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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Hepatocellular Carcinoma | Research

Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish

Authors: Juanjuan Luo, Chunjiao Lu, Meilan Feng, Lu Dai, Maya Wang, Yang Qiu, Huilu Zheng, Yao Liu, Li Li, Bo Tang, Chuan Xu, Yajun Wang, Xiaojun Yang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Liver cancer, mainly hepatocellular carcinoma, is one of the deadliest cancers worldwide and has a poor prognosis due to insufficient understanding of hepatocarcinogenesis. Previous studies have revealed that the mutations in PTEN and TP53 are the two most common genetic events in hepatocarcinogenesis. Here, we illustrated the crosstalk between aberrant Pten and Tp53 pathways during hepatocarcinogenesis in zebrafish.

Methods

We used the CRISPR/Cas9 system to establish several transgenic zebrafish lines with single or double tissue-specific mutations of pten and tp53 to genetically induce liver tumorigenesis. Next, the morphological and histological determination were performed to investigate the roles of Pten and Tp53 signalling pathways in hepatocarcinogenesis in zebrafish.

Results

We demonstrated that Pten loss alone induces hepatocarcinogenesis with only low efficiency, whereas single mutation of tp53 failed to induce tumour formation in liver tissue in zebrafish. Moreover, zebrafish with double mutations of pten and tp53 exhibits a much higher tumour incidence, higher-grade histology, and a shorter survival time than single-mutant zebrafish, indicating that these two signalling pathways play important roles in dynamic biological events critical for the initiation and progression of hepatocarcinogenesis in zebrafish. Further histological and pathological analyses showed significant similarity between the tumours generated from liver tissues of zebrafish and humans. Furthermore, the treatment with MK-2206, a specific Akt inhibitor, effectively suppressed hepatocarcinogenesis in zebrafish.

Conclusion

Our findings will offer a preclinical animal model for genetically investigating hepatocarcinogenesis and provide a useful platform for high-throughput anticancer drug screening.

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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.CrossRefPubMed

Lin DC, Mayakonda A, Dinh HQ, Huang P, Lin L, Liu X, et al. Genomic and epigenomic heterogeneity of hepatocellular carcinoma. Cancer Res. 2017;77(9):2255–65. https://doi.org/10.1158/0008-5472.CAN-16-2822.CrossRefPubMedPubMedCentral

Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin Cancer Res. 2014;20(8):2072–9. https://doi.org/10.1158/1078-0432.CCR-13-0547.CrossRefPubMed

Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301–14. https://doi.org/10.1016/S0140-6736(18)30010-2.CrossRefPubMed

Azmi AN, Chan WK, Goh KL. Sustained complete remission of advanced hepatocellular carcinoma with sorafenib therapy. J Digest Dis. 2015;16(9):537–40. https://doi.org/10.1111/1751-2980.12270.CrossRef

Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127(5):S5–S16. https://doi.org/10.1053/j.gastro.2004.09.011.CrossRefPubMed

Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol. 2012;56(6):1384–91. https://doi.org/10.1016/j.jhep.2011.10.027.CrossRefPubMed

Liu Y, Wu F. Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ Health Perspect. 2010;118(6):818–24. https://doi.org/10.1289/ehp.0901388.CrossRefPubMedPubMedCentral

Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis. 2007;27(1):55–76. https://doi.org/10.1055/s-2006-960171.CrossRefPubMed

10.

Khemlina G, Ikeda S, Kurzrock R. The biology of hepatocellular carcinoma: implications for genomic and immune therapies. Mol Cancer. 2017;16(1):149. https://doi.org/10.1186/s12943-017-0712-x.CrossRefPubMedPubMedCentral

11.

Shen S, Kong J, Qiu Y, Yang X, Wang W, Yan L. Identification of core genes and outcomes in hepatocellular carcinoma by bioinformatics analysis. J Cell Biochem. 2019;120(6):10069–81. https://doi.org/10.1002/jcb.28290.CrossRefPubMed

12.

Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology. 2015;149(5):1226–39. https://doi.org/10.1053/j.gastro.2015.05.061.CrossRefPubMed

13.

Pang R, Tse E, Poon RT. Molecular pathways in hepatocellular carcinoma. Cancer Lett. 2006;240(2):157–69. https://doi.org/10.1016/j.canlet.2005.08.031.CrossRefPubMed

14.

Subbiah IM, Falchook GS, Kaseb AO, Hess KR, Tsimberidou AM, Fu S, et al. Exploring response signals and targets in aggressive unresectable hepatocellular carcinoma: an analysis of targeted therapy phase 1 trials. Oncotarget. 2015;6(29):28453–62. https://doi.org/10.18632/oncotarget.4601.CrossRefPubMedPubMedCentral

15.

Watanabe S, Horie Y, Suzuki A. Hepatocyte-specific Pten-deficient mice as a novel model for nonalcoholic steatohepatitis and hepatocellular carcinoma. Hepatol Res. 2005;33(2):161–6. https://doi.org/10.1016/j.hepres.2005.09.026.CrossRefPubMed

16.

Stiles B, Wang Y, Stahl A, Bassilian S, Lee WP, Kim YJ, et al. Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity. Proc Natl Acad Sci U S A. 2004;101(7):2082–7. https://doi.org/10.1073/pnas.0308617100.CrossRefPubMedPubMedCentral

17.

Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44(6):694–8. https://doi.org/10.1038/ng.2256.CrossRefPubMedPubMedCentral

18.

Takai A, Dang HT, Wang XW. Identification of drivers from cancer genome diversity in hepatocellular carcinoma. Int J Mol Sci. 2014;15(6):11142–60. https://doi.org/10.3390/ijms150611142.CrossRefPubMedPubMedCentral

19.

Qi LN, Bai T, Chen ZS, Wu FX, Chen YY, De Xiang B, et al. The p53 mutation spectrum in hepatocellular carcinoma from Guangxi, China: role of chronic hepatitis B virus infection and aflatoxin B1 exposure. Liver Int. 2015;35(3):999–1009. https://doi.org/10.1111/liv.12460.CrossRefPubMed

20.

Muller PA, Vousden KH. p53 mutations in cancer. Nat Cell Biol. 2013 Jan;15(1):2–8. https://doi.org/10.1038/ncb2641.CrossRefPubMed

21.

Luo X, Zhou N, Wang L, Zeng Q, Tang H. Long noncoding RNA GATA3-AS1 promotes cell proliferation and metastasis in hepatocellular carcinoma by suppression of PTEN, CDKN1A, and TP53. Can J Gastroenterol Hepatol. 2019;2019:1389653.CrossRefPubMedPubMedCentral

22.

Akula SM, Abrams SL, Steelman LS, Emma MR, Augello G, Cusimano A, et al. RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 pathways and regulatory miRs as therapeutic targets in hepatocellular carcinoma. Expert Opin Ther Targets. 2019;23(11):915–29. https://doi.org/10.1080/14728222.2019.1685501.CrossRefPubMed

23.

Amatruda JF, Patton EE. Genetic models of cancer in zebrafish. Int Rev Cell Mol Biol. 2008;271:1–34. https://doi.org/10.1016/S1937-6448(08)01201-X.CrossRefPubMed

24.

Vensen L, Johansen PL, Koster G, Zhu K, Herfindal L, Speth M, et al. Zebrafish as a model system for characterization of nanoparticles against cancer. Nanoscale. 2016;8:862–77.CrossRef

25.

Goessling W, North TE, Zon LI. New waves of discovery: modeling cancer in zebrafish. J Clin Oncol. 2007;25(17):2473–9. https://doi.org/10.1200/JCO.2006.08.9821.CrossRefPubMed

26.

Langenau DM, Traver D, Ferrando AA, Kutok JL, Aster JC, Kanki JP, et al. Myc-induced T cell leukemia in transgenic zebrafish. Science. 2003;299(5608):887–90. https://doi.org/10.1126/science.1080280.CrossRefPubMed

27.

