Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas

Qian, Zhi Rong; Sendo, Toshiaki; Yoshimoto, Katsuhiko; Sylvia, L.; Yamada, Shozo; Mizusawa, Noriko; Kudo, Eiji

doi:10.1038/modpathol.3800965

Cited by 93 publications

(71 citation statements)

References 33 publications

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“…The present study showed that reduced or absent expression of E-cadherin and P120 was associated with the histological grade of tumors, which is consistent with reported data [17][18][19][20][21] . In well-differentiated tumors, there were obvious and strong staining along the cell-cell boundaries, whereas in poorly-differentiated tumors, the immunohistostaining was focally and heterogeneously distributed, with patchy or spotty features along the cellcell boundaries, indicating that the staining of E-cadheri and P120 is related with the differentiation of ICC, namely both E-cadherin and P120 may be regarded as differentiation markers of tumor.…”

Section: Discussionsupporting

confidence: 82%

Reduced expression of P120 catenin in cholangiocarcinoma correlated with tumor clinicopathologic parameters

Zhai¹,

Yan²,

Li³

et al. 2008

WJG

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AIM: To i nve s t i g a t e t h e re l a t i o n s h i p b e t w e e n the expression of P120 and the clinicopathologic parameters in intrahepatic cholangiocarcinoma (ICC). METHODS: An immunohistochemical study of E-cadherin and P120 catenin was performed on 42 specimens of ICC with a Dako Envision kit. RESULTS: The expression of E-cadherin and P120 was reduced in 27 cases (64.3%) and 31 cases (73.8%), respectively. Both E-cadherin and P120 expressions were significantly correlated with the tumor histological grade (χ 2 = 9.333, P = 009 and χ 2 = 11.71, P = 0.003), TNM stage (χ 2 = 8.627, P = 0.035 and χ 2 = 13.123, P = 0.004), intrahepatic metastasis (χ 2 = 7.292, P = 0.007 and χ 2 = 4.657, P = 0.041, respectively) and patients' survival (χ 2 = 6.351, P = 0.002 and χ 2 = 4.023, P = 0.000, respectively). In addition, the expression of P120 was in concordance with that of E-cadherin ( χ 2 = 1 3 .7 9 7, P = 0 . 0 0 0 ) , i n d i c a t i n g t h a t t h e expression of P120 may be dependent on that of E-cadherin. Finally, only P120 expression was found to be an independent prognostic factor in Cox regression model (r = 0.088, P = 0.049). CONCLUSION:D o w n-re g u la t e d e x p re s s io n o f E-cadherin and P120 occurs frequently in ICC and contributes to the progression and development of tumor. Both of them may be valuable biologic markers for predicting tumor invasion, metastasis and patients' survival, but only P120 is an independent prognostic factor for ICC.

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Section: Discussionsupporting

confidence: 82%

Reduced expression of P120 catenin in cholangiocarcinoma correlated with tumor clinicopathologic parameters

Zhai¹,

Yan²,

Li³

et al. 2008

WJG

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“…32 Our previous study also demonstrated that tumor-specific downregulation of E-cadherin and H-cadherin related to invasiveness of pituitary adenoma. 27 HMGA2 may be involved in tumor cell The value of let-7 expression in normal pituitary tissues was equal to onefold. The reduced expression of let-7 was found in 23 (41.8%) adenomas (blue square columns, downregulation rates were À1.10 to À16.41-fold, 17 cases showed over 2-fold change).…”

Section: Discussionmentioning

confidence: 99%

“…26,27 After deparaffinization and antigen retrieval using an autoclave oven technique, sections were incubated at 41C overnight with goat polyclonal anti-HMGA2 antibody (1:50; HMGI-C, S-15, Santa Cruz Biotechnology, Santa Cruz, CA, USA) or with Ki-67 antigen mouse monoclonal antibody (1:100; DakoCytomation, Glostrup, Denmark). Antigen-antibody complexes were detected using the cobalt-3,3 0 -diaminobenzidine reaction.…”

