Claudin-1 Is a Metastasis Suppressor and Correlates with Clinical Outcome in Lung Adenocarcinoma

Chao, Yu Chih; Pan, Szu-Hua; Yang, Shuenn Chen; Yu, Sung-Liang; Fang, Ting; Lin, Chung-Wu; Tsai, Mu Shiun; Chang, Gee Chen; Wu, Che Hsiang; Wu, Yi; Lee, Yung Chie; Hong, Tse-Ming; Yang, Pan Chyr

doi:10.1164/rccm.200803-456oc

Cited by 149 publications

(132 citation statements)

References 43 publications

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“…We previously designed a series of primers for lung cancer according to metastasis pathway in the GeneChip (39,40). CCN2, one of the genes from the list, was considered for the potential relationship of its function to lung cancer metastasis.…”

Section: Overexpression Of Gst-m2 Increases the Transcription Of Ccn2mentioning

confidence: 99%

Glutathione S-Transferase Mu2 Suppresses Cancer Cell Metastasis in Non–Small Cell Lung Cancer

Tang

Lai

et al. 2013

Molecular Cancer Research

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Glutathione S-transferase mu2 (GST-M2) is a phase II detoxification enzyme. Low expression of GST-M2 in lung cancers is due to hypermethylation of its promoter. Lung cancer with the GST mu-null genotype is associated with shorter survival. However, a correlation between GST-M2 and important clinical parameters, as well as the migration of GST-M2-defective cells in lung cancer, has not been established. In the present study, we investigate the role of GST-M2 in cell migration and actin disassembly in lung cancer cells. GST-M2 and CCN2 mRNA levels were significantly reduced in non-small cell lung cancer (NSCLC) tumors when compared with matched normal lung tissues in 82 patients with NSCLC. We found that high expressions of both GST-M2 and CCN2 are correlated with favorable survival of patients with lung cancer when compared with similar patients without GST-M2 or CCN2 expression. GST-M2 can induce CCN2 expression by driving the CCN2 proximal promoter. Overexpression of GST-M2 decreases the formation of filopodia, resulting in remodeling of the reorganized cytoskeletons. Overexpression of GST-M2 significantly suppressed cancer cell migration on wound-healing assay. In addition, overexpression of GST-M2 dramatically reduced tumor growth and metastasis in a xenograft mouse model. These data highlight the potential of GST-M2 as a novel tumor suppressor. GST-M2 increases the expression of CCN2 in lung cancer cells, which inhibits cancer cell migration in lung cancer and animal models. Mol Cancer Res; 11(5); 518-29. Ó2013 AACR.

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Section: Overexpression Of Gst-m2 Increases the Transcription Of Ccn2mentioning

confidence: 99%

Glutathione S-Transferase Mu2 Suppresses Cancer Cell Metastasis in Non–Small Cell Lung Cancer

Tang

Lai

et al. 2013

Molecular Cancer Research

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“…In tumor progression, tight junction assembly is often disrupted resulting in the loss of cell membrane localized tight junction proteins (Resnick et al 2005, Tokes et al 2005. For CLAUDIN-1, an altered protein expression as well as subcellular localization has been observed in common human malignancies including colon, lung and breast cancer and melanoma (Tokes et al 2005, Chao et al 2009, Nemeth et al 2010. Furthermore, subcellular CLAUDIN-1 expression has been associated with a more aggressive tumour behaviour (Miwa et al 2001).…”

Section: Introductionmentioning

confidence: 99%

The impact of CLAUDIN-1 on follicular thyroid carcinoma aggressiveness

Zwanziger¹,

Badziong²,

Ting³

et al. 2015

Endocrine-Related Cancer

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CLAUDIN-1 belongs to the family of transmembrane tight junction proteins tightening the paracellular cleft of epithelial cells. In human malignancies, CLAUDIN-1 is often dysregulated and located in subcellular compartments, particularly in the nucleus where it may influence cellular behaviour. Here, we studied CLAUDIN-1 in relation to the biological characteristics of follicular thyroid carcinoma (FTC). CLAUDIN-1 immuno-staining showed loss of membrane expression and increased nuclear CLAUDIN-1 localization in FTC metastases. CLAUDIN-1 function was further investigated in two different follicular thyroid carcinoma cell lines: FTC-133 isolated from a regional lymph node metastasis and FTC-238 derived from a lung metastasis. In both cell lines CLAUDIN-1 expression was demonstrated in the cell nuclei with a significantly higher protein expression in FTC-238 compared to FTC-133 cells. Interestingly, in vitro scratch assay revealed enriched nuclear CLAUDIN-1 expression near the scratch. Furthermore, the increase of the pathogenic character of FTC-133 cells by RASV12 transfection was associated with elevated CLAUDIN-1 expression and enhanced cell migration, invasion and proliferation. Likewise over-expression of nuclear CLAUDIN-1 in FTC-133 cells resulted in increased cell migration and invasion. Conversely, CLAUDIN-1 downregulation in FTC-238 cells by siRNA resulted in decreased cell migration and invasion and was accompanied by reduced phosphoPKC expression. Moreover, activation and inhibition of PKC resulted in CLAUDIN-1 up-and downregulation in FTC cells respectively. These data suggest an impact of CLAUDIN-1 on follicular thyroid carcinoma aggressiveness, which could potentially be influenced by PKC activity.

