Using data from The Cancer Genome Atlas, from the LIRI-JP (Liver Cancer - RIKEN, JP project), and from our transcriptomic, transfection and mouse transgenic experiments, we identify a GRN which functionally links LIN28B-dependent dedifferentiation with dysfunction of β-catenin (CTNNB1).
The liver cancer-specific signature 16, associated with alcohol, displays a unique feature of transcription-coupled damage and is the main source of CTNNB1 mutations.
Knockout of ASIC1a by CRISPR/CAS9 inhibited liver cancer cell proliferation and tumorigenicity in vitro and in vivo through β-catenin degradation and LEF-TCF inactivation.
Furthermore, using TOPflash and reverse transcription‑quantitative polymerase chain reaction analysis, Wnt/β‑catenin signaling and the transcriptional regulation of Wnt/β‑catenin target genes including dickkopf Wnt signaling pathway inhibitor 1, axis inhibition protein 2 and cyclin D1 were observed to be markedly upregulated in liver cancer SP cells.
Consistent with its enrichment for CTNNB1 mutations (69%), lncRNA profile of the CTNNB1-enriched EEC subgroup was highly similar to that of the CTNNB1-enriched liver cancer subgroup.
Aberrant β-catenin activation contributes to a third or more of human hepatocellular carcinoma (HCC), but β-catenin activation alone is not sufficient to induce liver cancer in mice.
Aberrant activation of the Wnt/β-catenin pathway is a major and frequent event in liver cancer, but inhibition of oncogenic β-catenin signaling has proven challenging.
We used immunohistochemical analysis to determine expression of β-catenin and Yap1 in liver cancer specimens collected from patients in Europe and the United States, consisting of 104 hepatocellular carcinoma, 62 intrahepatic cholangiocarcinoma, and 94 hepatoblastoma samples.
These results validate β-catenin as a target for liver cancer therapy and demonstrate the promise of RNAi in general and DsiRNAs in particular for reaching traditionally undruggable cancer targets.