Section: Immunohistochemicalmentioning

confidence: 99%

Overexpression of HMGA2 relates to reduction of the let-7 and its relationship to clinicopathological features in pituitary adenomas

et al. 2009

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High-mobility group A2 is highly expressed during embryogenesis and in various benign and malignant tumors. Recent studies report that high-mobility group A2 is negatively regulated by the let-7 microRNAs (miRNAs) family in vitro. The development of pituitary adenomas in high-mobility group A2 transgenic mice showed that high-mobility group A2 may be involved in pituitary tumorigenesis. However, no studies have investigated the clinical significance of high-mobility group A2 and its relationship to the let-7 miRNA family in human pituitary adenomas. Using immunohistochemistry, we analyzed high-mobility group A2 expression with respect to various clinicopathologic factors in 98 pituitary adenomas. Overexpression of high-mobility group A2 was observed in 39% (38/98) of pituitary adenomas compared with normal adenohypophysial tissue and was frequently found in adenomas including prolactin (PRL), adrenocorticotrophic hormone, or follicle-stimulating hormone/luteinizing hormone and in null cell adenomas, but relatively rare in growth hormone (GH) and mixed GH/PRL adenomas. High-mobility group A2 expression was significantly associated with tumor invasion (Po0.05) and was significantly higher in grade IV than in grades I, II, and III adenomas (Po0.05). High levels of high-mobility group A2 expression were more frequently observed in macroadenomas than in microadenomas (Po0.05). High levels of high-mobility group A2 expression also significantly correlated with the proliferation marker Ki-67 (Po0.0001). Real-time quantitative RT-PCR analysis was carried out to evaluate the expression of let-7 in 55 pituitary adenomas. Subsequently, decreased expression of let-7 was confirmed in 23 of 55 (42%) adenomas and was correlated with high-grade tumors (Po0.05). An inverse correlation between let-7 and highmobility group A2 expression was evident (R ¼ À0.33, Po0.05). These findings support a causal link between let-7 and high-mobility group A2 whereby loss of let-7 expression induces high-mobility group A2 upregulation that represents an important mechanism in pituitary tumorigenesis and progression.

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“…1,2 Hypermethylation of gene promoter regions has been implicated in the inactivation of several genes, including p16/ CDKN2A, RB1, DAPK, GADD45g, RASSF1A, E-cadherin, H-cadherin, Ikaros, and FGFR2. [3][4][5][6][7][8][9][10][11] GSTP1 encodes glutathione-S-transferase-p, a member of a family of enzymes, the glutathione-S-transferases (GSTs) that function as dimers composed of subunits from five main classes: a, m, p, s, and y. GSTs are phase 2 enzymes that catalyze the conjugation of glutathione with electrophilic and hydrophobic compounds including carcinogens, natural toxins, and exogenous drugs. [12][13][14] GSTs are believed to play an important role in protecting cells from cytotoxic and carcinogenic agents.…”

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confidence: 99%

Reduction of GSTP1 expression by DNA methylation correlates with clinicopathological features in pituitary adenomas

et al. 2008

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p-Class glutathione-S-transferase (GSTP1) located on chromosome 11q13 encodes a phase II metabolic enzyme that detoxifies reactive electrophilic intermediates. GSTP1 plays an important role in the protecting cells from cytotoxic and carcinogenic agents and is expressed in normal tissues at variable levels in different cell types. Altered GSTP1 activity and expression have been reported in many tumors and this is largely due to GSTP1 DNA hypermethylation. The role of GSTP1 in pituitary tumorigenesis has not been investigated. In this study, we evaluated the GSTP1 expression level and GSTP1 DNA methylation status in a series of pituitary adenomas. Using immunohistochemistry, we identified expression of GSTP1 in all of the various normal hormoneproducing adenohypophysial cell types. In pituitary adenomas, loss or reduced expression of GSTP1 was detected in 27 of 53 tumors (50.9%). Expression of GSTP1 was significantly lower in invasive adenomas than in noninvasive adenomas (Po0.05). Using methylation-specific polymerase chain reaction (MS-PCR), GSTP1 DNA promoter hypermethylation was detected in adenomas (38 of 53, 71.7%) but not in normal tissues. GSTP1 methylation was more frequent in grade II, III, and IV tumors (66.7, 85, and 83%, respectively) than in grade I tumors (33%, Po0.05). In addition, the frequency of GSTP1 methylation was higher in invasive tumors (85%) than in noninvasive tumors (59%; Po0.05). Methylation status correlated with significant downregulation of GSTP1 expression; the frequency of GSTP1 methylation was higher in tumors with reduced-GSTP1 expression (85%) than in tumors with normal or high GSTP1 expression (54%; Po0.05).These data indicate that GSTP1 inactivation through CpG hypermethylation is common in pituitary adenomas and may contribute to aggressive pituitary tumor behavior.

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Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas

Cited by 93 publications

References 33 publications

Reduced expression of P120 catenin in cholangiocarcinoma correlated with tumor clinicopathologic parameters

Reduced expression of P120 catenin in cholangiocarcinoma correlated with tumor clinicopathologic parameters

Overexpression of HMGA2 relates to reduction of the let-7 and its relationship to clinicopathological features in pituitary adenomas

Reduction of GSTP1 expression by DNA methylation correlates with clinicopathological features in pituitary adenomas

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