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“…The complexity of CLDN1 was proposed because its dual role as a tumor suppressor and promoter, as well as a positive and negative prognostic factor in different cancers, including breast (10,11), gastric (12), ovarian (13), lung (14) and colon (15)(16)(17). Decreased expression of CLDN1 is correlated with recurrence status in breast cancer (18).…”

Section: Introductionmentioning

confidence: 99%

“…The CLDN1 expression was correlated with subtypes in breast (25,26) and lung (27) cancer. Overexpression of CLDN1 in lung cancer cells inhibited cancer cell dissociation, and suppressed cancer cell migration, invasion and metastasis (14). CLDN1 expression can be regulated by many other transcriptional factors or signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

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The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer

Huang

et al. 2014

International Journal of Oncology

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Abstract. Claudin 1 is one of the tight junction proteins, which are critical in the maintenance of epithelial integrity. Aberrant regulation of CLDN1 and its correlation with β-catenin have been discovered in malignant tumors. The present study aimed to investigate the expression profile and clinical relevance of CLDN1 and β-catenin. The protein levels of CLDN1 and β-catenin were examined using immunohistochemical staining. The characteristics of expression profile and prognostic value were analyzed using Pearson's χ 2 test and Kaplan-Meier analysis, respectively. β-catenin overexpression and knockdown were used to investigate its role in regulating CLDN1 expression. We showed that CLDN1 was overexpressed in intestinal-type, presence of lymph node metastasis, higher TNM stage in gastric cancer patients and correlated with decreased overall survival. The characteristics of CLDN1 expression were associated with that of β-catenin. CLDN1 and β-catenin showed similar prognostic value in intestinal-type gastric cancers. β-catenin knockdown and overexpression in cell models revealed a positive relation between CLDN1 and β-catenin. Our study demonstrated that CLDN1 is a biomarker for intestinal-type gastric cancer with shorter survival. The expression of CLDN1 was strongly associated with β-catenin in gastric cancer patients and a gastric cancer cell model. IntroductionGastric cancer is the fourth most common cancer worldwide and is the second most common cause of cancer-related deaths.Gastric cancer has a poor prognosis (1). Although the 5-year survival rate in patients with early-stage disease is ~90%, since the vast majority present with distant metastasis, the overall 5-year survival rate is typically <20% (2). The 5-year survival rate has also been significantly correlated with the degree of tumor invasion, the presence of lymph node and/ or distant metastases and the TNM stage (3,4). However, very limited number of molecules that have clinicopathological significance in gastric cancer has been discovered.Claudin 1 (CLDN1) is one of the integral membrane proteins that constitute tight junctions. Tight junctions are essential for the tight sealing of cellular sheets and maintaining homeostasis (5). Absence of tight junctions or defective tight junctions is associated with the development of the neoplastic phenotype in epithelial cells (6). Thus it is accepted that the disruption of tight junctions leads to loss of cohesion, invasiveness and the lack of differentiation, thereby promoting tumorigenesis. CLDN1 is found to regulate intestinal epithelial homeostasis through the modulation of Notch-signaling (7). Many chemicals and nutrition can regulate CLDN1 expression through different pathways (8,9) to maintain the integrity of intestinal barrier function.The complexity of CLDN1 was proposed because its dual role as a tumor suppressor and promoter, as well as a positive and negative prognostic factor in different cancers, including breast (10,11), gastric (12), ovarian (13), lung (14) and colon (15-17). Decreased exp...

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Claudin-1 Is a Metastasis Suppressor and Correlates with Clinical Outcome in Lung Adenocarcinoma

Abstract: CLDN1 is a cancer invasion/metastasis suppressor. CLDN1 is also a useful prognostic predictor and potential drug treatment target for patients with lung adenocarcinoma.

Cited by 149 publications

References 43 publications

Glutathione S-Transferase Mu2 Suppresses Cancer Cell Metastasis in Non–Small Cell Lung Cancer

Glutathione S-Transferase Mu2 Suppresses Cancer Cell Metastasis in Non–Small Cell Lung Cancer

The impact of CLAUDIN-1 on follicular thyroid carcinoma aggressiveness

The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer

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