The Stress-Regulated Transcription Factor CHOP Promotes Hepatic Inflammatory Gene Expression, Fibrosis, and Oncogenesis

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Viral hepatitis, obesity, and alcoholism all represent major risk factors for hepatocellular carcinoma (HCC). Although these conditions also lead to integrated stress response (ISR) or unfolded protein response (UPR) activation, the extent to which these stress pathways influence the pathogenesis of HCC has not been tested. Here we provide multiple lines of evidence demonstrating that the ISR-regulated transcription factor CHOP promotes liver cancer. We show that CHOP expression is up-regulated in liver tumors in human HCC and two mouse models thereof. Chop-null mice are resistant to chemical hepatocarcinogenesis, and these mice exhibit attenuation of both apoptosis and cellular proliferation. Chop-null mice are also resistant to fibrosis, which is a key risk factor for HCC. Global gene expression profiling suggests that deletion of CHOP reduces the levels of basal inflammatory signaling in the liver. Our results are consistent with a model whereby CHOP contributes to hepatic carcinogenesis by promoting inflammation, fibrosis, cell death, and compensatory proliferation. They implicate CHOP as a common contributing factor in the development of HCC in a variety of chronic liver diseases.

Vyšlo v časopise: The Stress-Regulated Transcription Factor CHOP Promotes Hepatic Inflammatory Gene Expression, Fibrosis, and Oncogenesis. PLoS Genet 9(12): e32767. doi:10.1371/journal.pgen.1003937
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003937

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Zdroje

1. CenterMM, JemalA (2011) International trends in liver cancer incidence rates. Cancer Epidemiol Biomarkers Prev 20: 2362–2368.

2. AltekruseSF, McGlynnKA, ReichmanME (2009) Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 27: 1485–1491.

3. El-SeragHB, RudolphKL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132: 2557–2576.

4. ShenC, ZhaoCY, ZhangR, QiaoL (2012) Obesity-related hepatocellular carcinoma: roles of risk factors altered in obesity. Front Biosci 17: 2356–2370.

5. StarleyBQ, CalcagnoCJ, HarrisonSA (2010) Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51: 1820–1832.

6. RutkowskiDT, HegdeRS (2010) Regulation of basal cellular physiology by the homeostatic unfolded protein response. J Cell Biol 189: 783–794.

7. HardingHP, NovoaI, ZhangY, ZengH, WekR, et al. (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6: 1099–1108.

8. WalterP, RonD (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334: 1081–1086.

9. HardingHP, ZhangY, ZengH, NovoaI, LuPD, et al. (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11: 619–633.

10. DongD, NiM, LiJ, XiongS, YeW, et al. (2008) Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res 68: 498–505.

11. AshktorabH, GreenW, FinziG, SessaF, NouraieM, et al. (2012) SEL1L, an UPR response protein, a potential marker of colonic cell transformation. Dig Dis Sci 57: 905–912.

12. SoAY, de la FuenteE, WalterP, ShumanM, BernalesS (2009) The unfolded protein response during prostate cancer development. Cancer Metastasis Rev 28: 219–223.

13. PyrkoP, SchonthalAH, HofmanFM, ChenTC, LeeAS (2007) The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res 67: 9809–9816.

14. BartkowiakK, EffenbergerKE, HarderS, AndreasA, BuckF, et al. (2010) Discovery of a novel unfolded protein response phenotype of cancer stem/progenitor cells from the bone marrow of breast cancer patients. J Proteome Res 9: 3158–3168.

15. Bobrovnikova-MarjonE, GrigoriadouC, PytelD, ZhangF, YeJ, et al. (2010) PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene 29: 3881–3895.

16. ShudaM, KondohN, ImazekiN, TanakaK, OkadaT, et al. (2003) Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 38: 605–614.

17. OyadomariS, MoriM (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11: 381–389.

18. SchonthalAH (2009) Endoplasmic reticulum stress and autophagy as targets for cancer therapy. Cancer Lett 275: 163–169.

