Claudin-18 coupled with EGFR/ERK signaling contributes to the malignant potentials of bile duct cancer

Takasawa, Kumi; Takasawa, Akira; Osanai, Makoto; Aoyama, Tomoyuki; Ono, Yoshio; Kono, Tsuyoshi; Hirohashi, Yoshihiko; Murata, Masaki; Sawada, Norimasa

doi:10.1016/j.canlet.2017.05.033

Cited by 32 publications

(37 citation statements)

References 20 publications

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“…Intriguingly, claudin-18.2-deficient mice develop gastric mucosal neoplasia, which is associated with the activation of multiple pathways, including CD44, ephrin (EFN)/ ephrin receptor (EPH) and yes-associated protein-1 (YAP1)/HIPPO signaling (128). However, the existence of claudin-18.2 in primary and metastatic lesions of gastric cancer, along with its significant ectopic expression in various types of cancers (e.g., pancreatic adenocarcinomas, esophageal tumors, and bile duct cancers), indicates the underlying role of claudin-18.2 as a pan-cancer therapeutic target (129, 130). On the other hand, though lung-specific claudin-18 (claudin-18.1) is expressed in the colonic epithelia of UC patients and experimental colitis mice models, its significance awaits further analysis (131).…”

Section: Expression and Function Of Claudinsmentioning

confidence: 99%

Claudin Family Participates in the Pathogenesis of Inflammatory Bowel Diseases and Colitis-Associated Colorectal Cancer

Zhu

Han

et al. 2019

Front. Immunol.

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Claudins are a multigene transmembrane protein family comprising at least 27 members. In gastrointestinal tract, claudins are mainly located in the intestinal epithelia; many types of claudins form a network of strands in tight junction plaques within the intercellular space of neighboring epithelial cells and build paracellular selective channels, while others act as signaling proteins and mediates cell behaviors. Claudin dysfunction may contribute to epithelial permeation disorder and multiple intestinal diseases. Over recent years, the importance of claudins in the pathogenesis of inflammatory bowel diseases (IBD) has gained focus and is being investigated. This review analyzes the expression pattern and regulatory mechanism of claudins based on existing evidence and elucidates the fact that claudin dysregulation correlates with increased intestinal permeability, sustained activation of inflammation, epithelial-to-mesenchymal transition (EMT), and tumor progression in IBD as well as consequent colitis-associated colorectal cancer (CAC), possibly shedding new light on further etiologic research and clinical treatments.

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Section: Expression and Function Of Claudinsmentioning

confidence: 99%

Claudin Family Participates in the Pathogenesis of Inflammatory Bowel Diseases and Colitis-Associated Colorectal Cancer

Zhu

Han

et al. 2019

Front. Immunol.

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“…33 The subcellular alteration of CLDN1 from its typical membranous location may be on account of structural changes in TJs that would contribute to significant modifications in paracellular permeability, and thereby lead to an abnormal fluidity of nutrients and signaling proteins, which is suggested to be vital for tumor progression. 4,34 The results of the present study suggest that the cytoplasmic expression of CLDN12 was overexpressed in human osteosarcoma, and that this overexpression was involved with distant metastasis. To validate this hypothesis, a CLDN12-overexpressing fetal osteoblast cell line and a CLDN12-knockdown osteosarcoma cell line were created, and the results indicated that the loss of CLDN12 inhibited the ability of proliferation and migration in osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 57%

<p>The Cytoplasmic Expression Of CLDN12 Predicts An Unfavorable Prognosis And Promotes Proliferation And Migration Of Osteosarcoma</p>

