Up-regulation of Sonic Hedgehog Contributes to TGF-β1-induced Epithelial to Mesenchymal Transition in NSCLC Cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Jan 21

PMID 21249152

Citations 64

Authors

Main Y Maitah

Shadan Ali

Aamir Ahmad

Shirish Gadgeel

Fazlul H Sarkar

Affiliations

Soon will be listed here.

Abstract

Background: Lung cancer, especially non-small cell lung cancer (NSCLC) is the major cause of cancer-related deaths in the United States. The aggressiveness of NSCLC has been shown to be associated with the acquisition of epithelial-to-mesenchymal transition (EMT). The acquisition of EMT phenotype induced by TGF-β1in several cancer cells has been implicated in tumor aggressiveness and resistance to conventional therapeutics; however, the molecular mechanism of EMT and tumor aggressiveness in NSCLC remains unknown.

Methodology/principal Findings: In this study we found for the first time that the induction of EMT by chronic exposure of A549 NSCLC cells to TGF-β1 (A549-M cells) led to the up-regulation of sonic hedgehog (Shh) both at the mRNA and protein levels causing activation of hedgehog signaling. These results were also reproduced in another NSCLC cell line (H2030). Induction of EMT was found to be consistent with aggressive characteristics such as increased clonogenic growth, cell motility and invasion. The aggressiveness of these cells was attenuated by the treatment of A549-M cells with pharmacological inhibitors of Hh signaling in addition to Shh knock-down by siRNA. The inhibition of Hh signaling by pharmacological inhibitors led to the reversal of EMT phenotype as confirmed by the reduction of mesenchymal markers such as ZEB1 and Fibronectin, and induction of epithelial marker E-cadherin. In addition, knock-down of Shh by siRNA significantly attenuated EMT induction by TGF-β1.

Conclusions/significance: Our results show for the first time the transcriptional up-regulation of Shh by TGF-β1, which is mechanistically associated with TGF-β1 induced EMT phenotype and aggressive behavior of NSCLC cells. Thus the inhibitors of Shh signaling could be useful for the reversal of EMT phenotype, which would inhibit the metastatic potential of NSCLC cells and also make these tumors more sensitive to conventional therapeutics.

Citing Articles

Discovery of -substituted-2-oxoindolin benzoylhydrazines as c-MET/SMO modulators in EGFRi-resistant non-small cell lung cancer.

Tomassi S, Natale B, Roggia M, Amato L, De Rosa C, Della Corte C RSC Med Chem. 2024; .

PMID: 39512947 PMC: 11539002. DOI: 10.1039/d4md00553h.

EWS/FLI1 Characterization, Activation, Repression, Target Genes and Therapeutic Opportunities in Ewing Sarcoma.

Yasir M, Park J, Chun W Int J Mol Sci. 2023; 24(20).

PMID: 37894854 PMC: 10607184. DOI: 10.3390/ijms242015173.

3-Hydroxybenzaldehyde and 4-Hydroxybenzaldehyde enhance survival of mouse astrocytes treated with Angiostrongylus cantonensis young adults excretory/secretory products.

Chen K, Chen Y, Cheng C, Jhan K, Chiu C, Wang L Biomed J. 2022; 44(6 Suppl 2):S258-S266.

PMID: 35300947 PMC: 9068576. DOI: 10.1016/j.bj.2020.11.008.

Defining the Role of GLI/Hedgehog Signaling in Chemoresistance: Implications in Therapeutic Approaches.

Chai J, Sugumar V, Alshanon A, Wong W, Fung S, Looi C Cancers (Basel). 2021; 13(19).

PMID: 34638233 PMC: 8507559. DOI: 10.3390/cancers13194746.

Sulforaphane inhibits self-renewal of lung cancer stem cells through the modulation of sonic Hedgehog signaling pathway and polyhomeotic homolog 3.

