Hallmarks of alternative splicing in cancer

Oncogene

Volumn 33, Issue 46, 2014, Pages 5311-5318

  Oltean, S ^a   Bates, D O ^b  

^a UNIVERSITY OF BRISTOL   (United Kingdom)

^b UNIVERSITY OF NOTTINGHAM   (United Kingdom)

Author keywords

alternative splicing; cancer; hallmarks

Indexed keywords

ANTINEOPLASTIC AGENT; ISOPROTEIN; ONCOPROTEIN;

ALTERNATIVE RNA SPLICING; DISEASE COURSE; DRUG EFFECTS; EPITHELIAL MESENCHYMAL TRANSITION; GENETICS; HUMAN; METABOLISM; METASTASIS; NEOPLASMS; PATHOLOGY; SIGNAL TRANSDUCTION;

ALTERNATIVE SPLICING; ANTINEOPLASTIC AGENTS; DISEASE PROGRESSION; EPITHELIAL-MESENCHYMAL TRANSITION; HUMANS; NEOPLASM METASTASIS; NEOPLASMS; ONCOGENE PROTEINS; PROTEIN ISOFORMS; SIGNAL TRANSDUCTION;

EID: 85027941046     PISSN: 09509232     EISSN: 14765594     Source Type: Journal    
DOI: 10.1038/onc.2013.533     Document Type: Review

References (97)

