Skip to main content

Advertisement

SpringerLink
Log in

Alternative splicing modulates cancer aggressiveness: role in EMT/metastasis and chemoresistance

  • Review
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Enhanced metastasis and disease recurrence accounts for the high mortality rates associated with cancer. The process of Epithelial-Mesenchymal Transition (EMT) contributes towards the augmentation of cancer invasiveness along with the gain of stem-like and the subsequent drug-resistant behavior. Apart from the well-established transcriptional regulation, EMT is also controlled post-transcriptionally by virtue of alternative splicing (AS). Numerous genes including Fibroblast Growth Factor receptor (FGFR) as well as CD44 are differentially spliced during this trans-differentiation process which, in turn, governs cancer progression. These splicing alterations are controlled by various splicing factors including ESRP, RBFOX2 as well as hnRNPs. Here, we have depicted the mechanisms governing the splice isoform switching of FGFR and CD44. Moreover, the role of the splice variants generated by AS of these gene transcripts in modulating the metastatic potential and stem-like/chemoresistant behavior of cancer cells has also been highlighted. Additionally, the involvement of splicing factors in regulating EMT/invasiveness along with drug-resistance as well as the metabolic properties of the cells has been emphasized. Tumorigenesis is accompanied by a remodeling of the cellular splicing profile generating diverse protein isoforms which, in turn, control the cancer-associated hallmarks. Therefore, we have also briefly discussed about a wide variety of genes which are differentially spliced in the tumor cells and promote cancer progression. We have also outlined different strategies for targeting the tumor-associated splicing events which have shown promising results and therefore this approach might be useful in developing therapies to reduce cancer aggressiveness in a more specific manner.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

AS:

Alternative splicing

CD44:

Cluster of differentiation 44

CSC:

Cancer stem cell

EMT:

Epithelial-mesenchymal transition

ESRP:

Epithelial splicing regulatory protein

FGFR:

Fibroblast growth factor receptor

hnRNP:

Heterogeneous nuclear ribonucleoprotein

MET:

Mesenchymal-epithelial transition

References

  1. Pucci B, Kasten M, Giordano A (2000) Cell cycle and apoptosis. Neoplasia 2:291–299. https://doi.org/10.1038/sj.neo.7900101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cooper GM (2000) The cell: a molecular approach. The development and causes of cancer, 2nd edn. Sinauer Associates, Sunderland https://www.ncbi.nlm.nih.gov/books/NBK9963/

    Google Scholar 

  3. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  4. Koedoot E, Wolters L, van de Water B, Le Dévédec SE (2019) Splicing regulatory factors in breast cancer hallmarks and disease progression. Oncotarget 10:6021–6037. https://doi.org/10.18632/oncotarget.27215

    Article  PubMed  PubMed Central  Google Scholar 

  5. Oltean S, Bates DO (2014) Hallmarks of alternative splicing in cancer. Oncogene 33:5311–5318. https://doi.org/10.1038/onc.2013.533

    Article  CAS  PubMed  Google Scholar 

  6. El Marabti E, Younis I (2018) The cancer spliceome: reprograming of alternative splicing in cancer. Front Mol Biosci 5:80. https://doi.org/10.3389/fmolb.2018.00080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456:470–476. https://doi.org/10.1038/nature07509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen M, Manley JL (2009) Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol 10:741–754. https://doi.org/10.1038/nrm2777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sveen A, Kilpinen S, Ruusulehto A, Lothe RA, Skotheim RI (2016) Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes. Oncogene 35:2413–2427. https://doi.org/10.1038/onc.2015.318

    Article  CAS  PubMed  Google Scholar 

  10. Escobar-Hoyos L, Knorr K, Abdel-Wahab O (2019) Aberrant RNA splicing in Cancer. Annu Rev Cancer Biol 3:167–185. https://doi.org/10.1146/annurev-cancerbio-030617-050407

    Article  PubMed  Google Scholar 

  11. Shapiro IM, Cheng AW, Flytzanis NC, Balsamo M, Condeelis JS, Oktay MH, Burge CB, Gertler FB (2011) An EMT–driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet 7:e1002218. https://doi.org/10.1371/journal.pgen.1002218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428. https://doi.org/10.1172/JCI39104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Smith BN, Bhowmick NA (2016) Role of EMT in metastasis and therapy resistance. J Clin Med 5:17. https://doi.org/10.3390/jcm5020017

