Skip to main content
Log in

Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion

  • Research Article
  • Published:
Tumor Biology

Abstract

Hepatocellular carcinoma (HCC) is a major health concern with a high morbidity and mortality rate worldwide. However, the mechanism underlying hepatocarcinogenesis remains unclear. Forkhead box P2 (FOXP2) has been implicated in various human cancer types. However, the role of FOXP2 in HCC remains unknown. Western blot and immunohistochemistry were used to measure the expression of FOXP2 protein in HCC and adjacent normal tissues in 50 patients. Wound healing and transwell assays were used to determine the cell invasion ability. We showed that the level of FOXP2 was significantly reduced in HCC compared with the adjacent non-tumorous tissue. There was statistical significance between the expression of FOXP2 and vein invasion (P = 0.017), number of tumor nodes (P = 0.028), and AFP (P = 0.033). Low expression of FOXP2 correlated with poor survival. Moreover, wound healing and transwell assays showed that FOXP2 could decrease cell invasion and affect the expression of vimentin and E-cadherin. Our results suggested that FOXP2 expression was downregulated in HCC tumor tissues, and reduced FOXP2 expression was associated with poor overall survival. In addition, downregulation of FOXP2 significantly enhanced cell invasiveness. These findings uncover that FOXP2 might be a new prognostic factor and be closely correlated with HCC cell invasion.

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

Access this article

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  1. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907–17.

    Article  PubMed  Google Scholar 

  2. Yang JD, Roberts LR. Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol. 2010;7:448–58.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Poon RT, Ng IO, Fan ST, Lai EC, Lo CM, Liu CL, et al. Clinicopathologic features of long-term survivors and disease-free survivors after resection of hepatocellular carcinoma: a study of a prospective cohort. J Clin Oncol. 2001;19:3037–44.

    Article  CAS  PubMed  Google Scholar 

  4. Frau M, Biasi F, Feo F, et al. Prognostic markers and putative therapeutic targets for hepatocellular carcinoma. Mol Aspects Med. 2010;31:179–93.

    Article  CAS  PubMed  Google Scholar 

  5. Katoh M. Human FOX, gene family (Review). Int J Oncol. 2004;25:1495–500.

    CAS  PubMed  Google Scholar 

  6. Koon HB, Ippolito GC, Banham AH, et al. FOXP1: a potential therapeutic target in cancer. Expert Opin Ther Targets. 2007;11:955–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Green MR, Gandhi MK, Courtney MJ, et al. Relative abundance of full-length and truncated FOXP1 isoforms is associated with differential NF kappaB activity in follicular lymphoma. Leuk Res. 2009;33:1699–702.

    Article  CAS  PubMed  Google Scholar 

  8. Banham AH, Beasley N, Campo E, et al. The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p. Cancer Res. 2001;61:8820–9.

    CAS  PubMed  Google Scholar 

  9. Wang B, Weidenfeld J, Lu MM, et al. FOXP1 regulates cardiac outflow tract, endocardial cushion morphogenesis and myocyte proliferation and maturation. Development. 2004;131:4477–87.

    Article  CAS  PubMed  Google Scholar 

  10. Hu H, Wang B, Borde M, et al. FOXP1 is an essential transcriptional regulator of B cell development. Nat Immunol. 2006;7:819–26.

    Article  CAS  PubMed  Google Scholar 

  11. Shu W, Lu MM, Zhang Y, et al. FOXP2 and FOXP1 cooperatively regulate lung and esophagus development. Development. 2007;134:1991–2000.

    Article  CAS  PubMed  Google Scholar 

  12. Li C, Tucker PW. DNA-binding properties and secondary structural model of the hepatocyte nuclear factor 3/fork head domain. Proc Natl Acad Sci U S A. 1993;90:11583–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fox SB, Brown P, Han C, et al. Expression of the forkhead transcription factor FOXP1 is associated with estrogen receptor alpha and improved survival in primary human breast carcinomas. Clin Cancer Res. 2004;10:3521–7.

