Aberrant expression of β-catenin, Pin1 and cylin D1 in salivary adenoid cystic carcinoma: Relation to tumor proliferation and metastasis

Zhou, Chuan‐Xiang; Yan, Guoquan

doi:10.3892/or.16.3.505

Cited by 24 publications

(34 citation statements)

References 34 publications

(34 reference statements)

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“…These results are consistent with the previous finding that Pin1 increases ␤-catenin levels by inhibiting its degradation, with Pin1 expression tightly correlating with ␤-catenin levels in many human cancer tissues and cells (11,28,60,63,74,93). Tau and APP are also substrates for Pin1, and the A␤ peptide increases the number of newborn hippocampal neurons, with no changes in the rate of cell death or proliferation, suggesting that the A␤ peptide could act on hippocampal neuronal progenitors and promote their differentiation into neurons (37).…”

Section: Discussionsupporting

confidence: 93%

Prolyl Isomerase Pin1 Regulates Neuronal Differentiation via β-Catenin

Nakamura

Kosugi

Lee

et al. 2012

Molecular and Cellular Biology

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dThe Wnt/␤-catenin pathway promotes proliferation of neural progenitor cells (NPCs) at early stages and induces neuronal differentiation from NPCs at late stages, but the molecular mechanisms that control this stage-specific response are unclear. Pin1 is a prolyl isomerase that regulates cell signaling uniquely by controlling protein conformation after phosphorylation, but its role in neuronal differentiation is not known. Here we found that whereas Pin1 depletion suppresses neuronal differentiation, Pin1 overexpression enhances it, without any effects on gliogenesis from NPCs in vitro. Consequently, Pin1-null mice have significantly fewer upper layer neurons in the motor cortex and severely impaired motor activity during the neonatal stage. A proteomic approach identified ␤-catenin as a major substrate for Pin1 in NPCs, in which Pin1 stabilizes ␤-catenin. As a result, Pin1 knockout leads to reduced ␤-catenin during differentiation but not proliferation of NPCs in developing brains. Importantly, defective neuronal differentiation in Pin1 knockout NPCs is fully rescued in vitro by overexpression of ␤-catenin but not a ␤-catenin mutant that fails to act as a Pin1 substrate. These results show that Pin1 is a novel regulator of NPC differentiation by acting on ␤-catenin and provides a new postphosphorylation signaling mechanism to regulate developmental stage-specific functioning of ␤-catenin signaling in neuronal differentiation. N eurons are generated from neural stem/progenitor cells (NPCs) during brain development. Recently, it has been emerging that an array of extracellular factors, including Wnt, platelet-derived growth factor, vascular endothelial growth factor, and bone morphogenic proteins, trigger signaling cascades leading to activation of downstream transcription factors to regulate neuronal differentiation from NPCs (6,16,18,22,23,33,51,68,86,91). However, little is known about how these signaling pathways are integrated to control the highly ordered events of neuronal differentiation to generate neurons in different layers or subregions of the brain during development.A well-established key signaling pathway in neurogenesis is the Wnt/␤-catenin pathway (13,16,18,22,46,62). For example, overexpression of constitutively active ␤-catenin in NPCs induces neurogenesis and increases cortical size (12,23,90). Similarly, overexpression of Wnt3 increases neurogenesis in cortical progenitor cells (26, 43) and adult hippocampal stem/progenitor cells (34). Conversely, ablation of ␤-catenin inhibits neurogenesis, leading to reduced brain size (23, 90). Finally, activation of the Wnt/␤-catenin pathway leads to the formation of ␤-catenin-TCF complexes to transactivate Wnt target genes, including many proneural transcription factors (25,30,48,79). Significantly, the in vivo function of Wnt/␤-catenin signaling in neuronal differentiation depends on the developmental stage during brain development. It appears to promote proliferation of early NPCs (expansion phase) but induces neuronal differentiation of NPCs in the la...

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Section: Discussionsupporting

confidence: 93%

Prolyl Isomerase Pin1 Regulates Neuronal Differentiation via β-Catenin

Nakamura

Kosugi

Lee

et al. 2012

Molecular and Cellular Biology

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“…Cyclin D1 overexpression is a common event in many human tumour types and was present very frequently in our ACC series (50% intense, 32% moderate level), irrespective of histological subtype, in line with previous reports (13)(14)(15). This is the first report describing cyclin D1 immunoreactivity restricted to the epithelial component of ACC.…”

Section: Discussionsupporting

confidence: 91%

“…EGFR, C-Kit (cell surface protein receptors), p110· (component of the Akt signalling pathway), cyclin D1 (cell cycle regulatory protein), MYC (transcription factor) and MDM2 (p53 activity regulatory protein) are all encoded by oncogenes [ERBB1 (7p12-14), KIT (4q11-12), PIK3CA (3q26.3), CCND1 (11q13), MYC (8p24) and MDM2 (12q13- 14), respectively] that have been shown to be involved in human carcinogenesis. In a search for molecular alterations that could help in the outcome prediction of ACC patients, we set out to study the gene and protein status of these targets.…”

Section: Introductionmentioning

confidence: 99%

Oncogene amplification pattern in adenoid cystic carcinoma of the salivary glands

González¹

2009

Oncol Rep

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Abstract. The aim of the present study was the search of molecular alterations (oncogene amplification or protein overexpression) that could have an impact on the outcome of ACC patients. For this purpose, paraffin-embedded tissue samples of primary ACC of 24 patients were collected. Oncogenic amplification status of six targets previously described to be involved in human carcinogenesis (ERBB1, KIT, PIK3CA, CCND1, MYC and MDM2) were studied by a PCR-based semiquantitative approach. C-Kit, cyclin D1 and EGFR protein levels were immunohistochemically assessed. ERBB1, CCND1 and PIK3CA were frequent targets of oncogene amplification (67, 46 and 38%, respectively). C-Kit and cyclin D1 were overexpressed in 57 and 82%, respectively. CCND1 amplification was associated with advanced tumour stage and ERBB1 amplification to distant metastasis. ERBB1/CCND1/PIK3CA coamplification was the most consistently observed pattern (29%). The cases with this amplification pattern presented a reduced survival. This study points to the importance of ERBB1, CCND1 and PIK3CA oncogenic amplification status in ACC carcinogenesis.

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“…By this method, we found that Notch family members are deregulated in highly metastatic SACC cell lines, ACC-M, indicating a potential role of Notch signaling in SACC metastasis. SACC metastasis is a complex process that relates to a number of genes, such as ß-catenin, MMPs, and cyclin D1 (4,5). The Wnt signaling pathway also plays a pivotal role in SACC carcinogenesis and metastasis (5).…”

Section: Introductionmentioning

confidence: 99%

“…SACC metastasis is a complex process that relates to a number of genes, such as ß-catenin, MMPs, and cyclin D1 (4,5). The Wnt signaling pathway also plays a pivotal role in SACC carcinogenesis and metastasis (5).…”

Section: Introductionmentioning

confidence: 99%