M1994 Selective Up-Regulation of Claudin-1 and Claudin-2 in Colorectal Cancer

Kinugasa, Tetsushi

doi:10.1016/s0016-5085(08)62087-9

Cited by 69 publications

(86 citation statements)

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“…This protein is known to convert TJ from a tight to a leaky strand phenotype (20), and its expression is regulated by cingulin, another TJ cytoplasmic plaque protein that modulates proliferation in Madin-Darby canine kidney cells (27). The transcriptional regulation of CLDN2 by nuclear symplekin provides a potential explanation for the similarities of their expression pattern in human CRC, where claudin-2 also is overexpressed (23), and in healthy human and rodent colonic epithelia, where claudin-2 expression is restricted to the bottom section of the Lieberkühn crypts (28)(29)(30). In addition, because de novo experimental expression of claudin-2 restores the proliferation and anchorage-independent potential of cells with down-regulated symplekin, we conclude that claudin-2 is an essential mediator in the tumor-promoting role of symplekin.…”

Section: Discussionmentioning

confidence: 99%

“…Our results show that symplekin drives, at least in part, claudin-2 expression in HT29 CRC cells. The strong nuclear expression of symplekin in CRC cells thus could be involved in claudin-2 overexpression in CRC (23), and this overexpression recently was shown to increase the invasive potential of cancer cells (24). We therefore analyzed whether claudin-2 is involved in the biological effects of symplekin on tumorigenicity.…”

Section: Symplekin Down-regulation Increases the Polarization And Decmentioning

confidence: 99%

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Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Büchert

Papin

Bonnans

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Symplekin is a ubiquitously expressed protein involved in cytoplasmic RNA polyadenylation and transcriptional regulation and is localized at tight junctions (TJs) in epithelial cells. Nuclear symplekin cooperates with the Y-box transcription factor zonula occludens 1-associated nucleic acid-binding protein (ZONAB) to increase the transcription of cell cycle-related genes and also inhibits differentiation of intestinal cells. We detected high levels of nuclear symplekin in 8 of 12 human colorectal cancer (CRC) samples. shRNAmediated reduction of symplekin expression was sufficient to decrease significantly the anchorage-independent growth and proliferation of HT-29 CRC cells as well as their tumorigenicity when injected into immunodeficient animals. Symplekin downregulation also was found to alter ion transport through TJs, to promote the localization of ZONAB in the membrane rather than the nucleus, and strongly to enhance cell polarization in a 3D matrix, leading to the formation of spheroids organized around a central lumen. Claudin-2 expression was reduced following symplekin down-regulation, an effect mimicked when ZONAB expression was down-regulated using selective siRNA. Virus-mediated restoration of claudin-2 expression was found to restore nuclear expression of ZONAB in HT29ΔSym cells and to rescue the phenotypic alterations induced by symplekin down-regulation of cell polarity, paracellular transport, ZONAB localization, cyclin D1 expression, proliferation, and anchorage-independent growth. Finally, siRNA-mediated claudin-2 down-regulation increased the transepithelial resistance and decreased cyclin D1 expression and ZONAB nuclear localization, similar to observations in symplekindepleted cells. Our results suggest that nuclear overexpression of symplekin promotes tumorigenesis in the human colon and that the regulation of claudin-2 expression is instrumental in this effect.polarity | transcription | tumorigenesis | colorectal | tight junctions

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Section: Discussionmentioning

confidence: 99%

Section: Symplekin Down-regulation Increases the Polarization And Decmentioning

confidence: 99%

Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Büchert

Papin

Bonnans

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The expression of claudins-1, -3 and -4 was previously reported to be upregulated in human colorectal cancer (31). Furthermore, several studies have reported that the translocation of claudins is associated with tumor cell proliferation and survival (32,33). The expression of claudin-1 is upregulated in human colon cancers, particularly in the metastatic region, and is frequently mislocalized from the cell membrane to the cytoplasm and nucleus (19).…”