    Article  CAS  PubMed  Google Scholar 

  14. Bates GJ, Fox SB, Han C, et al. Expression of the forkhead transcription factor FOXP1 is associated with that of estrogen receptor-beta in primary invasive breast carcinomas. Breast Cancer Res Treat. 2008;111:453–9.

    Article  CAS  PubMed  Google Scholar 

  15. Toma MI, Weber T, Meinhardt M, et al. Expression of the forkhead transcription factor FOXP1 is associated with tumor grade and Ki67 expression in clear cell renal cell carcinoma. Cancer Investig. 2011;29:123–9.

    Article  Google Scholar 

  16. Banham AH, Boddy J, Launchbury R, et al. Expression of the forkhead transcription factor FOXP1 is associated both with hypoxia inducible factors (HIFs) and the androgen receptor in prostate cancer but is not directly regulated by androgens or hypoxia. Prostate. 2007;67:1091–8.

    Article  CAS  PubMed  Google Scholar 

  17. Takayama K, Horie-Inoue K, Ikeda K, et al. FOXP1 is an androgen-responsive transcription factor that negatively regulates androgen receptor signaling in prostate cancer cells. Biochem Biophys Res Commun. 2008;374:388–93.

    Article  CAS  PubMed  Google Scholar 

  18. Giatromanolaki A, Koukourakis MI, Sivridis E, et al. Loss of expression and nuclear/cytoplasmic localization of the FOXP1 forkhead transcription factor are common events in early endometrial cancer: relationship with estrogen receptors and HIF-1α expression. Mod Pathol. 2006;19:9–16.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang Y, Zhang S, et al. Prognostic significance of FOXP1 as an oncogene in hepatocellular carcinoma. J Clin Pathol. 2012;65:528–33.

    Article  PubMed  Google Scholar 

  20. Ebert LM, Tan BS, Browning J, Svobodova S, Russell SE, Kirkpatrick N, et al. The regulatory T cell-associated transcription factor FOXP3 is expressed by tumor cells. Cancer Res. 2008;68:3001–9.

    Article  CAS  PubMed  Google Scholar 

  21. Hinz S, Pagerols-Raluy L, Oberg HH, Ammerpohl O, Grussel S, Sipos B, et al. FOXP3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res. 2007;67:8344–50.

    Article  CAS  PubMed  Google Scholar 

  22. Howarth KD, Blood KA, Ng BL, et al. Array painting reveals a high frequency of balanced translocations in breast cancer cell lines that break in cancer-relevant genes. Oncogene. 2008;27:3345–59.

    Article  CAS  PubMed  Google Scholar 

  23. Teufel A, Wong EA, Mukhopadhyay M, et al. FOXP4, a novel forkhead transcription factor. Biochim Biophys Acta. 2003;1627:147–52.

    Article  CAS  PubMed  Google Scholar 

  24. Shu W, Yang H, Zhang L, et al. Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors. J Biol Chem. 2001;276:27488–97.

    Article  CAS  PubMed  Google Scholar 

  25. Wang B, Lin D, et al. Multiple domains define the expression and regulatory properties of FOXP1 forkhead transcriptional repressors. J Biol Chem. 2003;278:24259–68.

    Article  CAS  PubMed  Google Scholar 

  26. Li S, Weidenfeld J, et al. Transcriptional and DNA binding activity of the FOXP1/2/4 family is modulated by heterotypic and homotypic protein interactions. Mol Cell Biol. 2004;24:809–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Campbell AJ, Lyne L, Brown PJ, et al. Aberrant expression of the neuronal transcription factor FOXP2 in neoplastic plasma cells. Br J Haematol. 2010;149:221–30.

    Article  CAS  PubMed  Google Scholar 

  28. Schroeder DI, Myers RM. Multiple transcription start sites for FOXP2 with varying cellular specificities. Gene. 2008;413:42–8.

    Article  CAS  PubMed  Google Scholar 

  29. Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature. 2001;413:519–23.

    Article  CAS  PubMed  Google Scholar 

  30. Stumm L, Burkhardt L, Steurer S, et al. Strong expression of the neuronal transcription factor FOXP2 is linked to an increased risk of early PSA recurrence in ERG fusion-negative cancers. J Clin Pathol. 2013;66:563–8.

