Significance and prognostic value of Gli-1 and Snail/E-cadherin expression in progressive gastric cancer

Wang, Zhan-shan; Shen, Yang; Li, Xu; Zhou, Chongzhi; Wen, Yu-ming; Jin, Yubiao; Li, Jikun

doi:10.1007/s13277-013-1185-1

Cited by 41 publications

(32 citation statements)

References 24 publications

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“…Gli1 has been identified as the final transcriptional effector and the key marker of the Hh signaling pathway, and has been shown to be activated in various human malignancies such as prostate cancer and gastrointestinal cancer [30, 31]. Additionally, a previous study showed that, in GC, the levels of the Hh pathway marker Gli1 were associated with levels of the EMT markers E-cadherin and snail [32]. Interestingly, a recent study by Wang et al suggested that Gal-1 is required for Hh signaling pathway activation in pancreatic cancer [33].…”

Section: Discussionmentioning

confidence: 99%

Galectin-1 from cancer-associated fibroblasts induces epithelial–mesenchymal transition through β1 integrin-mediated upregulation of Gli1 in gastric cancer

Yan¹,

Tang²,

Xiong³

et al. 2016

J Exp Clin Cancer Res

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BackgroundGastric cancer (GC) is characterized by the excessive deposition of extracellular matrix, which is thought to contribute to this tumor’s malignant behavior. Epithelial-mesenchymal transition (EMT) is regarded as a crucial contributing factor to cancer progression. Galectin-1 (Gal-1), a β-galactoside-binding protein abundantly expressed in activated cancer-associated fibroblasts (CAFs), has been reported to be involved in GC progression and metastasis by binding to β1 integrin, which, in turn, can bind to matrix proteins and activate intracellular cascades that mediate EMT. Increasing evidence suggests that abnormal activation of the hedgehog (Hh) signaling pathway enhances GC cell migration and invasion. The purpose of our study is to explore the role of Gal-1 in the GC progression and metastasis as well as the regulatory mechanism.MethodsWe hypothesized that Gal-1 binding to β1 integrin would lead to paracrine signaling between CAFs and GC cells, mediating EMT by upregulating Gli1. Invasion and metastasis effects of the Gal-1 and Gli1 were evaluated using wound healing and invasion assay following transfection with mimics. Additionally, to facilitate the delineation of the role of the Hh signaling in GC, we monitored the expression level of associated proteins. We also evaluated the effects of β1 integrin on these processes. Furthermore, Gal-1 and Gli1 expression in GC patient samples were examined by immunohistochemistry and western blot to determine the correlation between their expression and clinicopathologic characteristics. The Kaplan-Meier method and Cox proportional hazards model were used to analyze the relationship of expression with clinical outcomes.ResultsGal-1 was found to induce EMT, GC cell migration and invasion. Further data showed that Gal-1 up-regulated Gli1 expression. β1 integrin was responsible for Gal-1-induced Gli1 expression and EMT. In clinical GC tissue, it confirmed a positive relationship between Gal-1 and Gli1 expression. Importantly, their high expression is correlated to poor prognosis.ConclusionGal-1 from CAFs binds to a carbohydrate structure in β1 integrin and plays an important role in the development of GC by inducing GC metastasis and EMT through targeting Gli1. This study highlights the potential therapeutic value of Gal-1 for suppression of GC metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0449-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Galectin-1 from cancer-associated fibroblasts induces epithelial–mesenchymal transition through β1 integrin-mediated upregulation of Gli1 in gastric cancer

Yan¹,

Tang²,

Xiong³

et al. 2016

J Exp Clin Cancer Res

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“…Out of several Hh target genes, Gli-1 is a major transcription factor of the Hh signaling pathway (6). High expression of Gli-1 has been reported in several cancers, including gastric and colon cancer, in contrast to normal cells (6,23). Wang et al (23) reported that Gli-1 expression increased markedly in progressive gastric cancer and was closely associated with increased Snail (EMT marker) expression and decreased E-cadherin expression.…”

Section: Discussionmentioning

confidence: 99%

“…High expression of Gli-1 has been reported in several cancers, including gastric and colon cancer, in contrast to normal cells (6,23). Wang et al (23) reported that Gli-1 expression increased markedly in progressive gastric cancer and was closely associated with increased Snail (EMT marker) expression and decreased E-cadherin expression. The positive Gli-1 expression group had a significantly increased invasion depth and a higher percentage of patients with lymph node (LN) invasion compared with the negative Gli-1 expression group.…”

Section: Discussionmentioning

confidence: 99%

“…To assess the expression of Gli-1 and Gli-2, a total of 10 high-power fields were selected from each section, and nuclear protein expression in ≥10% of cells was considered to indicate positive expression (23). E-cadherin was expressed in the cellular membrane of normal hepatocytes and cancer cells.…”