Patton EE, Widlund HR, Kutok JL, Kopani KR, Amatruda JF, Murphey RD, et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol. 2005;15(3):249–54. https://doi.org/10.1016/j.cub.2005.01.031.CrossRefPubMed

28.

Jung IH, Leem GL, Jung DE, Kim MH, Kim EY, Kim SH, et al. Glioma is formed by active Akt1 alone and promoted by active Rac1 in transgenic zebrafish. Neuro-Oncology. 2013;15(3):290–304. https://doi.org/10.1093/neuonc/nos387.CrossRefPubMedPubMedCentral

29.

Amsterdam A, Lai K, Komisarczuk AZ, Becker TS, Bronson RT, Hopkins N, et al. Zebrafish Hagoromo mutants up-regulate fgf8 postembryonically and develop neuroblastoma. Mol Cancer Res. 2009;7(6):841–50. https://doi.org/10.1158/1541-7786.MCR-08-0555.CrossRefPubMedPubMedCentral

30.

Berghmans S, Murphey RD, Wienholds E, Neuberg D, Kutok JL, Fletcher CD, et al. tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors. Proc Natl Acad Sci U S A. 2005;102(2):407–12. https://doi.org/10.1073/pnas.0406252102.CrossRefPubMedPubMedCentral

31.

Li Z, Huang X, Zhan H, Zeng Z, Li C, Spitsbergen JM, et al. Inducible and repressable oncogene-addicted hepatocellular carcinoma in Tet-on xmrk transgenic zebrafish. J Hepatol. 2012;56(2):419–25. https://doi.org/10.1016/j.jhep.2011.07.025.CrossRefPubMed

32.

Li Z, Zheng W, Wang Z, Zeng Z, Zhan H, Li C, et al. A transgenic zebrafish liver tumor model with inducible Myc expression reveals conserved Myc signatures with mammalian liver tumors. Dis Model Mech. 2013;6(2):414–23. https://doi.org/10.1242/dmm.010462.CrossRefPubMed

33.

Nguyen AT, Emelyanov A, Koh CH, Spitsbergen JM, Lam SH, Mathavan S, et al. A high level of liver-specific expression of oncogenic Kras(V12) drives robust liver tumorigenesis in transgenic zebrafish. Dis Model Mech. 2011;4(6):801–13. https://doi.org/10.1242/dmm.007831.CrossRefPubMedPubMedCentral

34.

Kalasekar SM, Kotiyal S, Conley C, Phan C, Young A, Evason KJ. Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish. Biol Open. 2019;8:bio047829.CrossRefPubMedPubMedCentral

35.

Huang SJ, Cheng CL, Chen JR, Gong HY, Liu W, Wu JL. Inducible liver-specific overexpression of gankyrin in zebrafish results in spontaneous intrahepatic cholangiocarcinoma and hepatocellular carcinoma formation. Biochem Biophys Res Commun. 2017;490(3):1052–8. https://doi.org/10.1016/j.bbrc.2017.06.164.CrossRefPubMed

36.

Zheng W, Li Z, Nguyen AT, Li C, Emelyanov A, Gong Z. Xmrk, kras and myc transgenic zebrafish liver cancer models share molecular signatures with subsets of human hepatocellular carcinoma. PLoS One. 2014;9(3):e91179. https://doi.org/10.1371/journal.pone.0091179.CrossRefPubMedPubMedCentral

37.

Liu Y, Qi X, Zeng Z, Wang L, Wang J, Zhang T, et al. CRISPR/Cas9-mediated p53 and Pten dual mutation accelerates hepatocarcinogenesis in adult hepatitis B virus transgenic mice. Sci Rep. 2017;7(1):2796. https://doi.org/10.1038/s41598-017-03070-8.CrossRefPubMedPubMedCentral

38.

