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

Alpha-Crystallin B chain (αB-Crystallin) is a heat shock chaperone protein that is encoded in humans by CRYAB gene. It has been extensively studied as a chaperone that binds to misfolded proteins to prevent their aggregation and as a structural protein that contributes to intracellular architecture. In cancer, αB-crystallin enables tumor cells to survive stress-induced tumor microenvironment by promoting proliferation and angiogenesis and inhibiting apoptosis. While CRYAB overexpression is considered as a marker for poor prognosis in a wide variety of cancers, some studies – particularly in ovarian and testicular cancer - have reported its downregulation to be associated with tumor progression. This has led to controversy surrounding the role of CRYAB as either a tumor suppressor or an oncogene. To determine the causal relationship of the overexpression of CRYAB in cancer, we have generated a Cryab overexpression mouse model where Cryab was overexpressed from the Rosa26 locus. 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, an extracellular matrix metalloproteinase inducer. In vitro, using 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 αB-Crystallin as an oncogene, where its upregulation is sufficient to induce tumors, promote cell survival and inhibit apoptosis.