The Keratin 17/YAP/IL6 Axis contributes to E-cadherin Loss and Aggressiveness of Diffuse Gastric Cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE171879 | GEO | 2021/11/24
REPOSITORIES: GEO
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Project description:The Keratin 17/YAP/IL6 Axis contributes to E-cadherin Loss and Aggressiveness of Diffuse Gastric Cancer
| PRJNA721315 | ENA
Project description:Memory B cells (MBCs) and long-lived plasma cells (LLPCs) are responsible for immunological "memory", which can last for many years. The long-term survival niche for LLPCs in the bone marrow is well characterized; however, the corresponding niche for MBCs is unclear. BILL-cadherin/cadherin-17 (CDH17) is the only member of the cadherin superfamily that is expressed on mouse B lymphocytes in a spatiotemporally regulated manner. Here, we show that half of all MBCs regain expression of CDH17 during the later stage of development. The maintenance of high affinity antigen-specific serum antibodies was impaired in CDH17(-/-) mice and the number of antigen-specific MBCs was reduced as compared to wild-type mice (WT). Also, specific responses to secondary antigens were ablated in CDH17(-/-) mice, whereas primary antibody responses were the same as those in WT mice. Cell cycle analysis revealed a decline in the proliferation of CDH17(-) MBCs as compared to CDH17(+) MBCs. In addition, we identified a subpopulation of splenic stromal cells, MAdCAM-1(+) blood endothelial cells (BEC), which was CDH17(+). Taken together, these results suggest that CDH17 plays a role in the long-term survival of MBCs, presumably via an "MBC niche" comprising, at least in part, BEC in the spleen.
| S-EPMC4303427 | biostudies-literature
Project description:PurposeWe investigated whether in human head and neck squamous cell carcinoma (HNSCC) high levels of expression of stress keratin 17 (K17) are associated with poor survival and resistance to immunotherapy.Experimental designWe investigated the role of K17 in regulating both the tumor microenvironment and immune responsiveness of HNSCC using a syngeneic mouse HNSCC model, MOC2. MOC2 gives rise to immunologically cold tumors that are resistant to immune-checkpoint blockade (ICB). We engineered multiple, independent K17 knockout (KO) MOC2 cell lines and monitored their growth and response to ICB. We also measured K17 expression in human HNSCC of patients undergoing ICB.ResultsMOC2 tumors were found to express K17 at high levels. When knocked out for K17 (K17KO MOC2), these cells formed tumors that grew slowly or spontaneously regressed and had a high CD8+ T-cell infiltrate in immunocompetent syngeneic C57BL/6 mice compared with parental MOC2 tumors. This phenotype was reversed when we depleted mice for T cells. Whereas parental MOC2 tumors were resistant to ICB treatment, K17KO MOC2 tumors that did not spontaneously regress were eliminated upon ICB treatment. In a cohort of patients with HNSCC receiving pembrolizumab, high K17 expression correlated with poor response. Single-cell RNA-sequencing analysis revealed broad differences in the immune landscape of K17KO MOC2 tumors compared with parental MOC2 tumors, including differences in multiple lymphoid and myeloid cell types.ConclusionsWe demonstrate that K17 expression in HNSCC contributes to immune evasion and resistance to ICB treatment by broadly altering immune landscapes of tumors.
| S-EPMC9250640 | biostudies-literature
Project description:BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) is characterised by an extensive tissue invasion and an early formation of metastasis. Alterations in the expression of cadherins have been reported in PDAC. Yet, how these changes contribute to tumour progression is poorly understood. Here, we investigated the relationship between cadherins expression and PDAC development. METHODS:Cadherins expression was assessed by immunostaining in both human and murine tissue specimens. We have generated pancreatic cancer cell lines expressing both cadherin-1 and cadherin-3 or only one of these cadherins. Functional implications of such genetic alterations were analysed both in vitro and in vivo. RESULTS:Cadherin-3 is detected early at the plasma membrane during progression of pancreatic intraepithelial neoplasia 1 (PanIN-1) to PDAC. Despite tumoural cells turn on cadherin-3, a significant amount of cadherin-1 remains expressed at the cell surface during tumourigenesis. We found that cadherin-3 regulates tumour growth, while cadherin-1 drives type I collagen organisation in the tumour. In vitro assays showed that cadherins differentially participate to PDAC aggressiveness. Cadherin-3 regulates cell migration, whereas cadherin-1 takes part in the invadopodia activity. CONCLUSIONS:Our results show differential, but complementary, roles for cadherins during PDAC carcinogenesis and illustrate how their expression conditions the PDAC aggressiveness.
| S-EPMC5830586 | biostudies-literature
Project description:High Mobility Group A1 (HMGA1) is an architectural chromatin factor that promotes neoplastic transformation and progression. However, the mechanism by which HMGA1 exerts its oncogenic function is not fully understood. Here, we show that cyclin E2 (CCNE2) acts downstream of HMGA1 to regulate the motility and invasiveness of basal-like breast cancer cells by promoting the nuclear localization and activity of YAP, the downstream mediator of the Hippo pathway. Mechanistically, the activity of MST1/2 and LATS1/2, the core kinases of the Hippo pathway, are required for the HMGA1- and CCNE2-mediated regulation of YAP localization. In breast cancer patients, high levels of HMGA1 and CCNE2 expression are associated with the YAP/TAZ signature, supporting this connection. Moreover, we provide evidence that CDK inhibitors induce the translocation of YAP from the nucleus to the cytoplasm, resulting in a decrease in its activity. These findings reveal an association between HMGA1 and the Hippo pathway that is relevant to stem cell biology, tissue homeostasis, and cancer.
| S-EPMC4662477 | biostudies-literature
Project description:Glioblastoma (GBM), a highly malignant and lethal brain tumor, is characterized by diffuse invasion into the brain and chemo-radiotherapy resistance resulting in poor prognosis. In this study, we examined the involvement of the cell adhesion molecule CD146/MCAM in regulating GBM aggressiveness. Analyses of GBM transcript expression databases revealed correlations of elevated CD146 levels with higher glioma grades, IDH-wildtype and unmethylated MGMT phenotypes, poor response to chemo-radiotherapy and worse overall survival. In a panel of GBM stem cells (GSCs) variable expression levels of CD146 were detected, which strongly increased upon adherent growth. CD146 was linked with mesenchymal transition since expression increased in TGF-ß-treated U-87MG cells. Ectopic overexpression of CD146/GFP in GG16 cells enhanced the mesenchymal phenotype and resulted in increased cell invasion. Conversely, GSC23-CD146 knockouts had decreased mesenchymal marker expression and reduced cell invasion in transwell and GBM-cortical assembloid assays. Moreover, using GSC23 xenografted zebrafish, we found that CD146 depletion resulted in more compact delineated tumor formation and reduced tumor cell dissemination. Stem cell marker expression and neurosphere formation assays showed that CD146 increased the stem cell potential of GSCs. Furthermore, CD146 mediated radioresistance by stimulating cell survival signaling through suppression of p53 expression and activation of NF-κB. Interestingly, CD146 was also identified as an inducer of the oncogenic Yes-associated protein (YAP). In conclusion, CD146 carries out various pro-tumorigenic roles in GBM involving its cell surface receptor function, which include the stimulation of mesenchymal and invasive properties, stemness, and radiotherapy resistance, thus providing an interesting target for therapy.
| S-EPMC9256581 | biostudies-literature
Project description:Onset of type I keratin 17 (K17) synthesis marks the adoption of an appendageal fate within embryonic ectoderm, and its expression persists in specific cell types within mature hair, glands, and nail. We report that K17 null mice develop severe alopecia during the first week postbirth, correlating with hair fragility, alterations in follicular histology, and apoptosis in matrix cells. These alterations are incompletely penetrant and normalize starting with the first postnatal cycle. Absence of a hair phenotype correlates with a genetic strain-dependent compensation by related keratins, including K16. These findings reveal a crucial role for K17 in the structural integrity of the first hair produced and the survival of hair-producing cells. Given that identical inherited mutations in this gene can cause either pachyonychia congenita or steatocystoma multiplex, the features of this mouse model suggest that this clinical heterogeneity arises from a cell type-specific, genetically determined compensation by related keratins.
| S-EPMC186322 | biostudies-literature
Project description:BACKGROUND:We previously demonstrated that the local immune status correlated with the glioma prognosis. Interleukin-6 (IL6) was identified as an important local immune-related risk marker related to unfavourable prognosis. In this study, we further investigated the role and regulation of IL6 signalling in glioma. METHODS:The expression and prognostic value of IL6 and the IL6 receptor (IL6R) were explored in The Cancer Genome Atlas (TCGA) and REMBRANDT databases and clinical samples. Functional effects of genetic knockdown and overexpression of IL6R or IL6 stimulation were examined in vitro and in tumours in vivo. The effects of the nuclear factor of activated T cells-1 (NFAT1) on the promoter activities of IL6R and IL6 were also examined. RESULTS:High IL6- and IL6R-expression were significantly associated with mesenchymal subtype and IDH-wildtype gliomas, and were predictors of poor survival. Knockdown of IL6R decreased cell proliferation, invasion and neurosphere formation in vitro, and inhibited tumorigenesis in vivo. IL6R overexpression or IL6 stimulation enhanced the invasion and growth of glioma cells. TCGA database searching revealed that IL6- and IL6R-expression were correlated with that of NFAT1. In glioma cells, NFAT1 enhanced the promoter activities of IL6R and IL6, and upregulated the expression of both IL6R and IL6. CONCLUSION:NFAT1-regulated IL6 signalling contributes to aggressive phenotypes of gliomas, emphasizing the role of immunomodulatory factors in glioma malignant progression.
| S-EPMC5735798 | biostudies-literature
Project description:Colon adenocarcinoma (COAD), having high malignancy and poor prognosis, is the main pathological type of colon cancer. Previous studies show that Keratin 17 (KRT17) plays an important role in the development of many malignant tumors. However, its role and the molecular mechanism underlying COAD remain unclear. Using TCGA and ONCOMINE databases, as well as immunohistochemistry, we found that the expression of KRT17 was higher in COAD tissues as compared to that in the adjacent normal tissues. Cell- and animal-based experiments showed that overexpression of KRT17 promoted the invasion and metastasis of colon cancer cells while knocking down KRT17 reversed these processes both in vitro and in vivo. In addition, we also showed that KRT17 promoted the formation of new blood vessels. Mechanistically, KRT17 could regulate the WNT/β-catenin signaling pathway, and APC may be involved in this process by interacting with KRT17. In summary, these findings suggested that high expression of KRT17 could promote cell metastasis and angiogenesis of colon cancer cells by regulating the WNT/β-catenin signaling pathway. Thus, KRT17 could be a potential therapeutic target for COAD treatment.
| S-EPMC8809968 | biostudies-literature
Project description:Keratin subtypes are selectively expressed depending on the cell type. They not only provide structural support, but regulate the metabolic processes and signaling pathways that control the growth of the epithelium. KRT17 (keratin 17) is induced in the regenerative epithelium and acts on diverse signaling pathways. Here, we demonstrate that KRT17 is invariably and permanently induced in oral squamous cell carcinoma (OSCC), as revealed by immunohistochemistry and cDNA microarray analysis. Two representative OSCC cell lines; KRT17-weakly expressing Ca9-22 and KRT17-highly expressing HSC3 were used to establish KRT17-overexpressing Ca9-22 and KRT17-knockdown HSC3 cells. Analysis of these cells revealed that KRT17 promoted cell proliferation and migration by stimulating the Akt/mTOR pathway. KRT17 also upregulated the expression of SLC2A1 (solute carrier family 2 member 1/Glut1) and glucose uptake. To further investigate the effect of KRT17 on tumorigenesis, KRT17-knockout HSC3 cells were established and were transplanted to the cephalic skin of nude mice. The tumors that developed from KRT17-knockout HSC3 cells had a lower Ki-67 labeling index and were significantly smaller compared to the controls. These results indicate that KRT17 stimulates the Akt/mTOR pathway and glucose uptake, thereby facilitating tumor growth. We could not confirm the relationship between KRT17 and SFN (stratifin) in the cells examined in this study. However, our study reinforces the concept that the cellular properties of cancer are regulated by a series of molecules similar to those found in wound healing. In OSCC, KRT17 acts as a pathogenic keratin that facilitates tumor growth through the stimulation of multiple signaling pathways, highlighting the importance of KRT17 as a multifunctional promoter of tumorigenesis.
| S-EPMC4981360 | biostudies-literature