Liang, Binyong and Zhou, Yi and Qian, Manning and Xu, Meng and Wang, Jingxiao and Zhang, Yi and Song, Xinhua and Wang, Haichuan and Lin, Shumei and Ren, Chuanli and Monga, Satdarshan P. and Wang, Bruce and Evert, Matthias and Chen, Yifa and Chen, Xiaoping and Huang, Zhiyong and Calvisi, Diego F. and Chen, Xin (2021) TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis. JOURNAL OF HEPATOLOGY, 75 (1). pp. 120-131. ISSN 0168-8278, 1600-0641
Full text not available from this repository. (Request a copy)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/beta-catenin pathway and thought to be an oncogene mediating activated beta-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 Delta N90-beta-catenin (c-Met/beta-catenin) in Tbx3(flox/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 Tbx3(flox/flox) mice, we found that ablation of Tbx3 significantly accelerates c-Met/beta-catenin-driven HCC formation. Moreover, Tbx3(-) HCC demonstrated increased YAP/TAZ activity. The accelerated tumor growth induced by loss of TBX3 in c-Met/beta-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/beta-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. (C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | YES-ASSOCIATED PROTEIN; BETA-CATENIN; HEPATOCELLULAR-CARCINOMA; HIPPO PATHWAY; LIVER; INDUCTION; CANCER; INSTABILITY; EXPRESSION; GROWTH; Hepatocellular carcinoma; T-box transcription factor 3; beta-Catenin; HIPPO cascade |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 21 Sep 2022 07:58 |
| Last Modified: | 21 Sep 2022 07:58 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47782 |
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