Aberrant expression of claudin‐6 contributes to malignant potentials and drug resistance of cervical adenocarcinoma

Ito, Yui; Takasawa, Akira; Takasawa, Kumi; Murakami, Taro; Akimoto, Taishi; Kyuno, Daisuke; Kawata, Yuka; Shano, Kodai; Kirisawa, Kurara; Ota, Misaki; Aoyama, Tomoyuki; Murata, Masaki; Sugimoto, Kotaro; Chiba, Hideki; Saito, Tsuyoshi; Osanai, Makoto

doi:10.1111/cas.15284

Cited by 12 publications

(11 citation statements)

References 80 publications

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“…In our study, the functional annotation of FLVCR2 revealed that cell–cell adhesion, cellular defense response, translational initiation, and ribonucleoprotein complex biogenesis were closely associated with FLVCR2 expression. Studies have shown that adhesion molecules are closely related to tumorigenesis and development ( Sisto et al, 2021 ; Ito et al, 2022 ), which is consistent with our results. The cell–cell adhesion events enriched in the high FLVCR2 expression group show that FLVCR2 plays a critical role in AML tumorigenesis.…”

Section: Discussionsupporting

confidence: 93%

The prognostic marker FLVCR2 associated with tumor progression and immune infiltration for acute myeloid leukemia

Ma²,

Bai³

et al. 2022

Front. Cell Dev. Biol.

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Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies in adults. The tumor microenvironment (TME) has a critical effect on AML occurrence, recurrence, and progression. The gene feline leukemia virus subgroup C cellular receptor family member 2 (FLVCR2) belongs to the major facilitator superfamily of transporter protein members, which is primarily involved in transporting small molecules. The potential role of FLVCR2 in the TME in AML has not been investigated. To clarify the expression and role of FLVCR2 in AML, we analyzed the Gene Expression Omnibus and The Cancer Genome Atlas databases and found that FLVCR2 mRNA expression significantly increased among patients with AML. Furthermore, based on an analysis of the Gene Expression Profiling Interactive Analysis database, FLVCR2 upregulation predicted dismal overall survival of patients with AML. Our validation analysis revealed the significant upregulation of FLVCR2 within the bone marrow of AML relative to healthy controls by western blotting and qPCR assays. Gene set enrichment analysis was conducted to explore FLVCR2’s related mechanism in AML. We found that high FLVCR2 expression was related to infiltration degrees of immune cells and immune scores among AML cases, indicating that FLVCR2 possibly had a crucial effect on AML progression through the immune response. Specifically, FLVCR2 upregulation was negatively related to the immune infiltration degrees of activated natural killer cells, activated memory CD4+ T cells, activated dendritic cells, and CD8+ T cells using CIBERSORT analysis. According to the in vitro research, FLVCR2 silencing suppressed AML cell growth and promoted their apoptosis. This study provides insights into FLVCR2’s effect on tumor immunity, indicating that it might serve as an independent prognostic biomarker and was related to immune infiltration within AML.

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Section: Discussionsupporting

confidence: 93%

The prognostic marker FLVCR2 associated with tumor progression and immune infiltration for acute myeloid leukemia

Ma²,

Bai³

et al. 2022

Front. Cell Dev. Biol.

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“…Cell proliferation is an important life activity of organisms, which is the basis of growth, development, reproduction and inheritance. According to our results, cell proliferation rates increased significantly in bovine CCs 72 h after transfection with the siRNA targeting CLDN6 gene, which was are consistent with previous studies in cervical cancer cells [ 18 ], whereas it was contrary with the results in gastric cancer cell lines and human endometrial adenocarcinoma cells [ 19 , 20 ]. For proliferation-related genes, CCND2 is the rate-limiting factor of cell mitosis from the G1 phase to S phase and positively accelerates proliferation during folliculogenesis [ 35 ].…”

Section: Discussionsupporting

confidence: 88%

“…The altered expression of CLDN6 was linked to the development of various cancers whose malignant phenotypes include proliferation and apoptosis, migration and invasion and drug resistance [ 17 ]. In cervical cancer cells, the expression of CLDN6 was down-regulated and overexpression of CLDN6 suppressed cell proliferation, colony formation in vitro and tumor growth in vivo, which were accompanied and potentially caused by the promotion of tumor cell apoptosis [ 18 ]. However, in gastric cancer tissues and cell lines, the expression of CLDN6 protein was up-regulated and an increased CLDN6 level was associated with enhanced proliferation and invasion abilities of gastric cancer [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of CLAUDIN-6 Inhibited Apoptosis and Induced Proliferation of Bovine Cumulus Cells

