Transcription factor glioma-associated oncogene homolog 1 is required for transforming growth factor-β1-induced epithelial-mesenchymal transition of non-small cell lung cancer cells

Li,Hua; Da,Li‑Jun; Fan,Wei‑Dong; Long,Xiao‑Hong; Zhang,Xian‑Quan

doi:10.3892/mmr.2015.3150

Transcription factor glioma-associated oncogene homolog 1 is required for transforming growth factor-β1-induced epithelial-mesenchymal transition of non-small cell lung cancer cells

Authors:
- Hua Li
- Li‑Jun Da
- Wei‑Dong Fan
- Xiao‑Hong Long
- Xian‑Quan Zhang
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Affiliations: Department of Oncology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China
Published online on: January 7, 2015 https://doi.org/10.3892/mmr.2015.3150
Pages: 3259-3268
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Epithelial‑mesenchymal transition (EMT) is the process by which epithelial cells depolarize and acquire a mesenchymal phenotype, and is a common early step in the process of metastasis. Patients with lung cancer frequently already have distant metastases when they are diagnosed, highlighting the requirement for early and effective interventions to control metastatic disease. Transforming growth factor‑β1 (TGF‑β1) is able to induce EMT, however the molecular mechanism of this remains unclear. In the current study, TGF‑β1 was reported to induce EMT and promote the migration of non‑small cell lung cancer (NSCLC) cells. A notable observation was that EMT induction was accompanied by the upregulation of human glioma‑associated oncogene homolog 1 (Gli1) mRNA and protein levels. Furthermore, Gli1 levels were depleted by small interfering RNA, and the Gli1 inhibitor GANT 61 attenuated the TGF‑β1‑mediated induction of EMT and cell migration. The results of the current study suggest that Gli1 regulates TGF‑β1‑induced EMT, which may provide a novel therapeutic target to inhibit metastasis in patients with NSCLC.

