TGF-β Signaling Alters the Pattern of Liver Tumorigenesis Induced by Pten Inactivation

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2014 Aug 19

PMID 25132272

Citations 11

Authors

S M Morris

K T Carter

J Y Baek

A Koszarek

M M Yeh

S E Knoblaugh

W M Grady

Affiliations

Soon will be listed here.

Abstract

Hepatocarcinogenesis results from the accumulation of genetic and epigenetic changes in liver cells. A common mechanism through which these alterations induce liver cancer is by deregulating signaling pathways. A number of signaling pathways, including the PI3K/PTEN/AKT and transforming growth factor β (TGF-β) pathways have been implicated in normal liver development as well as in cancer formation. In this study, we assessed the effect of the TGF-β signaling pathway on liver tumors induced by phosphatase and tensin homolog (Pten) loss. Inactivation of only the TGF-β receptor type II, Tgfbr2, in the mouse liver (Tgfbr2(LKO)) had no overt phenotype, while inactivation of Pten alone (Pten(LKO)), resulted in the formation of both hepatocellular carcinomas and cholangiocarcinomas (CC). Interestingly, deletion of both Pten and Tgfbr2 (Pten(LKO);Tgfbr2(LKO)) in the mouse liver resulted in a dramatic shift in tumor type to predominantly CC. Assessment of the PI3K/PTEN/AKT pathway revealed increased phosphorylation of AKT and glycogen synthase kinase 3 beta (GSK-3β) in both the Pten(LKO) and Pten(LKO);Tgfbr2(LKO) mice, suggesting that this pathway is constitutively active regardless of the status of the TGF-β signaling pathway. However, phosphorylation of p70 S6 kinase was observed in the liver of all three phenotypes (Tgfbr2(LKO), Pten(LKO), Pten(LKO);Tgfbr2(LKO)) indicating that the loss of Tgfbr2 and/or Pten leads to an increase in this signaling pathway. Analysis of markers of liver progenitor/stem cells revealed that the loss of TGF-β signaling resulted in increased expression of c-Kit and CD133. Furthermore, in addition to increased c-Kit and CD133, Scf and EpCam expression were also increased in the double knock-out mice. These results suggest that the alteration in tumor types between the Pten(LKO) mice and Pten(LKO);Tgfbr2(LKO) mice is secondary to the altered regulation of stem-cell features induced by the loss of TGF-β signaling.

Citing Articles

Cell Plasticity and Prostate Cancer: The Role of Epithelial-Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance.

Papanikolaou S, Vourda A, Syggelos S, Gyftopoulos K Cancers (Basel). 2021; 13(11).

PMID: 34199763 PMC: 8199975. DOI: 10.3390/cancers13112795.

Withaferin A inhibits proliferation of human endometrial cancer cells via transforming growth factor-β (TGF-β) signalling.

Xu K, Shi H, Du Y, Ou J 3 Biotech. 2021; 11(7):323.

PMID: 34194907 PMC: 8192617. DOI: 10.1007/s13205-021-02878-6.

Long-Term Infection Switches Gastric Epithelium Reprogramming Towards Cancer Stem Cell-Related Differentiation Program in -Activated Gastric Fibroblast-TGFβ Dependent Manner.

Krzysiek-Maczka G, Targosz A, Szczyrk U, Wrobel T, Strzalka M, Brzozowski T Microorganisms. 2020; 8(10).

PMID: 33023180 PMC: 7599721. DOI: 10.3390/microorganisms8101519.

Identification of miR-135b as a novel regulator of TGFβ pathway in gastric cancer.

Bai M, Wang P, Yang J, Zuo M, Ba Y J Physiol Biochem. 2020; 76(4):549-560.

PMID: 32737704 DOI: 10.1007/s13105-020-00759-9.

A Transforming Growth Factor-β and H19 Signaling Axis in Tumor-Initiating Hepatocytes That Regulates Hepatic Carcinogenesis.

Zhang J, Han C, Ungerleider N, Chen W, Song K, Wang Y Hepatology. 2018; 69(4):1549-1563.

PMID: 30014520 PMC: 6335184. DOI: 10.1002/hep.30153.