Section: Methodsmentioning

confidence: 99%

“…These transcription factors induce changes in the spreading ability and morphology of cancer cells through suppression of E-cadherin expression, and epithelial cancer cells then acquire mesenchymal markers (22). The Hh signaling pathway may be one of the signaling pathways in the tumor microenvironment that involves EMT (23). However, the association between the Hh signaling pathway and EMT in HCC is remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Significance of the hedgehog pathway-associated proteins Gli-1 and Gli-2 and the epithelial-mesenchymal transition-associated proteins Twist and E-cadherin in hepatocellular carcinoma

Chun

Ren

2016

Oncology Letters

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It has been found that abnormal activation of the hedgehog (Hh) signaling pathway is involved in the occurrence, invasion and metastasis of malignant tumors. In addition, epithelial-mesenchymal transition (EMT) also performs an important function in the invasion and metastasis of malignant tumors. However, the significance of the Hh signaling pathway and EMT in hepatocellular carcinoma (HCC) remains unknown. In the present study, the expression of Gli family zinc finger 1 (Gli-1) and Gli family zinc finger 2 (Gli-2), which are key transcriptional factors in the Hh signaling pathway, and Twist and E-cadherin, which are two factors involved in EMT, was examined in 42 patients with HCC and 20 cases of non-tumorous liver (NTL) tissue by immunohistochemistry. Clinicopathological information was collected in order to analyze the correlation of the Hh signaling pathway with EMT. The present study aimed to examine the difference in the expression of Gli-1, Gli-2, E-cadherin and Twist in HCC and NTL to assess the diagnostic value of these factors in HCC. Additionally, the present study aimed to elucidate the correlation between those proteins and other clinicopathological parameters. Whether abnormal activation of the Hh signaling pathway is closely associated with EMT was also evaluated. Gli-1 and Twist expression was found to be significantly increased and E-cadherin expression was found to be decreased in HCC in contrast to NTL (Gli-1, P=0.019; Twist, P=0.003; E-cadherin, P<0.001). Increased Twist expression was associated with the tumor size (P=0.043), and loss of or decreased E-cadherin expression was associated with the histological type of HCC (P=0.021). There was an inverse association between the expression of Twist and E-cadherin (P=0.006). These results showed that Twist overexpression by induction of EMT changes is involved in the occurrence and progression of HCC. However, the role of Hh signaling pathway-associated proteins in HCC may require elucidation by additional studies using additional materials in the future.

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The role and molecular mechanism of Trop2 induced epithelial‐mesenchymal transition through mediated β‐catenin in gastric cancer

et al. 2019

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The present study elucidates the potential role of Trop2 in tumor invasion and the promotion of epithelial‐mesenchymal transition (EMT) when binding β‐catenin in GC. The role of Trop2 in promoting EMT in GC cells was examined by a variety of experimental assays. Moreover, the underlying molecular mechanism of Trop2 in promoting EMT was studied by in vivo and in vitro assays. The Trop2 expression in relation to tumor metastasis status was detected by IHC in 248 cases of GC tissues and 86 cases of matched adjacent tissues. Trop2 promoted the metastasis and induces EMT in GC. Meanwhile, the elevated protein levels of Trop2 and mesenchymal markers were also found in the TGF‐β1‐induced EMT model in GC cells. Importantly, Trop2 physically bound and activated β‐catenin to promote EMT; moreover, Trop2 increased the accumulation of β‐catenin in the nucleus to accelerate metastasis in GC cells. Inhibition of Trop2 expression in GC cells prevented the migration and invasion of GC cells in vivo. Trop2+/vimentin+ expression was higher in GC tissues than that in matched adjacent tissues, and Trop2+/vimentin+ expression in GC was associated with the differentiation, TNM stage, and distant metastases. These sets of data reveal a novel regulatory network of Trop2 in EMT and GC metastasis, suggesting Trop2 as a useful marker for inducing EMT and metastasis of GC, which may help to lead a better understanding of the pathogenesis of the GC.

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Significance and prognostic value of Gli-1 and Snail/E-cadherin expression in progressive gastric cancer

Cited by 41 publications

References 24 publications

Galectin-1 from cancer-associated fibroblasts induces epithelial–mesenchymal transition through β1 integrin-mediated upregulation of Gli1 in gastric cancer

Galectin-1 from cancer-associated fibroblasts induces epithelial–mesenchymal transition through β1 integrin-mediated upregulation of Gli1 in gastric cancer

Significance of the hedgehog pathway-associated proteins Gli-1 and Gli-2 and the epithelial-mesenchymal transition-associated proteins Twist and E-cadherin in hepatocellular carcinoma

The role and molecular mechanism of Trop2 induced epithelial‐mesenchymal transition through mediated β‐catenin in gastric cancer

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