Expression and prognostic significance of <i>PTEN</i> product protein in patients with esophageal squamous cell carcinoma

Tachibana, Mitsuo; Shibakita, Muneaki; Ohno, Satoshi; Kinugasa, Shoichi; Yoshimura, Hiroshi; Ueda, Shuhei; Fujii, Toshiyuki; Rahman, Mohammad Atiqur; Dhar, Dipok Kumar; Nagasue, Naofumi

doi:10.1002/cncr.0678

Cited by 98 publications

(102 citation statements)

References 25 publications

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“…IHC analysis revealed that the PTEN expression inversely correlated with ESCC grade and positively correlated with patient survival (n ¼ 207; Fig. 7a, upper panel, and Supplementary Table 5), which was consistent with a previous report 27 . In the same cohort study, the INPP4A levels were also found to be correlated with patient survival time (n ¼ 207; Po0.001) (Fig.…”

Section: Overexpression Of Mir-508 Correlates With Escc Progressionsupporting

confidence: 91%

miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma

et al. 2014

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The strength and duration of phosphoinositide signalling from phosphatidylinositol-3-kinase (PI3K) activation to Akt is tightly balanced by phosphoinositide kinases and phosphatases. However, how phosphatase-mediated negative regulatory effects are concomitantly disrupted in cancers, which commonly exhibit constitutively activated PI3K/Akt signalling, remains undefined. Here we report that miR-508 directly suppresses multiple phosphatases, including inositol polyphosphate-5-phosphatase J (INPP5J), phosphatase and tensin homologue (PTEN) and inositol polyphosphate 4-phosphatase type I (INPP4A), resulting in constitutive activation of PI3K/Akt signalling. Furthermore, we find that overexpressing miR-508 promotes, while silencing miR-508 impairs, the aggressive phenotype of oesophageal squamous cell carcinoma (ESCC) both in vitro and in vivo. Importantly, the level of miR-508 correlates with poor survival and activated PI3K/Akt signalling in a large cohort of ESCC specimens. These findings uncover a mechanism for constitutive PI3K/Akt activation in ESCC, and support a functionally and clinically relevant epigenetic mechanism in cancer progression.

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Section: Overexpression Of Mir-508 Correlates With Escc Progressionsupporting

confidence: 91%

miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma

et al. 2014

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“…In ESCC, PTEN mutation was only detected in 1 of 33 human ESCC specimens, whereas the mutation was located in intron 7 rather than the mutation hot spot region, exon 5 (32). However, another study have shown that negative or decreased nuclear expression of PTEN is a predictor for poor survival of ESCC patients, suggesting that decreased expression of PTEN might be an important event in ESCC progression (33). This result was further confirmed by another group studying a Chinese ESCC patient cohort (34).…”

Section: Dj-1 Is An Independent Predictor For Escc Patientmentioning

confidence: 81%

DJ-1 Could Predict Worse Prognosis in Esophageal Squamous Cell Carcinoma

Yuen

Chan²,

Law

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Recent studies have revealed an oncogenic role of DJ-1 through its ability to transform normal cells, prevent oxidative damage, and inhibit apoptosis. However, its role in esophageal squamous cell carcinoma (ESCC) is unknown. In this study, by immunohistochemistry, we analyzed the expression of DJ-1 in 81 ESCC tumors, 31 paired nonneoplastic esophageal epithelia, and 19 paired ESCC lymph node metastases. We found that cytoplasmic DJ-1 expression was significantly higher in ESCC and ESCC lymph node metastases than in nonneoplastic esophageal epithelium. ESCC specimens with high distant metastatic potential also had a significantly higher level of nuclear DJ-1 expression (P = 0.018). By Kaplan-Meier analysis, we found that a high level of nuclear DJ-1 was significantly associated with poorer patient survival in our cohort (P = 0.028). To investigate whether DJ-1 promotes ESCC progression through phosphatidylinositol 3-kinase pathway and modulation of apoptosis, we performed immunohistochemistry of pAkt and Daxx. We found that DJ-1 expression was significantly associated with pAkt, whereas nuclear DJ-1 expression was significantly correlated with nuclear expression of Daxx. These results suggest that phosphatidylinositol 3-kinase pathway and Daxx-regulated apoptosis might be important in DJ-1-mediated ESCC progression. By using multivariate Cox regression, we further showed that T 4 stage (P = 0.003) and DJ-1 (P = 0.034) are independent predictors of patient survival. In conclusion, our results suggest that DJ-1 plays a very important role in transformation and progression of ESCC and may be used as a prognostic marker in ESCC. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3593 -602)