19. MoonDO, ParkSY, ChoiYH, AhnJS, KimGY (2011) Guggulsterone sensitizes hepatoma cells to TRAIL-induced apoptosis through the induction of CHOP-dependent DR5: involvement of ROS-dependent ER-stress. Biochem Pharmacol 82: 1641–1650.

20. CrozatA, AmanP, MandahlN, RonD (1993) Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 363: 640–644.

21. RabbittsTH, ForsterA, LarsonR, NathanP (1993) Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat Genet 4: 175–180.

22. PanagopoulosI, HoglundM, MertensF, MandahlN, MitelmanF, et al. (1996) Fusion of the EWS and CHOP genes in myxoid liposarcoma. Oncogene 12: 489–494.

23. DupuyAJ (2010) Transposon-based screens for cancer gene discovery in mouse models. Semin Cancer Biol 20: 261–268.

24. DupuyAJ, RogersLM, KimJ, NannapaneniK, StarrTK, et al. (2009) A modified sleeping beauty transposon system that can be used to model a wide variety of human cancers in mice. Cancer Res 69: 8150–8156.

25. RiordanJD, KengVW, TschidaBR, ScheetzTE, BellJB, et al. (2013) Identification of rtl1, a retrotransposon-derived imprinted gene, as a novel driver of hepatocarcinogenesis. PLoS Genet 9: e1003441.

26. MarciniakSJ, YunCY, OyadomariS, NovoaI, ZhangY, et al. (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18: 3066–3077.

27. OhokaN, YoshiiS, HattoriT, OnozakiK, HayashiH (2005) TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. Embo J 24: 1243–1255.

28. LeeAH, IwakoshiNN, GlimcherLH (2003) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23: 7448–7459.

29. WuJ, RutkowskiDT, DuboisM, SwathirajanJ, SaundersT, et al. (2007) ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell 13: 351–364.

30. ZinsznerH, KurodaM, WangX, BatchvarovaN, LightfootRT, et al. (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12: 982–995.

31. StarkelP, LeclercqIA (2011) Animal models for the study of hepatic fibrosis. Best Pract Res Clin Gastroenterol 25: 319–333.

32. VesselinovitchSD, MihailovichN (1983) Kinetics of diethylnitrosamine hepatocarcinogenesis in the infant mouse. Cancer Res 43: 4253–4259.

33. MaedaS, KamataH, LuoJL, LeffertH, KarinM (2005) IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121: 977–990.

34. BaffyG, BruntEM, CaldwellSH (2012) Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 56: 1384–1391.

35. TamakiN, HatanoE, TauraK, TadaM, KodamaY, et al. (2008) CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am J Physiol Gastrointest Liver Physiol 294: G498–505.

36. MalhiH, KroppEM, ClavoVF, KobrossiCR, HanJ, et al. (2013) C/EBP Homologous Protein-induced Macrophage Apoptosis Protects Mice from Steatohepatitis. J Biol Chem 288: 18624–18642.

37. SakuraiT, MaedaS, ChangL, KarinM (2006) Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci U S A 103: 10544–10551.

38. SunB, KarinM (2012) Obesity, inflammation, and liver cancer. J Hepatol 56: 704–713.

39. ZhengJF, LiangLJ (2008) Intra-portal transplantation of bone marrow stromal cells ameliorates liver fibrosis in mice. Hepatobiliary Pancreat Dis Int 7: 264–270.

40. QiZ, AtsuchiN, OoshimaA, TakeshitaA, UenoH (1999) Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat. Proc Natl Acad Sci U S A 96: 2345–2349.

41. SchifferE, HoussetC, CacheuxW, WendumD, Desbois-MouthonC, et al. (2005) Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology 41: 307–314.

42. JenkinsSA, GrandisonA, BaxterJN, DayDW, TaylorI, et al. (1985) A dimethylnitrosamine-induced model of cirrhosis and portal hypertension in the rat. J Hepatol 1: 489–499.

43. BatallerR, BrennerDA (2005) Liver fibrosis. J Clin Invest 115: 209–218.

44. HanJ, BackSH, HurJ, LinYH, GildersleeveR, et al. (2013) ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 15: 481–490.

