Abstract
The transforming growth factor beta (TGF-β) signaling pathway plays important roles in cell differentiation, stem cell modulation, organ lineage, and immune suppression. TGF-β signaling is negatively regulated by the ubiquitin–proteasome pathway. Although mouse models of cancer arising from a defective TGF-β pathway clearly demonstrate the tumor-suppressive role of TGF-β, the underlying mechanism by which a defective TGF-β pathway triggers liver cancer development is poorly understood. This review summarizes key findings from our recent studies connecting TGF-β to hepatic oncogenesis and highlights the vulnerability of TGF-β signaling to PJA1-mediated ubiquitination. TGF-β, together with the chromatin insulator CCCTC-binding factor (CTCF), epigenetically and transcriptionally regulate tumor promoter genes, including IGF2 and TERT, in TGF-β–defective mice and in human liver cancers. Dysfunction of the TGF-β–regulated SPTBN1/SMAD3/CTCF complex increases stem cell–like properties in hepatocellular carcinoma (HCC) cells and enhances tumorigenesis in tumor-initiating cells in a mouse model. PJA1, a novel E3 ubiquitin ligase, is a key negative regulator of TGF-β signaling. PJA1 overexpression is detected in HCCs and is sufficient to suppress SMAD3- and SPTBN1-mediated TGF-β tumor suppressor signaling, promoting HCC proliferation. Dysregulated PJA1-TGF-β signaling activates oncogenic genes and promotes tumorigenesis in human liver cancers. In addition, inhibition of PJA1 by treatment with E3 ligase inhibitors restores TGF-β tumor-suppressor function and suppresses liver cancer progression. These new findings suggest potential therapeutic avenues for targeting dysregulated PJA1-TGF-β signaling via cancer stem cells in liver cancers.
Highlights
Hepatocellular carcinoma (HCC) is the solid tumor type with the fastest-rising incidence in the United States as well as the second-leading cause of cancer-related death worldwide [1, 2]
We previously showed that disruptions in TGF-β signaling, coupled with loss of the SMAD adaptor SPTBN1, resulted in the spontaneous development of multiple tumors and a high incidence of liver cancer in human fibroblast and mouse models [20]
There was a negative correlation between TGF-β pathway activity and stem cell–like character. These results indicate that impairment of TGF-β signaling may contribute to cancer stem cell–associated HCC development [22, 23]
Summary
Hepatocellular carcinoma (HCC) is the solid tumor type with the fastest-rising incidence in the United States as well as the second-leading cause of cancer-related death worldwide [1, 2]. We previously showed that disruptions in TGF-β signaling, coupled with loss of the SMAD adaptor SPTBN1, resulted in the spontaneous development of multiple tumors and a high incidence of liver cancer in human fibroblast and mouse models [20]. Dysfunction of the TGF-β–regulated SPTBN1/SMAD3/CTCF complex increases stem cell–like properties in HCC cells and enhances tumorigenesis in tumor-initiating cells in a mouse model (Figure 1) [20].
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