Skip to main content
Top
Published in: Tumor Biology 12/2015

01-12-2015 | Research Article

Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion

Authors: Xia Yan, Huiling Zhou, Tingting Zhang, Pan Xu, Shusen Zhang, Wei Huang, Linlin Yang, Xingxing Gu, Runzhou Ni, Tianyi Zhang

Published in: Tumor Biology | Issue 12/2015

Login to get access

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.
Literature
3.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
4.
go back to reference Frau M, Biasi F, Feo F, et al. Prognostic markers and putative therapeutic targets for hepatocellular carcinoma. Mol Aspects Med. 2010;31:179–93.CrossRefPubMed Frau M, Biasi F, Feo F, et al. Prognostic markers and putative therapeutic targets for hepatocellular carcinoma. Mol Aspects Med. 2010;31:179–93.CrossRefPubMed
5.
go back to reference Katoh M. Human FOX, gene family (Review). Int J Oncol. 2004;25:1495–500.PubMed Katoh M. Human FOX, gene family (Review). Int J Oncol. 2004;25:1495–500.PubMed
7.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
8.
go back to reference 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.PubMed 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.PubMed
9.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
10.
go back to reference Hu H, Wang B, Borde M, et al. FOXP1 is an essential transcriptional regulator of B cell development. Nat Immunol. 2006;7:819–26.CrossRefPubMed Hu H, Wang B, Borde M, et al. FOXP1 is an essential transcriptional regulator of B cell development. Nat Immunol. 2006;7:819–26.CrossRefPubMed
11.
go back to reference Shu W, Lu MM, Zhang Y, et al. FOXP2 and FOXP1 cooperatively regulate lung and esophagus development. Development. 2007;134:1991–2000.CrossRefPubMed Shu W, Lu MM, Zhang Y, et al. FOXP2 and FOXP1 cooperatively regulate lung and esophagus development. Development. 2007;134:1991–2000.CrossRefPubMed
12.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
13.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
14.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
15.
go back to reference 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.CrossRef 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.CrossRef
16.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
17.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
18.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
19.
go back to reference Zhang Y, Zhang S, et al. Prognostic significance of FOXP1 as an oncogene in hepatocellular carcinoma. J Clin Pathol. 2012;65:528–33.CrossRefPubMed Zhang Y, Zhang S, et al. Prognostic significance of FOXP1 as an oncogene in hepatocellular carcinoma. J Clin Pathol. 2012;65:528–33.CrossRefPubMed
20.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
21.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
22.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
23.
go back to reference Teufel A, Wong EA, Mukhopadhyay M, et al. FOXP4, a novel forkhead transcription factor. Biochim Biophys Acta. 2003;1627:147–52.CrossRefPubMed Teufel A, Wong EA, Mukhopadhyay M, et al. FOXP4, a novel forkhead transcription factor. Biochim Biophys Acta. 2003;1627:147–52.CrossRefPubMed
24.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
25.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
26.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
27.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
28.
go back to reference Schroeder DI, Myers RM. Multiple transcription start sites for FOXP2 with varying cellular specificities. Gene. 2008;413:42–8.CrossRefPubMed Schroeder DI, Myers RM. Multiple transcription start sites for FOXP2 with varying cellular specificities. Gene. 2008;413:42–8.CrossRefPubMed
29.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
30.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
31.
go back to reference 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.CrossRef 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.CrossRef
32.
go back to reference 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.PubMed 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.PubMed
33.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
34.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
35.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
36.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
37.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
38.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
39.
go back to reference Tallon B, Bhawan J. FOXP3 expression is increased in cutaneous squamous cell carcinoma with perineural invasion. J Cutan Pathol. 2010;37:1184–5.CrossRefPubMed Tallon B, Bhawan J. FOXP3 expression is increased in cutaneous squamous cell carcinoma with perineural invasion. J Cutan Pathol. 2010;37:1184–5.CrossRefPubMed
40.
go back to reference Zhang HY, Sun H. Up-regulation of FOXP3 inhibits cell proliferation, migration and invasion in epithelial ovarian cancer. Cancer Lett. 2010;287:91–7.CrossRefPubMed Zhang HY, Sun H. Up-regulation of FOXP3 inhibits cell proliferation, migration and invasion in epithelial ovarian cancer. Cancer Lett. 2010;287:91–7.CrossRefPubMed
41.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
42.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
43.
go back to reference Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.CrossRefPubMed Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.CrossRefPubMed
44.
go back to reference Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.CrossRefPubMed Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.CrossRefPubMed
45.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
46.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
47.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
Metadata
Title
Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion
Authors
Xia Yan
Huiling Zhou
Tingting Zhang
Pan Xu
Shusen Zhang
Wei Huang
Linlin Yang
Xingxing Gu
Runzhou Ni
Tianyi Zhang
Publication date
01-12-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3701-y

Other articles of this Issue 12/2015

Tumor Biology 12/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine