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TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis
Binyong Liang1, Yi Zhou2, Manning Qian3
1Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA.
Background & Aims:
Gain of function (GOF) mutations in the CTNNB1 gene are one of the most frequent genetic events in hepatocellular carcinoma (HCC). T-box transcription factor 3 (TBX3) is a liver-specific target of the Wnt/β-catenin pathway and thought to be an oncogene mediating activated β-catenin-driven HCC formation.
Methods:
We evaluated the expression pattern of TBX3 in human HCC specimens. Tbx3 was conditionally knocked out in murine HCC models by hydrodynamic tail vein injection of Cre together with c-Met and ΔN90-β-catenin (c-Met/β-catenin) in Tbx3flox/flox mice. TBX3 was overexpressed in human HCC cell lines to investigate the functions of TBX3 in vitro.
Results:
A bimodal expression pattern of TBX3 in human HCC samples was detected: high expression of TBX3 in GOF CTNNB1 HCC and downregulation of TBX3 in non-CTNNB1 mutant tumors. High expression of TBX3 was associated with increased differentiation and decreased expression signatures of tumor growth. Using Tbx3flox/flox mice, we found that ablation of Tbx3 significantly accelerates c-Met/β-catenin-driven HCC formation. Moreover, Tbx3(-) HCC demonstrated increased YAP/TAZ activity. The accelerated tumor growth induced by loss of TBX3 in c-Met/β-catenin mouse HCC was successfully prevented by overexpression of LATS2, which inhibited YAP/TAZ activity. In human HCC cell lines, overexpression of TBX3 inhibited HCC cell growth as well as YAP/TAZ activation. A negative correlation between TBX3 and YAP/TAZ target genes was observed in human HCC samples. Mechanistically, phospholipase D1 (PLD1), a known positive regulator of YAP/TAZ, was identified as a novel transcriptional target repressed by TBX3.
Conclusion:
Our study suggests that TBX3 is induced by GOF CTNNB1 mutants and suppresses HCC growth by inactivating PLD1, thus leading to the inhibition of YAP/TAZ oncogenes.
Lay Summary:
TBX3 is a liver-specific target of the Wnt/β-catenin pathway and thought to be an oncogene in promoting liver cancer development. Herein, we demonstrate that TBX3 is in fact a tumor suppressor gene that restricts liver tumor growth. Strategies which increase TBX3 expression and/or activities may be effective for HCC treatment.
Insights
T-box transcription factor 3 (TBX3) suppresses hepatocellular carcinoma (HCC) growth by inhibiting YAP/TAZ activity, contrary to previous assumptions. Increasing TBX3 may offer a new therapeutic strategy for HCC treatment.
Area of Science:
- Hepatocellular Carcinoma Research
- Molecular Oncology
- Signal Transduction
Background:
- Gain of function (GOF) mutations in CTNNB1 are common in hepatocellular carcinoma (HCC).
- T-box transcription factor 3 (TBX3) was previously thought to be an oncogene in HCC, driven by the Wnt/β-catenin pathway.
- This study re-evaluates the role of TBX3 in HCC development.
Purpose of the Study:
- To investigate the expression pattern and function of TBX3 in human HCC.
- To determine the relationship between TBX3 and the Wnt/β-catenin pathway in HCC.
- To elucidate the mechanism by which TBX3 influences HCC growth and signaling pathways.
Main Methods:
- TBX3 expression was analyzed in human HCC specimens and cell lines.
- Conditional knockout of Tbx3 was performed in murine HCC models.
- Overexpression of TBX3 and LATS2 was used to investigate functional effects in vitro.
- YAP/TAZ activity and phospholipase D1 (PLD1) expression were assessed.
Main Results:
- TBX3 exhibited bimodal expression in HCC: high in CTNNB1-mutant HCC, downregulated in others.
- Loss of TBX3 accelerated c-Met/β-catenin-driven HCC formation in mice, increasing YAP/TAZ activity.
- Overexpression of TBX3 inhibited HCC cell growth and YAP/TAZ activation in vitro.
- TBX3 was found to repress PLD1, a positive regulator of YAP/TAZ.
Conclusions:
- TBX3 acts as a tumor suppressor in HCC, induced by CTNNB1 mutations.
- TBX3 suppresses HCC growth by inhibiting PLD1 and consequently YAP/TAZ oncogenes.
- Strategies to enhance TBX3 expression or activity could be beneficial for HCC treatment.
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