Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-catenin

Emergence of the Dedifferentiated Phenotype in Hepatocyte‐Derived Tumors in Mice: Roles of Oncogene‐Induced Epigenetic Alterations

“…(35) Myc-induced hepatocarcinogenesis has been reported to be facilitated by the expression of activated βcatenin, resulting in the generation of DLK1-positive hepatoblastoma-like tumors. (36) We demonstrated here that the combination of HRAS and Myc also induced dedifferentiated tumors with hepatoblastic features, suggesting that Myc plays an essential role in the reprogramming of hepatocytes toward hepatoblastic cells. Although it has been long argued that the hepatoblastoma-like subtype of HCC and combined hepatocellular-cholangiocarcinoma could be derived from hepatic stem/progenitor cells, (1,37) our data indicate that even fully matured hepatocytes could be the cells of origin of such tumors through oncogeneinduced transformation and dedifferentiation.…”

“…In mice, the combination of activated β‐catenin and YAP has been shown to generate hepatoblastoma‐like tumors with the spontaneous activation of Myc expression . Myc‐induced hepatocarcinogenesis has been reported to be facilitated by the expression of activated β‐catenin, resulting in the generation of DLK1‐positive hepatoblastoma‐like tumors . We demonstrated here that the combination of HRAS and Myc also induced dedifferentiated tumors with hepatoblastic features, suggesting that Myc plays an essential role in the reprogramming of hepatocytes toward hepatoblastic cells.…”

Down‐regulation of dishevelled‐2 inhibits cell proliferation and invasion in hepatoblastoma

“…Also, it not only downregulated Dvl‐2 expression in a dose‐dependent manner but also inhibited the expression of truncated β‐catenin in HepG2 cells. Like most HBs, HepG2 cells harbor a truncated form of β‐catenin due to significant deletions in β‐catenin exon 3, and this mutant β‐catenin actually contributes to the HB development . Surprisingly, niclosamide could specifically eliminate the mutant β‐catenin.…”

“…Several mechanisms have been proposed for the constitutive activation of canonical Wnt effector β‐catenin in HB, including point mutation or deletion affecting the CTNNB1 gene, loss of function of APC (especially in familial FAP‐related HB) or AXIN1/2 , and other nonmutational mechanisms . The active form of β‐catenin can possibly produce a protumorigenic field for the development of HB . A recent study revealed that the transcriptome of hepatocellular carcinoma (HCC) expressing high levels of JNK1 overlaps with those of HB or HB‐type HCC .…”

“…8 The active form of -catenin can possibly produce a protumorigenic field for the development of HB. 9 A recent study revealed that the transcriptome of hepatocellular carcinoma (HCC) expressing high levels of JNK1 overlaps with those of HB or HB-type HCC. 10 Also, a noncanonical Wnt cascade can activate JNK1 signaling, suggesting a possible link between JNK signaling and HB.…”