Altered Expression of β-Catenin without Genetic Mutation in Intrahepatic Cholangiocarcinoma

Taguchi, Kenichi; Aishima, Shinichi; Tanaka, Shinji; Shimada, Mitsuo; Kawakami, Kiyoshi; Sugimachi, Keizō; Tsuneyoshi, Masazumi

doi:10.1038/modpathol.3880409

Cited by 110 publications

(99 citation statements)

References 23 publications

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“…Furthermore, accumulation of nuclear localization of β-catenin was found in the precancerous lesions (90 days p.i) and increased positive nuclear staining cells with high intensity was found when CCA had fully developed (180 days p.i). These results support previous studies that demonstrated the accumulation of nuclear β-catenin in CCA tissues (Sugimachi et al, 2001;Lim et al, 2008;Loilome et al, 2014).…”

Section: Discussionsupporting

confidence: 93%

Opisthorchis viverrini Infection Activates the PI3K/AKT/PTEN and Wnt/β-catenin Signaling Pathways in a Cholangiocarcinogenesis Model

Yothaisong¹,

Thanee²,

Namwat³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Opisthorchis viverrini (Ov) infection is the major etiological factor for cholangiocarcinoma (CCA), especially in northeast Thailand. We have previously reported significant involvement of PI3K/AKT/PTEN and Wnt/β-catenin in human CCA tissues. The present study, therefore, examined the expression and activation of PI3K/ AKT/PTEN and Wnt/β-catenin signaling components during Ov-induced cholangiocarcinogenesis in a hamster animal model. Hamsters were divided into two groups; non-treated and Ov plus NDMA treated. The results of immunohistochemical staining showed an upregulation of PI3K/AKT signaling as determined by elevated expression of the p85α-regulatory and p110α-catalytic subunits of PI3K as well as increased expression and activation of AKT during cholangiocarcinogenesis. Interestingly, the staining intensity of activated AKT (p-AKT) increased in the apical regions of the bile ducts and strong staining was detected where the liver fluke resides. Moreover, PTEN, a negative regulator of PI3K/AKT, was suppressed by decreased expression and increased phosphorylation during cholangiocarcinogenesis. We also detected upregulation of Wnt/β-catenin signaling as determined by increased positive staining of Wnt3, Wnt3a, Wnt5a, Wnt7b and β-catenin, corresponded with the period of cholangiocarcinogenesis. Furthermore, nuclear staining of β-catenin was observed in CCA tissues. Our results suggest the liver fluke infection causes chronic inflammatory conditions which lead to upregulation of the PI3K/AKT and Wnt/β-catenin signaling pathways which may drive CCA carcinogenesis. These results provide useful information for drug development, prevention and treatment of CCA.

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Section: Discussionsupporting

confidence: 93%

Opisthorchis viverrini Infection Activates the PI3K/AKT/PTEN and Wnt/β-catenin Signaling Pathways in a Cholangiocarcinogenesis Model

Yothaisong¹,

Thanee²,

Namwat³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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“…It was reported that altered expression of E-cadherin/ catenins complex in ICC occurs frequently and is significantly correlated with tumor histological features and/or vascular invasion and metastasis [9][10][11][12][13][14] . It was recently reported that P120 plays a role in the occurrence of various cancers, and that P120 may behave either as a tumor suppressor or as a metastasis promoter, depending on the loss of E-cadherin and P120.…”

Section: Discussionmentioning

confidence: 99%

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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“…These findings are consistent with similar studies in other human tumors, in which b-catenin accumulation was a frequent event but b-catenin mutations were infrequent. 31,32 The role of many proteins that work in regulating b-catenin including Axin, Axin2, GSK-3b, b-TrCP, PP2a and FRAT (frequently rearranged in advanced T-cell lymphomas) are currently being investigated. Preliminary date show wild-type Axin2 in most cases.…”

Section: Discussionmentioning

confidence: 99%

Frequent β-catenin overexpression without exon 3 mutation in cutaneous lymphomas

et al. 2004

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b-Catenin is a ubiquitously cytoplasmic protein that has a critical role in embryonic development and mature tissue homeostasis through its effects on E-cadherin-mediated cell adhesion and Wnt-dependent signal transduction. Mutations that alter specific b-catenin residues important for GSK-3b phosphorylation, or increase the half-life of the protein, were identified in human cancer. However, the role of the Wnt pathway in B-and T-cell oncogenesis has not been extensively investigated. To assess the role of b-catenin defects in primary cutaneous lymphomas, we examined the expression pattern and the genetic alteration of b-catenin on 79 samples from 74 patients with primary cutaneous lymphomas from B-and T-cell origin. Immunohistochemical analysis revealed b-catenin deregulation in five primary cutaneous B-cell lymphomas (21%) and in 21 primary cutaneous T-cell lymphomas (42%) without nuclear accumulation suggesting that activation and accumulation of b-catenin may play an important role in the development of skin lymphomas. Mutation analysis of b-catenin exon 3, which included the responsible element for Wnt signaling, was therefore done in 19 samples. However, genetic alterations of b-catenin exon 3 were not detected in any of these cases suggesting that other regulatory mechanisms may be relevant in activating b-catenin signaling in cutaneous lymphomas.

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Altered Expression of β-Catenin without Genetic Mutation in Intrahepatic Cholangiocarcinoma

Cited by 110 publications

References 23 publications

Opisthorchis viverrini Infection Activates the PI3K/AKT/PTEN and Wnt/β-catenin Signaling Pathways in a Cholangiocarcinogenesis Model

Opisthorchis viverrini Infection Activates the PI3K/AKT/PTEN and Wnt/β-catenin Signaling Pathways in a Cholangiocarcinogenesis Model

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

Frequent β-catenin overexpression without exon 3 mutation in cutaneous lymphomas

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