Hedgehog signaling is activated in subsets of esophageal cancers.
The hedgehog pathway plays a critical role in the development of the foregut. However, the role of the hedgehog pathway in primary esophageal cancers is not well studied. Here, we report that elevated expression of hedgehog target genes occurs in 14 of 22 primary esophageal cancers. The hedgehog signaling activation is not associated with tumor subtypes, stages, or differentiation. While the sonic hedgehog (Shh) transcript is localized to the tumor tissue, expression of Gli1 and PTCH1 is observed both in the tumor and in the stroma. We discovered that 4 esophageal squamous cell carcinomas, which overexpress Shh, have genomic amplification of the Shh gene. Treatment of esophageal cancer cells with smoothened antagonist, KAAD-cyclopamine, or the neutralizing antibodies of Shh reduces cell growth and induces apoptosis. Overexpression of Gli1 under the CMV promoter renders these cells resistant to the treatments. Thus, our results indicate that elevated expression of Shh and its target genes is quite common in esophageal cancers. Our data also indicate that downregulation of Gli1 expression may be an important mechanism by which KAAD-cyclopamine inhibits growth and induces apoptosis in esophageal cancer cells.
Ma
Xiaoli
X
Institute of Developmental Biology, School of Life Sciences, Shandong University, Jinan, China.
Sheng
Tao
T
Zhang
Yuanxin
Y
Zhang
Xiaoli
X
He
Jing
J
Huang
Shuhong
S
Chen
Kai
K
Sultz
Josh
J
Adegboyega
Patrick A
PA
Zhang
Hongwei
H
Xie
Jingwu
J
D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000503:physiopathology*; D049109:Cell Proliferation / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D015513:Oncogene Proteins / Q000096:biosynthesis; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis* / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
D053823:Hedgehog Proteins; D015513:Oncogene Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine