Dataset Information

The novel interplay between CD44 standard isoform and the caspase-1/IL1B pathway to induce hepatocellular carcinoma progression.

ABSTRACT: Accumulating data indicate caspase-1 (CASP1), one of the inflammatory caspases, promotes hepatocellular carcinoma (HCC) progression in tumor proliferation, invasion, EMT phenotype and sorafenib resistance. However, the molecular basis of regulating caspase-1 expression and caspase-1/IL1B (interleukin-1?) pathway in HCC remains unclear. Here, we demonstrated the novel interplay between caspase-1/IL1B activation and cluster differentiation 44 standard isoform (CD44s) in HCC. In this study, we observed that CD44s is responsible for caspase-1/IL1B activation both in HCC tissues and five HCC cell lines. In normoxia conditions, CD44s knockdown repressed the activation of caspase-1/IL1B via stimulating AMPK-mediated autophagy. Moreover, our data suggested that p62-induced autophagic degradation of caspase-1 accounted for caspase-1/IL1B inactivation in CD44s deficient cells. Administration of recombinant human IL1B could rescue impaired proliferation, invasion, and EMT phenotype in CD44s deficient HCC cells. Lastly, hypoxia-mediated caspase-1/IL1B overexpression could be abolished by CD44s downregulation through decreasing HIF1A and enhancing autophagic activity. Overall, targeting CD44s is a novel inhibitory mechanism of caspase-1/IL1B expression, both in normoxia and hypoxia conditions.

SUBMITTER: Li J

PROVIDER: S-EPMC7652828 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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The novel interplay between CD44 standard isoform and the caspase-1/IL1B pathway to induce hepatocellular carcinoma progression.

Li Jun J Zhang Yongwei Y Ruan Ran R He Wei W Qian Yeben Y

Cell death & disease 20201109 11

Accumulating data indicate caspase-1 (CASP1), one of the inflammatory caspases, promotes hepatocellular carcinoma (HCC) progression in tumor proliferation, invasion, EMT phenotype and sorafenib resistance. However, the molecular basis of regulating caspase-1 expression and caspase-1/IL1B (interleukin-1β) pathway in HCC remains unclear. Here, we demonstrated the novel interplay between caspase-1/IL1B activation and cluster differentiation 44 standard isoform (CD44s) in HCC. In this study, we obse ...[more]

PMID: 33168816

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Project description:BACKGROUND: A blockade of CD44 is considered a therapeutic option for the elimination of leukemia initiating cells. However, anti-panCD44 can interfere with hematopoiesis. Therefore we explored, whether a CD44 variant isoform (CD44v)-specific antibody can inhibit leukemia growth without attacking hematopoiesis. As a model we used CD44v10 transfected EL4 thymoma cells (EL4-v10). METHODS: The therapeutic efficacy of anti-panCD44 and anti-CD44v10 was evaluated after intravenous application of EL4/EL4-v10. Ex vivo and in vitro studies evaluated the impact of anti-panCD44 and anti-CD44v10 as well as of EL4 and EL4-v10 on hematopoietic stem cells (HSC) in cocultures with bone marrow stroma cells with a focus on adhesion, migration, cell cycle progression and apoptosis resistance. RESULTS: Intravenously injected EL4-v10 grow in bone marrow and spleen. Anti-panCD44 and, more pronounced anti-CD44v10 prolong the survival time. The higher efficacy of anti-CD44v10 compared to anti-panCD44 does not rely on stronger antibody-dependent cellular cytotoxicity or on promoting EL4-v10 apoptosis. Instead, EL4 compete with HSC niche embedding. This has consequences on quiescence and apoptosis-protecting signals provided by the stroma. Anti-panCD44, too, more efficiently affected embedding of HSC than of EL4 in the bone marrow stroma. EL4-v10, by catching osteopontin, migrated on bone marrow stroma and did not or weakly interfere with HSC adhesion. Anti-CD44v10, too, did not affect the HSC--bone marrow stroma crosstalk. CONCLUSION: The therapeutic effect of anti-panCD44 and anti-CD44v10 is based on stimulation of antibody-dependent cellular cytotoxicity. The superiority of anti-CD44v10 is partly due to blocking CD44v10-stimulated osteopontin expression that could drive HSC out of the niche. However, the main reason for the superiority of anti-CD44v10 relies on neither EL4-v10 nor anti-CD44v10 severely interfering with HSC--stroma cell interactions that, on the other hand, are affected by EL4 and anti-panCD44. Anti-panCD44 disturbing HSC embedding in the osteogenic niche weakens its therapeutic effect towards EL4. Thus, as far as leukemic cells express CD44v isoforms, the therapeutic use of anti-panCD44 should be avoided in favor of CD44v-specific antibodies.

Project description:CD44 is commonly used as a cell surface marker of cancer stem-like cells in epithelial tumours, and we have previously demonstrated the existence of two different CD44(high) cancer stem-like cell populations in squamous cell carcinoma, one having undergone epithelial-to-mesenchymal transition and the other maintaining an epithelial phenotype. Alternative splicing of CD44 variant exons generates a great many isoforms, and it is not known which isoforms are expressed on the surface of the two different cancer stem-like cell phenotypes. Here, we demonstrate that cancer stem-like cells with an epithelial phenotype predominantly express isoforms containing the variant exons, whereas the cancer stem-like cells that have undergone an epithelial-to-mesenchymal transition down-regulate these variant isoforms and up-regulate expression of the standard CD44 isoform that contains no variant exons. In addition, we find that enzymatic treatments used to dissociate cells from tissue culture or fresh tumour specimens cause destruction of variant CD44 isoforms at the cell surface whereas expression of the standard CD44 isoform is preserved. This results in enrichment within the CD44(high) population of cancer stem-like cells that have undergone an epithelial-to-mesenchymal transition and depletion from the CD44(high) population of cancer stem-like cells that maintain an epithelial phenotype, and therefore greatly effects the characteristics of any cancer stem-like cell population isolated based on expression of CD44. As well as effecting the CD44(high) population, enzymatic treatment also reduces the percentage of the total epithelial cancer cell population staining CD44-positive, with potential implications for studies that aim to use CD44-positive staining as a prognostic indicator. Analyses of the properties of cancer stem-like cells are largely dependent on the ability to accurately identify and assay these populations. It is therefore critical that consideration be given to use of multiple cancer stem-like cell markers and suitable procedures for cell isolation in order that the correct populations are assayed.

Dataset Information

The novel interplay between CD44 standard isoform and the caspase-1/IL1B pathway to induce hepatocellular carcinoma progression.

Publications

The novel interplay between CD44 standard isoform and the caspase-1/IL1B pathway to induce hepatocellular carcinoma progression.

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