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.

TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis / Liang, B.; Zhou, Y.; Qian, M.; Xu, M.; Wang, J.; Zhang, Y.; Song, X.; Wang, H.; Lin, S.; Ren, C.; Monga, S. P.; Wang, B.; Evert, M.; Chen, Y.; Chen, X.; Huang, Z.; Calvisi, D. F.; Chen, X.. - In: JOURNAL OF HEPATOLOGY. - ISSN 0168-8278. - 75:1(2021), pp. 120-131. [10.1016/j.jhep.2021.01.044]

TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis

Calvisi D. F.;
2021-01-01

Abstract

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.
2021
TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis / Liang, B.; Zhou, Y.; Qian, M.; Xu, M.; Wang, J.; Zhang, Y.; Song, X.; Wang, H.; Lin, S.; Ren, C.; Monga, S. P.; Wang, B.; Evert, M.; Chen, Y.; Chen, X.; Huang, Z.; Calvisi, D. F.; Chen, X.. - In: JOURNAL OF HEPATOLOGY. - ISSN 0168-8278. - 75:1(2021), pp. 120-131. [10.1016/j.jhep.2021.01.044]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/277393
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