nach oben

Erschienen in:

28.05.2019 | Original Article

Alteration of splicing factors’ expression during liver disease progression: impact on hepatocellular carcinoma outcome

verfasst von: Hualin Wang, Bouchra Lekbaby, Nadim Fares, Jeremy Augustin, Tarik Attout, Aurelie Schnuriger, Anne-Marie Cassard, Ganna Panasyuk, Gabriel Perlemuter, Ivan Bieche, Sophie Vacher, Janick Selves, Jean-Marie Péron, Brigitte Bancel, Philippe Merle, Dina Kremsdorf, Janet Hall, Isabelle Chemin, Patrick Soussan

Erschienen in: Hepatology International | Ausgabe 4/2019

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Trans-acting splicing factors (SF) shape the eukaryotic transcriptome by regulating alternative splicing (AS). This process is recurrently modulated in liver cancer suggesting its direct contribution to the course of liver disease. The aim of our study was to investigate the relationship between the regulation of SFs expression and liver damage.

Methods

The expression profile of 10 liver-specific SF and the AS events of 7 genes associated with liver disorders was assessed by western-blotting in 6 murine models representing different stages of liver damage, from inflammation to hepatocellular carcinoma (HCC). Relevant SFs (PSF, SRSF3, and SRSF6) and target genes (INSR, SRSF3, and SLK) modulated in mice were investigated in a cohort of 179 HCC patients.

Results

Each murine model of liver disease was characterized by a unique SF expression profile. Changes in the SF profile did not affect AS events of the selected genes despite the presence of corresponding splicing sites. In human HCC expression of SFs, including the tumor-suppressor SRSF3, and AS regulation of genes studied were frequently upregulated in tumor versus non-tumor tissues. Risk of tumor recurrence positively correlated with AS isoform of the INSR gene. In contrast, increased levels of SFs expression correlated with an extended overall survival of patients.

Conclusions

Dysregulation of SF expression is an early event occurring during liver injury and not just at the stage of HCC. Besides impacting on AS regulation, overexpression of SF may contribute to preserving hepatocyte homeostasis during liver pathogenesis.

Nur mit Berechtigung zugänglich

Pohl M, Bortfeldt RH, Grutzmann K, Schuster S. Alternative splicing of mutually exclusive exons—a review. Biosystems 2013;114:31–38CrossRefPubMed

Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 2008;40:1413–1415CrossRefPubMed

Tress ML, Abascal F, Valencia A. Most alternative isoforms are not functionally important. Trends Biochem Sci 2017;42:408–410CrossRefPubMedPubMedCentral

Tress ML, Abascal F, Valencia A. Alternative splicing may not be the key to proteome complexity. Trends Biochem Sci 2017;42:98–110CrossRefPubMed

Grosso AR, Gomes AQ, Barbosa-Morais NL, Caldeira S, Thorne NP, Grech G, et al. Tissue-specific splicing factor gene expression signatures. Nucleic Acids Res 2008;36:4823–4832CrossRefPubMedPubMedCentral

Lee BP, Pilling LC, Emond F, Flurkey K, Harrison DE, Yuan R, et al. Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans. Aging Cell 2016;15:903–913CrossRefPubMedPubMedCentral

de la Grange P, Gratadou L, Delord M, Dutertre M, Auboeuf D. Splicing factor and exon profiling across human tissues. Nucleic Acids Res 2010;38:2825–2838CrossRefPubMedPubMedCentral

Berasain C, Goni S, Castillo J, Latasa MU, Prieto J, Avila MA. Impairment of pre-mRNA splicing in liver disease: mechanisms and consequences. World J Gastroenterol 2010;16:3091–3102CrossRefPubMedPubMedCentral

Venables JP. Aberrant and alternative splicing in cancer. Cancer Res 2004;64:7647–7654CrossRefPubMed

10.

Li S, Hu Z, Zhao Y, Huang S, He X. Transcriptome-wide analysis reveals the landscape of aberrant alternative splicing events in liver cancer. Hepatology 2019;69:359–375CrossRefPubMed

11.

Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 2007;14:185–193CrossRefPubMedPubMedCentral

12.

Sen S, Langiewicz M, Jumaa H, Webster NJ. Deletion of serine/arginine-rich splicing factor 3 in hepatocytes predisposes to hepatocellular carcinoma in mice. Hepatology 2015;61:171–183CrossRefPubMed

13.