Westerfield M. The zebrafish book: a guide for the laboratory use of zebrafish (Danio Rerio). Corvallis: University of Oregon Press; 2007.

39.

Labun K, Montague TG, Krause M, Torres Cleuren YN, Tjeldnes H, Valen E. CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing. Nucleic Acids Res. 2019;47(W1):W171–4. https://doi.org/10.1093/nar/gkz365.CrossRefPubMedPubMedCentral

40.

Padmanabhan A, Lee JS, Ismat FA, Lu MM, Lawson ND, Kanki JP, et al. Cardiac and vascular functions of the zebrafish orthologues of the type I neurofibromatosis gene NFI. Proc Natl Acad Sci U S A. 2009;106(52):22305–10. https://doi.org/10.1073/pnas.0901932106.CrossRefPubMedPubMedCentral

41.

Luo JJ, Bian WP, Liu Y, Huang HY, Yin Q, Yang XJ, et al. CRISPR/Cas9-based genome engineering of zebrafish using a seamless integration strategy. FASEB J. 2018;32(9):5132–42. https://doi.org/10.1096/fj.201800077RR.CrossRefPubMed

42.

Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48900 necropsies. Cancer. 1954;7(3):462–503. https://doi.org/10.1002/1097-0142(195405)7:3<462::AID-CNCR2820070308>3.0.CO;2-E.CrossRefPubMed

43.

Zhou L, Rui JA, Zhou WX, Wang SB, Chen SG, Qu Q. Edmondson-steiner grade: a crucial predictor of recurrence and survival in hepatocellular carcinoma without microvascular invasion. Pathol Res Pract. 2017;213(7):824–30. https://doi.org/10.1016/j.prp.2017.03.002.CrossRefPubMed

44.

Stroescu C, Dragnea A, Ivanov B, Pechianu C, Herlea V, Sgarbura O, et al. Expression of p53, Bcl-2, VEGF, Ki67 and PCNA and prognostic significance in hepatocellular carcinoma. J Gastrointestin Liver Dis. 2008;17(4):411–7.PubMed

45.

Ma S, Yang J, Li J, Song J. The clinical utility of the proliferating cell nuclear antigen expression in patients with hepatocellular carcinoma. Tumor Biol. 2016;37(6):7405–12. https://doi.org/10.1007/s13277-015-4582-9.CrossRef

46.

Yan C, Yang Q, Gong Z. Tumor-associated neutrophils and macrophages promote gender disparity in hepatocellular carcinoma in zebrafish. Cancer Res. 2017;77(6):1395–407. https://doi.org/10.1158/0008-5472.CAN-16-2200.CrossRefPubMed

47.

Deveau H, Garneau JE, Moineau S. CRISPR/Cas system and its role in phage-bacteria interactions. Annu Rev Microbiol. 2010;64(1):475–93. https://doi.org/10.1146/annurev.micro.112408.134123.CrossRefPubMed

48.

Kim HJ, Lee HJ, Kim H, Cho SW, Kim JS. Targeted genome editing in human cells with zinc finger nucleases constructed via modular assembly. Genome Res. 2009;19(7):1279–88. https://doi.org/10.1101/gr.089417.108.CrossRefPubMedPubMedCentral

49.

Ablain J, Durand EM, Yang S, Zhou Y, Zon LI. A CRISPR/Cas9 vector system for tissue-specific gene disruption in zebrafish. Dev Cell. 2015;32(6):756–64. https://doi.org/10.1016/j.devcel.2015.01.032.CrossRefPubMedPubMedCentral

50.

Kawakami K, Takeda H, Kawakami N, Kobayashi M, Matsuda N, Mishina M. A transposon-mediated gene trap approach identifies developmentally regulated genes in zebrafish. Dev Cell. 2004;7(1):133–44. https://doi.org/10.1016/j.devcel.2004.06.005.CrossRefPubMed

51.

