Transforming growth factor beta (TGF-β) signals through intermediary SMAD proteins, which

activate differentiation programs and inhibit cell-cycle progression during early carcinogenesis.38 In TISC-driven hepatocarcinogenesis, the loss Cobimetinib datasheet of intermediary regulators, such as β2-Spectrin, results in the malignant transformation of liver stem and progenitor cells to TISCs via loss of differentiation and growth-arrest signals (Fig. 1).39 Within liver TISC populations, increased expression of ESC transcription factors Oct4 and Nanog, driven by loss of TGF-β differentiation signals, propagates self-renewal characteristics. Small molecule promoters of TGF-β signaling, which may restore growth-arrest and differentiation signals in TISCs, have been proposed as a TISC-targeting strategy. In related work, targeting of the fifth subunit of the COP9 signalosome (CSN5), which is functionally buy R788 interconnected with TGF-β signaling, resulted in decreased tumor growth of human HCC cell lines in vivo.40 Because chronic hepatitis C virus (HCV) infection is the primary cause of HCC in the United States, murine models of HCV-induced HCC are highly relevant. In HCV core+ or NS5A+ transgenic mice, up-regulation of Toll-like receptor-4 (TLR4)

expression during HCV-induced chronic injury was associated with impaired TGF-β signaling, up-regulated Nanog expression, and increased malignant potential, a process that is exacerbated by a high-fat diet.41, 42 TLR4 activation occurred predominantly in Nanog-dependent

CD133+CD49f+ TISCs. Targeting Nanog directly in these TISCs results in decreased tumor initiation, by down-regulating cellular growth regulators. TLR4-initiated and Nanog-dependent activation of yes-associated protein 1 (YAP1), a regulator of Hippo signaling, results in inhibition of TGF-β through suppression of nuclear translocation of SMAD3. Silencing Yap1 results in suppression of Nanog transcription, restoration of TGF-β/SMAD3 signaling, and sensitization of TISCs to rapamycin and sorafenib. Canonical β-catenin signaling through activation of TCF/LEF promoters is a general mechanism of stem cell function, resulting in stem cell proliferation, survival, and MCE公司 inhibition of differentiation. Mutations in β-catenin and related complex proteins often result in β-catenin activation without Wnt initiation.43 Although β-catenin mutations are well characterized in HCC, mutations that protect β-catenin from degradation are not, by themselves, sufficient to induce HCC in murine models.43, 44 β-catenin activation is also found in normal LPCs, proliferating in response to chronic liver injury. Conversely, in liver-specific β-catenin knockout mice, LPC proliferation is reduced in response to the DDC diet.