Activation of the hedgehog pathway in a subset of lung cancers

Chi, Sumin; Huang, Shuhong; Li, Chang-Jiu; Zhang, Xiaoli; He, Nonggao; Bhutani, Manoop S.; Jones, D. T. W.; Castro, Claudia Y.; Logroño, Roberto; Haque, Abida K.; Zwischenberger, Joseph B.; Tyring, Stephen K.; Zhang, Hongwei; Xie, Jingwu

doi:10.1016/j.canlet.2005.11.036

Cited by 51 publications

(42 citation statements)

References 29 publications

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“…PTCH1 gene is a known tumor suppressor gene in the HH pathway. Loss of function mutation and epigenetic regulation has been found in many kinds of tumors [3,6,13,14] . PTCH1 gene has three main isoforms of the first exon, PTCH1a, PTCH1b, and PTCH1c, which code for different N-sequence PTCH1 proteins PTCH1-l, PTCH1-m and PTCH1-s, respectively [18] .…”

Section: Discussionmentioning

confidence: 99%

“…This liberates the Smoothened protein, which allows glioma-associated oncogene homolog 1 zinc finger protein (GLI) and MYCN transcription factors to turn on target genes, including the PTCH1 gene itself, in a negative feedback loop as a tumor suppressor gene. More recently, abnormal activation of the HH pathway has been reported in subsets of human basal cell carcinoma [1] , medulloblastoma [2] , pancreatic cancer [3][4][5] , lung cancer [6] , prostate cancer [7] and gastrointestinal cancer [8][9][10] . Gastric cancer is one of the most common cancers worldwide, and has high mortality.…”

Section: Introductionmentioning

confidence: 99%

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Methylation of PTCH1a gene in a subset of gastric cancers

Du¹,

Ye²,

Gao³

et al. 2009

WJG

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RESULTS: Methylation of PTCH1a TRR was observedin AGS cells and a subset of gastric cancer tissues (32%, 55/170), while no methylation amplification products were observed in any normal tissues by MSP. The methylation of PTCH1a TRR was correlated negatively with PTCH1 expression (Spearman's r = -0.380, P = 0.000). However, methylation of PTCH1a TRR was not related to the gastric cancer patients' clinical features, such as sex, age of onset, clinical stage, lymph node metastasis or histological grade. The methylation of PTCH1a TRR in AGS cells was almost converted to non-methylation after 5-Aza-dC treatment, which increased PTCH1 expression (5.3 ± 2.5 times; n = 3) and apoptosis rate (3.0 ± 0.26 times; P < 0.05; n = 3). CONCLUSION:Methylation of PTCH1a TRR is present in a subset of gastric cancers and correlated negatively with PTCH1 expression. This may be an early event in gastric tumorigenesis and a new treatment target.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Methylation of PTCH1a gene in a subset of gastric cancers

Du¹,

Ye²,

Gao³

et al. 2009

WJG

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“…Interestingly, inhibition of the Hh pathway reduces the expression of a-SMA, collagen 1 and fibronectin and abrogates the effect of TGF-b on these proteins [111], highlighting the importance of the TGF-b/Hh crosstalk that may promote a mesenchymal phenotype in pathological contexts. In different types of lung cancer, the Shh pathway has also been found to be re-activated [99,[113][114][115][116], and is involved in the mesenchymal transition of tumoural cells associated with the formation of metastases. In a model of lung metastases, colon carcinoma cells injected into nude mice induced pulmonary lesions.…”

Section: Hedgehog Signallingmentioning

confidence: 99%

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

Pain

Bermúdez

Lacoste

et al. 2014

European Respiratory Review

169

128

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Airway remodelling is a critical feature of chronic bronchial diseases, characterised by aberrant repair of the epithelium and accumulation of fibroblasts, which contribute to extracellular matrix (ECM) deposition resulting in fixed bronchial obstruction. Recently, epithelial-mesenchymal transition (EMT) has been identified as a new source of fibroblasts that could contribute to the remodelling of the airways. This phenomenon consists of the loss of the epithelial phenotype by bronchial epithelial cells and the acquisition of a mesenchymal phenotype. These cells are then able to migrate and secrete ECM molecules. Herein, we review the different types of EMT. We will then focus on the signalling pathways that are involved, such as transforming growth factor-b and Wnt, as well as the more recently described Sonic Hedgehog pathway. Finally, we will highlight the implication of EMT in airway remodelling in specific chronic bronchial pathologies, such as asthma, chronic obstructive pulmonary disease and bronchiolitis obliterans following lung transplantation. Despite the limitations of in vitro models, future studies of EMT in vivo are warranted to shed new light on the pathomechanisms of bronchial obstruction. @ERSpublications Epithelial-mesenchymal transition in chronic bronchial remodelling diseases

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“…In several cases, Smo-independent activation mechanisms have been documented, such as mutations in or loss of heterozygosity of the SUFU gene, which was found in medulloblastoma (20,21), prostate cancer (22), rhabdomyosarcoma (7), and a human lung cancer cell line (23). In addition, other downstream pathway activation mechanisms have been revealed, such as REN deletions (15), GLI gene amplifications (24)(25)(26), GLI1 chromosomal translocations (27), or GLI2 protein stabilization (28).…”

mentioning

confidence: 99%

Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists

Lauth

Bergström²,

Shimokawa³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

724

693

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The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.

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Activation of the hedgehog pathway in a subset of lung cancers

Cited by 51 publications

References 29 publications

Methylation of PTCH1a gene in a subset of gastric cancers

Methylation of PTCH1a gene in a subset of gastric cancers

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists

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