Sen S, Jumaa H, Webster NJ. Splicing factor SRSF3 is crucial for hepatocyte differentiation and metabolic function. Nat Commun 2013;4:1336CrossRefPubMedPubMedCentral

14.

Karni R, Hippo Y, Lowe SW, Krainer AR. The splicing-factor oncoprotein SF2/ASF activates mTORC1. Proc Natl Acad Sci USA 2008;105:15323–15327CrossRefPubMed

15.

Duriez M, Mandouri Y, Lekbaby B, Wang H, Redelsperger F, Guerrera C, et al. Alternative splicing of Hepatitis B virus: a novel virus/host interaction regulating liver immunity. J Hepatol 2017;67:687–699CrossRefPubMedPubMedCentral

16.

Pol JG, Lekbaby B, Redelsperger F, Klamer S, Mandouri Y, Ahodantin J, et al. Alternative splicing-regulated protein of hepatitis B virus hacks the TNF-alpha-stimulated signaling pathways and limits the extent of liver inflammation. FASEB J 2015;29:1879–1889CrossRefPubMed

17.

Gustot T, Lemmers A, Moreno C, Nagy N, Quertinmont E, Nicaise C, et al. Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. Hepatology 2006;43:989–1000CrossRefPubMed

18.

Ki SH, Park O, Zheng M, Morales-Ibanez O, Kolls JK, Bataller R, et al.. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology 2010;52:1291–1300CrossRefPubMedPubMedCentral

19.

Bertola A, Mathews S, Ki SH, Wang H, Gao B. Mouse model of chronic and binge ethanol feeding (the NIAAA model). Nat Protoc 2013;8:627–637CrossRefPubMedPubMedCentral

20.

Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 2004;113:1774–1783CrossRefPubMedPubMedCentral

21.

Patitucci C, Couchy G, Bagattin A, Caneque T, de Reynies A, Scoazec JY, et al. Hepatocyte nuclear factor 1alpha suppresses steatosis-associated liver cancer by inhibiting PPARgamma transcription. J Clin Invest 2017;127:1873–1888CrossRefPubMedPubMedCentral

22.

Shav-Tal Y, Lee B, Bar-Haim S, Vandekerckhove J, Zipori D. Enhanced proteolysis of pre-mRNA splicing factors in myeloid cells. Exp Hematol 2000;28:1029–1038CrossRefPubMed

23.

de la Grange P, Dutertre M, Correa M, Auboeuf D. A new advance in alternative splicing databases: from catalogue to detailed analysis of regulation of expression and function of human alternative splicing variants. BMC Bioinform 2007;8:180CrossRef

24.

Bhate A, Parker DJ, Bebee TW, Ahn J, Arif W, Rashan EH, et al. ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation. Nat Commun 2015;6:8768CrossRefPubMedPubMedCentral

25.

Huang CK, Yu T, de la Monte SM, Wands JR, Derdak Z, Kim M. Restoration of Wnt/beta-catenin signaling attenuates alcoholic liver disease progression in a rat model. J Hepatol 2015;63:191–198CrossRefPubMedPubMedCentral

26.

Zhao Y, Gao L, Xu L, Tong R, Lin N, Su Y, et al. Ubiquitin-specific protease 4 is an endogenous negative regulator of metabolic dysfunctions in nonalcoholic fatty liver disease. Hepatology 2018. https://doi.org/10.1002/hep.29889 CrossRefPubMedPubMedCentral

27.

Heljasvaara R, Aikio M, Ruotsalainen H, Pihlajaniemi T. Collagen XVIII in tissue homeostasis and dysregulation—lessons learned from model organisms and human patients. Matrix Biol 2017;57–58:55–75CrossRefPubMed

28.

Aikio M, Elamaa H, Vicente D, Izzi V, Kaur I, Seppinen L, et al. Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition. Proc Natl Acad Sci USA 2014;111:3043–3052CrossRef

29.

Chettouh H, Fartoux L, Aoudjehane L, Wendum D, Claperon A, Chretien Y, et al. Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors. Cancer Res 2013;73:3974–3986CrossRefPubMed

30.

Sakurai Y, Kubota N, Takamoto I, Obata A, Iwamoto M, Hayashi T, et al. Role of insulin receptor substrates in the progression of hepatocellular carcinoma. Sci Rep 2017;7:5387CrossRefPubMedPubMedCentral

31.

Kubota T, Kubota N, Kadowaki T. Imbalanced insulin actions in obesity and type 2 diabetes: key mouse models of insulin signaling pathway. Cell Metab 2017;25:797–810CrossRefPubMed

32.