Wang F, Sun Y, Huang X, Qiao C, Zhang W, Liu P AMB Express. 2021; 11(1):121.

PMID: 34424425 PMC: 8382806. DOI: 10.1186/s13568-021-01281-x.

References

Larue L, Bellacosa A . Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene. 2005; 24(50):7443-54. DOI: 10.1038/sj.onc.1209091. View

Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C . let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007; 131(6):1109-23. DOI: 10.1016/j.cell.2007.10.054. View

Sanchez-Tillo E, Lazaro A, Torrent R, Cuatrecasas M, Vaquero E, Castells A . ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene. 2010; 29(24):3490-500. DOI: 10.1038/onc.2010.102. View

Gupta P, Onder T, Jiang G, Tao K, Kuperwasser C, Weinberg R . Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009; 138(4):645-659. PMC: 4892125. DOI: 10.1016/j.cell.2009.06.034. View

Kasai H, Allen J, Mason R, Kamimura T, Zhang Z . TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res. 2005; 6:56. PMC: 1177991. DOI: 10.1186/1465-9921-6-56. View

Travis W, Travis L, Devesa S . Lung cancer. Cancer. 1995; 75(1 Suppl):191-202. DOI: 10.1002/1097-0142(19950101)75:1+<191::aid-cncr2820751307>3.0.co;2-y. View

Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N . Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res. 2005; 65(20):9455-62. DOI: 10.1158/0008-5472.CAN-05-1058. View

BAILEY J, Mohr A, Hollingsworth M . Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene. 2009; 28(40):3513-25. PMC: 2910592. DOI: 10.1038/onc.2009.220. View

Kang Y, Massague J . Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004; 118(3):277-9. DOI: 10.1016/j.cell.2004.07.011. View

10.

Zhao C, Chen A, Jamieson C, Fereshteh M, Abrahamsson A, Blum J . Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009; 458(7239):776-9. PMC: 2946231. DOI: 10.1038/nature07737. View

11.

Yoo Y, Kang M, Kim J, Oh S . Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Carcinogenesis. 2008; 29(3):480-90. DOI: 10.1093/carcin/bgm281. View

12.

Hogan B . Morphogenesis. Cell. 1999; 96(2):225-33. DOI: 10.1016/s0092-8674(00)80562-0. View

13.

Scales S, de Sauvage F . Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. 2009; 30(6):303-12. DOI: 10.1016/j.tips.2009.03.007. View

14.

Witta S, Gemmill R, Hirsch F, Coldren C, Hedman K, Ravdel L . Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res. 2006; 66(2):944-50. DOI: 10.1158/0008-5472.CAN-05-1988. View

15.

Turley E, Veiseh M, Radisky D, Bissell M . Mechanisms of disease: epithelial-mesenchymal transition--does cellular plasticity fuel neoplastic progression?. Nat Clin Pract Oncol. 2008; 5(5):280-90. PMC: 2846172. DOI: 10.1038/ncponc1089. View

16.

Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M . Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 2007; 67(5):2187-96. PMC: 3073370. DOI: 10.1158/0008-5472.CAN-06-3281. View

17.

Fendrich V, Waldmann J, Esni F, Ramaswamy A, Mullendore M, Buchholz M . Snail and Sonic Hedgehog activation in neuroendocrine tumors of the ileum. Endocr Relat Cancer. 2007; 14(3):865-74. DOI: 10.1677/ERC-07-0108. View

18.

Sabbah M, Emami S, Redeuilh G, Julien S, Prevost G, Zimber A . Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. Drug Resist Updat. 2008; 11(4-5):123-51. DOI: 10.1016/j.drup.2008.07.001. View

19.

Katoh Y, Katoh M . Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). Int J Mol Med. 2008; 22(3):271-5. View

20.

Watkins D, Berman D, Burkholder S, Wang B, Beachy P, Baylin S . Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature. 2003; 422(6929):313-7. DOI: 10.1038/nature01493. View