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bioRxiv · 10.1101/2022.07.27.501790

Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice

Rashidieh, B.·Bain, A. L.·Tria, S. M.·Sharma, S.·Stewart, C. A.·Simmons, J. L.·Apaja, P. M.·Duijf, P. H. G.·Finnie, J.·Khanna, K. K.
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Abstract

B-Crystallin is a heat shock chaperone protein which binds to misfolded proteins to prevent their aggregation. It is overexpressed in a wide-variety of cancers. Previous studies using human cancer cell lines and human xenograft models have reported tumor suppressor or tumor promoter (oncogene) roles for B-Crystallin depending on cellular context and environmental conditions. To determine the causal relationship between CRYAB overexpression and cancer, we generated a Cryab overexpression knock-in mouse model. This model revealed that constitutive overexpression of Cryab results in the formation of a variety of lethal spontaneous primary and metastatic tumors in mice. In vivo, the overexpression of Cryab correlated with the upregulation of epithelial-to-mesenchymal (EMT) markers, angiogenesis and some oncogenic proteins including Basigin. In vitro, using E1A/Ras transformed mouse embryonic fibroblasts (MEFs), we observed that the overexpression of Cryab led to the promotion of cell survival via upregulation of Akt signaling and downregulation of pro-apoptotic pathway mediator JNK, with subsequent attenuation of apoptosis as assessed by cleaved caspase-3. Overall, through the generation and characterization of Cryab overexpression model, we provide evidence supporting the role of B-Crystallin as an oncogene, where its upregulation is sufficient to induce tumors, promote cell survival and inhibit apoptosis.

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Rashidieh, B., Bain, A. L., Tria, S. M., Sharma, S., Stewart, C. A., Simmons, J. L., Apaja, P. M., Duijf, P. H. G., Finnie, J., Khanna, K. K.. 2022-07-29. Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice. https://doi.org/10.1101/2022.07.27.501790

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