    Article  CAS  PubMed Central  Google Scholar 

  14. Geiger TR, Peeper DS (2009) Metastasis mechanisms. Biochim Biophys Acta Rev Cancer 1796:293–308. https://doi.org/10.1016/j.bbcan.2009.07.006

    Article  CAS  Google Scholar 

  15. Warzecha CC, Jiang P, Amirikian K, Dittmar KA, Lu H, Shen S, Guo W, Xing Y, Carstens RP (2010) An ESRP-regulated splicing programme is abrogated during the epithelial–mesenchymal transition. EMBO J 29:3286–3300. https://doi.org/10.1038/emboj.2010.195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Reinke LM, Xu Y, Cheng C (2012) Snail represses the splicing regulator epithelial splicing regulatory protein 1 to promote epithelial-mesenchymal transition. J Biol Chem 287:36435–36442. https://doi.org/10.1074/jbc.m112.397125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu HT, Zhong HT, Li GW, Shen JX, Ye QQ, Zhang ML, Liu J (2020) Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer. J Transl Med 18:51. https://doi.org/10.1186/s12967-020-02240-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Venables JP, Brosseau JP, Gadea G, Klinck R, Prinos P, Beaulieu JF, Lapointe E, Durand M, Thibault P, Tremblay K, Rousset F (2013) RBFOX2 is an important regulator of mesenchymal tissue-specific splicing in both normal and cancer tissues. Mol Cell Biol 33:396–405. https://doi.org/10.1128/MCB.01174-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Aponte PM, Caicedo A (2017) Stemness in cancer: stem cells, cancer stem cells, and their microenvironment. Stem Cells Int 2017:5619472. https://doi.org/10.1155/2017/5619472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bhattacharya R, Mitra T, Ray Chaudhuri S, Roy SS (2018) Mesenchymal splice isoform of CD44 (CD44s) promotes EMT/invasion and imparts stem-like properties to ovarian cancer cells. J Cell Biochem 119:3373–3383. https://doi.org/10.1002/jcb.26504

    Article  CAS  PubMed  Google Scholar 

  21. Zhou P, Li B, Liu F, Zhang M, Wang Q, Liu Y, Yao Y, Li D (2017) The epithelial to mesenchymal transition (EMT) and cancer stem cells: implication for treatment resistance in pancreatic cancer. Mol Cancer 16:52. https://doi.org/10.1186/s12943-017-0624-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mitra T, Prasad P, Mukherjee P, Chaudhuri SR, Chatterji U, Roy SS (2018) Stemness and chemoresistance are imparted to the OC cells through TGFβ1 driven EMT. J Cell Biochem 119:5775–5787. https://doi.org/10.1002/jcb.26753

    Article  CAS  PubMed  Google Scholar 

  23. Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, Bapat SA (2009) Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27:2059–2068. https://doi.org/10.1002/stem.154

    Article  CAS  PubMed  Google Scholar 

  24. Wellner U, Brabletz T, Keck T (2010) ZEB1 in pancreatic cancer. Cancers (Basel) 2:1617–1628. https://doi.org/10.3390/cancers2031617

    Article  CAS  Google Scholar 

  25. Venables JP, Lapasset L, Gadea G, Fort P, Klinck R, Irimia M, Vignal E, Thibault P, Prinos P, Chabot B, Elela SA, Roux P, Lemaitre JM, Tazi J (2013) MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation. Nat Commun 4:2480. https://doi.org/10.1038/ncomms3480

    Article  CAS  PubMed  Google Scholar 

  26. Pradella D, Naro C, Sette C, Ghigna C (2017) EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression. Mol Cancer 16:8. https://doi.org/10.1186/s12943-016-0579-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Begicevic RR, Falasca M (2017) ABC transporters in cancer stem cells: beyond chemoresistance. Int J Mol Sci 18:2362. https://doi.org/10.3390/ijms18112362

    Article  CAS  PubMed Central  Google Scholar 

  28. Yuan S, Tao F, Zhang X, Zhang Y, Sun X, Wu D (2020) Role of Wnt/β-catenin signaling in the Chemoresistance modulation of colorectal Cancer. Biomed Res Int 2020:9390878. https://doi.org/10.1155/2020/9390878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Banerjee AK, Bhattacharya R, Mal C (2020) HMG2D: a tool to identify miRNAs/drugs/genes associated with diseases like cancers. Meta Gene 24:100699. https://doi.org/10.1016/j.mgene.2020.100699

