Expression of Transforming Growth Factor beta1 and E-Cadherin Proteins in Pulmonary Adenocarcinoma: Its Significance in Tumor Progression

Kim, Chi Hong; Park, Sonya Youngju; Yoo, Jinyoung

doi:10.4143/crt.2013.45.2.118

Cited by 7 publications

(5 citation statements)

References 17 publications

(24 reference statements)

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“…E-cadherin was expressed in the majority of our sample too, but contrary to the above studies, we observed different levels of its expression. E-cadherin’s expression in primary lung cancers is down-regulated in invasive component of 62% adenocarcinoma [ 44 ], and in another study in 72% of SCC and adenocarcinoma [ 45 ]. In 2 investigated cases of carcinosarcoma 70% of cells showed E-cadherin’s down-regulation [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Brain Metastases from Lung Cancer Show Increased Expression of DVL1, DVL3 and Beta-Catenin and Down-Regulation of E-Cadherin

Kafka

Tomas

Beroš

et al. 2014

IJMS

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The susceptibility of brain to secondary formation from lung cancer primaries is a well-known phenomenon. In contrast, the molecular basis for invasion and metastasis to the brain is largely unknown. In the present study, 31 brain metastases that originated from primary lung carcinomas were analyzed regarding over expression of Dishevelled-1 (DVL1), Dishevelled-3 (DVL3), E-cadherin (CDH1) and beta-catenin (CTNNB1). Protein expressions and localizations were analyzed by immunohistochemistry. Genetic alterations of E-cadherin were tested by polymerase chain reaction (PCR)/loss of heterozygosity (LOH). Heteroduplex was used to investigate mutations in beta-catenin. DVL1 and DVL3 showed over expression in brain metastasis in 87.1% and 90.3% of samples respectively. Nuclear staining was observed in 54.8% of cases for DVL1 and 53.3% for DVL3. The main effector of the Wnt signaling, beta-catenin, was up-regulated in 56%, and transferred to the nucleus in 36% of metastases. When DVL1 and DVL3 were up-regulated the number of cases with nuclear beta-catenin significantly increased (p = 0.0001). Down-regulation of E-cadherin was observed in 80% of samples. Genetic analysis showed 36% of samples with LOH of the CDH1. In comparison to other lung cancer pathologies, the diagnoses adenocarcinoma and small cell lung cancer (SCLC) were significantly associated to CDH1 LOH (p = 0.001). Microsatellite instability was detected in one metastasis from adenocarcinoma. Exon 3 of beta-catenin was not targeted. Altered expression of Dishevelled-1, Dishevelled-3, E-cadherin and beta-catenin were present in brain metastases which indicates that Wnt signaling is important and may contribute to better understanding of genetic profile conditioning lung cancer metastasis to the brain.

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Section: Discussionmentioning

confidence: 99%

Brain Metastases from Lung Cancer Show Increased Expression of DVL1, DVL3 and Beta-Catenin and Down-Regulation of E-Cadherin

Kafka

Tomas

Beroš

et al. 2014

IJMS

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“…The molecular mechanisms involved in lung carcinogenesis are associated with dysregulation of many signaling pathways. Among these, transforming growth factor-β (TGF-β) signaling plays an important role in development and progression of lung cancer [4–6]. TGF-β displays a dual role in cancer development.…”

Section: Introductionmentioning

confidence: 99%

High p-Smad2 expression in stromal fibroblasts predicts poor survival in patients with clinical stage I to IIIA non-small cell lung cancer

et al. 2014

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BackgroundIncreasing evidence indicates that the TGFβ/Smad signaling pathway plays a prominent role in tumor initiation, progression, and metastasis. Therefore, we investigate the expression of p-Smad2 in surgical resection specimens from non-small cell lung cancer, and evaluate the prognostic significance of p-Smad2 expression in stromal fibroblasts and cancer cells for patients with clinical stage I to IIIA non-small cell lung cancer.MethodsThe immunohistochemical expression of p-Smad2 was evaluated in 78 formalin-fixed paraffin-embedded surgical resection specimens from clinical stage I to IIIA non-small cell lung cancer. Correlations between p-Smad2 expression and clinicopathologic characteristics were determined by Chi-square test. The prognostic significance of p-Smad2 expression in stromal fibroblasts and cancer cells with regard to overall survival was determined by Kaplan-Meier.ResultsThere were 38.5% (30/78) and 92.3% (72/78) patients with high p-Smad2 expression in stromal fibroblasts and cancer cells, respectively. There was a positive correlation between the p-Smad2 expression level in stromal fibroblasts and the p-Smad2 expression level in cancer cells (χ2 = 4.176, P =0.045). No significant correlation of p-Smad2 expression in stromal fibroblasts or cancer cells with any of clinicopathologic characteristics was found. The 3-year overall survival rates with low and high p-Smad2 expression in stromal fibroblasts were 53.7% and 37.7%, respectively (χ2 = 3.86, P = 0.049). No significant association was found between low and high p-Smad2 expression in cancer cells with respect to overall survival, respectively (χ2 = 0.34, P =0.562).ConclusionsThe results suggested that high p-Smad2 expression in stromal fibroblasts predicted poor survival in patients with clinical stage I to IIIA non-small cell lung cancer.