Wang

Zou

Chen

et al. 2022

IJMS

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This study aims to investigate the effects of CLAUDIN-6 (CLDN6) on cell apoptosis and proliferation of bovine cumulus cells (CCs). Immunofluorescence staining was used to localize CLDN6 protein in CCs. Three pairs of siRNA targeting CLDN6 and one pair of siRNA universal negative sequence as control were transfected into bovine CCs. Then, the effective siRNA was screened by real-time quantitative PCR (RT-qPCR) and Western blotting. The mRNA expression levels of apoptosis related genes (CASPASE-3, BAX and BCL-2) and proliferation related genes (PCNA, CDC42 and CCND2) were evaluated by RT-qPCR in CCs with CLDN6 knockdown. Cell proliferation, apoptosis and cell cycle were detected by flow cytometry with CCK-8 staining, Annexin V-FITC staining and propidium iodide staining, respectively. Results showed that the CLDN6 gene was expressed in bovine CCs and the protein was localized in cell membranes and cytoplasms. After CLDN6 was knocked down in CCs, the cell apoptosis rate significantly decreased and the pro-apoptotic genes BAX and CASPASE-3 were down-regulated significantly, whereas the anti-apoptotic gene BCL-2 was markedly up-regulated (p < 0.05). Additionally, CLDN6 knockdown significantly enhanced cell proliferation of CCs at 72 h after siRNA transfection. The mRNA levels of proliferation-related genes PCNA, CCND2 and CDC42 increased obviously in CCs with CLDN6 knockdown (p < 0.05). After CLDN6 was down-regulated, the percentage of CCs at S phase was significantly increased (p < 0.05). However, there was no remarkable difference in the percentages of cells at the G0/G1 phase and G2/M phase between CCs with or without CLDN6 knockdown (p > 0.05). Therefore, the expression of CLDN6 and its effects on cell proliferation, apoptosis and cell cycle of bovine CCs were first studied. CLDN6 low expression inhibited cell apoptosis, induced cell proliferation and cell cycle arrest of bovine CCs.

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“…54 Gene Ontology (GO) analysis revealed that cell-cell adhesion-related proteins and drug metabolismrelated aldo-keto reductases (AKR1B1, AKR1C1, AKR1C2, and AKR1C3) were significantly upregulated in claudin-6-overexpressing cervical adenocarcinoma cells compared with those in control cells, suggesting a contribution of aberrantly expressed claudin-6 to drug resistance. 47 Indeed, we confirmed that overexpression of claudin-6 attenuated the sensitivity to anticancer drugs including doxorubicin, daunorubicin, and cisplatin. These results help us to understand the molecular mechanisms as well as to discover new biomarkers and/or therapeutic targets in TJP-associated cancers (Figure 6).…”

Section: Insight From Mass Spectrometry-based Proteomicssupporting

confidence: 59%

“…48,49,83 Recently, claudin-6-targeting chimeric antigen receptor (CAR)-T cell therapy has emerged. 84,85 In conjunction with our finding that a high expression level of claudin-6 is associated with poor prognosis of cervical adenocarcinoma, 47 claudin-6targeting CAR-T cell therapy seems to be a promising therapy for improving prognosis of cervical adenocarcinoma in the future.…”

Section: Transmembrane-type Tjps As Therapeutic Targetsmentioning

confidence: 67%

Emerging roles of transmembrane‐type tight junction proteins in cancers

Takasawa

Murata

et al. 2023

Pathology International

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Tight junctions (TJs) are the most apical components of the cell–cell adhesion machinery in epithelial and endothelial cells and they play essential roles in homeostasis. Recent studies have revealed that aberrant expression of tight junction proteins (TJPs) is frequently observed in various type of cancers. Here we review cancer‐associated aberrant expression of TJPs with focus on transmembrane‐type TJPs including claudins, junctional adhesion molecule‐A (JAM‐A), and occludin. Some transmembrane‐type TJPs are upregulated at the early neoplastic stage and their expression persists during dedifferentiation. Aberrant expression of TJPs contributes to proliferation, invasion, and dysregulated signaling of cancer cells. In addition to an increase in their expression level, their localization is altered from a TJ‐restricted pattern to distribution throughout the whole cell membrane, making them suitable as therapeutic targets. Extracellular domains of transmembrane‐type TJPs can be approached by target drugs not only from the lumen side (apical side) but also from the extracellular matrix side (basal side), including blood vessels. Aberrantly expressed TJPs are potential useful diagnostic markers as well as therapeutic targets for cancers.

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Aberrant expression of claudin‐6 contributes to malignant potentials and drug resistance of cervical adenocarcinoma

Cited by 12 publications

References 80 publications

The prognostic marker FLVCR2 associated with tumor progression and immune infiltration for acute myeloid leukemia

The prognostic marker FLVCR2 associated with tumor progression and immune infiltration for acute myeloid leukemia

Knockdown of CLAUDIN-6 Inhibited Apoptosis and Induced Proliferation of Bovine Cumulus Cells

Emerging roles of transmembrane‐type tight junction proteins in cancers

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