Paz I, Akerman M, Dror I, Kosti I, Mandel-Gutfreund Y. SFmap: a web server for motif analysis and prediction of splicing factor binding sites. Nucleic Acids Res 2010;38:281–285CrossRef

33.

Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2016;2:16018CrossRefPubMed

34.

Kozlovski I, Siegfried Z, Amar-Schwartz A, Karni R. The role of RNA alternative splicing in regulating cancer metabolism. Hum Genet 2017;26:1113–1127CrossRef

35.

Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 2009;30:586–623CrossRefPubMed

36.

Chen YW, Boyartchuk V, Lewis BC. Differential roles of insulin-like growth factor receptor- and insulin receptor-mediated signaling in the phenotypes of hepatocellular carcinoma cells. Neoplasia 2009;11:835–845CrossRefPubMedPubMedCentral

37.

Besic V, Shi H, Stubbs RS, Hayes MT. Aberrant liver insulin receptor isoform a expression normalises with remission of type 2 diabetes after gastric bypass surgery. PLoS One 2015;10:e0119270CrossRefPubMedPubMedCentral

38.

Braeutigam C, Rago L, Rolke A, Waldmeier L, Christofori G, Winter J. The RNA-binding protein Rbfox2: an essential regulator of EMT-driven alternative splicing and a mediator of cellular invasion. Oncogene 2014;33:1082–1092CrossRefPubMed

39.

Warzecha CC, Jiang P, Amirikian K, Dittmar KA, Lu H, Shen S, et al. An ESRP-regulated splicing programme is abrogated during the epithelial-mesenchymal transition. EMBO J 2010;29:3286–3300CrossRefPubMedPubMedCentral

40.

Jumaa H, Nielsen PJ. The splicing factor SRp20 modifies splicing of its own mRNA and ASF/SF2 antagonizes this regulation. EMBO J 1997;16:5077–5085.CrossRefPubMedPubMedCentral

41.

Takayama KI, Suzuki T, Fujimura T, Yamada Y, Takahashi S, Homma Y, et al. Dysregulation of spliceosome gene expression in advanced prostate cancer by RNA-binding protein PSF. Proc Natl Acad Sci USA 2017;114:10461–10466CrossRefPubMed

42.

Jaafar L, Li Z, Li S, Dynan WS. SFPQ*NONO and XLF function separately and together to promote DNA double-strand break repair via canonical nonhomologous end joining. Nucleic Acids Res 2017;45:1848–1859CrossRefPubMed

43.

Morozumi Y, Takizawa Y, Takaku M, Kurumizaka H. Human PSF binds to RAD51 and modulates its homologous-pairing and strand-exchange activities. Nucleic Acids Res 2009;37:4296–4307CrossRefPubMedPubMedCentral

Titel: Alteration of splicing factors’ expression during liver disease progression: impact on hepatocellular carcinoma outcome
verfasst von: Hualin Wang
Bouchra Lekbaby
Nadim Fares
Jeremy Augustin
Tarik Attout
Aurelie Schnuriger
Anne-Marie Cassard
Ganna Panasyuk
Gabriel Perlemuter
Ivan Bieche
Sophie Vacher
Janick Selves
Jean-Marie Péron
Brigitte Bancel
Philippe Merle
Dina Kremsdorf
Janet Hall
Isabelle Chemin
Patrick Soussan
Publikationsdatum: 28.05.2019
Verlag: Springer India
Erschienen in: Hepatology International / Ausgabe 4/2019
Print ISSN: 1936-0533
Elektronische ISSN: 1936-0541
DOI: https://doi.org/10.1007/s12072-019-09950-7

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

24.04.2024 | DGIM 2024 | Kongressbericht | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Alteration of splicing factors’ expression during liver disease progression: impact on hepatocellular carcinoma outcome

Abstract

Purpose

Methods

Results

Conclusions

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2019

Hepatology through the crystal ball

Prediction and clinical implications of HBV reactivation in lymphoma patients with resolved HBV infection: focus on anti-HBs and anti-HBc antibody titers

Prognostic subclass of intrahepatic cholangiocarcinoma by integrative molecular–clinical analysis and potential targeted approach

Bacteroides in colonic mucosa-associated microbiota affects the development of minimal hepatic encephalopathy in patients with cirrhosis

Biliary features in liver histology of children with autoimmune liver disease

CCN2–MAPK–Id-1 loop feedback amplification is involved in maintaining stemness in oxaliplatin-resistant hepatocellular carcinoma

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin