Aberrant claudin-6–adhesion signal promotes endometrial cancer progression via estrogen receptor α
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ABSTRACT:
PROVIDER: PRJNA677985 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13050524.fastq.gz | Fastqsanger.gz | |||
| SRR13050524_1.fastq.gz | Fastqsanger.gz | |||
| SRR13050524_2.fastq.gz | Fastqsanger.gz | |||
| SRR13050525.fastq.gz | Fastqsanger.gz | |||
| SRR13050525_1.fastq.gz | Fastqsanger.gz |
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Project description:Cell adhesion proteins not only maintain tissue integrity but also possess signaling abilities to organize diverse cellular events in a variety of physiological and pathological processes; however, the underlying mechanism remains obscure. Among cell adhesion molecules, the claudin (CLDN) family often possesses aberrant expression in various cancers, but the biological relevance and molecular basis have not yet been established. Here, we show that high CLDN6 expression accelerates cellular proliferation and migration in human endometrial cancer cells in vitro. Using xenograft model, we also revealed that aberrant CLDN6 expression promotes tumor growth and invasion in endometrial cancer tissues. The second extracellular domain and Y196/200 of CLDN6 were required to recruit and activate Src-family kinases (SFKs) and to stimulate malignant phenotypes. Importantly, we demonstrate that the CLDN6/SFK/PI3K-dependent AKT and SGK (serum- and glucocorticoid-regulated kinase) signalings target Ser518 in the human estrogen receptor α and ligand-independently activate target genes in endometrial cancer cells, resulting in cancer development. CLDN6, at least in part, also regulated gene expression in an ERα-independent manner.
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Project description:Cell adhesion molecules exhibit the signaling abilities to control a variety of physiological and pathological processes; however, the underlying molecular basis remains poorly defined. Here, we demonstrate that the claudin-4 (CLDN4)-adhesion signaling accelerates breast cancer metabolism and progression via the nuclear receptor LXRb (liver X receptor b). Knockout and rescue experiments revealed that the CLDN4 signaling targets S432 in LXRb, leading to enhanced cell proliferation and tumor growth in breast cancer cells. In addition, RT-qPCR analysis showed the CLDN4-regulated genes are classified into at least six groups by distinct LXRb- and LXRbS432-dependence. Collectively, our results provide a link between cell adhesion and nuclear receptor signalings to coordinate cancer metabolism and advancement.
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Project description:Among the claudin (CLDN) family, CLDN6 exhibits aberrant expression in various cancers, but its biological relevance has not yet been established. We generated a monoclonal antibody (mAb) against human CLDN6 and verified its specificity. By immunohistochemical staining and semi-quantification, we evaluated the relationship between CLDN6 expression and clinicopathological parameters in tissues from 173 cases of endometrial cancer. The established mAb selectively recognized CLDN6 protein. Ten of the 173 cases (5.8%) showed high CLDN6 expression (score 3+), whereas 19 (11.0%), 18 (10.4%) and 126 (72.4%) cases revealed low CLDN6 expression (score 2+, 1+ and 0, respectively). In addition, intratumor heterogeneity of CLDN6 expression was observed even in the cases with high CLDN6 expression. The 5-year survival rates in the high and low CLDN6 groups was approximately 30% and 90%, respectively. Among the clinicopathological factors, the high CLDN6 expression was significantly associated with surgical stage III/IV, histological grade 3, lymphovascular space involvement, lymph node metastasis and distant metastasis. Furthermore, the high CLDN6 expression was an independent prognostic marker for overall survival of endometrial cancer patients (hazard ratio 3.50, p = 0.014). It can be concluded that aberrant CLDN6 expression is useful to predict poor outcome for endometrial cancer and might be a promising therapeutic target.
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Project description:Claudin-4–adhesion signaling drives breast cancer metabolism and progression via liver X receptor β
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Project description:Epithelial-mesenchymal transition (EMT) is an important mechanism in carcinogenesis. To determine the mechanisms that are involved in the regulation of EMT is crucial to develop new biomarkers and therapeutic targets towards cancers. In this study, when TGFß1 and TNFa were used to induce EMT in human lung carcinoma A549 cells, we were surprised to find an increase in an epithelial cell tight junction marker, Claudin 1. We further identified that it was the TNFa and not the TGFß1 that induced the fibroblast-like morphology changes. TNFa also caused the increase in Claudin-1 gene expression and protein levels in Triton X-100 soluble cytoplasm fraction. Down-regulation of Claudin-1, using small interfering RNA (siRNA), inhibited 75% of TNFa-induced gene expression changes. Claudin-1 siRNA effectively blocked TNFa-induced molecular functional networks related to inflammation and cell movement. Wound-healing assay showed that Claudin-1 siRNA was able to significantly reduce TNF-enhanced cell migration. Furthermore, over expression of Claudin 1 with a Claudin 1-pcDNA3.1/V5-His vector enhanced cell migration. In conclusion, these observations indicate that Claudin 1 acts as a critical signal mediator in TNFa-induced gene expression and cell migration in human lung cancer cells. Further analyses of these cellular processes may be helpful in developing novel therapeutic strategies.
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Project description:Epithelial-mesenchymal transition (EMT) is an important mechanism in carcinogenesis. To determine the mechanisms that are involved in the regulation of EMT is crucial to develop new biomarkers and therapeutic targets towards cancers. In this study, when TGFÃ1 and TNFa were used to induce EMT in human lung carcinoma A549 cells, we were surprised to find an increase in an epithelial cell tight junction marker, Claudin 1. We further identified that it was the TNFa and not the TGFÃ1 that induced the fibroblast-like morphology changes. TNFa also caused the increase in Claudin-1 gene expression and protein levels in Triton X-100 soluble cytoplasm fraction. Down-regulation of Claudin-1, using small interfering RNA (siRNA), inhibited 75% of TNFa-induced gene expression changes. Claudin-1 siRNA effectively blocked TNFa-induced molecular functional networks related to inflammation and cell movement. Wound-healing assay showed that Claudin-1 siRNA was able to significantly reduce TNF-enhanced cell migration. Furthermore, over expression of Claudin 1 with a Claudin 1-pcDNA3.1/V5-His vector enhanced cell migration. In conclusion, these observations indicate that Claudin 1 acts as a critical signal mediator in TNFa-induced gene expression and cell migration in human lung cancer cells. Further analyses of these cellular processes may be helpful in developing novel therapeutic strategies. 4 groups (with or without TNFα, control or Claudin 1 siRNA) of human lung adenocarcinoma A549 cells with 3 replicates per group.
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