Halbig KM, Lekven AC, Kunkel GR. Zebrafish U6 small nuclear RNA gene promoters contain a SPH element in an unusual location. Gene. 2008;421(1-2):89–94. https://doi.org/10.1016/j.gene.2008.06.019.CrossRefPubMed

52.

Urasaki A, Morvan G, Kawakami K. Functional dissection of the Tol2 transposable element identified the minimal cis-sequence and a highly repetitive sequence in the subterminal region essential for transposition. Genetics. 2006;174(2):639–49. https://doi.org/10.1534/genetics.106.060244.CrossRefPubMedPubMedCentral

53.

Menke AL, Spitsbergen JM, Wolterbeek AP, Woutersen RA. Normal anatomy and histology of the adult zebrafish. Toxicol Pathol. 2011;39(5):759–75. https://doi.org/10.1177/0192623311409597.CrossRefPubMed

54.

Lee YR, Chen M, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol. 2018;19(9):547–62. https://doi.org/10.1038/s41580-018-0015-0.CrossRefPubMed

55.

Blackburn JS, Liu S, Wilder JL, Dobrinski KP, Lobbardi R, Moore FE, et al. Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation. Cancer Cell. 2014;25(3):366–78. https://doi.org/10.1016/j.ccr.2014.01.032.CrossRefPubMedPubMedCentral

56.

El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118–27. https://doi.org/10.1056/NEJMra1001683.CrossRefPubMed

57.

Ding J, Wang H. Multiple interactive factors in hepatocarcinogenesis. Cancer Lett. 2014;346(1):17–23. https://doi.org/10.1016/j.canlet.2013.12.024.CrossRefPubMed

58.

Dimri M, Satyanarayana A. Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma. Cancers (Basel). 2020;12:491.CrossRef

59.

Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet. 2012;44(7):760–4. https://doi.org/10.1038/ng.2291.CrossRefPubMed

60.

McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, et al. RB and p53 cooperate to prevent liver tumorigenesis in response to tissue damage. Gastroenterology. 2011;141(4):1439–50. https://doi.org/10.1053/j.gastro.2011.06.046.CrossRefPubMed

61.

Hussain SP, Schwank J, Staib F, Wang XW, Harris CC. TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene. 2007;26(15):2166–76. https://doi.org/10.1038/sj.onc.1210279.CrossRefPubMed

62.

Nishimura T, Kohara M, Izumi K, Kasama Y, Hirata Y, Huang Y, et al. Hepatitis C virus impairs p53 via persistent overexpression of 3beta-hydroxysterol Delta24-reductase. J Biol Chem. 2009;284(52):36442–52. https://doi.org/10.1074/jbc.M109.043232.CrossRefPubMedPubMedCentral

63.

Wang C, Yang W, Yan HX, Luo T, Zhang J, Tang L, et al. Hepatitis B virus X (HBx) induces tumorigenicity of hepatic progenitor cells in 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated HBx transgenic mice. Hepatology. 2012;55(1):108–20. https://doi.org/10.1002/hep.24675.CrossRefPubMed

64.

Cieply B, Zeng G, Proverbs-Singh T, Geller DA, Monga SP. Unique phenotype of hepatocellular cancers with exon-3 mutations in beta-catenin gene. Hepatology. 2009;49(3):821–31. https://doi.org/10.1002/hep.22695.CrossRefPubMed

65.

Hu TH, Huang CC, Lin PR, Chang HW, Ger LP, Lin YW, et al. Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma. Cancer. 2003;97(8):1929–40. https://doi.org/10.1002/cncr.11266.CrossRefPubMed

66.

Khalid A, Hussain T, Manzoor S, Saalim M, Khaliq S. PTEN: a potential prognostic marker in virus-induced hepatocellular carcinoma. Tumour Biol. 2017;39:1010428317705754.CrossRefPubMed

67.

Shearn CT, Petersen DR. Understanding the tumor suppressor PTEN in chronic alcoholism and hepatocellular carcinoma. Adv Exp Med Biol. 2015;815:173–84. https://doi.org/10.1007/978-3-319-09614-8_10.CrossRefPubMed

68.

