Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas

Abstract

BackgroundSquamous cell carcinomas (SCC) account for approximately 30% of non-small cell lung cancer. Investigation of the mechanism of invasion and metastasis of lung SCC will be of great help for the development of meaningful targeted therapeutics. This study is intended to understand whether the activation of Hedgehog (Hh) pathway is involved in lung SCC, and whether activated Hh signaling regulates metastasis through epithelial-mesenchymal transition (EMT) in lung SCC.MethodsTwo cohorts of patients with lung SCC were studied. Protein expression was examined by immunohistochemistry, Western blot, or immunofluorescence. Protein expression levels in tissue specimens were scored and correlations were analyzed. Vismodegib and a Gli inhibitor were used to inhibit Shh/Gli activity, and recombinant Shh proteins were used to stimulate the Hh pathway in lung SCC cell lines. Cell migration assay was performed in vitro.ResultsShh/Gli pathway components were aberrantly expressed in lung SCC tissue samples. Gli1 expression was reversely associated with the expression of EMT markers E-Cadherin and β-Catenin in lung SCC specimens. Inhibition of the Shh/Gli pathway suppressed migration and up-regulated E-Cadherin expression in lung SCC cells. Stimulation of the pathway increased migration and down-regulated E-Cadherin expression in lung SCC cells.ConclusionsOur results suggested that the Shh/Gli pathway may be critical for lung SCC recurrence, metastasis and resistance to chemotherapy. Inhibition of the Shh/Gli pathway activity/function is a potential therapeutic strategy for the treatment of lung SCC patients.

Casticin inhibits the epithelial-mesenchymal transition in ovarian carcinoma via the hedgehog signaling pathway

“…Cyclopamine has been demonstrated to exert effects on numerous types of tumor, including lung, ovarian, and breast cancer (41)(42)(43). However, poor oral solubility hinders its clinical development.…”

“…It was reported that Hh signaling might induce EMT in pancreatic cancer (9,15). In addition, Yue et al (16) reported that Hh also promoted EMT progression in lung squamous cell carcinoma. Notably, glioma-associated oncogene-1 (Gli-1), a major Hh signaling effector, decreases levels of E-cadherin and increases those of N-cadherin (17,18), indicating that Hh signaling is important for EMT occurrence.…”

Detecting disease genes of non-small lung cancer based on consistently differential interactions

“…The identified gene sets by CDI-based method are colored yellow in pathway. Fraction score of the complex or processes, which are labeled in rectangles, is the number of the predicted genes to the number of overall genes [44][45][46][47]. For LUSC, PTPN11, PDGFC, ERBB2, HMGA1, HIPK2, and NR4A1 were also proved to be key regulators of metastatic processes in previous reports [48][49][50][51][52].…”

“…On the other hand, in the other edge biomarkers for LUAD, STK36~GLI1 facilitates an important post-transcriptional control of Hedgehog (HH)/GLI signaling and also shows strong correlation with EGFR (P-value=2.317×10 −7 ). Such Hedgehog-EGFR cooperation can activate many downstream genes involved in cancer metastasis [47,55].…”

Targeting GLI proteins in human cancer by small molecules (WO2014116651 A1): a patent evaluation

“…In addition to developed resistance for Smo antagonists, mutations in Hh pathway components downstream of Smo have also been identified and cancers driven by these forms of constitutive Hh signaling would not be susceptible to treatment with Smo antagonists [11]. Finally, recent studies have identified cellular mechanisms for oncogenic Gli activation that are independent of canonical Hh/Smo signaling [12][13][14]. Taken together, these findings have led to numerous drug design efforts directly targeting Gli as a means to inhibit its ability to serve as a transcription factor that activates oncogenic signaling [3,[15][16][17][18][19].…”