    Article  Google Scholar 

  30. Wang BD, Lee NH (2018) Aberrant RNA splicing in cancer and drug resistance. Cancers (Basel) 10:458. https://doi.org/10.3390/cancers10110458

    Article  CAS  Google Scholar 

  31. Siegfried Z, Karni R (2018) The role of alternative splicing in cancer drug resistance. Curr Opin Genet Dev 48:16–21. https://doi.org/10.1016/j.gde.2017.10.001

    Article  CAS  PubMed  Google Scholar 

  32. Yang Q, Zhao J, Zhang W, Chen D, Wang Y (2019) Aberrant alternative splicing in breast cancer. J Mol Cell Biol 11:920–929. https://doi.org/10.1093/jmcb/mjz033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bhattacharya R, Ray Chaudhuri S, Roy SS (2018) FGF9-induced ovarian cancer cell invasion involves VEGF-A/VEGFR2 augmentation by virtue of ETS1 upregulation and metabolic reprogramming. J Cell Biochem 119:8174–8189. https://doi.org/10.1002/jcb.26820

    Article  CAS  PubMed  Google Scholar 

  34. Mitra T, Bhattacharya R (2020) Phytochemicals modulate cancer aggressiveness: a review depicting the anticancer efficacy of dietary polyphenols and their combinations. J Cell Physiol 235:7645–8863. https://doi.org/10.1002/jcp.29703

    Article  CAS  Google Scholar 

  35. Bielli P, Pagliarini V, Pieraccioli M, Caggiano C, Sette C (2019) Splicing dysregulation as oncogenic driver and passenger factor in brain tumors. Cells 9:10. https://doi.org/10.3390/cells9010010

    Article  CAS  PubMed Central  Google Scholar 

  36. Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:16–129. https://doi.org/10.1038/nrc2780

    Article  CAS  Google Scholar 

  37. Rebscher N, Deichmann C, Sudhop S, Fritzenwanker JH, Green S, Hassel M (2009) Conserved intron positions in FGFR genes reflect the modular structure of FGFR and reveal stepwise addition of domains to an already complex ancestral FGFR. Dev Genes Evol 219:455–468. https://doi.org/10.1007/s00427-009-0309-5

    Article  CAS  PubMed  Google Scholar 

  38. Holzmann K, Grunt T, Heinzle C, Sampl S, Steinhoff H, Reichmann N, Kleiter M, Hauck M, Marian B (2012) Alternative splicing of fibroblast growth factor receptor IgIII loops in cancer. J Nucleic Acids 2012:950508. https://doi.org/10.1155/2012/950508

    Article  CAS  PubMed  Google Scholar 

  39. Acevedo VD, Ittmann M, Spencer DM (2009) Paths of FGFR-driven tumorigenesis. Cell Cycle 8:580–588. https://doi.org/10.4161/cc.8.4.7657

    Article  CAS  PubMed  Google Scholar 

  40. Matsuda Y, Ueda J, Ishiwata T (2012) Fibroblast growth factor receptor 2: expression, roles, and potential as a novel molecular target for colorectal cancer. Pathol Res Int 2012:574768. https://doi.org/10.1155/2012/574768

    Article  Google Scholar 

  41. Oltean S, Sorg BS, Albrecht T, Bonano VI, Brazas RM, Dewhirst MW, Garcia-Blanco MA (2006) Alternative inclusion of fibroblast growth factor receptor 2 exon IIIc in dunning prostate tumors reveals unexpected epithelial mesenchymal plasticity. Proc Natl Acad Sci U S A 103:14116–14121. https://doi.org/10.1073/pnas.0603090103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Amann T, Bataille F, Spruss T, Dettmer K, Wild P, Liedtke C, Mühlbauer M, Kiefer P, Oefner PJ, Trautwein C, Bosserhoff AK (2010) Reduced expression of fibroblast growth factor receptor 2IIIb in hepatocellular carcinoma induces a more aggressive growth. Am J Pathol 176:1433–1442. https://doi.org/10.2353/ajpath.2010.090356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhao Q, Caballero OL, Davis ID, Jonasch E, Tamboli P, Yung WA, Weinstein JN, Shaw K, Strausberg RL, Yao J (2013) Tumor-specific isoform switch of the fibroblast growth factor receptor 2 underlies the mesenchymal and malignant phenotypes of clear cell renal cell carcinomas. Clin Cancer Res 19:2460–2472. https://doi.org/10.1158/1078-0432.CCR-12-3708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ishiwata T (2018) Role of fibroblast growth factor receptor-2 splicing in normal and cancer cells. Front Biosci (Landmark Ed) 23:626–639. https://doi.org/10.2741/4609

