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


METHODS
Two 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.


RESULTS
Shh/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.


CONCLUSIONS
Our 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.
Dongsheng
D
Yue
Hui
H
Li
Juanjuan
J
Che
Yi
Y
Zhang
Hsin-Hui K
HH
Tseng
Joy Q
JQ
Jin
Thomas M
TM
Luh
Etienne
E
Giroux-Leprieur
Minli
M
Mo
Qingfeng
Q
Zheng
Huaiyin
H
Shi
Hua
H
Zhang
Department of Lung Cancer, Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. yuedongsheng_cg@163.com.
Xishan
X
Hao
Changli
C
Wang
David M
DM
Jablons
Biao
B
He
D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1