Sonic hedgehog relates to colorectal carcinogenesis

Yoshikawa, Kozo; Shimada, Mitsuo; Miyamoto, Hidenori; Higashijima, Jun; Miyatani, Tomohiko; Nishioka, Masanori; Kurita, Nobuhiro; Iwata, Takashi; Uehara, Hisanori

doi:10.1007/s00535-009-0110-2

Cited by 69 publications

(89 citation statements)

References 22 publications

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“…He did not observe expression of GLI1 protein in the stroma, indicating that the stroma did not have an active Hh-GLI signaling (Varnat et al, 2009). Yoshikawa found that colorectal adenomas expressed SHH more frequently compared with normal mucosa and adenocarcinoma, which suggested that SHH expression might increase during carcinogenesis and then decrease during tumor progression in the adenoma-carcinoma sequence (Yoshikawa et al, 2009). By contrast, in a clinical study for SHH, IHH and GLI1 genes in 36 CRC patients, Fu found the expressions of SHH and GLI1 proteins were increased significantly in tumor tissues compared with those in hyperplastic polyps and colorectal adenomas.…”

Section: Discussionmentioning

confidence: 93%

“…PTCH was not expressed in colon tumor cell lines (0/11), although a few of these cell lines expressed GLI1 in the absence of PTCH. As PTCH and GLI1 were indicators of Hh pathway activity, He concluded that the Hh pathway was not active in these CRC cell lines (Yoshikawa et al, 2009). Chatel analyzed the gene and protein expressions DOI:http://dx.doi.org/10.7314/APJCP.2012.13.5.2319 of the main key members of the Hh pathway (SHH, IHH, PTCH, SMO, GLI1, GLI2, GLI3, SUFU and HHIP) in 7 colon cancer cell lines and found none of them expressed the complete set of Hh pathway members (Chatel et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…The data about the roles they play on CRC have not been well documented. Some of them even remained controversial (Berman et al, 2003;Douard et al, 2006;Monzo et al, 2006;Chatel et al, 2007;Varnat et al, 2009; 2320 Yoshikawa et al, 2009;Fu et al, 2010;Saqui-Salces and Merchant, 2010;You et al, 2010;Tapati et al, 2011). There were disagreements in the roles of downstream Hh signaling components i.e.…”

Section: Expression and Clinical Significance Of Hedgehog Signaling Pmentioning

confidence: 99%

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Expression and Clinical Significance of Hedgehog Signaling Pathway Related Components in Colorectal Cancer

Wang

Li²,

Wu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Aim: To investigate the expression of three components of the Hedgehog (Hh) signaling pathway (SHH, SMO and GLI1) in human colorectal cancer (CRC) tissues and evaluate their association with clinicopathologic characteristics of the patients. Methods: Fresh tumor tissues and matched tissues adjacent to the tumor were collected from 43 CRC patients undergoing surgery. Normal colorectal tissues from 20 non-CRC cases were also sampled as normal controls. The expression of SHH, SMO, GLI1 mRNAs was assessed by RT-PCR and proteins were detected by immunohistochemical staining. Associations with clinicopathological characteristics of patients were analyzed. Results: SHH mRNA was expressed more frequently in tumor tissues than in normal tissues, but the difference did not reach significance in comparison to that in the adjacent tissues. SMO and GLI1 mRNAs were expressed more frequently in tumor tissues than in both adjacent andnormal tissues. The expression intensities of SHH, SMO, GLI1 mRNA in tumor tissues were significantly higher than those in adjacent tissues and normal tissues. Proteins were also detected more frequently in tumors than other tissues. No significant links were apparent with gender, age, location, degree of infiltration or Dukes stage. Conclusion: Positive rates and intensities of mRNA and protein expression of Hh signaling pathway related genes SHH, SMO, GLI1 were found to be significantly increased in CRC tissues. However, over-expression did not appear to be associated with particular clinicopathological characteristics.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Expression and Clinical Significance Of Hedgehog Signaling Pmentioning

confidence: 99%

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Expression and Clinical Significance of Hedgehog Signaling Pathway Related Components in Colorectal Cancer

Wang

Li²,

Wu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…Gli1 is a transcriptional activator [18] , which induces the expression of numerous target genes that regulates proliferation, differentiation, and extracellular matrix interactions [19,20] . Increasing evidence has demonstrated that the Hh signaling pathway plays an important role in multiple tumor types, for example, basal cell carcinoma [21,22] , pancreatic cancer [23] , colon carcinoma [24] , gastric cancer [25] , small cell lung cancer [26] , prostate cancer [27][28][29] , breast cancer [30,31] , early childhood hepatoblastoma [32] , and esophageal cancers [33] .…”