    Article  CAS  PubMed  Google Scholar 

  31. Benjamin GC, Antoine C, George WB, et al. MSC-regulated MicroRNAs converge on the transcription factor FOXP2 and promote breast cancer metastasis. Cell Stem Cell. 2014;15:762–74.

    Article  Google Scholar 

  32. Xu X, Yamamoto H, Sakon M, Yasui M, Ngan CY, Fukunaga H, et al. Over-expression of CDC25A phosphatase is associated with hyper-growth activity and poor prognosis of human hepatocellular carcinomas. Clin Cancer Res. 2003;9(5):1764–72.

    CAS  PubMed  Google Scholar 

  33. Yu C, Chen K, Zheng H, et al. Overexpression of astrocyte elevated gene-1 (AEG-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis. Carcinogenesis. 2009;30:894–901.

    Article  CAS  PubMed  Google Scholar 

  34. Wang Y, Yang S, Ni Q, He S, Zhao Y, Yuan Q, et al. Over-expression of forkhead box J2 can decrease the migration of breast cancer cells. J Cell Biochem. 2012;113(8):2729–37.

    Article  CAS  PubMed  Google Scholar 

  35. Du J, Li L, Ou Z, Kong C, Zhang Y, Dong Z, et al. FOXC1, a target of polycomb, inhibits metastasis of breast cancer cells. Breast Cancer Res Treat. 2011;131:65–73.

    Article  PubMed  Google Scholar 

  36. Malin D, Kim IM, Boetticher E, Kalin TV, Ramakrishna S, Meliton L, et al. Forkhead box F1 is essential for migration of mesenchymal cells and directly induces integrin-beta3 expression. Mol Cell Biol. 2007;27:2486–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang IC, Chen YJ, Hughes DE, Ackerson T, Major ML, Kalinichenko VV, et al. FOXM1 regulates transcription of JNK1 to promote the G1/S transition and tumor cell invasiveness. J Biol Chem. 2008;283:20770–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bao B, Wang Z, Ali S, Kong D, Banerjee S, Ahmad A, et al. Over-expression of FOXM1 leads to epithelial–mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. J Cell Biochem. 2011;112:2296–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tallon B, Bhawan J. FOXP3 expression is increased in cutaneous squamous cell carcinoma with perineural invasion. J Cutan Pathol. 2010;37:1184–5.

    Article  PubMed  Google Scholar 

  40. Zhang HY, Sun H. Up-regulation of FOXP3 inhibits cell proliferation, migration and invasion in epithelial ovarian cancer. Cancer Lett. 2010;287:91–7.

    Article  CAS  PubMed  Google Scholar 

  41. Storz P, Doppler H, Copland JA, Simpson KJ, Toker A. FOXO3a promotes tumor cell invasion through the induction of matrix metalloproteinases. Mol Cell Biol. 2009;29:4906–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schrader J, Gordon-Walker TT, Aucott RL, et al. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology. 2011;53:1192–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.

    Article  CAS  PubMed  Google Scholar 

  44. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.

    Article  CAS  PubMed  Google Scholar 

  45. Yang MH, Chen CL, Chau GY, Chiou SH, Su CW, Chou TY, et al. Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology. 2009;50:1464–74.

    Article  CAS  PubMed  Google Scholar 

  46. Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, Wang XH, et al. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res. 2006;12:5369–76.

    Article  CAS  PubMed  Google Scholar 

  47. Chen L, Chan TH, Yuan YF, Hu L, Huang J, Ma S, et al. CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients. J Clin Invest. 2010;120:1178–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Compliance with ethical standards

We investigated 50 cases of liver cancer provided by the Surgery Department at the Affiliated Hospital of Nantong University. Ethics committee approval was obtained from the Institutional Ethics Committee of Affiliated Hospital of Nantong University to the commencement of the study, and written informed consent was obtained from every patient.

Conflicts of interest

None

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tianyi Zhang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yan, X., Zhou, H., Zhang, T. et al. Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion. Tumor Biol. 36, 9611–9619 (2015). https://doi.org/10.1007/s13277-015-3701-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3701-y

Keywords

Navigation