Tian¹,

He²,

Han³

et al. 2019

CMAR

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Background: To date, the impact and potential molecular mechanisms of CLDN12 and its association with malignancy in osteosarcoma have not been determined. Materials and methods: In the present study, the expression profiles of CLDN12 in osteosarcoma cell lines and tissues were explored by immunohistochemistry. A fetal osteoblast cell line was transfected with a eukaryotic expression plasmid, and endogenous CLDN12 in osteosarcoma cells were silenced through an RNA interference (RNAi) method. These transfections were verified, and the activation state of Thr308 site in protein kinase B (Akt) was explored by Western blotting. Moreover, the malignant phenotype of osteosarcoma cells was evaluated by cell counting kit-8 (CCK-8), colony formation, Transwell, and wound-healing assays. Furthermore, osteoblast cells were treated with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 to determine the impact of the PI3K/Akt signaling pathway on cell migration ability. Results: The results revealed that CLDN12 was overexpressed and localized in the cytoplasm of osteosarcoma cells, and its overexpression was associated with an unfavorable prognosis, irrespective of tumor node metastasis stage. In addition, the knockdown of CLDN12 in cultured osteosarcoma cells markedly attenuated cell proliferation and migration, as indicated by the Cell Counting Kit-8 assay, colony formation assay, scratch wound healing assay and Transwell migration assay. The results also demonstrated that the overexpression of CLDN12 increased the activation of Thr308 site in Akt in fetal osteoblast cells, and the PI3K inhibitor LY294002 partially decreased CLDN12-promoted proliferation and metastasis. Conclusion: In conclusion, the results of the present study indicated that CLDN12 promoted cell proliferation and migration through the PI3K/Akt signaling pathway in osteosarcoma cells, suggesting that CLDN12 may be a potential agent in the treatment of patients with osteosarcoma.

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“…CLDN18 may play an important role in the physiological regulation of lung morphology. In contrast, overexpression of CLDN18 has been reported in human pancreatic cancer 23) and bile duct carcinoma. 24) CLDN18 has two splice variants, lung-specific isoform 1 (CLDN18.1) and stomach-specific isoform 2 (CLDN18.2).…”

Section: Discussionmentioning

confidence: 90%

ZO-2 Suppresses Cell Migration Mediated by a Reduction in Matrix Metalloproteinase 2 in Claudin-18-Expressing Lung Adenocarcinoma A549 Cells

Akizuki

Eguchi

Endo

et al. 2019

Biological & Pharmaceutical Bulletin

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Abnormal expression of the tight junctional components claudins (CLDNs) is observed in various malignant tissues. We reported recently that CLDN18 expression is down-regulated in human lung adenocarcinoma tissues. In the present study, we investigated the biological functions of CLDN18 using lung adenocarcinoma A549 cells. Microarray analysis showed that CLDN18 increases zonula occludens (ZO)-2 expression in A549 cells. The ectopic expression of CLDN18 increased nuclear ZO-2 levels, which were inhibited by N-[2-[[3-(4-bromophenyl)-2-propen-1-yl]amino]ethyl]5-isoquinolinesulfonamide (H-89), a nonspecific protein kinase A (PKA) inhibitor, but not by a PKA inhibitor 14-22 amide. In addition, dibutyryl cyclic adenosine monophosphate, an analogue of PKA, did not increase ZO-2 levels. These results suggest that H-89 sensitive factors without PKA are involved in the CLDN18-induced elevation of ZO-2. The cell cycle was affected by neither ZO-2 knockdown in CLDN18-expresssing A549 (CLDN18/A549) cells nor ZO-2 overexpression in A549 cells, suggesting that ZO-2 does not play an important role in the regulation of cell proliferation. The introduction of ZO-2 small interfering RNA (siRNA) into CLDN18/A549 cells increased migration, the expression and activity of matrix metalloproteinase 2 (MMP2), and the reporter activity of an MMP2 promoter construct. Furthermore, H-89 enhanced both mRNA levels and reporter activity of MMP2 in CLDN18/A549 cells. These results suggested that a reduction in CLDN18-dependent ZO-2 expression enhances MMP2 expression in lung adenocarcinoma cells, resulting in the promotion of the cell migration. CLDN18 may be a novel marker for metastasis in lung adenocarcinoma.

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Claudin-18 coupled with EGFR/ERK signaling contributes to the malignant potentials of bile duct cancer

Cited by 32 publications

References 20 publications

Claudin Family Participates in the Pathogenesis of Inflammatory Bowel Diseases and Colitis-Associated Colorectal Cancer

Claudin Family Participates in the Pathogenesis of Inflammatory Bowel Diseases and Colitis-Associated Colorectal Cancer

<p>The Cytoplasmic Expression Of CLDN12 Predicts An Unfavorable Prognosis And Promotes Proliferation And Migration Of Osteosarcoma</p>

ZO-2 Suppresses Cell Migration Mediated by a Reduction in Matrix Metalloproteinase 2 in Claudin-18-Expressing Lung Adenocarcinoma A549 Cells

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