Section: Introductionmentioning

confidence: 99%

Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

Lü

Zhao

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the role of Hedgehog (Hh) signaling pathway in the invasion and metastasis of human hepatocellular carcinoma (HCC). Methods: Eighty six HCC tissues samples and HCC cell line Bel-7402 were examined. The protein expression of sonic hedgehog (Shh), nuclear glioma-associated oncogene-1 (Gli1), MMP-9 and p-ERK1/2 in HCC was analyzed using immunohistochemistry and Western blot analysis. Boyden chamber assay and wound-healing assay were used to quantify the invasion and metastasis of Bel-7402 cells. Results: In 86 HCC tissue samples, the positive ratio of Shh and nucleus Gli1 was 67.44% (58/86) and 60.47% (52/86), respectively; the expression of nucleus Gli1 was correlated with the tumor pathological grade (P=0.034), and with the ability of the tumor to invade and metastasize (P=0.001); the expression of nucleus Gli1 was also correlated with p-ERK1/2 (P=0.031) and with MMP-9 (P=0.034). Neither Shh, nor nucleus Gli1 was observed in normal liver tissue. KAAD-cyclopamine (KAAD-cyc), a specific inhibitor of the Hh pathway, at the concentrations of 1 and 4 μmol/L inhibited the invasion and migration of Bel-7402 cells and decreased the expression of Gli1 in nucleus and MMP-9, p-ERK1/2 proteins in Bel-7402 cells. On the other hand, Shh, a ligand of the Hh pathway, at the concentration of 0.5 μg/mL produced opposite effects. The MAPK pathway inhibitors U0126 and PD98059 at the concentrations of 5 and 10 μmol/L inhibited invasion and metastasis of Bel-7402 cells induced by Shh, and decreased the expression of p-ERK1/2 and MMP-9. However, U0126 and PD98059 had no effect on the expression of Gli1. Conclusion: Hh signaling pathway mediates invasion and metastasis of human HCC by up-regulating the protein expression of MMP-9 via ERK pathway.

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“…Expression of IHH, which is included in the differentiation of enterocytes, has been suggested to be lost in early phases of human colorectal carcinogenesis (van den Brink et al 2004). It is suggested, however, that Hh signaling increases with colon cancer progression (Yoshikawa et al 2009). It was found further that Hh signaling components are actually activated in advanced human colon cancer cells and their CSCs, where GLI1 expression was higher in CD133 ?…”

Section: Hedgehog (Hh) Pathwaymentioning

confidence: 99%

Immunobiology and signaling pathways of cancer stem cells: implication for cancer therapy

Salem

El-Badawy

2014

Cytotechnology

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Cancer stem cells (CSCs) need to survive cancer treatments with a specific end goal to provide new, more differentiated, metastatic-prone cancerous cells. This happens through diverse signals delivered within the tumor microenvironment where ample evidence indicates that altered developmental signaling pathways play an essential role in maintaining CSCs and accordingly the survival and the progression of the tumor itself. This review summarizes findings on the immunobiological properties of CSCs as compared with cancerous non-stem cells involving the expression of immunological molecules, cytokines and tumor antigens as well as the roles of the Notch, Wnt and Hedgehog pathways in the brain, breast and colon CSCs. We concluded that if CSCs are the main driving force behind tumor support and growth then understanding the molecular mechanisms and the immunological properties directing these cells for immune tolerance is of great clinical significance. Such knowledge will contribute to designing better targeted therapies that could prevent tumor recurrence and accordingly significantly improve cancer treatments and patient survival.

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Sonic hedgehog relates to colorectal carcinogenesis

Abstract: This result indicates that Shh-related carcinogenesis and Shh expression may be a trigger for the adenoma-carcinoma sequence. This study suggests a potential therapeutic target of hedgehog blockade in carcinogenesis.

Cited by 69 publications

References 22 publications

Expression and Clinical Significance of Hedgehog Signaling Pathway Related Components in Colorectal Cancer

Expression and Clinical Significance of Hedgehog Signaling Pathway Related Components in Colorectal Cancer

Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

Immunobiology and signaling pathways of cancer stem cells: implication for cancer therapy

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