Bioinformatic analysis reveals potential properties of human Claudin-6 regulation and functions

Lin, Dongjing; Guo, Yanping; Li, Yanru; Ruan, Yuanyuan; Zhang, Mingzi; Jin, Xiangshu; Yang, Minlan; Lü, Yan; Song, Peiye; Zhao, Shuai; Dong, Bing; Xie, Yinping; Dang, Qihua; Quan, Chengshi

doi:10.3892/or.2017.5756

Cited by 12 publications

(8 citation statements)

References 31 publications

(33 reference statements)

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“…CLDN6 is a 26-kDa TJ protein containing four transmembrane helices with a carboxyl-terminal tail extending into the cytoplasm [20]. The PDZ-domain-binding motif in the carboxy-terminal tail allows CLDN6 to interact with cytoplasmic TJassociated proteins such as ZO1, β-catenin and cadherins thus regulating various signalling pathways [21]. We found that CLDN6 was transcriptionally upregulated by HIF-1α in three breast cancer cell lines.…”

Section: Introductionmentioning

confidence: 93%

A SUMOylation-dependent HIF-1α/CLDN6 negative feedback mitigates hypoxia-induced breast cancer metastasis

Jia

Guo

Qiu

et al. 2020

J Exp Clin Cancer Res

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Background: We have previously described CLDN6 as a tumor suppressor gene in breast cancer. Here, a new finding is that CLDN6 was upregulated under hypoxia, a commonly recognized factor that promotes tumor metastasis. In this study, we aim to explain this confusing finding and delineate the role of CLDN6 in the breast cancer metastasis induced by hypoxia. Methods: RNAi and ChIP assays were used to confirm that CLDN6 is transcriptional regulated by HIF-1α. mRNA seq and KEGG analysis were performed to define the downstream pathways of CLDN6. The roles of the CLDN6/SENP1/ HIF-1α signaling on tumor metastasis were evaluated by function experiments and clinical samples. Finally, the possible transcription factor of SENP1 was suspected and then validated by ChIP assay. Results: We demonstrated a previously unrecognized negative feedback loop exists between CLDN6 and HIF-1α. CLDN6 was transcriptionally up-regulated by HIF-1α under hypoxia. On the other hand, in cytoplasm CLDN6 combines and retains β-catenin, a transcription factor of SENP1, causing β-catenin degradation and preventing its nuclear translocation. This process reduced SENP1 expression and prevented the deSUMOylation of HIF-1α, ultimately leading to HIF-1α degradation and breast cancer metastasis suppression. Conclusions: Our data provide a molecular mechanistic insight indicating that CLDN6 loss may lead to elevated HIF-1α-driven breast cancer metastasis in a SUMOylation-dependent manner.

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Section: Introductionmentioning

confidence: 93%

A SUMOylation-dependent HIF-1α/CLDN6 negative feedback mitigates hypoxia-induced breast cancer metastasis

Jia

Guo

Qiu

et al. 2020

J Exp Clin Cancer Res

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“…Silencing the CLDN6 gene causes increased growth and migratory ability, as well as increased MMP-2 expression and activity, which may be mediated by the MAPK pathway (129). CLDN6 expression is linked to apoptosis signal-regulating kinase 1 (ASK1) expression, and restoring CLDN6 expression in breast cancer cells reduces ASK1 phosphorylation, activates the downstream target proteins JNK and p38 kinase, and induces apoptosis (130)(131)(132)(133). 17b-Estradiol (E2) enhances CLDN6 expression via estrogen receptor a (ERa) and estrogen receptor b (ERb) (44, 134).…”

Section: Cldn6mentioning

confidence: 99%

The role and mechanism of claudins in cancer

et al. 2022

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Claudins are a tetraspan membrane protein multigene family that plays a structural and functional role in constructing tight junctions. Claudins perform crucial roles in maintaining cell polarity in epithelial and endothelial cell sheets and controlling paracellular permeability. In the last two decades, increasing evidence indicates that claudin proteins play a major role in controlling paracellular permeability and signaling inside cells. Several types of claudins are dysregulated in various cancers. Depending on where the tumor originated, claudin overexpression or underexpression has been shown to regulate cell proliferation, cell growth, metabolism, metastasis and cell stemness. Epithelial-to-mesenchymal transition is one of the most important functions of claudin proteins in disease progression. However, the exact molecular mechanisms and signaling pathways that explain why claudin proteins are so important to tumorigenesis and progression have not been determined. In addition, claudins are currently being investigated as possible diagnostic and treatment targets. Here, we discuss how claudin-related signaling pathways affect tumorigenesis, tumor progression, and treatment sensitivity.

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“…CLDN6 has four transmembrane domains and a PDZ-binding region at the carboxyl end of the cytoplasm. This CLDN can bind with signal proteins and cytoskeletal proteins, and participate in the cellular response to external and intracellular signal transmission ( 13 ). CLDN6 is the only CLDN to potentially show specificity, as it can activate cell adhesion signals and regulate the activity of nuclear receptors ( 14 ).…”

Section: Structural Characteristics Of Cldn6mentioning

confidence: 99%

Claudin 6: Therapeutic prospects for tumours, and mechanisms of expression and regulation (Review)

Yang

Fan

et al. 2021

Mol Med Rep

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Tight junctions (TJs) are an important component of cell connectivity; they maintain cell polarity, permeability and adhesion, and participate in the regulation of cell proliferation and differentiation. The claudin (cldn) family is integral to TJs, and cldn6 is an important member of this family. abnormal expression of cldn6 can destroy the integrity of TJs through various mechanisms and can serve multiple roles in the occurrence and development of tumours. cldn6 is widely expressed in various tumours but rarely expressed in healthy adult tissues. The aim of this review is to critically examine the recent literature on cldn6, including its structure, expression in different tumours, regulatory mechanisms and therapeutic prospects. although some conclusions are controversial, in certain tumours, such as liver, ovarian, endometrial and oesophageal cancer, and atypical teratoid/rhabdoid tumours, research consistently shows that cldn6 is expressed in tumour tissues but is not expressed or is expressed at low levels in surrounding tissues. in these tumours, cldn6 has potential as a carcinoembryonic antigen and a therapeutic target. Contents1. introduction 2. Structural characteristics of cldn6 3. expression and regulation mechanisms of cldn6 in tumours 4. cldn6 and drug resistance in cancer 5. Prospect of cldn6 in the treatment of tumours 6. discussion conclusionHuan du 1,2 , XiYue YanG 2 , JinJia Fan 2 and XiaoBo du 1

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Bioinformatic analysis reveals potential properties of human Claudin-6 regulation and functions

Cited by 12 publications

References 31 publications

A SUMOylation-dependent HIF-1α/CLDN6 negative feedback mitigates hypoxia-induced breast cancer metastasis

A SUMOylation-dependent HIF-1α/CLDN6 negative feedback mitigates hypoxia-induced breast cancer metastasis

The role and mechanism of claudins in cancer

Claudin 6: Therapeutic prospects for tumours, and mechanisms of expression and regulation (Review)

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