1. 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: 1413–1415.
2. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C et al. Alternative isoform regulation in human tissue transcriptomes. Nature 2008; 456: 470–476. DOI: 10.1038/nature07509
3. Venables JP. Aberrant and alternative splicing in cancer. Cancer Res 2004; 64: 7647–7654.
4. Ghigna C, Valacca C, Biamonti G. Alternative splicing and tumor progression. Curr Genomics 2008; 9: 556–570.
5. David CJ, Manley JL. Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev 2010; 24: 2343–2364.
6. Venables JP, Klinck R, Koh C, Gervais-Bird J, Bramard A, Inkel L et al. Cancer-associated regulation of alternative splicing. Nat Struct Mol Biol 2009; 16: 670–676.
7. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70.
8. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.
9. 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: 185–193.
10. Zhang Z, Krainer AR. Involvement of SR proteins in mRNA surveillance. Mol Cell 2004; 16: 597–607.
11. Huang Y, Gattoni R, Stevenin J, Steitz JA. SR splicing factors serve as adapter proteins for TAP-dependent mRNA export. Mol Cell 2003; 11: 837–843.
12. Michlewski G, Sanford JR, Caceres JF. The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E-BP1. Mol Cell 2008; 30: 179–189.
13. Sanford JR, Gray NK, Beckmann K, Caceres JF. A novel role for shuttling SR proteins in mRNA translation. Genes Dev 2004; 18: 755–768.
14. Zhou Z, Qiu J, Liu W, Zhou Y, Plocinik RM, Li H et al. The Akt-SRPK-SR axis constitutes a major pathway in transducing EGF signaling to regulate alternative splicing in the nucleus. Mol Cell 2011; 47: 422–433.
15. Olshavsky NA, Comstock CE, Schiewer MJ, Augello MA, Hyslop T, Sette C et al. Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene. Cancer Res 2010; 70: 3975–3984.
16. Anczukow O, Rosenberg AZ, Akerman M, Das S, Zhan L, Karni R et al. The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat Struct Mol Biol 2012; 19: 220–228.
17. Shultz JC, Goehe RW, Murudkar CS, Wijesinghe DS, Mayton EK, Massiello A et al. SRSF1 regulates the alternative splicing of caspase 9 via a novel intronic splicing enhancer affecting the chemotherapeutic sensitivity of non-small cell lung cancer cells. Mol Cancer Res 2011; 9: 889–900.
18. Amin EM, Oltean S, Hua J, Gammons MV, Hamdollah-Zadeh M, Welsh GI et al. WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. Cancer Cell 2011; 20: 768–780.
19. Ghigna C, Giordano S, Shen H, Benvenuto F, Castiglioni F, Comoglio PM et al. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol Cell 2005; 20: 881–890.
20. Liu Y, Wu BQ, Zhong HH, Tian XX, Fang WG. Quantification of alternative splicing variants of human telomerase reverse transcriptase and correlations with telomerase activity in lung cancer. PLoS One 2012; 7: e38868.
21. Rha SY, Jeung HC, Park KH, Kim JJ, Chung HC. Changes of telomerase activity by alternative splicing of full-length and beta variants of hTERT in breast cancer patients. Oncol Res 2009; 18: 213–220.
22. Xu JH, Wang YC, Geng X, Li YY, Zhang WM. Changes of the alternative splicing variants of human telomerase reverse transcriptase during gastric carcinogenesis. Pathobiology 2009; 76: 23–29.
23. Amor S, Remy S, Dambrine G, Le Vern Y, Rasschaert D, Laurent S. Alternative splicing and nonsense-mediated decay regulate telomerase reverse transcriptase (TERT) expression during virus-induced lymphomagenesis in vivo. BMC Cancer 2010; 10: 571.
24. Wang H, Zhou M, Shi B, Zhang Q, Jiang H, Sun Y et al. Identification of an exon 4-deletion variant of epidermal growth factor receptor with increased metastasis-promoting capacity. Neoplasia 2011; 13: 461–471.
25. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363: 809–819.
26. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011; 480: 387–390.
27. Abubaker J, Bavi P, Al-Haqawi W, Sultana M, Al-Harbi S, Al-Sanea N et al. Prognostic significance of alterations in KRAS isoforms KRAS-4A/4B and KRAS mutations in colorectal carcinoma. J Pathol 2009; 219: 435–445.
28. Okumura N, Yoshida H, Kitagishi Y, Nishimura Y, Matsuda S. Alternative splicings on p53, BRCA1 and PTEN genes involved in breast cancer. Biochem Biophys Res Commun 2011; 413: 395–399.
29. Fregoso OI, Das S, Akerman M, Krainer AR. Splicing-factor oncoprotein SRSF1 stabilizes p53 via RPL5 and induces cellular senescence. Mol Cell 2013; 50: 56–66.
30. Zhang K, Nowak I, Rushlow D, Gallie BL, Lohmann DR. Patterns of missplicing caused by RB1 gene mutations in patients with retinoblastoma and association with phenotypic expression. Hum Mutat 2008; 29: 475–484.
31. Lohmann DR. RB1 gene mutations in retinoblastoma. Hum Mutat 1999; 14: 283–288.
32. Cloutier P, Toutant J, Shkreta L, Goekjian S, Revil T, Chabot B. Antagonistic effects of the SRp30c protein and cryptic 5' splice sites on the alternative splicing of the apoptotic regulator Bcl-x. J Biol Chem 2008; 283: 21315–21324.
33. Reeve JG, Xiong J, Morgan J, Bleehen NM. Expression of apoptosis-regulatory genes in lung tumour cell lines: relationship to p53 expression and relevance to acquired drug resistance. Br J Cancer 1996; 73: 1193–1200.
34. Krajewska M, Krajewski S, Epstein JI, Shabaik A, Sauvageot J, Song K et al. Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. Am J Pathol 1996; 148: 1567–1576.
35. Krajewska M, Moss SF, Krajewski S, Song K, Holt PR, Reed JC. Elevated expression of Bcl-X and reduced Bak in primary colorectal adenocarcinomas. Cancer Res 1996; 56: 2422–2427.
36. Shultz JC, Vu N, Shultz MD, Mba MU, Shapiro BA, Chalfant CE. The Proto-oncogene PKCiota regulates the alternative splicing of Bcl-x pre-mRNA. Mol Cancer Res 2012; 10: 660–669.
37. Bonnal S, Martinez C, Forch P, Bachi A, Wilm M, Valcarcel J. RBM5/Luca-15/H37 regulates Fas alternative splice site pairing after exon definition. Mol Cell 2008; 32: 81–95.
38. Himeji D, Horiuchi T, Tsukamoto H, Hayashi K, Watanabe T, Harada M. Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade. Blood 2002; 99: 4070–4078.
39. Pan D, Boon-Unge K, Govitrapong P, Zhou J. Emetine regulates the alternative splicing of caspase 9 in tumor cells. Oncol Lett 2011; 2: 1309–1312.
40. Shultz JC, Goehe RW, Wijesinghe DS, Murudkar C, Hawkins AJ, Shay JW et al. Alternative splicing of caspase 9 is modulated by the phosphoinositide 3-kinase/Akt pathway via phosphorylation of SRp30a. Cancer Res 2010; 70: 9185–9196.
41. Merdzhanova G, Edmond V, De Seranno S, Van den Broeck A, Corcos L, Brambilla C et al. E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35. Cell Death Differ 2008; 15: 1815–1823.
42. Shkreta L, Froehlich U, Paquet ER, Toutant J, Elela SA, Chabot B. Anticancer drugs affect the alternative splicing of Bcl-x and other human apoptotic genes. Mol Cancer Ther 2008; 7: 1398–1409.
43. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335–2342.
44. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001; 7: 192–198.
45. Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 1992; 267: 26031–26037.
46. Nowak DG, Amin EM, Rennel ES, Hoareau-Aveilla C, Gammons M, Damodoran G et al. Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to anti-angiogenic isoforms: a novel therapeutic strategy for angiogenesis. J Biol Chem 2010; 285: 5532–5540.
47. Bates DO, Cui TG, Doughty JM, Winkler M, Sugiono M, Shields JD et al. VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res 2002; 62: 4123–4131.
48. Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI. Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc Natl Acad Sci USA 1996; 93: 1988–1992.
49. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 1996; 15: 1751.
50. Maglione D, Guerriero V, Viglietto G, Ferraro MG, Aprelikova O, Alitalo K et al. Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14. Oncogene 1993; 8: 925–931.
51. Ergorul C, Ray A, Huang W, Darland D, Luo ZK, Grosskreutz CL. Levels of vascular endothelial growth factor-A165b (VEGF-A165b are elevated in experimental glaucoma). Mol Vis 2008; 14: 1517–1524.
