Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions

Wang, Lihui; Choi, Yoon‐La; Hua, Xuan-Yan; Shin, Young Kee; Song, Young‐Jin; Youn, Sei-jin; Yun, Hyo-Young; Park, Seon-Mee; Kim, Wun-Jae; Kim, Hee‐Jin; Choi, Jihye; Kim, Seok-Hyung

doi:10.1038/modpathol.3800573

Cited by 89 publications

(68 citation statements)

References 23 publications

(32 reference statements)

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“…Recently, promoter methylation of Shh and Hh-interacting protein has been reported as another regulatory mechanism of the Hh pathway. (28,29) In ovarian carcinomas, the expression of Shh, Dhh, Ptch, Smo and Gli1 was highly correlated with cell proliferation assessed by the Ki-67 positivity index, suggesting that Hh signal molecules are actually involved in cell proliferation. To investigate further the mechanisms of Hh signaling for cell proliferation, we blocked the Hh signal pathway with cyclopamine, a known Hh pathway inhibitor, or by interfering with the mRNA expression of Gli1 in ovarian carcinoma cell lines.…”

Section: Discussionmentioning

confidence: 97%

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis

et al. 2006

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The hedgehog (Hh) signal pathway has recently been shown to be activated in human malignancies. However, little is known about its role in the development or patient prognosis of epithelial ovarian carcinoma. In the present study, we examined in vivo and in vitro E pithelial ovarian carcinoma, which comprises the majority of malignant ovarian tumors, is the leading cause of death from gynecologic malignancy in women.(1) The survival of ovarian carcinoma patients has not improved significantly for years, indicating that further understanding of the biology of ovarian carcinoma cells is critical for the development of new treatments against this neoplasm.(2) Several studies have reported that the poor prognosis of ovarian carcinoma is related not only to the unique metastasis but also to the high proliferative activity of carcinoma cells.(3-5) However, the molecular mechanisms of the proliferation of ovarian carcinoma cells are not fully understood. Recent studies suggest that the hedgehog (Hh) signal pathway contributes to cell proliferation and differentiation in several human neoplasms, such as pancreas, prostate and skin carcinomas.

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Section: Discussionmentioning

confidence: 97%

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis

et al. 2006

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“…Increased SHH expression in gastric cancer and its related lesions correlates with the altered SHH promoter methylation (Wang et al 2006). Ma et al (2006) reported that the SHH gene is amplified in esophageal cancer.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation

Ding²,

Rao³

et al. 2012

Endocrine-Related Cancer

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The sonic hedgehog (SHH) pathway is activated in several types of malignancy and plays an important role in tumor cell proliferation and tumorigenesis. SHH binding to a 12-pass transmembrane receptor, Patched (PTCH), leads to freeing of Smoothened (SMO) and subsequent activation of GLI transcription factors. In the present study, we analyzed the expression of SHH, PTCH, SMO, and GLI1 in 31 follicular thyroid adenomas (FTA), 8 anaplastic thyroid carcinomas (ATC), and 51 papillary thyroid carcinomas (PTC) by immunohistochemical staining. More than 65% of FTA, PTC, and ATC specimens stained positive for SHH, PTCH, SMO, and GLI. However, the expression of the genes encoding these four molecules did not correlate with any clinicopathologic parameters, including the age, gender, the status of BRAF gene mutation, tumor stage, local invasion, and metastasis. Three thyroid tumor cell lines (KAT-18, WRO82, and SW1736) all expressed the genes encoding these four molecules. 5-Bromo-2-deoxyuridine labeling and MTT cell proliferation assays revealed that cyclopamine (CP), an inhibitor of the SHH pathway, was able to inhibit the proliferation of KAT-18 and WRO82 cells more effectively than SW1736 cells. CP led to the arrest of cell cycle or apoptosis. Knockdown of SHH and GLI expression by miRNA constructs that target SHH or GLI mRNA in KAT-18 and SW1736 cells led to the inhibition of cell proliferation. Our results suggest that the SHH pathway is widely activated in thyroid neoplasms and may have potential as an early marker of thyroid cancer or as a potential therapeutic target for thyroid cancer treatment.

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“…Immunostaining of SMAD4 and SMAD2/3 was done on consecutive sections obtained from paraffin-embedded material, using mouse monoclonal anti-SMAD4 antibody (B-8; Santa Cruz Biotechnology, Santa Cruz, CA), and goat polyclonal anti-SMAD2/3 antibody (N-19; Santa Cruz Biotechnology). The experimental procedures were done as previously described (28).…”

Section: Methodsmentioning

confidence: 99%

Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression

Wang

Kim

Lee

et al. 2007

Clinical Cancer Research

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100

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Purpose: Mothers against decapentaplegic homologue 4 (SMAD4) is a tumor suppressor gene associated with gastrointestinal carcinogenesis. The aim of the present study is to more precisely characterize its role in the development and progression of human gastric carcinoma. Experimental Design: The expression of SMAD4 was investigated in 283 gastric adenocarcinomas and related lesions, as well as in 9 gastric carcinoma cell lines. We also analyzed the methylation status of SMAD4 gene by using methylation-specific PCR, examined loss of heterozygosity (LOH) of this gene locus by using a vicinal marker, and detected exon mutation of SMAD4 through exon-by-exon amplification. Moreover, we assessed whether MG132, a proteasome inhibitor, affected the SMAD4 protein level. Results: We found loss of SMAD4 protein expression in the cytoplasm (36 of 114, 32%) and in the nucleus (46 of 114, 40%) of gastric cancer cells. The loss of nuclear SMAD4 expression in primary tumors correlated significantly with poor survival, and was an independent prognostic marker in multivariate analysis.We also found a substantial decrease in SMAD4 expression at both the RNA and protein level in several human gastric carcinoma cell lines. In addition, we found that LOH (20 of 70, 29%) and promoter hypermethylation (4 of 73, 5%) were associated with the loss of SMAD4 expression. SMAD4 protein levels were also affected in certain gastric carcinoma cell lines following incubation with MG132. Conclusion: Taken together, our results indicate that the loss of SMAD4, especially loss of nuclear SMAD4 expression, is involved in gastric cancer progression. The loss of SMAD4 in gastric carcinomas was due to several mechanisms, including LOH, hypermethylation, and proteasome degradation.

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Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions

Cited by 89 publications

References 23 publications

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis

Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation

Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression

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