Zhang J, Xu E, Ren C, Yan W, Zhang M, Chen M, et al. Mice deficient in Rbm38, a target of the p53 family, are susceptible to accelerated aging and spontaneous tumors. Proc Natl Acad Sci U S A. 2014;111(52):18637–42. https://doi.org/10.1073/pnas.1415607112.CrossRefPubMedPubMedCentral

69.

Hanahan D, Weinberg RA. Hallmarks of Cancer: the next generation. Cell. 2011;144(5):646–74. https://doi.org/10.1016/j.cell.2011.02.013.CrossRefPubMed

70.

Stambolic V, Suzuki A, Pompa JL, Brothers GM, Mirtsos C, Sasaki T, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998;95(1):29–39. https://doi.org/10.1016/S0092-8674(00)81780-8.CrossRefPubMed

71.

Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1998;95(26):15587–91. https://doi.org/10.1073/pnas.95.26.15587.CrossRefPubMedPubMedCentral

72.

Hollander MC, Blumethal GM, Dennis PA. PTEN loss in the continuum of common cancers, rare syndromes and mouse model. Nat Rev Cancer. 2011;11(4):289–301. https://doi.org/10.1038/nrc3037.CrossRefPubMedPubMedCentral

73.

Dey N, Crosswell HE, De P, Parsons R, Peng Q, Su JD, et al. The protein phosphatase activity of PTEN regulates SRC family kinases and controls glioma migration. Cancer Res. 2008;68(6):1862–71. https://doi.org/10.1158/0008-5472.CAN-07-1182.CrossRefPubMed

74.

Davidson L, Maccario H, Perera NM, Yang X, Spinelli L, Tibarewal P, et al. Suppression of cellular proliferation and invasion by the concerted lipid and protein phosphatase activities of PTEN. Oncogene. 2010;29(5):687–97. https://doi.org/10.1038/onc.2009.384.CrossRefPubMed

75.

Hlobilkova A, Guldberg P, Thullberg M, Zeuthen J, Lukas J, Bartek J. Cell cycle arrest by the PTEN tumor suppressor is target cell specific and may require protein phosphatase activity. Exp Cell Res. 2000;256(2):571–7. https://doi.org/10.1006/excr.2000.4867.CrossRefPubMed

76.

Manning B, Cantley L. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261–74. https://doi.org/10.1016/j.cell.2007.06.009.CrossRefPubMedPubMedCentral

77.

Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, et al. Two TOR complexs, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell. 2002;10(3):457–68. https://doi.org/10.1016/S1097-2765(02)00636-6.CrossRefPubMed

78.

Song MS, Salmena L, Pandofi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 2012;13(5):283–96. https://doi.org/10.1038/nrm3330.CrossRefPubMed

79.

Namba R, Young LJT, Abbey CK, Kim L, Damonte P, Borowsky AD, et al. Rapamycin inhibits growth of premalignant and malignant mammary lesions in a mouse models of ductal carcinoma in situ. Clin Cancer Res. 2006;12(8):2613–21. https://doi.org/10.1158/1078-0432.CCR-05-2170.CrossRefPubMed

80.

Chiu CW, Nozawa H, Hanahan D. Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis. J Clin Oncol. 2010;28(29):4425–33. https://doi.org/10.1200/JCO.2010.28.0198.CrossRefPubMedPubMedCentral

81.

Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271–81. https://doi.org/10.1056/NEJMoa066838.CrossRefPubMed

82.

Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Cutsem EV, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–23. https://doi.org/10.1056/NEJMoa1009290.CrossRefPubMedPubMedCentral

83.

Aubrey BJ, Strasser A, Kelly GL. Tumor-suppressor functions of the TP53 pathway. Cold Spring Harb Perspect Med. 2016;6(5):a026062. https://doi.org/10.1101/cshperspect.a026062.CrossRefPubMedPubMedCentral

84.

