Overexpression of TBX3 suppresses tumorigenesis in experimental and human cholangiocarcinoma.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
22 Jun 2024
22 Jun 2024
Historique:
received:
11
11
2023
accepted:
17
06
2024
revised:
12
06
2024
medline:
23
6
2024
pubmed:
23
6
2024
entrez:
22
6
2024
Statut:
epublish
Résumé
TBX3 behaves as a tumor suppressor or oncoprotein across cancer. However, TBX3 function remains undetermined in intrahepatic cholangiocarcinoma (iCCA), a deadly primary liver malignancy with few systemic treatment options. This study sought to investigate the impact of TBX3 on iCCA. We found that overexpression of TBX3 strongly inhibited human iCCA cell growth. In the Akt/FBXW7ΔF mouse iCCA model, overexpression of Tbx3 reduced cholangiocarcinogenesis in vivo, while inducible genetic knockout of Tbx3 accelerated iCCA growth. RNA-seq identified MAD2L1 as a downregulated gene in TBX3-overexpressing cells, and ChIP confirmed that TBX3 binds to the MAD2L1 promoter. CRISPR-mediated knockdown of Mad2l1 significantly reduced the growth of two iCCA models in vivo. Finally, we found that TBX3 expression is upregulated in ~20% of human iCCA samples, and its high expression is associated with less proliferation and better survival. MAD2L1 expression is upregulated in most human iCCA samples and negatively correlated with TBX3 expression. Altogether, our findings suggest that overexpression of TBX3 suppresses CCA progression via repressing MAD2L1 expression.
Identifiants
pubmed: 38909034
doi: 10.1038/s41419-024-06839-8
pii: 10.1038/s41419-024-06839-8
doi:
Substances chimiques
T-Box Domain Proteins
0
TBX3 protein, human
0
Tbx3 protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
441Subventions
Organisme : Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
ID : R01CA228483
Organisme : Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
ID : R01CA239251
Organisme : Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
ID : R01CA250227
Organisme : UC | UC San Francisco | Claude D. Pepper Older Americans Independence Center, University of California San Francisco
ID : P30DK026743
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 82202981
Informations de copyright
© 2024. The Author(s).
Références
Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma—evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15:95–111.
doi: 10.1038/nrclinonc.2017.157
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.
doi: 10.3322/caac.21708
pubmed: 35020204
Yi X, Zhu J, Liu W, Peng L, Lu C, Sun P, et al. Proteome landscapes of human hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Mol Cell Proteomics. 2023:100604.
Kendall T, Verheij J, Gaudio E, Evert M, Guido M, Goeppert B, et al. Anatomical, histomorphological and molecular classification of cholangiocarcinoma. Liver international : official journal of the International Association for the Study of. the Liver. 2019;39:7–18.
Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17:557–88.
doi: 10.1038/s41575-020-0310-z
pubmed: 32606456
pmcid: 7447603
Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise. Oncologist. 2016;21:594–9.
doi: 10.1634/theoncologist.2015-0446
pubmed: 27000463
pmcid: 4861366
Sirica AE, Gores GJ, Groopman JD, Selaru FM, Strazzabosco M, Wei Wang X, et al. Intrahepatic cholangiocarcinoma: continuing challenges and translational advances. Hepatology. 2019;69:1803–15.
doi: 10.1002/hep.30289
pubmed: 30251463
Javle M, Lee S, Azad NS, Borad MJ, Kate Kelley R, Sivaraman S, et al. Temporal changes in cholangiocarcinoma incidence and mortality in the United States from 2001 to 2017. Oncologist. 2022;27:874–83.
doi: 10.1093/oncolo/oyac150
pubmed: 35972334
pmcid: 9526482
Hu LS, Zhang XF, Weiss M, Popescu I, Marques HP, Aldrighetti L, et al. Recurrence patterns and timing courses following curative-intent resection for intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2019;26:2549–57.
doi: 10.1245/s10434-019-07353-4
pubmed: 31020501
Altman AM, Kizy S, Marmor S, Hui JYC, Tuttle TM, Jensen EH, et al. Adjuvant chemotherapy for intrahepatic cholangiocarcinoma: approaching clinical practice consensus? Hepatobiliary Surg Nutr. 2020;9:577–86.
doi: 10.21037/hbsn.2019.06.12
pubmed: 33163508
pmcid: 7603918
Krenzien F, Nevermann N, Krombholz A, Benzing C, Haber P, Fehrenbach U, et al. Treatment of intrahepatic cholangiocarcinoma—a multidisciplinary approach. Cancers. 2022;14.
Moris D, Palta M, Kim C, Allen PJ, Morse MA, Lidsky ME. Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians. CA Cancer J Clin. 2023;73:198–222.
doi: 10.3322/caac.21759
pubmed: 36260350
Yoo C, Hyung J, Chan SL. Recent advances in systemic therapy for advanced intrahepatic cholangiocarcinoma. Liver Cancer. 2023:1.
Cheng CY, Chen CP, Wu CE. Precision medicine in cholangiocarcinoma: past, present, and future. Life (Basel). 2022;12.