52. Schumacher VA, Jeruschke S, Eitner F, Becker JU, Pitschke G, Ince Y et al. Impaired glomerular maturation and lack of VEGF165b in Denys-Drash syndrome. J Am Soc Nephrol 2007; 18: 719–729.
53. Merdzhanova G, Gout S, Keramidas M, Edmond V, Coll JL, Brambilla C et al. The transcription factor E2F1 and the SR protein SC35 control the ratio of pro-angiogenic versus antiangiogenic isoforms of vascular endothelial growth factor-A to inhibit neovascularization in vivo. Oncogene 2010; 29: 5392–5403.
54. Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard-Jones RO et al. VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res 2004; 64: 7822–7835.
55. Varey AH, Rennel ES, Qiu Y, Bevan HS, Perrin RM, Raffy S et al. VEGF 165 b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy. Br J Cancer 2008; 98: 1366–1379.
56. Rennel E, Waine E, Guan H, Schuler Y, Leenders W, Woolard J et al. The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice. Br J Cancer 2008; 98: 1250–1257.
57. Pritchard-Jones RO, Dunn DB, Qiu Y, Varey AH, Orlando A, Rigby H et al. Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma. Br J Cancer 2007; 97: 223–230.
58. Peiris-Pages M, Harper SJ, Bates DO, Ramani P. Balance of pro- versus anti-angiogenic splice isoforms of vascular endothelial growth factor as a regulator of neuroblastoma growth. J Pathol 2010; 222: 138–147.
59. Diaz R, Pena C, Silva J, Lorenzo Y, Garcia JM, Sanchez A et al. p73 isoforms affect VEGF, VEGF165b and PEDF expression in human colorectal tumours.VEGF165b downregulation as a marker for poor prognosis. Int J Cancer 2008; 123: 1060–1067.
60. Nowak DG, Woolard J, Amin EM, Konopatskaya O, Saleem MA, Churchill AJ et al. Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors. J Cell Sci 2008; 121 (Pt 20): 3487–3495.
61. Gammons MV, Federov O, Ivison D, Du C, Clark TL, Hopkins C et al. Topical anti-angiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative-AMD. Invest Ophthalmol Vis Sci 2013; 54: 6052–6062.
62. Fukuhara T, Hosoya T, Shimizu S, Sumi K, Oshiro T, Yoshinaka Y et al. Utilization of host SR protein kinases and RNA-splicing machinery during viral replication. Proc Natl Acad Sci USA 2006; 103: 11329–11333.
63. Keriel A, Mahuteau-Betzer F, Jacquet C, Plays M, Grierson D, Sitbon M et al. Protection against retrovirus pathogenesis by SR protein inhibitors. PLoS One 2009; 4: e4533.
64. Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 1993; 90: 10705–10709.
65. Boeckel JN, Guarani V, Koyanagi M, Roexe T, Lengeling A, Schermuly RT et al. Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1. Proc Natl Acad Sci USA 2011; 108: 3276–3281.
66. Albuquerque RJ, Hayashi T, Cho WG, Kleinman ME, Dridi S, Takeda A et al. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med 2009; 15: 1023–1030.
67. Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell 2011; 147: 275–292.
68. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119: 1420–1428.
69. Shapiro IM, Cheng AW, Flytzanis NC, Balsamo M, Condeelis JS, Oktay MH et al. An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet 2011; 7: e1002218.
70. Venables JP, Brosseau JP, Gadea G, Klinck R, Prinos P, Beaulieu JF et al. RBFOX2 is an important regulator of mesenchymal tissue-specific splicing in both normal and cancer tissues. Mol Cell Biol 2013; 33: 396–405.
71. 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: 3286–3300.
72. Warzecha CC, Sato TK, Nabet B, Hogenesch JB, Carstens RP. ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Mol Cell 2009; 33: 591–601.
73. Carstens RP, Wagner EJ, Garcia-Blanco MA. An intronic splicing silencer causes skipping of the IIIb exon of fibroblast growth factor receptor 2 through involvement of polypyrimidine tract binding protein. Mol Cell Biol 2000; 20: 7388–7400.
74. Baraniak AP, Chen JR, Garcia-Blanco MA. Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice. Mol Cell Biol 2006; 26: 1209–1222.
75. Baraniak AP, Lasda EL, Wagner EJ, Garcia-Blanco MA. A stem structure in fibroblast growth factor receptor 2 transcripts mediates cell-type-specific splicing by approximating intronic control elements. Mol Cell Biol 2003; 23: 9327–9337.
