Impairment of carbonic anhydrase IX ectodomain cleavage reinforces tumorigenic and metastatic phenotype of cancer cells.,British Journal of Cancer

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Impairment of carbonic anhydrase IX ectodomain cleavage reinforces tumorigenic and metastatic phenotype of cancer cells.
British Journal of Cancer ( IF 6.4 ) Pub Date : 2020-03-25 , DOI: 10.1038/s41416-020-0804-z
Ivana Kajanova ₁ , Miriam Zatovicova ₁ , Lenka Jelenska ₁ , Olga Sedlakova ₁ , Monika Barathova ₁ , Lucia Csaderova ₁ , Michaela Debreova ₁ , Lubomira Lukacikova ₁ , Katarina Grossmannova ₁ , Martina Labudova ₁ , Tereza Golias ₁ , Eliska Svastova ₁ , Andreas Ludwig ₂ , Petr Muller ₃ , Borivoj Vojtesek ₃ , Jaromir Pastorek ₁ , Silvia Pastorekova ₁

Affiliation

Background

Carbonic anhydrase IX (CA IX) is a hypoxia-induced enzyme regulating tumour pH and facilitating cell migration/invasion. It is primarily expressed as a transmembrane cell-surface protein, but its ectodomain can be shed by ADAM17 to extracellular space. This study aims to elucidate the impact of CA IX shedding on cancer cells.

Methods

We generated a non-shed CA IX mutant by deletion of amino acids 393–402 from the stalk region and studied its phenotypic effects compared to full-length, shedding-competent CA IX using a range of assays based on immunodetection, confocal microscopy, in vitro real-time cell monitoring and in vivo tumour cell inoculation using xenografted NMRI and C57BL/6J female mice.

Results

We demonstrated that the impairment of shedding does not alter the ability of CA IX to bind ADAM17, internalise, form oligomers and regulate pH, but induces cancer-promoting changes in extracellular proteome. Moreover, it affects intrinsic properties of cells expressing the non-shed variant, in terms of their increased ability to migrate, generate primary tumours and form metastatic lesions in lungs.

Conclusions

Our results show that the ectodomain shedding controls pro-tumorigenic and pro-metastatic roles of the cell-associated CA IX and suggest that this phenomenon should be considered when developing CA IX-targeted therapeutic strategies.

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