αB-Crystallin (Cryab), a member of the mammalian small heat shock protein (sHsp) superfamily, functions as a cytoprotective molecular chaperone by preventing stress-induced aggregation of denatured proteins and keeping aggregation-prone proteins in reservoirs of nonnative, refoldable intermediates within large, soluble, multimeric structures.2 The expression of Cryab in a temporally and spatially controlled fashion during development has led to the speculation that this sHsp may have important roles in the regulation of cellular physiology and growth.3 Indeed, ectopic expression
of Cryab in diverse cell types has been demonstrated to confer protection against a broad range of apoptotic stimuli, including tumor necrosis factor alpha (TNF-α), TNF-related Saracatinib order apoptosis-inducing ligand,4 oxidative stress,5 and exposure to anticancer drugs,6 while silencing Cryab expression by RNA interference (RNAi) sensitizes cells to apoptosis.7 Elevated expression of Cryab has been linked to cancer pathology.8 For example, Cryab overexpression has been clinically detected in a variety of human malignancies and is associated with poor prognosis for several different types of tumors, including renal, breast, hepatoma,
selleck chemicals and lung cancer.9-12 However, the mechanism remains unclear. Given the significant role of Cryab in tumor progression of human cancers, further investigation into the role and mechanism of Cryab in HCC is needed. Most HCC deaths are due to metastasis, a multistep process that mediates the spread of tumor cells from primary tumors to distant sites.13 Although the molecular and genetic events BCKDHA underlying tumor metastasis are still not well understood, intense investigation into this process has led to the notion that molecules involved in epithelial-mesenchymal transition (EMT)
are critical in tumor invasion and metastasis.14 On the other hand, recent studies have shown that a multikinase inhibitor, sorafenib, can inhibit serine/threonine kinases (c-RAF, and mutant and wildtype BRAF) and be used as a “gold” treatment for advanced HCC patients.15 However, the efficiency of sorafenib remains unstable. An investigation to discriminate patients with sorafenib treatment into discrete prognostic groups is lacking. Here, functional and genetic screens demonstrated that Cryab overexpression fosters tumor progression in HCC by inducing EMT by way of activation of extracellular-regulated protein kinase (ERK) signaling, which is subsequently shown to mediate this EMT and sorafenib resistance. Overexpression of αB-Crystallin in HCC cells induces EMT progression through an ERK1/2/Fra-1/slug signaling pathway. Remarkably, these studies demonstrated that Cryab complexes with and elevates 14-3-3ζ protein, leading to up-regulation of ERK1/2 activity. Moreover, high levels of Cryab are associated with impaired sorafenib response with respect to overall survival (OS).