Contrasting activity of Hedgehog and Wnt pathways according to gastric cancer cell differentiation: relevance of crosstalk mechanisms.
Gastric cancer displays different biological behaviors according to histological differentiation. The different biological behavior might involve the activation of distinct signaling pathways necessary for the growth and survival of cancer cells in gastric cancer. We investigated the differentiation-related signal interaction between Hedgehog and Wnt pathways in gastric cancer cells. Differentiation of gastric cancer cells was induced by sodium butyrate. The sonic Hedgehog (SHH) signal expressions were increased during cellular differentiation. In contrast, the expression of Wnt signaling was decreased during differentiation. Ectopic expression of glioma-associated oncogene-1 (GLI1) increased the level of secreted frizzled related protein-1 (SFRP1) transcript, whereas inhibition of GLI1 reduced the level of SFRP1 transcript. ChIP assay showed that GLI1 induced the transcriptional regulation of SFRP1 gene expression. Ectopic expression of GLI1 decreased the nuclear beta-catenin staining, but the inhibition of GLI1 induced the reversal of nuclear beta-catenin overexpression. Ectopic expression of beta-catenin also decreased the expression of GLI1 in the butyrate treated cancer cells. SHH and GLI1 immunoexpression was greater in well differentiated gastric cancer tissues compared to poorly differentiated tissues, and nuclear beta-catenin immunoexpression was lower in well differentiated compared to poorly differentiated tissues. The SHH and Wnt pathways are differentially involved according to gastric cancer cell differentiation.
Kim
Jie-Hyun
JH
Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
Shin
Hyun Soo
HS
Lee
Sang Hun
SH
Lee
Inohk
I
Lee
Yeo Song
YS
Park
Jun Chul
JC
Kim
Yu Jin
YJ
Chung
Jae Bock
JB
Lee
Yong Chan
YC
D002454:Cell Differentiation; D045744:Cell Line, Tumor; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000032:analysis / Q000502:physiology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000473:pathology*; D015534:Trans-Activators / Q000032:analysis / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin / Q000032:analysis; D000094742:Secreted Frizzled-Related Proteins
D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D015513:Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins