Prognostic Significance of Aberrant Claudin-6 Expression in Endometrial Cancer

Kojima, Masayasu; Sugimoto, Kotaro; Tanaka, Mizuko; Endo, Yuta; Kato, Hitomi; Honda, Tsuyoshi; Furukawa, Shigenori; Nishiyama, Hiroshi; Watanabe, Takafumi; Soeda, Shu; Fujimori, Keiya; Chiba, Hideki

doi:10.3390/cancers12102748

Cited by 25 publications

(35 citation statements)

References 34 publications

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“…Since then, we confirmed clinical stage, primary therapy outcome, and CLDN6 expression level as independent risk factors in OS, DSS, and PFI of UCEC through univariate and multivariate Cox regression analyses. The results are further supported by the prior research involving prognostic significance of aberrant CLDN6 expression in UCEC ( Kojima et al, 2020 ), which established a monoclonal antibody, then performed immunohistochemical staining and semi-quantification to assess the associations between CLDN6 and clinical characteristics in 173 cases, and finally identified stages III/IV, distant metastasis, and high CLDN6 expression as independent prognostic variables for the OS. It is of great importance that our findings provide a more comprehensive and further supplement and strengthen the role of CLDN6 played in UCEC, and that we precisely analyze the correlations between CLDN6 expression and different prognosis conditions (OS, DSS, or PFI) in various clinical subgroups of UCEC.…”

Section: Discussionsupporting

confidence: 63%

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

Zhang

Guo

et al. 2021

Front. Cell Dev. Biol.

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Claudin-6 (CLDN6) is one of the 27 family members of claudins and majorly involved in the tight junction and cell-to-cell adhesion of epithelial cell sheets, playing a significant role in cancer initiation and progression. To provide a more systematic and comprehensive dimension of identifying the diverse significance of CLDN6 in a variety of malignant tumors, we explored CLDN6 through multiple omics data integrative analysis, including gene expression level in pan-cancer and comparison of CLDN6 expression in different molecular subtypes and immune subtypes of pan-cancer, targeted protein, biological functions, molecular signatures, diagnostic value, and prognostic value in pan-cancer. Furthermore, we focused on uterine corpus endometrial carcinoma (UCEC) and further investigated CLDN6 from the perspective of the correlations with clinical characteristics, prognosis in different clinical subgroups, co-expression genes, and differentially expressed genes (DEGs), basing on discussing the validation of its established monoclonal antibody by immunohistochemical staining and semi-quantification reported in the previous study. As a result, CLDN6 expression differs significantly not only in most cancers but also in different molecular and immune subtypes of cancers. Besides, high accuracy in predicting cancers and notable correlations with prognosis of certain cancers suggest that CLDN6 might be a potential diagnostic and prognostic biomarker of cancers. Additionally, CLDN6 is identified to be significantly correlated with age, stage, weight, histological type, histologic grade, and menopause status in UCEC. Moreover, CLDN6 high expression can lead to a worse overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in UCEC, especially in different clinical subgroups of UCEC. Taken together, CLDN6 may be a remarkable molecular biomarker for diagnosis and prognosis in pan-cancer and an independent prognostic risk factor of UCEC, presenting to be a promising molecular target for cancer therapy.

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Section: Discussionsupporting

confidence: 63%

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

Zhang

Guo

et al. 2021

Front. Cell Dev. Biol.

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“…We have recently reported that aberrant CLDN6 expression in endometrial cancer tissues is significantly associated with several clinicopathological variables, such as surgical stage III/IV, histological type, histological grade 3, lymphovascular space involvement, lymph node metastasis, and distant metastasis. 82 Additionally, we showed that the high CLDN6 expression in endometrial cancer represents an independent prognosis marker, and the 5-y survival rate was approximately 30%, which was one-third of that in the low-expression group.…”

Section: Aberrant Cldn–transcription Factor Signaling In Cancermentioning

confidence: 79%

The claudin–transcription factor signaling pathway

Sugimoto

Chiba

2021

Tissue Barriers

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Claudins (CLDNs) represent major transmembrane proteins of tight junctions and contribute to the barrier function. They also serve as anchors for several signaling proteins, but the underlying molecular basis has yet to be established. The present review covers the recent progress in our understanding of the CLDN signaling pathway in health and disease. We discuss the functional relevance of phosphotyrosine motifs in the C-terminal cytoplasmic domain of CLDNs and define mutual regulation between CLDNs and Src-family kinases (SFKs). In addition, we focus on the crosstalk between CLDN and transcription factor signaling. We also describe how aberrant CLDNtranscription factor signaling promotes or inhibits cancer progression. We propose that a link between various cell adhesion molecules and transcription factors coordinates a range of physiological and pathological events via activation or suppression of target genes.

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“…CLDN6 had been demonstrated abnormal expression and can be a prognostic marker in cancers including ovarian cancer ( Wang et al, 2013 ), endometrial cancer ( Kojima et al, 2020 ), gastric cancer ( Kohmoto et al, 2020 ), breast carcinoma ( Liu et al, 2016 ; Jia et al, 2019 ), and lung cancer ( Micke et al, 2014 ). Bioinformatic analysis has revealed that CLDN6 is regulated by a diverse set of transcription factors and promotes cancer cell behavior via the ASK1-p38/JNK MAPK secretory signaling pathway ( Lin et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Association of CLDN6 and CLDN10 With Immune Microenvironment in Ovarian Cancer: A Study of the Claudin Family

et al. 2021

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BackgroundThe claudin family is a group of transmembrane proteins related to tight junctions. While their involvement in cancer has been studied extensively, their relationship with the tumor immune microenvironment remains poorly understood. In this research, we focused on genes related to the prognosis of ovarian cancer and explored their relationship with the tumor immune microenvironment.MethodsThe cBioPortal for Cancer Genomics database was used to obtain the genetic variation pattern of the claudin family in ovarian cancer. The ONCOMINE and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to explore the mRNA expression of claudins in cancers. The prognostic potential of these genes was examined via the Kaplan-Meier plotter. The enrichment of immunological signatures was determined by gene set enrichment analysis (GSEA). The correlations between claudins and the tumor immune microenvironment in ovarian cancer were investigated via the Tumor Immune Estimation Resource (TIMER).ResultsClaudin genes were altered in 363 (62%) of queried patients/samples. Abnormal expression levels of claudins were observed in various cancers. Among them, CLDN3, CLDN4, CLDN6, CLDN10, CLDN15, and CLDN16 were significantly correlated with overall survival in patients with ovarian cancer. GSEA revealed that CLDN6 and CLDN10 were significantly enriched in immunological signatures of B cell, CD4 T cell, and CD8 T cell. Furthermore, CLDN6 and CLDN10 were negatively correlated and positively correlated, respectively, with immune cell infiltration in ovarian cancer. The expression levels of CLDN6 and CLDN10 were also negatively correlated and positively correlated, respectively, with various gene markers of immune cells in ovarian cancer. Thus, CLDN6 and CLDN10 may participate in immune cell infiltration in ovarian cancer, and these mechanisms may be the reason for poor prognosis.ConclusionOur study showed that CLDN6 and CLDN10 were prognostic biomarkers correlated with the immune microenvironment in ovarian cancer. These results reveal new roles for CLDN6 and CLDN10 as potential therapeutic targets in the treatment of ovarian cancer.

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Prognostic Significance of Aberrant Claudin-6 Expression in Endometrial Cancer

Cited by 25 publications

References 34 publications

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

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

The claudin–transcription factor signaling pathway

Association of CLDN6 and CLDN10 With Immune Microenvironment in Ovarian Cancer: A Study of the Claudin Family

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