CUTL1 induces epithelial-mesenchymal transition in non-small cell lung cancer.

The homeobox transcription factor CUTL1 has been associated with cellular proliferation and cell cycle progression, and CUTL1 functions as an oncogene. The aim of the present study was to investigate whether CUTL1 participates in epithelial-mesenchymal transition (EMT). The expression levels of CUTL1, E-cadherin, N-cadherin and Snail were determined by immunohistochemistry assay, immunofluorescence assay or real-time quantitative reverse transcription PCR. Their roles in non-small cell lung cancer (NSCLC) were assessed by functional analyses. Protein expression was detected by western blot analysis. The CUTL1 expression levels are higher in non-small cell lung cancer (NSCLC) tissues. High CUTL1 expression in NSCLC is associated with the mesenchymal-like phenotype. Mechanistically, CUTL1 upregulates transforming growth factor β receptor I (TβR-I) expression, and the TβR-I inhibitor SB431542 abolishes EMT elicited by ectopic CUTL1 expression. Transforming growth factor β (TGF-β) signaling is essential for CUTL1-induced EMT in NSCLC cells. CUTL1 is downstream of TGF-β signaling and CUTL1 is involved in the expression of the TβR-I. This study indicates that CUTL1 may be a potential target for anti-lung cancer therapy.

[1]  G. Stein,et al.  The CCAAT displacement protein/cut homeodomain protein represses osteocalcin gene transcription and forms complexes with the retinoblastoma protein-related protein p107 and cyclin A. , 1999, Cancer research.

[2]  A. Nepveu,et al.  Role of the multifunctional CDP/Cut/Cux homeodomain transcription factor in regulating differentiation, cell growth and development. , 2001, Gene.

[3]  J. Massagué,et al.  Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus , 2003, Cell.

[4]  B. Goulet,et al.  CDP/Cux Stimulates Transcription from the DNA Polymerase α Gene Promoter , 2003, Molecular and Cellular Biology.

[5]  Gerhard Christofori,et al.  Cell adhesion and signalling by cadherins and Ig-CAMs in cancer , 2004, Nature Reviews Cancer.

[6]  C. D'Arrigo,et al.  CUTL1 is a target of TGFβ signaling that enhances cancer cell motility and invasiveness , 2005 .

[7]  R. Derynck,et al.  SPECIFICITY AND VERSATILITY IN TGF-β SIGNALING THROUGH SMADS , 2005 .

[8]  J. Thiery,et al.  Complex networks orchestrate epithelial–mesenchymal transitions , 2006, Nature Reviews Molecular Cell Biology.

[9]  J. Downward,et al.  CUTL1: A Key Mediator of TGFβ-Induced Tumor Invasion , 2006 .

[10]  A. Rajasekaran,et al.  Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. , 2006, Cancer research.

[11]  Kohei Miyazono,et al.  Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β , 2007 .

[12]  G. Wichert,et al.  CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation , 2007, Oncogene.

[13]  J. Downward,et al.  WNT5A--target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer. , 2007, Carcinogenesis.

[14]  C. Heldin,et al.  Signaling networks guiding epithelial–mesenchymal transitions during embryogenesis and cancer progression , 2007, Cancer science.

[15]  Laurent Sansregret,et al.  The multiple roles of CUX1: insights from mouse models and cell-based assays. , 2008, Gene.

[16]  C. Gurrola-Díaz,et al.  TGF‐β1 serum concentration as a complementary diagnostic biomarker of lung cancer: establishment of a cut‐point value , 2011, Journal of clinical laboratory analysis.

[17]  Jian-ming Li,et al.  Snail as a key regulator of PRL-3 gene in colorectal cancer , 2011, Cancer biology & therapy.

[18]  M. Tatari,et al.  EMT as the ultimate survival mechanism of cancer cells. , 2012, Seminars in cancer biology.

[19]  P. Massion,et al.  Smoking Induces Epithelial-to-Mesenchymal Transition in Non–Small Cell Lung Cancer through HDAC-Mediated Downregulation of E-Cadherin , 2012, Molecular Cancer Therapeutics.

[20]  Massimo Broggini,et al.  Epithelial-mesenchymal transition and breast cancer: role, molecular mechanisms and clinical impact. , 2012, Cancer treatment reviews.

[21]  Jing Yang,et al.  Epithelial–mesenchymal plasticity in carcinoma metastasis , 2013, Genes & development.

[22]  Zhaogang Dong,et al.  N-Cadherin Expression Is Associated with Acquisition of EMT Phenotype and with Enhanced Invasion in Erlotinib-Resistant Lung Cancer Cell Lines , 2013, PloS one.

[23]  K. Rabe,et al.  Management of non-small-cell lung cancer: recent developments , 2013, The Lancet.

[24]  Meng Zhao,et al.  Cutl1: a potential target for cancer therapy. , 2013, Cellular signalling.

[25]  Y. Chou,et al.  Identification of subgroup patients with stage IIIB/IV non-small cell lung cancer at higher risk for brain metastases. , 2013, Lung cancer.

[26]  Yibin Kang,et al.  Multilayer control of the EMT master regulators , 2014, Oncogene.

[27]  I. Fabregat,et al.  TGF-beta signaling in cancer treatment. , 2014, Current pharmaceutical design.

[28]  Ravi Salgia,et al.  Molecular pathways and therapeutic targets in lung cancer , 2014, Oncotarget.

[29]  Samy Lamouille,et al.  Molecular mechanisms of epithelial–mesenchymal transition , 2014, Nature Reviews Molecular Cell Biology.

[30]  The transcription factor CUTL1 is associated with proliferation and prognosis in malignant melanoma , 2014, Melanoma research.

[31]  Shuang Huang,et al.  SHOX2 is a direct miR-375 target and a novel epithelial-to-mesenchymal transition inducer in breast cancer cells. , 2014, Neoplasia.