Low Expression of Claudin-4 is Associated with Poor Prognosis in Esophageal Squamous Cell Carcinoma

Sung, Chang Ohk; Han, Seong Ho; Kim, Seok-Hyung

doi:10.1245/s10434-010-1289-4

Cited by 53 publications

(42 citation statements)

References 24 publications

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“…6). Furthermore, given the prognostic value of claudin 4 total protein expression in various tumor types (Ersoz et al, 2011;Sung et al, 2011;Szasz et al, 2011) and the association between loss of TJs and metastatic behavior (Martin et al, 2011), our results also provide additional evidence that IQGAP1 might be a potential therapeutic target for the treatment of advanced cancers.…”

Section: Discussionmentioning

confidence: 55%

IQGAP1 Controls Tight Junction Formation Through Differential Regulation of Claudin Recruitment

Tanos

Bay

Salvarezza

et al. 2015

Journal of Cell Science

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IQGAP1 is a scaffolding protein previously implicated in adherens junction formation. However, its role in the establishment or maintenance of tight junctions (TJs) has not been explored. We hypothesized that IQGAP1 could regulate TJ formation by modulating the expression and/or localization of junctional proteins, and we systematically tested this hypothesis in the model Madin-Darby canine kidney (MDCK) cell line. We find that IQGAP1 silencing enhances a transient increase in transepithelial electrical resistance (TER) observed during the early stages of TJ formation (Cereijido et al., 1978). Quantitative microscopy and biochemical experiments suggest that this effect of IQGAP1 on TJ assembly is accounted for by reduced expression and TJ recruitment of claudin 2, and increased TJ recruitment of claudin 4. Furthermore, we show that IQGAP1 also regulates TJ formation through its interactor CDC42, because IQGAP1 knockdown increases the activity of the CDC42 effector JNK and dominantnegative CDC42 prevents the increase in TER caused by IQGAP1 silencing. Hence, we provide evidence that IQGAP1 modulates TJ formation by a twofold mechanism: (1) controlling the expression and recruitment of claudin 2 and recruitment of claudin 4 to the TJ, and (2) transient inhibition of the CDC42-JNK pathway.

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Section: Discussionmentioning

confidence: 55%

IQGAP1 Controls Tight Junction Formation Through Differential Regulation of Claudin Recruitment

Tanos

Bay

Salvarezza

et al. 2015

Journal of Cell Science

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“…1 Despite the development of multimodal therapies including surgery, chemotherapy, radiotherapy, and chemo-radiotherapy, the 5-year survival rate of patients remains in the range of 10 to 25%, 1 underscoring the need for identifying the signaling pathways and downstream targets that lead to esophageal cancer progression and metastasis. 2,3 Recently, the mammalian target of rapamycin (mTOR)-S6 kinase (S6K1) signaling pathway-has emerged as a critical regulator of cellular metabolism, proliferation, and survival in response to growth factor and nutrient availability. [4][5][6][7] Upon growth factor stimulation, mTOR-dependent activation of S6K1 induces phosphorylation of S6, the 40S ribosomal protein at Ser235, Ser236, Ser240, Ser244, and Ser247.…”

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confidence: 99%

Prognostic significance and function of phosphorylated ribosomal protein S6 in esophageal squamous cell carcinoma

et al. 2013

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Ribosomal protein S6 is a key regulator of 40S ribosome biogenesis, and its phosphorylation is closely related to cell growth capacity. However, as a downstream target of S6 kinases, the clinical significance and the roles of S6 and S6 phosphorylation in cell viability and motility of esophageal squamous cell carcinoma remain unclear. Here, we show that high level of phosphorylated-ribosomal protein S6 (p-S6) (immunohistochemistry score Z5) and an increased ratio of p-S6/S6 (immunohistochemistry score Z0.75) were significantly associated with shortened disease-free survival in patients with esophageal squamous cell carcinoma in univariate analysis (P ¼ 0.049 and Po0.001, respectively). After adjusting for age, tumor-nodes-metastasis stage, chemotherapy, and radiation therapy in multivariate analysis, both p-S6 (hazard ratio 2.21, P ¼ 0.005) and p-S6/S6 (hazard ratio 2.40, Po0.001) remained independent adverse prognostic factors. In addition, S6 and S6 kinase 1 knockdown resulted in attenuation of viability by suppressing cyclin D1 expression in esophageal cancer cells. Furthermore, depletion of S6 and S6 kinase 1 resulted in a reduction in esophageal cancer cell migration and invasion. This was paralleled by a reduction in focal adhesion and by suppression of extracellular signal-regulated kinase and c-jun N-terminal kinase phosphorylation, which control cell motility. Collectively, these findings suggest that p-S6 and the ratio of p-S6/S6 are closely relevant to tumor progression and have prognostic significance in esophageal squamous cell carcinoma. Modern Pathology (2013) 26, 327-335; doi:10.1038/modpathol.2012.161; published online 21 September 2012Keywords: esophagus squamous cell carcinoma; phosphorylation; S6 Esophageal squamous cell carcinoma is one of the most aggressive malignant tumors of the gastrointestinal tract, and has a high mortality rate. 1 The prognosis of esophagus squamous cell carcinoma is poor due to a high incidence of metastasis to lymph nodes, liver, and lung. 1 Despite the development of multimodal therapies including surgery, chemotherapy, radiotherapy, and chemo-radiotherapy, the 5-year survival rate of patients remains in the range of 10 to 25%, 1 underscoring the need for identifying the signaling pathways and downstream targets that lead to esophageal cancer progression and metastasis. 2,3 Recently, the mammalian target of rapamycin (mTOR)-S6 kinase (S6K1) signaling pathway-has emerged as a critical regulator of cellular metabolism, proliferation, and survival in response to growth factor and nutrient availability. [4][5][6][7] Upon growth factor stimulation, mTOR-dependent activation of S6K1 induces phosphorylation of S6, the 40S ribosomal protein at Ser235, Ser236, Ser240, Ser244, and Ser247. 8,9 The importance of S6 phosphorylation is underscored by the finding that mouse embryonic fibroblasts from S6 knock-in mice in which all phosphorylatable serine residues in S6 are substituted by alanines exhibit small cell size, 10 indicating the potential role of S6 phosphorylation in r...

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“…The similar claudin expression profile of Barrett's esophagus and adenocarcinoma supports their sequential development (Győrffy et al, 2005). The low expression of the claudin4 is associated with the poor prognosis in the most common tumour of the esophagus, squamous cell carcinoma (Sung et al, 2011). Gastric intestinal metaplasia showed higher expression of claudin2, -3 and -4 as compared with normal antral foveolar mucosa (Győrffy, 2009).…”

Section: Claudins and Tumour Of The Gastrointestinal Tractmentioning

confidence: 87%

Mucosal expression of claudins in children with celiac disease

Veres¹,

Nagy-Szakal²,

Györffy³

et al. 2012

Celiac Disease - From Pathophysiology to Advanced Therapies

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Low Expression of Claudin-4 is Associated with Poor Prognosis in Esophageal Squamous Cell Carcinoma

Abstract: Our study indicates that claudin-4 expression is deregulated in ESCC, implying its potential use as a prognostic biomarker in ESCC.

Cited by 53 publications

References 24 publications

IQGAP1 Controls Tight Junction Formation Through Differential Regulation of Claudin Recruitment

IQGAP1 Controls Tight Junction Formation Through Differential Regulation of Claudin Recruitment

Prognostic significance and function of phosphorylated ribosomal protein S6 in esophageal squamous cell carcinoma

Mucosal expression of claudins in children with celiac disease

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