Section: Introductionmentioning

confidence: 97%

Nuclear expression of claudin‑3 in human colorectal adenocarcinoma cell lines and tissues

et al. 2017

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Abstract.Claudins are members of a large family of transmembrane proteins, which are essential for the formation of tight junctions and have a significant effect on the biological behavior of tumor progression. Previous studies have demonstrated that several claudins show aberrant expression patterns in numerous types of cancer. The present study investigated the expression and localization of claudin-3 and claudin-7 in human colorectal adenocarcinoma cell lines and tissues. The protein expression levels of claudin-3 and claudin-7 were determined using immunocytochemical and immunohistochemical staining. Claudin-3, but not claudin-7, exhibited nuclear localization in the human colorectal adenocarcinoma Caco-2 and SW620 cell lines. Surgically resected colorectal adenocarcinoma tissue specimens were obtained, and the associations between the expression of claudin-3 or claudin-7 and various clinicopathological parameters were analyzed. The membranous expression rates of claudin-3 and claudin-7 were 58.0 and 50.0%, while their nuclear expression rates were 22.0 and 2.0%, respectively. The membranous expression of claudin-3 and claudin-7 was not associated with any clinicopathological factors, whereas the nuclear expression of claudin-3 was associated with histological type and was significantly increased in colorectal mucinous adenocarcinomas compared with that in well-to moderately-differentiated colorectal adenocarcinomas (P<0.01). However, no associations were observed between the nuclear expression of claudin-7 and any clinicopathological parameter. In conclusion, the nuclear expression of claudin-3 in colorectal mucinous adenocarcinoma may be involved in the biological transformation of tumors. The results from the present study indicated that claudin-3 is an important protein associated with histological type and has potential as a prognostic marker. Although the mechanisms underlying the nuclear localization of claudin-3 in tumorigenesis have not yet been elucidated in detail, the present results indicated the potential of claudin-3 as a histopathological biomarker for colorectal adenocarcinomas.

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“…In breast cancer, claudin-2 expression has been shown to be downregulated in breast tumors compared with normal tissue, and diminished levels of claudin-2 are observed in breast cancers of increasing grade, arguing that claudin-2 has a tumor-suppressive role in breast cancer (Kim et al, 2008). In contrast, claudin-2 is important for the invasive characteristics of gastric carcinomas and its overexpression is observed in colorectal cancers, two types of cancer that preferentially metastasize to the liver (Aung et al, 2006;Kinugasa et al, 2007). Recently, claudin-2 was shown to be a critical mediator of symplekin-induced colorectal cancer cell proliferation and anchorage-independent growth (Buchert et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes

et al. 2010

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The liver represents the third most frequent site of metastasis in patients with breast cancer. We performed in vivo selection using 4T1 breast cancer cells to identify genes associated with the liver metastatic phenotype. Coincident with the loss of numerous tight-junctional proteins, we observe claudin-2 overexpression, specifically in liver-aggressive breast cancer cells. We further demonstrate that claudin-2 is both necessary and sufficient for the ability of 4T1 breast cancer cells to colonize and grow in the liver. The liver-aggressive breast cancer cells display a claudin-2-mediated increase in their ability to adhere to extracellular matrix (ECM) components, such as fibronectin and type IV collagen. Claudin-2 facilitates these cell/matrix interactions by increasing the cell surface expression of a 2 b 1 -and a 5 b 1 -integrin complexes in breast cancer cells. Indeed, claudin-2-mediated adhesion to fibronectin and type IV collagen can be blocked with neutralizing antibodies that target a 5 b 1 and a 2 b 1 complexes, respectively. Immunohistochemical analyses reveal that claudin-2, although weakly expressed in primary human breast cancers, is readily detected in all liver metastasis samples examined to date. Together, these results uncover novel roles for claudin-2 in promoting breast cancer adhesion to the ECM and define its importance during breast cancer metastasis to the liver.

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M1994 Selective Up-Regulation of Claudin-1 and Claudin-2 in Colorectal Cancer

Cited by 69 publications

References 0 publications

Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Nuclear expression of claudin‑3 in human colorectal adenocarcinoma cell lines and tissues

Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes

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