76. Oltean S, Sorg BS, Albrecht T, Bonano VI, Brazas RM, Dewhirst MW et al. Alternative inclusion of fibroblast growth factor receptor 2 exon IIIc in Dunning prostate tumors reveals unexpected epithelial mesenchymal plasticity. Proc Natl Acad Sci USA 2006; 103: 14116–14121.
77. Oltean S, Febbo PG, Garcia-Blanco MA. Dunning rat prostate adenocarcinomas and alternative splicing reporters: powerful tools to study epithelial plasticity in prostate tumors in vivo. Clin Exp Metastasis 2008; 25: 611–619.
78. Reinke LM, Xu Y, Cheng C. Snail represses the splicing regulator epithelial splicing regulatory protein 1 to promote epithelial-mesenchymal transition. J Biol Chem 2012; 287: 36435–36442.
79. Horiguchi K, Sakamoto K, Koinuma D, Semba K, Inoue A, Inoue S et al. TGF-beta drives epithelial-mesenchymal transition through deltaEF1-mediated downregulation of ESRP. Oncogene 2012; 31: 3190–3201.
80. Konrad L, Scheiber JA, Volck-Badouin E, Keilani MM, Laible L, Brandt H et al. Alternative splicing of TGF-betas and their high-affinity receptors T beta RI, T beta RII and T beta RIII (betaglycan) reveal new variants in human prostatic cells. BMC Genomics 2007; 8: 318.
81. Warzecha CC, Carstens RP. Complex changes in alternative pre-mRNA splicing play a central role in the epithelial-to-mesenchymal transition (EMT). Semin Cancer Biol 2012; 22: 417–427.
82. Sharma S, Liao W, Zhou X, Wong DT, Lichtenstein A. Exon 11 skipping of E-cadherin RNA downregulates its expression in head and neck cancer cells. Mol Cancer Ther 2011; 10: 1751–1759.
83. Brown RL, Reinke LM, Damerow MS, Perez D, Chodosh LA, Yang J et al. CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest 2011; 121: 1064–1074.
84. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 2005; 436: 123–127.
85. Warburg O. On respiratory impairment in cancer cells. Science 1956; 124: 269–270.
86. Warburg O. On the origin of cancer cells. Science 1956; 123: 309–314.
87. David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 2010; 463: 364–368.
88. Koslowski M, Tureci O, Bell C, Krause P, Lehr HA, Brunner J et al. Multiple splice variants of lactate dehydrogenase C selectively expressed in human cancer. Cancer Res 2002; 62: 6750–6755.
89. Rouas-Freiss N, Bruel S, Menier C, Marcou C, Moreau P, Carosella ED. Switch of HLA-G alternative splicing in a melanoma cell line causes loss of HLA-G1 expression and sensitivity to NK lysis. Int J Cancer 2005; 117: 114–122.
90. Rodriguez-Cruz TG, Liu S, Khalili JS, Whittington M, Zhang M, Overwijk W et al. Natural splice variant of MHC class I cytoplasmic tail enhances dendritic cell-induced CD8+ T-cell responses and boosts anti-tumor immunity. PLoS One 2011; 6: e22939.
91. Goncalves V, Matos P, Jordan P. Antagonistic SR proteins regulate alternative splicing of tumor-related Rac1b downstream of the PI3-kinase and Wnt pathways. Hum Mol Genet 2009; 18: 3696–3707.
92. Thorsen K, Mansilla F, Schepeler T, Oster B, Rasmussen MH, Dyrskjot L et al. Alternative splicing of SLC39A14 in colorectal cancer is regulated by the Wnt pathway. Mol Cell Proteomics 2011; 10: M110 002998.
93. Das S, Anczukow O, Akerman M, Krainer AR. Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC. Cell Rep 2012; 1: 110–117.
94. Yea S, Narla G, Zhao X, Garg R, Tal-Kremer S, Hod E et al. Ras promotes growth by alternative splicing-mediated inactivation of the KLF6 tumor suppressor in hepatocellular carcinoma. Gastroenterology 2008; 134: 1521–1531.
95. Cheng C, Yaffe MB, Sharp PA. A positive feedback loop couples Ras activation and CD44 alternative splicing. Genes Dev 2006; 20: 1715–1720.
96. Bedford MT, Reed R, Leder P. WW domain-mediated interactions reveal a spliceosome-associated protein that binds a third class of proline-rich motif: the proline glycine and methionine-rich motif. Proc Natl Acad Sci USA 1998; 95: 10602–10607.
97. Woolard J, Vousden W, Moss SJ, Krishnakumar A, Gammons MV, Nowak DG et al. Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms. Chem Sci 2011; 2011: 273–278.