Identification of Claudin-6 as a Molecular Biomarker in Pan-Cancer Through Multiple Omics Integrative Analysis

Zhang, Chiyuan; Guo, Cuishan; Li, Yan; Liu, Kuiran; Zhao, Qi; Ouyang, Liang

doi:10.3389/fcell.2021.726656

Cited by 31 publications

(27 citation statements)

References 41 publications

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“…CLDN6 is an ideal target for antibody approaches of high potency in cancers with high CLDN6 expression based on the fact that CLDN6 is undetectable in the adult tissues [ 24 , 25 , 26 ]. Notably, CLDN6 exerts carcinogenic or anti–carcinogenic effects depending on the tissue or cell type [ 27 ]. As for proliferation, CLDN6 promotes cell proliferation in human hepatocellular carcinoma, gastric cancer, and endometrial carcinoma [ 28 , 29 , 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

Wang

et al. 2021

IJMS

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Claudin 6 (CLDN6) was found to be a breast cancer suppressor gene, which is lowly expressed in breast cancer and inhibits breast cancer cell proliferation upon overexpression. However, the mechanism by which CLDN6 inhibits breast cancer proliferation is unclear. Here, we investigated this issue and elucidated the molecular mechanisms by which CLDN6 inhibits breast cancer proliferation. First, we verified that CLDN6 was lowly expressed in breast cancer tissues and that patients with lower CLDN6 expression had a worse prognosis. Next, we confirmed that CLDN6 inhibited breast cancer proliferation through in vitro and in vivo experiments. As for the mechanism, we found that CLDN6 inhibited c–MYC–mediated aerobic glycolysis based on a metabolomic analysis of CLDN6 affecting cellular lactate levels. CLDN6 interacted with a transcriptional co–activator with PDZ-binding motif (TAZ) and reduced the level of TAZ, thereby suppressing c–MYC transcription, which led to a reduction in glucose uptake and lactate production. Considered together, our results suggested that CLDN6 suppressed c–MYC–mediated aerobic glycolysis to inhibit the proliferation of breast cancer by TAZ, which indicated that CLDN6 acted as a novel regulator of aerobic glycolysis and provided a theoretical basis for CLDN6 as a biomarker of progression in breast cancer.

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Section: Discussionmentioning

confidence: 99%

CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

Wang

et al. 2021

IJMS

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“…Claudin-6 ( Cldn6 ) is of particular interest, given that changes in gene expression and pathway regulation appeared to be centered around this specific claudin protein. Prior studies suggest claudin-6 is involved in initiating cell adhesion signaling through its role in regulating nuclear receptor gene expression and subsequent activity [ 42 , 43 ]. Expression is predominantly observed in several types of embryonic epithelial cells compared to adult cells.…”

Section: Discussionmentioning

confidence: 99%

High-Frequency Irreversible Electroporation (H-FIRE) Induced Blood–Brain Barrier Disruption Is Mediated by Cytoskeletal Remodeling and Changes in Tight Junction Protein Regulation

et al. 2022

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Glioblastoma is the deadliest malignant brain tumor. Its location behind the blood–brain barrier (BBB) presents a therapeutic challenge by preventing effective delivery of most chemotherapeutics. H-FIRE is a novel tumor ablation method that transiently disrupts the BBB through currently unknown mechanisms. We hypothesized that H-FIRE mediated BBB disruption (BBBD) occurs via cytoskeletal remodeling and alterations in tight junction (TJ) protein regulation. Intracranial H-FIRE was delivered to Fischer rats prior to sacrifice at 1-, 24-, 48-, 72-, and 96 h post-treatment. Cytoskeletal proteins and native and ubiquitinated TJ proteins (TJP) were evaluated using immunoprecipitation, Western blotting, and gene-expression arrays on treated and sham control brain lysates. Cytoskeletal and TJ protein expression were further evaluated with immunofluorescent microscopy. A decrease in the F/G-actin ratio, decreased TJP concentrations, and increased ubiquitination of TJP were observed 1–48 h post-H-FIRE compared to sham controls. By 72–96 h, cytoskeletal and TJP expression recovered to pretreatment levels, temporally corresponding with increased claudin-5 and zonula occludens-1 gene expression. Ingenuity pathway analysis revealed significant dysregulation of claudin genes, centered around claudin-6 in H-FIRE treated rats. In conclusion, H-FIRE is capable of permeating the BBB in a spatiotemporal manner via cytoskeletal-mediated TJP modulation. This minimally invasive technology presents with applications for localized and long-lived enhanced intracranial drug delivery.

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“…The Human Protein Atlas (HPA) ( www.proteinatlas.org ) was used to validate the protein levels of MCM2 (HPA031496) based on an immunohistochemistry platform across cancers ( Asplund et al, 2012 ), the transcription level of MCM2 in normal tissues and cell lines and the localization of MCM2. The workflow of this study is shown in Figure 1 ( Wu et al, 2021 ; Zhang et al, 2021a ; Mi et al, 2022 ). We explored the correlations between MCM2 expression and molecular subtypes or immune subtypes across cancers from the TISIDB database ( http://cis.hku.hk/TISIDB ), which integrates multiple data types to assess tumor and immune system interactions ( Ru et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

Multi-Omics Analysis of MCM2 as a Promising Biomarker in Pan-Cancer

Yuan

Lan

Huang

et al. 2022

Front. Cell Dev. Biol.

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Minichromosome maintenance 2 (MCM2) is a member of the minichromosomal maintenance family of proteins that mainly regulates DNA replication and the cell cycle and is involved in regulating cancer cell proliferation in various cancers. Previous studies have reported that MCM2 plays a pivotal role in cell proliferation and cancer development. However, few articles have systematically reported the pathogenic roles of MCM2 across cancers. Therefore, the present pan-cancer study was conducted. Various computational tools were used to investigate the MCM2 expression level, genetic mutation rate, and regulating mechanism, immune infiltration, tumor diagnosis and prognosis, therapeutic response and drug sensitivity of various cancers. The expression and function of MCM2 were examined by Western blotting and CCK-8 assays. MCM2 was significantly upregulated in almost all cancers and cancer subtypes in The Cancer Genome Atlas and was closely associated with tumor mutation burden, tumor stage, and immune therapy response. Upregulation of MCM2 expression may be correlated with a high level of alterations rate. MCM2 expression was associated with the infiltration of various immune cells and molecules and markedly associated with a poor prognosis. Western blotting and CCK-8 assays revealed that MCM2 expression was significantly upregulated in melanoma cell lines. Our results also suggested that MCM2 promotes cell proliferation in vitro by activating cell proliferation pathways such as the Akt signaling pathways. This study explored the oncogenic role of MCM2 across cancers, provided data on the underlying mechanisms of these cancers for further research and demonstrated that MCM2 may be a promising target for cancer immunotherapy.

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Identification of Claudin-6 as a Molecular Biomarker in Pan-Cancer Through Multiple Omics Integrative Analysis

Cited by 31 publications

References 41 publications

CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

High-Frequency Irreversible Electroporation (H-FIRE) Induced Blood–Brain Barrier Disruption Is Mediated by Cytoskeletal Remodeling and Changes in Tight Junction Protein Regulation

Multi-Omics Analysis of MCM2 as a Promising Biomarker in Pan-Cancer

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