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“…TGFβ1 is associated with poor prognosis of esophageal cancer [ 34 ]. TGFβ1-mediated down-regulation of E-cadherin contributes to tumor invasion and proliferation [ 31 ]. Here, we show that TGFβ1 treatment (4 days) induces E-cadherin down-regulation in a dose dependent manner in esophageal cancer cell line OE19 (Figure 6 A).…”

Section: Resultsmentioning

confidence: 99%

“…TGFβ1 signaling has been shown to play an important role in down-regulation of E-cadherin. It appears, that many epithelial tumors escape growth inhibition by TGFβ1, and TGFβ1 secretion by cancer may contribute to late tumor progression [ 31 , 32 ]. It has been shown that TGFβ1 expression is higher in esophageal cancer tissues, compared to normal squamous epithelium and non-malignant Barrett’s mucosa [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation

et al. 2014

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BackgroundRac3 is a small GTPase multifunctional protein that regulates cell adhesion, migration, and differentiation. It has been considered as an oncogene in breast cancer; however, its role in esophageal cancer and the regulation of its stability have not been studied. F-box proteins are major subunits within the Skp1-Cullin-1-F-box (SCF) E3 ubiquitin ligases that recognize particular substrates for ubiquitination and proteasomal degradation. Recently, we have shown that SCFFBXL19 targets Rac1 and RhoA, thus regulating Rac1 and RhoA ubiquitination and degradation. Here, we demonstrate the role of FBXL19 in the regulation of Rac3 site-specific ubiquitination and stability. Expression of TGFβ1 is associated with poor prognosis of esophageal cancer. TGFβ1 reduces tumor suppressor, E-cadherin, expression in various epithelial-derived cancers. Here we investigate the role of FBXL19-mediated Rac3 degradation in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells.MethodsFBXL19-regulated endogenous and over-expressed Rac3 stability were determined by immunoblotting and co-immunoprecipitation. Esophageal cancer cells (OE19 and OE33) were used to investigate TGFβ1-induced E-cadherin down-regulation by Immunoblotting and Immunostaining.ResultsOverexpression of FBXL19 decreased endogenous and over-expressed Rac3 expression by interacting and polyubiquitinating Rac3, while down-regulation of FBXL19 suppressed Rac3 degradation. Lysine166 within Rac3 was identified as an ubiquitination acceptor site. The FBXL19 variant with truncation at the N-terminus resulted in an increase in Rac3 degradation; however, the FBXL19 variant with truncation at the C-terminus lost its ability to interact with Rac3 and ubiquitinate Rac3 protein. Further, we found that Rac3 plays a critical role in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells. Over-expression of FBXL19 attenuated TGFβ1-induced E-cadherin down-regulation and esophageal cancer cells elongation phenotype.ConclusionsCollectively these data unveil that FBXL19 functions as an antagonist of Rac3 by regulating its stability and regulates the TGFβ1-induced E-cadherin down-regulation. This study will provide a new potential therapeutic strategy to regulate TGFβ1 signaling, thus suppressing esophageal tumorigenesis.

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Expression of Transforming Growth Factor beta1 and E-Cadherin Proteins in Pulmonary Adenocarcinoma: Its Significance in Tumor Progression

Cited by 7 publications

References 17 publications

Brain Metastases from Lung Cancer Show Increased Expression of DVL1, DVL3 and Beta-Catenin and Down-Regulation of E-Cadherin

Brain Metastases from Lung Cancer Show Increased Expression of DVL1, DVL3 and Beta-Catenin and Down-Regulation of E-Cadherin

High p-Smad2 expression in stromal fibroblasts predicts poor survival in patients with clinical stage I to IIIA non-small cell lung cancer

F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation

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