References

Morris S, Baek J, Koszarek A, Kanngurn S, Knoblaugh S, Grady W . Transforming growth factor-beta signaling promotes hepatocarcinogenesis induced by p53 loss. Hepatology. 2011; 55(1):121-31. PMC: 3237853. DOI: 10.1002/hep.24653. View

Bierie B, Moses H . TGF-beta and cancer. Cytokine Growth Factor Rev. 2005; 17(1-2):29-40. DOI: 10.1016/j.cytogfr.2005.09.006. View

Yamashita T, Wang X . Cancer stem cells in the development of liver cancer. J Clin Invest. 2013; 123(5):1911-8. PMC: 3635728. DOI: 10.1172/JCI66024. View

Hollander M, Blumenthal G, Dennis P . PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer. 2011; 11(4):289-301. PMC: 6946181. DOI: 10.1038/nrc3037. View

Lesche R, Groszer M, Gao J, Wang Y, Messing A, Sun H . Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. Genesis. 2002; 32(2):148-9. DOI: 10.1002/gene.10036. View

Shi Y, Paluch B, Wang X, Jiang X . PTEN at a glance. J Cell Sci. 2012; 125(Pt 20):4687-92. PMC: 3517091. DOI: 10.1242/jcs.093765. View

Kitisin K, Ganesan N, Tang Y, Jogunoori W, Volpe E, Kim S . Disruption of transforming growth factor-beta signaling through beta-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation. Oncogene. 2007; 26(50):7103-10. PMC: 4211268. DOI: 10.1038/sj.onc.1210513. View

Forbes S, Bhamra G, Bamford S, Dawson E, Kok C, Clements J . The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr Protoc Hum Genet. 2008; Chapter 10:Unit 10.11. PMC: 2705836. DOI: 10.1002/0471142905.hg1011s57. View

Chytil A, Magnuson M, Wright C, Moses H . Conditional inactivation of the TGF-beta type II receptor using Cre:Lox. Genesis. 2002; 32(2):73-5. DOI: 10.1002/gene.10046. View

10.

Hu T, Huang C, Lin P, Chang H, Ger L, Lin Y . Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma. Cancer. 2003; 97(8):1929-40. DOI: 10.1002/cncr.11266. View

11.

Whittaker S, Marais R, Zhu A . The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene. 2010; 29(36):4989-5005. DOI: 10.1038/onc.2010.236. View

12.

Mansuroglu T, Baumhoer D, Dudas J, Haller F, Cameron S, Lorf T . Expression of stem cell factor receptor c-kit in human nontumoral and tumoral hepatic cells. Eur J Gastroenterol Hepatol. 2009; 21(10):1206-11. DOI: 10.1097/MEG.0b013e328317f4ef. View

13.

Yao Y, Ping X, Zhang H, Chen F, Lee P, Ahsan H . PTEN/MMAC1 mutations in hepatocellular carcinomas. Oncogene. 1999; 18(20):3181-5. DOI: 10.1038/sj.onc.1202659. View

14.

Stiles B, Wang Y, Stahl A, Bassilian S, Lee W, Kim Y . Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. Proc Natl Acad Sci U S A. 2004; 101(7):2082-7. PMC: 357055. DOI: 10.1073/pnas.0308617100. View

15.

Chalhoub N, Baker S . PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol. 2008; 4:127-50. PMC: 2710138. DOI: 10.1146/annurev.pathol.4.110807.092311. View

16.

Singal A, Vauthey J, Grady J, Stroehlein J . Intra-hepatic cholangiocarcinoma--frequency and demographic patterns: thirty-year data from the M.D. Anderson Cancer Center. J Cancer Res Clin Oncol. 2011; 137(7):1071-8. DOI: 10.1007/s00432-010-0971-z. View

17.

Thoolen B, Maronpot R, Harada T, Nyska A, Rousseaux C, Nolte T . Proliferative and nonproliferative lesions of the rat and mouse hepatobiliary system. Toxicol Pathol. 2010; 38(7 Suppl):5S-81S. DOI: 10.1177/0192623310386499. View

18.

Postic C, Shiota M, Niswender K, Jetton T, Chen Y, Moates J . Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem. 1998; 274(1):305-15. DOI: 10.1074/jbc.274.1.305. View

19.

Chen C, Tsukamoto H, Liu J, Kashiwabara C, Feldman D, Sher L . Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells. J Clin Invest. 2013; 123(7):2832-49. PMC: 3696549. DOI: 10.1172/JCI65859. View

20.

Fabregat I . Dysregulation of apoptosis in hepatocellular carcinoma cells. World J Gastroenterol. 2009; 15(5):513-20. PMC: 2653340. DOI: 10.3748/wjg.15.513. View