    Article  CAS  Google Scholar 

  45. Ueda J, Matsuda Y, Yamahatsu K, Uchida E, Naito Z, Korc M, Ishiwata T (2014) Epithelial splicing regulatory protein 1 is a favorable prognostic factor in pancreatic cancer that attenuates pancreatic metastases. Oncogene 33:4485–4495. https://doi.org/10.1038/onc.2013.392

    Article  CAS  PubMed  Google Scholar 

  46. Ranieri D, Belleudi F, Magenta A, Torrisi MR (2015) HPV16 E5 expression induces switching from FGFR2b to FGFR2c and epithelial-mesenchymal transition. Int J Cancer 137:61–72. https://doi.org/10.1002/ijc.29373

    Article  CAS  PubMed  Google Scholar 

  47. Teles SP, Oliveira P, Ferreira M, Carvalho J, Ferreira P, Oliveira C (2020) Integrated analysis of structural variation and RNA expression of FGFR2 and its splicing modulator ESRP1 highlight the ESRP1amp-FGFR2norm-FGFR2-IIIchigh Axis in diffuse gastric Cancer. Cancers 12:70. https://doi.org/10.3390/cancers12010070

    Article  CAS  Google Scholar 

  48. Osada AH, Endo K, Kimura Y, Sakamoto K, Nakamura R, Sakamoto K, Ueki K, Yoshizawa K, Miyazawa K, Saitoh M (2019) Addiction of mesenchymal phenotypes on the FGF/FGFR axis in oral squamous cell carcinoma cells. PLoS One 14:e0217451. https://doi.org/10.1371/journal.pone.0217451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hopkins A, Coatham ML, Berry FB (2017) FOXC1 regulates FGFR1 isoform switching to promote invasion following TGFβ-induced EMT. Mol Cancer Res 15:1341–1353. https://doi.org/10.1158/1541-7786.MCR-17-0185

    Article  CAS  PubMed  Google Scholar 

  50. Sonvilla G, Allerstorfer S, Heinzle C, Stättner S, Karner J, Klimpfinger M, Wrba F, Fischer H, Gauglhofer C, Spiegl-Kreinecker S, Grasl-Kraupp B, Holzmann K, Grusch M, Berger W, Marian B (2010) Fibroblast growth factor receptor 3-IIIc mediates colorectal cancer growth and migration. Br J Cancer 102:1145–1156. https://doi.org/10.1038/sj.bjc.6605596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Qian X, Anzovino A, Kim S, Suyama K, Yao J, Hulit J, Agiostratidou G, Chandiramani N, McDaid HM, Nagi C, Cohen HW, Phillips GR, Norton L, Hazan RB (2014) N-cadherin/FGFR promotes metastasis through epithelial-to-mesenchymal transition and stem/progenitor cell-like properties. Oncogene 33:3411–3421. https://doi.org/10.1038/onc.2013.310

    Article  CAS  PubMed  Google Scholar 

  52. Maehara O, Suda G, Natsuizaka M, Ohnishi S, Komatsu Y, Sato F, Nakai M, Sho T, Morikawa K, Ogawa K, Shimazaki T, Kimura M, Asano A, Fujimoto Y, Ohashi S, Kagawa S, Kinugasa H, Naganuma S, Whelan KA, Nakagawa H, Nakagawa K, Takeda H, Sakamoto N (2017) Fibroblast growth factor-2–mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma. Carcinogenesis 38:1073–1083. https://doi.org/10.1093/carcin/bgx095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Saito S, Morishima K, Ui T, Hoshino H, Matsubara D, Ishikawa S, Aburatani H, Fukayama M, Hosoya Y, Sata N, Lefor AK (2015) The role of HGF/MET and FGF/FGFR in fibroblast-derived growth stimulation and lapatinib-resistance of esophageal squamous cell carcinoma. BMC Cancer 15:82. https://doi.org/10.1186/s12885-015-1065-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Marek L, Ware KE, Fritzsche A, Hercule P, Helton WR, Smith JE, McDermott LA, Coldren CD, Nemenoff RA, Merrick DT, Helfrich BA, Bunn PA, Heasley LE (2009) Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells. Mol Pharmacol 75:196–207. https://doi.org/10.1124/mol.108.049544