Bath NM, Pawlik TM. Narrative review: current management and novel targeted therapies in intrahepatic cholangiocarcinoma. Chin Clin Oncol. 2023;12:5.
doi: 10.21037/cco-22-109
pubmed: 36922354
Khan SF, Damerell V, Omar R, Du Toit M, Khan M, Maranyane HM, et al. The roles and regulation of TBX3 in development and disease. Gene. 2020;726:144223.
doi: 10.1016/j.gene.2019.144223
pubmed: 31669645
Bamshad M, Lin RC, Law DJ, Watkins WC, Krakowiak PA, Moore ME, et al. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet. 1997;16:311–5.
doi: 10.1038/ng0797-311
pubmed: 9207801
Willmer T, Cooper A, Peres J, Omar R, Prince S. The T-Box transcription factor 3 in development and cancer. Biosci Trends. 2017;11:254–66.
doi: 10.5582/bst.2017.01043
pubmed: 28579578
Omar R, Cooper A, Maranyane HM, Zerbini L, Prince S. COL1A2 is a TBX3 target that mediates its impact on fibrosarcoma and chondrosarcoma cell migration. Cancer Lett. 2019;459:227–39.
doi: 10.1016/j.canlet.2019.06.004
pubmed: 31202624
Aliwaini, Lubbad S, Shourfa AM, Hamada HAA A, Ayesh, Abu Tayem HEM B, et al. Overexpression of TBX3 transcription factor as a potential diagnostic marker for breast cancer. Mol Clin Oncol. 2019;10:105–12.
pubmed: 30655984
Liang B, Zhou Y, Qian M, Xu M, Wang J, Zhang Y, et al. TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis. J Hepatol. 2021;75:120–31.
doi: 10.1016/j.jhep.2021.01.044
pubmed: 33577921
pmcid: 8217095
Renard CA, Labalette C, Armengol C, Cougot D, Wei Y, Cairo S, et al. Tbx3 is a downstream target of the Wnt/beta-catenin pathway and a critical mediator of beta-catenin survival functions in liver cancer. Cancer Res. 2007;67:901–10.
doi: 10.1158/0008-5472.CAN-06-2344
pubmed: 17283120
Carlson CM, Frandsen JL, Kirchhof N, McIvor RS, Largaespada DA. Somatic integration of an oncogene-harboring Sleeping Beauty transposon models liver tumor development in the mouse. Proc Natl Acad Sci USA 2005;102:17059–64.
doi: 10.1073/pnas.0502974102
pubmed: 16286660
pmcid: 1287966
Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J, Robertson AG, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 2017;18:2780–94.
doi: 10.1016/j.celrep.2017.02.033
pubmed: 28297679
pmcid: 5493145
Andersen JB, Spee B, Blechacz BR, Avital I, Komuta M, Barbour A, et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology. 2012;142:1021–31.e15.
doi: 10.1053/j.gastro.2011.12.005
pubmed: 22178589
Castro-Mondragon JA, Riudavets-Puig R, Rauluseviciute I, Lemma RB, Turchi L, Blanc-Mathieu R, et al. JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 2022;50:D165–D73.
doi: 10.1093/nar/gkab1113
pubmed: 34850907
Raney BJ, Dreszer TR, Barber GP, Clawson H, Fujita PA, Wang T, et al. Track data hubs enable visualization of user-defined genome-wide annotations on the UCSC Genome Browser. Bioinformatics. 2014;30:1003–5.
doi: 10.1093/bioinformatics/btt637
pubmed: 24227676
Zhang S, Wang J, Wang H, Fan L, Fan B, Zeng B, et al. Hippo cascade controls lineage commitment of liver tumors in mice and humans. Am J Pathol. 2018;188:995–1006.
doi: 10.1016/j.ajpath.2017.12.017
pubmed: 29378174
pmcid: 5866106
Chen X, Calvisi DF. Hydrodynamic transfection for generation of novel mouse models for liver cancer research. Am J Pathol. 2014;184:912–23.
doi: 10.1016/j.ajpath.2013.12.002
pubmed: 24480331
pmcid: 3969989
Wang J, Wang H, Peters M, Ding N, Ribback S, Utpatel K, et al. Loss of Fbxw7 synergizes with activated Akt signaling to promote c-Myc dependent cholangiocarcinogenesis. J Hepatol. 2019;71:742–52.
doi: 10.1016/j.jhep.2019.05.027
pubmed: 31195063
pmcid: 6773530
Fan W, Huang X, Chen C, Gray J, Huang T. TBX3 and its isoform TBX3+2a are functionally distinctive in inhibition of senescence and are overexpressed in a subset of breast cancer cell lines. Cancer Res. 2004;64:5132–9.
doi: 10.1158/0008-5472.CAN-04-0615
pubmed: 15289316
Gao Y, Liu Y, Sun L, Ouyang X, Zhu C, Qin X. MAD2L1 functions as a novel diagnostic and predictive biomarker in cholangiocarcinoma. Genet Test Mol Biomarkers. 2021;25:685–95.
doi: 10.1089/gtmb.2021.0122
pubmed: 34788140
Khosla D, Misra S, Chu PL, Guan P, Nada R, Gupta R, et al. Cholangiocarcinoma: recent advances in molecular pathobiology and therapeutic approaches. Cancers. 2024;16.