45. McCulloughKD, MartindaleJL, KlotzLO, AwTY, HolbrookNJ (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21: 1249–1259.

46. PuthalakathH, O'ReillyLA, GunnP, LeeL, KellyPN, et al. (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129: 1337–1349.

47. ZagorodnaO, MartinSM, RutkowskiDT, KuwanaT, SpitzDR, et al. (2011) 2-Deoxyglucose-induced toxicity is regulated by Bcl-2 family members and is enhanced by antagonizing Bcl-2 in lymphoma cell lines. Oncogene 31: 2738–2749.

48. CanbayA, FriedmanS, GoresGJ (2004) Apoptosis: the nexus of liver injury and fibrosis. Hepatology 39: 273–278.

49. MaassT, SfakianakisI, StaibF, KruppM, GallePR, et al. (2010) Microarray-based gene expression analysis of hepatocellular carcinoma. Curr Genomics 11: 261–268.

50. DaltonLE, HealeyE, IrvingJ, MarciniakSJ (2012) Phosphoproteins in stress-induced disease. Prog Mol Biol Transl Sci 106: 189–221.

51. BiM, NaczkiC, KoritzinskyM, FelsD, BlaisJ, et al. (2005) ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. Embo J 24: 3470–3481.

52. BlaisJD, AddisonCL, EdgeR, FallsT, ZhaoH, et al. (2006) Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress. Mol Cell Biol 26: 9517–9532.

53. AxtenJM, MedinaJR, FengY, ShuA, RomerilSP, et al. (2012) Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem 55: 7193–7207.

54. HardingHP, ZyryanovaAF, RonD (2012) Uncoupling proteostasis and development in vitro with a small molecule inhibitor of the pancreatic endoplasmic reticulum kinase, PERK. J Biol Chem 287: 44338–44344.

55. AdelmantG, GilbertJD, FreytagSO (1998) Human translocation liposarcoma-CCAAT/enhancer binding protein (C/EBP) homologous protein (TLS-CHOP) oncoprotein prevents adipocyte differentiation by directly interfering with C/EBPbeta function. J Biol Chem 273: 15574–15581.

56. ClarkeSL, RobinsonCE, GimbleJM (1997) CAAT/enhancer binding proteins directly modulate transcription from the peroxisome proliferator-activated receptor gamma 2 promoter. Biochem Biophys Res Commun 240: 99–103.

57. BatchvarovaN, WangXZ, RonD (1995) Inhibition of adipogenesis by the stress-induced protein CHOP (Gadd153). Embo J 14: 4654–4661.

58. OcknerRK, KaikausRM, BassNM (1993) Fatty-acid metabolism and the pathogenesis of hepatocellular carcinoma: review and hypothesis. Hepatology 18: 669–676.

59. ChikkaMR, McCabeDD, TyraHM, RutkowskiDT (2013) C/EBP homologous protein (CHOP) contributes to suppression of metabolic genes during endoplasmic reticulum stress in the liver. J Biol Chem 288: 4405–4415.

60. RaskK, ThornM, PontenF, KraazW, SundfeldtK, et al. (2000) Increased expression of the transcription factors CCAAT-enhancer binding protein-beta (C/EBBeta) and C/EBzeta (CHOP) correlate with invasiveness of human colorectal cancer. Int J Cancer 86: 337–343.

61. DaltonLE, ClarkeHJ, KnightJ, LawsonMH, WasonJ, et al. (2013) The endoplasmic reticulum stress marker CHOP predicts survival in malignant mesothelioma. Br J Cancer 108: 1340–1347.

62. ScaiewiczV, NahmiasA, ChungRT, MuellerT, TiroshB, et al. (2013) CCAAT/Enhancer-Binding Protein omologous (CHOP) Protein Promotes Carcinogenesis in the DEN-Induced Hepatocellular Carcinoma Model. PLoS ONE 8(12): e81065 doi:10.1371/journal.pone.0081065

63. RutkowskiDT, ArnoldSM, MillerCN, WuJ, LiJ, et al. (2006) Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol 4: e374.