Stracquadanio G, Wang X, Wallace MD, Grawenda AM, Zhang P, Hewitt J. The importance of p53 pathway genetics in inherited and somatic cancer genomes. Nat Rev Cancer. 2016;16(4):251–65. https://doi.org/10.1038/nrc.2016.15.CrossRefPubMedPubMedCentral

85.

Schwaederlé M, Lazar V, Validire P, Hansson J, Lacroix L, Soria JC, et al. VEGF-A expression correlates with TP53 mutations in non-small cell lung cancer: implications for antiangiogenesis therapy. Cancer Res. 2015;75(7):1187–90. https://doi.org/10.1158/0008-5472.CAN-14-2305.CrossRefPubMed

86.

Takai A, Dang HT, Wang XW. Identification of drivers form cancer genome diversity in hepatocellular carcinoma. Int J Mol Sci. 2014;15(6):11142–60. https://doi.org/10.3390/ijms150611142.CrossRefPubMedPubMedCentral

87.

Page JM, Harrison SA. NASH and HCC. Clin Liver Dis. 2009;13(4):631–47. https://doi.org/10.1016/j.cld.2009.07.007.CrossRefPubMed

88.

Wang Q, Yu WN, Chen X, Peng XD, Jeon SM, Birnbaum MJ, et al. Spontaneous hepatocellular carcinoma after the combinaed deletion of Akt isoforms. Cancer Cell. 2016;29(4):523–35. https://doi.org/10.1016/j.ccell.2016.02.008.CrossRefPubMedPubMedCentral

89.

Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7(8):606–19. https://doi.org/10.1038/nrg1879.CrossRefPubMed

90.

Molife LR, Yan L, Vitfell-Rasmussen J, Zernhelt AM, Sullivan DM, Cassier PA, et al. Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors. J Hematol Oncol. 2014;7(1):1. https://doi.org/10.1186/1756-8722-7-1.CrossRefPubMedPubMedCentral

91.

Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol. 2011;29(35):4688–95. https://doi.org/10.1200/JCO.2011.35.5263.CrossRefPubMed

92.

Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501. https://doi.org/10.1038/nrc839.CrossRefPubMed

93.

Sun SY. Enhancing perifosine’s anticancer efficacy by preventing autophagy. Autophagy. 2010;6(1):184–5. https://doi.org/10.4161/auto.6.1.10816.CrossRefPubMed

94.

Gills JJ, Dennis PA. Perfosine: update on a novel Akt inhibitor. Curr Oncol Rep. 2009;11(2):102–10. https://doi.org/10.1007/s11912-009-0016-4.CrossRefPubMedPubMedCentral

95.

Li Z, Tan F, Liewehr DJ, Steinberg SM, Thiele CJ. In vitro and in vivo inhibition of neuroblastoma tumor cell growth by AKT inhibitor perifosine. J Natl Cancer Inst. 2010;102(11):758–70. https://doi.org/10.1093/jnci/djq125.CrossRefPubMedPubMedCentral

96.

Murphy AG, Zahurak M, Shah M, Weekes CD, Hansen A, Sui LL, et al. A phase I study of dinaciclib in combination with MK-2206 in patients with advanced pancreatic cancer. Clin Transl Sci. 2020;13(6):1178–88. https://doi.org/10.1111/cts.12802.CrossRefPubMedPubMedCentral

97.

Ma CX, Sanchez C, Gao F, Crowder R, Naughton M, Pluard T, et al. A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausal women with estrogen receptor-positive metastatic breast cancer. Clin Cancer Res. 2016;22(11):2650–8. https://doi.org/10.1158/1078-0432.CCR-15-2160.CrossRefPubMedPubMedCentral

Title: Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish
Authors: Juanjuan Luo
Chunjiao Lu
Meilan Feng
Lu Dai
Maya Wang
Yang Qiu
Huilu Zheng
Yao Liu
Li Li
Bo Tang
Chuan Xu
Yajun Wang
Xiaojun Yang
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-02061-y

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