyclin-dependent kinase 7 can decrease the proliferation of human esophageal squamous cell carcinoma. Dig Dis Sci. 2013;58(7):2028–37. doi:10.1007/s10620-013-2597-x.

    Article  CAS  PubMed  Google Scholar 

  31. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi:10.3322/caac.20107.

    Article  PubMed  Google Scholar 

  32. Eccles SA, Welch DR. Metastasis: recent discoveries and novel treatment strategies. Lancet. 2007;369(9574):1742–57. doi:10.1016/S0140-6736(07)60781-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chuangui C, Peng T, Zhentao Y. The expression of high mobility group box 1 is associated with lymph node metastasis and poor prognosis in esophageal squamous cell carcinoma. Pathol Oncol Res: POR. 2012;18(4):1021–7. doi:10.1007/s12253-012-9539-3.

    Article  PubMed  Google Scholar 

  34. Wang Y, Zhou S, Yang X, Shi H, Li M, Xue Q, et al. Low expression of cyclic AMP response element modulator-1 can increase the migration and invasion of esophageal squamous cell carcinoma. Tumour Biol J Int Soc Oncodev Biol Med. 2013;34(6):3649–57. doi:10.1007/s13277-013-0946-1.

    Article  CAS  Google Scholar 

  35. Paliwal S, Ho N, Parker D, Grossman SR. CtBP2 promotes human cancer cell migration by transcriptional activation of Tiam1. Genes Cancer. 2012;3(7–8):481–90. doi:10.1177/1947601912463695.

    PubMed  PubMed Central  Google Scholar 

  36. Paliwal S, Kovi RC, Nath B, Chen YW, Lewis BC, Grossman SR. The alternative reading frame tumor suppressor antagonizes hypoxia-induced cancer cell migration via interaction with the COOH-terminal binding protein corepressor. Cancer Res. 2007;67(19):9322–9. doi:10.1158/0008-5472.CAN-07-1743.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Natural Science Foundation of China (No. 81272708).

Conflicts of interest

None

Author information

Author notes

    Authors and Affiliations

    1. Department of Oncology, The Second Affiliated Hospital, Soochow University, Suzhou, 215000, Jiangsu, China

      Jianguo Zhang & Ye Tian

    2. Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China

      Junya Zhu, Lei Yang, Chengqi Guan, Runzhou Ni, Yuchan Wang & Lili Ji

    Authors
    1. Jianguo Zhang
      View author publications

      Search author on:PubMed Google Scholar

    2. Junya Zhu
      View author publications

      Search author on:PubMed Google Scholar

    3. Lei Yang
      View author publications

      Search author on:PubMed Google Scholar

    4. Chengqi Guan
      View author publications

      Search author on:PubMed Google Scholar

    5. Runzhou Ni
      View author publications

      Search author on:PubMed Google Scholar

    6. Yuchan Wang
      View author publications

      Search author on:PubMed Google Scholar

    7. Lili Ji
      View author publications

      Search author on:PubMed Google Scholar

    8. Ye Tian
      View author publications

      Search author on:PubMed Google Scholar

    Corresponding author

    Correspondence to Ye Tian.

    Additional information

    Jianguo Zhang and Junya Zhu 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

    Zhang, J., Zhu, J., Yang, L. et al. Interaction with CCNH/CDK7 facilitates CtBP2 promoting esophageal squamous cell carcinoma (ESCC) metastasis via upregulating epithelial-mesenchymal transition (EMT) progression. Tumor Biol. 36, 6701–6714 (2015). https://doi.org/10.1007/s13277-015-3354-x

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue date:

    • DOI: https://doi.org/10.1007/s13277-015-3354-x

    Keywords