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“…PI3K-Akt pathway activity has been an important prognostic determinant of ESCC. [45][46][47] COX-2 inhibition reduces Akt phosphorylation in ovarian, prostate, and esophageal cancers, 48 -50 implying that COX-2 might be a key intermediate between Pea3 and Akt. However, COX-2 mRNA expression levels were not significantly different between EC109 shScr, shPea3-1, and shPea3-2 cells.…”

Section: Discussionmentioning

confidence: 99%

The Role of Pea3 Group Transcription Factors in Esophageal Squamous Cell Carcinoma

Yuen

McCrudden

Chan

et al. 2011

The American Journal of Pathology

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The transcription factors Pea3, Erm, and Er81 can promote cancer initiation and progression in various types of solid tumors. However, their role in esophageal squamous cell carcinoma (ESCC) has not been elucidated. In this study, we found that the expression levels of Pea3 and Erm, but not that of Er81, were significantly higher in ESCC compared with nontumor esophageal epithelium. A high level of Pea3 expression was significantly correlated with a shorter overall survival in a cohort of 81 patients with ESCC and the subgroup with N1 stage tumor (WilcoxonGehan test, P ‫؍‬ 0.016 and P ‫؍‬ 0.001, respectively). Pea3 was overexpressed in seven ESCC cell lines compared with two immortalized esophageal cell lines. Pea3 knockdown reduced cell proliferation and suppressed nonadherent growth, migration, and invasion in ESCC cells in vitro. In addition, Pea3 knockdown in ESCC cells resulted in a down-regulation of phospho-Akt and matrix metalloproteinase 13, whereas a significant positive correlation in the expression levels was observed between Pea3 and phospho-Akt (r ‫؍‬ 0.281, P < 0.013) and between Pea3 and matrix metalloproteinase 13 in the human specimens (r ‫؍‬ 0.462, P < 0.001). Moreover, Pea3 modulated the sensitivity of EC109 cells to doxorubicin, probably via reduced activity of the phosphatidylinositol 3-kinase-Akt-mammalian target of Rapamycin complex 1 pathway on Pea3 knockdown. In conclusion, our results suggest that Pea3 plays an important role in the progression of ESCC. Esophageal squamous cell carcinoma (ESCC) is common among Asian populations. 1 Despite recent advances in the detection of the premalignant lesions and the development of combination therapies, its incidence is increasing, and its outcome remains poor. [2][3][4] Given the poor prognosis of ESCC and its high incidence rate, it is increasingly important to understand the initiation and progression of this type of cancer and to identify the associated prognostic factors.Pea3, Erm, and Er81 belong to the Pea3 subgroup of the Ets transcription factor family. This group of proteins contains several functional domains, and the individual members demonstrate extensive amino acid sequence similarities. 5 The roles of these proteins in mammary gland development and tumorigenesis have also been extensively studied and reviewed. 6 -8 Pea3 group transcription factors promote metastatic development and cancer progression through transcriptional activation of metastasis-related genes, such as matrix metalloproteinases (MMPs) 9 -13 and cyclooxygenase (COX)-2. 14,15 Overexpression of Pea3 also increases the motility and invasiveness of lung cancer cells via activation of the pathway and an increase in COX-2 expression. 16 -18 The prognostic significance of Pea3 has also been demonstrated in various solid tumors. Pea3 is overexpressed in mouse metastatic mammary adenocarcinoma 19 and in human breast cancer, in which its overexpression is also correlated with HER-2 expression and poor prognosis. 20 -23

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Expression and prognostic significance of PTEN product protein in patients with esophageal squamous cell carcinoma

Cited by 98 publications

References 25 publications

miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma

miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma

DJ-1 Could Predict Worse Prognosis in Esophageal Squamous Cell Carcinoma

The Role of Pea3 Group Transcription Factors in Esophageal Squamous Cell Carcinoma

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