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1	Cagle PT, Allen TC, Dacic S, et al: Revolution in lung cancer: new challenges for the surgical pathologist. Arch Pathol Lab Med. 135:110–116. 2011.PubMed/NCBI
2	Juergens R and Brahmer J: Targeting the epidermal growth factor receptor in non-small-cell lung cancer: who, which, when, and how? Curr Oncol Rep. 9:255–264. 2007. View Article : Google Scholar : PubMed/NCBI
3	Alberg AJ, Ford JG and Samet JM; American College of Chest Physicians. Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 132(Suppl): 29S–55S. 2007. View Article : Google Scholar : PubMed/NCBI
4	Gavert N and Ben-Ze’ev A: Epithelial-mesenchymal transition and the invasive potential of tumors. Trends Mol Med. 14:199–209. 2008. View Article : Google Scholar : PubMed/NCBI
5	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
6	Prudkin L, Liu DD, Ozburn NC, et al: Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung. Mod Pathol. 22:668–678. 2009. View Article : Google Scholar : PubMed/NCBI
7	Li LP, Lu CH, Chen ZP, et al: Subcellular proteomics revealed the epithelial-mesenchymal transition phenotype in lung cancer. Proteomics. 11:429–439. 2011. View Article : Google Scholar : PubMed/NCBI
8	Wang G, Dong W, Shen H, et al: A comparison of Twist and E-cadherin protein expression in primary non-small-cell lung carcinoma and corresponding metastases. Eur J Cardiothorac Surg. 39:1028–1032. 2011. View Article : Google Scholar : PubMed/NCBI
9	Pirozzi G, Tirino V, Camerlingo R, et al: Epithelial to mesenchymal transition by TGFβ-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PLoS One. 6:e215482011. View Article : Google Scholar
10	Soltermann A, Tischler V, Arbogast S, et al: Prognostic significance of epithelial-mesenchymal and mesenchymal-epithelial transition protein expression in non-small cell lung cancer. Clin Cancer Res. 14:7430–7437. 2008. View Article : Google Scholar : PubMed/NCBI
11	Lee JM, Dedhar S, Kalluri R and Thompson EW: The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 172:973–981. 2006. View Article : Google Scholar : PubMed/NCBI
12	Zhang HJ, Wang HY, Zhang HT, et al: Transforming growth factor-β1 promotes lung adenocarcinoma invasion and metastasis by epithelial-to-mesenchymal transition. Mol Cell Biochem. 355:309–314. 2011. View Article : Google Scholar : PubMed/NCBI
13	Gialmanidis IP, Bravou V, Amanetopoulou SG, Varakis J, Kourea H and Papadaki H: Overexpression of hedgehog pathway molecules and FOXM1 in non-small cell lung carcinomas. Lung Cancer. 66:64–74. 2009. View Article : Google Scholar : PubMed/NCBI
14	Stecca B and Ruiz I Altaba A: Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals. J Mol Cell Biol. 2:84–95. 2010. View Article : Google Scholar : PubMed/NCBI
15	Aokage K, Ishii G, Ohtaki Y, et al: Dynamic molecular changes associated with epithelial-mesenchymal transition and subsequent mesenchymal-epithelial transition in the early phase of metastatic tumor formation. Int J Cancer. 128:1585–1595. 2011. View Article : Google Scholar
16	Kasai H, Allen JT, Mason RM, Kamimura T and Zhang Z: TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res. 6:562005. View Article : Google Scholar : PubMed/NCBI
17	Kim JH, Jang YS, Eom KS, et al: Transforming growth factor beta1 induces epithelial-to-mesenchymal transition of A549 cells. J Korean Med Sci. 22:898–904. 2007. View Article : Google Scholar : PubMed/NCBI
18	Sporn MB: The war on cancer. Lancet. 347:1377–1381. 1996. View Article : Google Scholar : PubMed/NCBI
19	Maitah MY, Ali S, Ahmad A, Gadgeel S and Sarkar FH: Up-regulation of sonic hedgehog contributes to TGF-β1-induced epithelial to mesenchymal transition in NSCLC cells. PLoS One. 6:e160682011. View Article : Google Scholar
20	Zhu H and Lo HW: The human glioma-associated oncogene homolog 1 (GLI1) family of transcription factors in gene regulation and diseases. Curr Genomics. 11:238–245. 2010. View Article : Google Scholar : PubMed/NCBI
21	Zheng X, Vittar NB, Gai X, et al: The transcription factor GLI1 mediates TGFβ1 driven EMT in hepatocellular carcinoma via a SNAI1-dependent mechanism. PLoS One. 7:e495812012. View Article : Google Scholar
22	Massagué J, Blain SW and Lo RS: TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 103:295–309. 2000. View Article : Google Scholar : PubMed/NCBI
23	Ko H, So Y, Jeon H, Jeong MH, et al: TGF-β1-induced epithelial-mesenchymal transition and acetylation of Smad2 and Smad3 are negatively regulated by EGCG in human A549 lung cancer cells. Cancer Lett. 10:205–213. 2013. View Article : Google Scholar
24	Gunaratne A, Thai BL and Di Guglielmo GM: Atypical protein kinase C phosphorylates Par6 and facilitates transforming growth factor β-induced epithelial-to-mesenchymal transition. Mol Cell Biol. 33:874–886. 2013. View Article : Google Scholar :
25	Liu LC, Tsao TC, Hsu SR, Wang HC, Tsai TC, Kao JY and Way TD: EGCG inhibits transforming growth factor-β-mediated epithelial-to-mesenchymal transition via the inhibition of Smad2 and Erk1/2 signaling pathways in nonsmall cell lung cancer cells. J Agric Food Chem. 60:9863–9873. 2012. View Article : Google Scholar : PubMed/NCBI
26	Cao M, Seike M, Soeno C, et al: MiR-23a regulates TGF-β-induced epithelial-mesenchymal transition by targeting E-cadherin in lung cancer cells. Int J Oncol. 41:869–875. 2012.PubMed/NCBI
27	Pasca di Magliano M and Hebrok M: Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 3:903–911. 2003. View Article : Google Scholar
28	Ruel L, Rodriguez R, Gallet A, Lavenant-Staccini L and Thérond PP: Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Nat Cell Biol. 5:907–913. 2003. View Article : Google Scholar : PubMed/NCBI
29	Wang B, Fallon JF and Beachy PA: Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell. 100:423–434. 2000. View Article : Google Scholar : PubMed/NCBI
30	Bai CB, Stephen D and Joyner AL: All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev Cell. 6:103–115. 2004. View Article : Google Scholar : PubMed/NCBI
31	Teglund S and Toftgård R: Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta. 1805.181–208. 2010.
32	Katoh Y and Katoh M: Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr Mol Med. 9:873–886. 2009. View Article : Google Scholar : PubMed/NCBI
33	Yuan Z, Goetz JA, Singh S, et al: Frequent requirement of hedgehog signaling in non-small cell lung carcinoma. Oncogene. 26:1046–1055. 2007. View Article : Google Scholar
34	Yoo YA, Kang MH, Lee HJ, et al: Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer. Cancer Res. 71:7061–7070. 2011. View Article : Google Scholar : PubMed/NCBI
35	LoRusso PM, Rudin CM, Reddy JC, et al: Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res. 17:2502–2511. 2011. View Article : Google Scholar : PubMed/NCBI
36	Ruiz I Altaba A, Mas C and Stecca B: The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol. 17:438–447. 2007. View Article : Google Scholar : PubMed/NCBI
37	Chen XF, Zhang HJ, Wang HB, et al: Transforming growth factor-β1 induces epithelial-to mesenchymal transition in human lung cancer cells via PI3K/Akt and MEK/Erk1/2 signaling pathways. Mol Biol Rep. 39:3549–3556. 2012. View Article : Google Scholar
38	Yauch RL, Januario T, Eberhard DA, et al: Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res. 11:8686–8698. 2005. View Article : Google Scholar : PubMed/NCBI
39	Shintani Y, Okimura A, Sato K, et al: Epithelial to mesenchymal transition is a determinant of sensitivity to chemoradiotherapy in non-small cell lung cancer. Ann Thorac Surg. 92:1794–1804. 2011. View Article : Google Scholar : PubMed/NCBI
40	Jung JW, Hwang SY, Hwang JS, Oh ES, Park S and Han IO: Ionising radiation induces changes associated with epithelial-mesenchymal transdifferentiation and increased cell motility of A549 lung epithelial cells. Eur J Cancer. 43:1214–1224. 2007. View Article : Google Scholar : PubMed/NCBI
41	Zhou YC, Liu JY, Li J, et al: Ionizing radiation promotes migration and invasion of cancer cells through transforming growth factor-beta-mediated epithelial-mesenchymal transition. Int J Radiat Oncol Biol Phys. 81:1530–1537. 2011. View Article : Google Scholar : PubMed/NCBI
42	Theys J, Jutten B, Habets R, et al: E-Cadherin loss associated with EMT promotes radioresistance in human tumor cells. Radiother Oncol. 99:392–397. 2011. View Article : Google Scholar : PubMed/NCBI