Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF- -mediated activation of the ALK5-Smad 3 pathway

Yoo, Young A.; Kang, Myoung Hee; Kim, Jun Suk; Oh, Sang Cheul

doi:10.1093/carcin/bgm281

Cited by 147 publications

(120 citation statements)

References 37 publications

Supporting

Mentioning

109

Contrasting

Order By: Relevance

“…Previously, several laboratories reported cross-talks between Hh signaling and the TGF␤ pathway (25)(26)(27). In these reports, they showed direct up-regulation of Gli1/2 by TGF␤-SMAD signaling.…”

Section: Discussionmentioning

confidence: 99%

Requirement of TGFβ Signaling for SMO-mediated Carcinogenesis

Fan

Sheng

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Hedgehog (Hh) signaling, via the key signal transducer Smoothened (SMO) and Gli transcription factors, is essential for embryonic development and carcinogenesis. At present, the molecular mechanism of Hh signaling-mediated carcinogenesis is not completely understood. Using a mouse model (K14cre/ R26SmoM2) of SMO-mediated basal cell carcinoma development, we identified TGF␤2 as a major Hh-regulated gene. TGF␤2 expression was high in the keratinocytes, with activated TGF␤ signaling (indicated by elevated expression of phosphorylated SMAD2/3) detected in both tumor and stroma. The significance of TGF␤ signaling for SMO function was demonstrated in two assays. Down-regulation of TGF␤2 expression prevented Hh signaling-dependent osteoblast differentiation and motor neuron differentiation. Furthermore, inhibition of TGF␤ signaling by TGF␤ receptor I inhibitor SD208 significantly reduced tumor area in K14cre/R26SmoM2 mice. Tumor shrinkage in mice was associated with an increased number of lymphocytes, suggesting an immune suppression role of TGF␤ signaling. The relevance of our results to human cancer is reflected by the fact that human basal cell carcinomas, which almost always harbor activated Hh signaling, have activated TGF␤ signaling, as indicated by high levels of phosphorylated SMAD2 and SMAD3 in tumor and stroma. Together, our data indicate that TGF␤ signaling is critical for Hh signaling-mediated carcinogenesis.The Hedgehog pathway plays an important role in cell differentiation, tissue polarity, cell proliferation, and carcinogenesis (1-4). The seven-transmembrane domain-containing protein Smoothened (SMO) 4 serves as the key player for signal transduction of this pathway, whose function is inhibited by another transmembrane protein, Patched (PTC), in the absence of Hh ligands. Binding of Hh to its receptor PTC releases this inhibition, allowing SMO to signal downstream, leading to formation of active forms of Gli transcription factors. As transcription factors, Gli molecules can regulate target gene expression by direct association with a specific consensus sequence located at the promoter region of the target genes (5). In addition to the canonical pathways (ligand overexpression, altered expression of Hh signaling molecules, or gene mutations), recent studies indicate that Hh signaling can also be activated by other signaling pathways, such as K-Ras. Both canonical and non-canonical Hh signaling activation are found in many types of human cancer, including brain tumors, gastrointestinal, prostate, lung, and breast cancers (6 -8).Mounting evidence indicates that Hh signaling activation occurs frequently in a number of human cancers (9), but the underlying molecular basis remains largely elusive. To understand the molecular basis by which Hh signaling regulates carcinogenesis, we analyzed gene expression of a mouse model of basal cell carcinoma in which an activated form of SMO (SmoM2) replaces the wild type SMO allele and is expressed under the control of the keratin 14 promoter. Our results indicated that ...

show abstract

Section: Discussionmentioning

confidence: 99%

Requirement of TGFβ Signaling for SMO-mediated Carcinogenesis

Fan

Sheng

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…76 Nuclear translocation of Gli1 was higher in undifferentiated-type tumors and positively correlated with lymph node metastasis in gastric carcinoma. 77 Hh signaling was found to promote gastric cancer cells proliferation, 78 epithelial-mesenchymal transition, 66 mobility and invasiveness 79 and inhibit apoptosis.…”

Section: Activation Of the Hh Pathway In Gastric Cancermentioning

confidence: 99%

Activation of the hedgehog pathway in gastroesophageal cancers

Yang

Xie²,

Su³

2011

JST

View full text Add to dashboard Cite

The hedgehog pathway is a major regulator for cell differentiation, tissue polarity and cell proliferation in embryonic development and homeostasis in adult tissue. Studies from many laboratories reveal activation of this pathway in a variety of human cancer, including basal cell carcinomas, medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast and prostate cancers. It is thus believed that targeted inhibition of hedgehog signaling may be effective in treatment and prevention of human cancer. Even more exciting is the discovery and synthesis of specific signaling antagonists for the hedgehog pathway, which have significant clinical implications in novel cancer therapeutics. In this review, we will summarize major advances in the last two years in our understanding of hedgehog signaling activation in human gastroesophageal cancer, and their potential in clinical treatment with hedgehog pathway inhibitors.

show abstract

“…MMP-2 and MMP-9 are considered to be particularly significant in metastasis (22,23). It is well known that the activation of Hh has been implicated in the development of cancers in various sites, including prostatic, gastric, esophageal and ovarian organs (24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway

Zheng

Cai

et al. 2016

Oncology Letters

View full text Add to dashboard Cite

Abstract. Pancreatic cancer (PC) is a highly lethal malignancy with few effective therapies. Deguelin, a natural compound of the flavonoid family of products, has been reported to have an inhibitory effect on various cancers. In the present study, we investigated whether deguelin had antitumor efficacy in PC. Deguelin treatment was observed to inhibit growth and induce apoptosis in two PC cell lines (Bxpc-3 and Panc-1). In addition, it inhibited migration and invasion in these two cell lines. The activation of the hedgehog (Hh) signaling pathway, as well as matrix metalloproteinases (MMP)-2 and MMP-9, was suppressed by deguelin. These results suggest that deguelin may be a potential chemotherapeutic agent for PC, possibly through the suppression of the Hh signaling pathway.

show abstract

Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF- -mediated activation of the ALK5-Smad 3 pathway

Cited by 147 publications

References 37 publications

Requirement of TGFβ Signaling for SMO-mediated Carcinogenesis

Requirement of TGFβ Signaling for SMO-mediated Carcinogenesis

Activation of the hedgehog pathway in gastroesophageal cancers

Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway

Contact Info

Product

Resources

About