Study of Sonic hedgehog signaling pathway related molecules in gastric carcinoma

Li, Xiao; Sun, Hai Ji; Wang, Yun Shan; Huang, Shu Hong; Xie, Jingwu; Zhang, Hong Wei

doi:10.3748/wjg.v12.i25.3965

Cited by 21 publications

(17 citation statements)

References 17 publications

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“…Smo signaling in turn triggers a cascade of intracellular events, leading to the activation of the pathway through Glioma-associated oncogene (Gli)-dependent transcription [13]. In gastric cancers, the activation of the Shh signaling pathway has been described [14,15,16,17] and can influence prognosis [18]. However, the expression patterns of Shh signal-associated proteins are yet to be investigated in GAFG.…”

Section: Introductionmentioning

confidence: 99%

Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma

Tajima

Murakami²,

Saito³

et al. 2017

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Background/Aims: Gastric adenocarcinoma of fundic gland type (GAFG), which is a rare variant of gastric cancer, is reportedly associated with both Wnt/β-catenin signaling activation and guanine nucleotide binding protein, alpha stimulating complex (GNAS) mutations. This study aimed to elucidate potential roles of the Sonic hedgehog (Shh) signaling pathway in GAFG. Methods: We performed immunostaining for β-catenin and Shh signal-associated proteins, including Patched (Ptch), Smoothened (Smo), and Glioma-associated oncogene-1 (Gli1), and the direct sequencing of GNAS/BRAF/KRAS in 27 GAFGs, and compared them with 30 conventional gastric adenocarcinomas (CGAs). Results: GAFGs exhibited significantly lower immunoreactivity scores for Ptch, Smo, and Gli1 than CGAs. Moreover, while the Ptch score was significantly lower in the GAFG tumor areas than in the non-neoplastic areas adjacent to GAFG, the score was significantly higher in the CGA tumor areas than in the non-neoplastic areas. Similar trends were observed in the scores for Smo and Gli1. β-Catenin expression and GNAS mutations were found in 22 (81%) and 8 (30%) of the 27 GAFGs respectively. Gli1 expression was significantly associated with mutations in GNAS. Conclusion: GAFG and CGA exhibited distinct Ptch, Smo, and Gli1 expression patterns. Downregulation of the Shh signaling pathway, as well as activation of the Wnt/β-catenin signaling pathway, may therefore be associated with tumorigenesis in GAFG.

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Section: Introductionmentioning

confidence: 99%

Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma

Tajima

Murakami²,

Saito³

et al. 2017

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“…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%

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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“…Overexpression of Shh leads to carcinogenesis through the aberrant activation of the Hh pathway Thayer et al, 2003;Cengel, 2004;Sanchez et al, 2004). It is also believed that Shh has an important role during the progression of gastric cancer, because Shh expression is much higher in the diffuse type than in the intestinal type in human gastric cancer (Ma et al, 2005(Ma et al, , 2006.…”

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confidence: 99%

Oestrogen receptor-α contributes to the regulation of the hedgehog signalling pathway in ERα-positive gastric cancer

et al. 2010

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BACKGROUND: Oestrogen receptor-alpha (ERa) is highly expressed in diffuse-type gastric cancer and oestrogen increases the proliferation of ERa-positive gastric cancer. However, a detailed mechanism by which oestrogen increases the proliferation of these cells is still unclear. METHODS: We used 17-b-oestradiol (E2) as a stimulator against the ERa pathway. Pure anti-oestrogen drug ICI 182 780 (ICI) and small interfering RNA against ERa (ERa siRNA) were used as inhibitors. Cyclopamine (Cyc) was used as the hedgehog (Hh) pathway inhibitor. Two human ERa-positive gastric cancer cells were used as target cells. Effects of the stimulator and inhibitor on E2-induced cell proliferation were also examined. RESULTS: In ERa-positive cells, E2 increased not only cell proliferation but also one of the ligands of the Hh pathway, Shh expression. 17-b-Oestradiol-induced cell proliferation was suppressed by ICI, ERa siRNA or Cyc. The increased expression of Shh induced by E2 was suppressed by ICI and ERa siRNA but not by Cyc. Furthermore, recombinant Shh activated the Hh pathway and increased cell proliferation, whereas anti-Shh antibody suppressed E2-induced cell proliferation. When a relationship between ERa and Shh expressions was analysed using surgically resected gastric cancer specimens, a positive correlation was found, suggesting a linkage between the ERa and Hh pathways. CONCLUSION: Our data indicate that activation of the ERa pathway promotes cell proliferation by activating the Hh pathway in a ligand-dependent manner through Shh induction of ERa-positive gastric cancer.

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Study of Sonic hedgehog signaling pathway related molecules in gastric carcinoma

Cited by 21 publications

References 17 publications

Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma

Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma

Methylation of PTCH1a gene in a subset of gastric cancers

Oestrogen receptor-α contributes to the regulation of the hedgehog signalling pathway in ERα-positive gastric cancer

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