Transforming growth factor‐β induces epithelial to mesenchymal transition by down‐regulation of claudin‐1 expression and the fence function in adult rat hepatocytes

Kojima, Takashi; Takano, Kenichi; Yamamoto, Takumi; Murata, Masaki; Son, Seiichi; Imamura, Masafumi; Yamaguchi, Hiroshi; Osanai, Makoto; Chiba, Hideki; Himi, Tetsuo; Sawada, Norimasa

doi:10.1111/j.1478-3231.2007.01631.x

Cited by 73 publications

(43 citation statements)

References 43 publications

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“…The basal level of E-cadherin expression in untreated cells was un-detectable by Western blotting, probably due to the high basal expression of TCF8/ZEB1, which impairs the E-cadherin expression. Because Snail acts as transcription repressor of the genes of claudin/occludin, EMT tight junction proteins [53], we further investigated the expression of claudin-1, which is known to be expressed in various types of epithelial cells, playing an important role in epithelial cell polarity, cancer invasion and metastasis [54], [55]. Parallel to the reduction of the Snail and TCF8/ZEB1 levels, down-regulation of 5-HT 1B and 5-HT 1D receptors was accompanied with obvious up-regulation of claudin-1 expression in both PANC-1 and MIAPaCa-2 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Down-Regulation of 5-HT1B and 5-HT1D Receptors Inhibits Proliferation, Clonogenicity and Invasion of Human Pancreatic Cancer Cells

et al. 2014

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Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B– and 5-HT1D–mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new therapeutic targets for managing pancreatic cancer.

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Section: Resultsmentioning

confidence: 99%

Down-Regulation of 5-HT1B and 5-HT1D Receptors Inhibits Proliferation, Clonogenicity and Invasion of Human Pancreatic Cancer Cells

et al. 2014

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“…For analysis of gene expression, total RNA was isolated from WIF-B9 cells and Sprague-Dawley (SD) rat liver tissue using TRIzol reagent (Invitrogen), and RT-PCR was performed as previously described Kojima et al 2008). The primers used to detect occludin, ZO-1, JAM-A, claudin-1, -2, -3, -5, -7, -8, -12, -14 and glucose-3-phosphate dehydrogenase (G3PDH) are indicated in Table 2.…”

Section: Rna Isolation and Reverse Transcription-polymerase Chain Reamentioning

confidence: 99%

“…In the rat liver, claudin-2 shows a lobular gradient increasing from periportal to pericentral hepatocytes, whereas claudin-1 and -3 are expressed in the whole liver lobule (Rahner et al 2001;Yamamoto et al 2005). Although it is thought that claudin-2 may be a key molecule in hepatic tight junctions (Imamura et al 2007; Kojima et al 2008;Yamamoto et al 2005), the physiological functions and regulation of claudin-2 in hepatocytes remain unclear. To elucidate these questions we used WIF-B9 cells that present the advantage of being well polarized and expressing a robust level of claudin-2, without expression of claudin-1, -3 and -5 (present study and B. Grosse and D. Cassio, unpublished results).…”

Section: Introductionmentioning

confidence: 95%

Knockdown of tight junction protein claudin-2 prevents bile canalicular formation in WIF-B9 cells

Son

Kojima

Decaëns

et al. 2008

Histochem Cell Biol

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The polarization of hepatocytes involves formation of functionally distinct sinusoidal (basolateral) and bile canalicular (apical) plasma membrane domains that are separated by tight junctions. Although various molecular mechanisms and signaling cascades including polarity complex proteins may contribute to bile canalicular formation in hepatocytes, the role of tight junction proteins in bile canalicular formation remains unclear. To investigate the role of the integral tight junction protein claudin-2 in bile canalicular formation, we depleted claudin-2 expression by siRNA in the polarized hepatic cell line WIF-B9 after treatment with or without phenobarbital. When WIF-B9 cells were treated with phenobarbital, claudin-2 expression and tight junction strands were markedly increased together with induction of canalicular formation with a biliary secretion function. Knockdown of claudin-2 prevented bile canalicular formation after treatment with or without phenobarbital. Furthermore, knockdown of claudin-2 caused a change from a hepatic polarized phenotype to a simple polarized phenotype, together with upregulation of pLKB1, pMAPK, pAkt and pp38 MAPK, but not pMLC, PTEN or cdc42, and an increase of intracellular vacuoles, which were present before bile canalicular formation. These results suggest that claudin-2 may affect not only the bile canalicular seal but also bile canalicular formation.

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“…On the other hand, although association between increase in Claudin expression and carcinogenesis is not clearly understood, it is suggested that matrix metalloproteinase activation due to overexpression of Claudin increases invasiveness of cancer (Singh et al, 2010). The role of Claudin expression in epithelial cell polarity, invasion and metastasis of cancer has been reported (Kojima et al, 2008;Yoon et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Expression Pattern and Prognostic Significance of Claudin 1, 4 and 7 in Pancreatic Cancer

Ali̇kanoğlu¹,

Gündüz²,

Demirpençe³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Background: Tight junctions (TJs) organise paracellular permeability and they have an important role in epithelial and endothelial cell polarity and permanence of barrier function. It has been demonstrated that the Claudin family constitutes an important component of them. In this study, we assessed expression patterns of of Claudin1, 4 and 7 and whether they have any relation with prognosis in patients with pancreatic cancer. Materials and Methods: Expression patterns of Claudin 1,4 and 7 were examined by immunohistochemistry in 25 patients with a histopathological diagnosis of pancreatic cancer using a semiquantitative scoring of the extent and intensity of staining. After grouping the staining scores as low (final score 0-2) and high (final score 3-9) the relation between expression of Claudin 1,4 and 7 and survival was evaluated. Results: There was no significant relation between expression of Claudin 1,4 and 7 and gender and stage. No statistically significant relation was found between Claudin 1 and 4 expression and survival whereas a statistically significant relation was found between decrease in Claudin 7 expression and decrease in survival. Conclusions: Claudins have important functions other than their popular function known as adhesion. Supporting this hypothesis, we found a statistically significant relationship between increased Claudin 7 expression and increased survival time, and this suggests that Claudin 7 may exert different tumorigenic effects in pancreatic cancer other than its wellknown adhesion effect.

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Transforming growth factor‐β induces epithelial to mesenchymal transition by down‐regulation of claudin‐1 expression and the fence function in adult rat hepatocytes

Abstract: These results suggest that in mature hepatocytes in vitro, TGF-beta induces EMT by down-regulation of claudin-1 and the fence function via distinct signalling pathways.

Cited by 73 publications

References 43 publications

Down-Regulation of 5-HT1B and 5-HT1D Receptors Inhibits Proliferation, Clonogenicity and Invasion of Human Pancreatic Cancer Cells

Down-Regulation of 5-HT1B and 5-HT1D Receptors Inhibits Proliferation, Clonogenicity and Invasion of Human Pancreatic Cancer Cells

Knockdown of tight junction protein claudin-2 prevents bile canalicular formation in WIF-B9 cells

Expression Pattern and Prognostic Significance of Claudin 1, 4 and 7 in Pancreatic Cancer

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