    Article  CAS  PubMed  Google Scholar 

  55. Liu J, Chen G, Liu Z, Liu S, Cai Z, You P, Ke Y, Lai L, Huang Y, Gao H, Zhao L, Pelicano H, Huang P, McKeehan WL, Wu CL, Wang C, Zhong W, Wang F (2018) Aberrant FGFR tyrosine kinase signaling enhances the Warburg effect by reprogramming LDH isoform expression and activity in prostate cancer. Cancer Res 78:4459–4470. https://doi.org/10.1158/0008-5472.CAN-17-3226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Xu M, Chen S, Yang W, Cheng X, Ye Y, Mao J, Wu X, Huang L, Ji J (2018) FGFR4 links glucose metabolism and chemotherapy resistance in breast cancer. Cell Physiol Biochem 47:151–160. https://doi.org/10.1159/000489759

    Article  CAS  PubMed  Google Scholar 

  57. Chen C, Zhao S, Karnad A, Freeman JW (2018) The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol 11:64. https://doi.org/10.1186/s13045-018-0605-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Brown RL, Reinke LM, Damerow MS, Perez D, Chodosh LA, Yang J, Cheng C (2011) CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Inv 121:1064–1074. https://doi.org/10.1172/JCI44540

    Article  CAS  Google Scholar 

  59. Yin T, Wang G, He S, Liu Q, Sun J, Wang Y (2016) Human cancer cells with stem cell-like phenotype exhibit enhanced sensitivity to the cytotoxicity of IL-2 and IL-15 activated natural killer cells. Cell Immunol 300:41–45. https://doi.org/10.1016/j.cellimm.2015.11.009

    Article  CAS  PubMed  Google Scholar 

  60. Zhao S, Chen C, Chang K, Karnad A, Jagirdar J, Kumar AP, Freeman JW (2016) CD44 expression level and isoform contributes to pancreatic Cancer cell plasticity, invasiveness, and response to therapy. Clin Cancer Res 22:5592–5604. https://doi.org/10.1158/1078-0432.CCR-15-3115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lin J, Ding D (2017) The prognostic role of the cancer stem cell marker CD44 in ovarian cancer: a meta-analysis. Cancer Cell Int 17:1–11. https://doi.org/10.1186/s12935-016-0376-4

    Article  CAS  Google Scholar 

  62. Zöller M (2011) CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer 11:254–267. https://doi.org/10.1038/nrc3023

    Article  CAS  PubMed  Google Scholar 

  63. Skandalis SS, Karalis TT, Chatzopoulos A, Karamanos NK (2019) Hyaluronan-CD44 axis orchestrates cancer stem cell functions. Cell Signal 63:109377. https://doi.org/10.1016/j.cellsig.2019.109377

    Article  CAS  PubMed  Google Scholar 

  64. Bourguignon LYW (2019) Matrix Hyaluronan-CD44 interaction activates MicroRNA and LncRNA signaling associated with Chemoresistance, invasion, and tumor progression. Front Oncol 9:492. https://doi.org/10.3389/fonc.2019.00492

    Article  PubMed  PubMed Central  Google Scholar 

  65. Xu H, Wu K, Tian Y, Liu Q, Han N, Yuan X, Zhang L, Wu GS, Wu K (2016) CD44 correlates with clinicopathological characteristics and is upregulated by EGFR in breast cancer. Int J Oncol 49:1343–1350. https://doi.org/10.3892/ijo.2016.3639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chen Q, Gu M, Cai ZK, Zhao H, Sun SC, Liu C, Zhan M, Chen YB, Wang Z (2020) TGF β1 promotes epithelial to mesenchymal transition and stemness of prostate cancer cells by inducing PCBP1 degradation and alternative splicing of CD44. Cell Mol Life Sci (Epub ahead of print). https://doi.org/10.1007/s00018-020-03544-5

  67. Larsen JE, Nathan V, Osborne JK, Farrow RK, Deb D, Sullivan JP, Dospoy PD, Augustyn A, Hight SK, Sato M, Girard L, Behrens C, Wistuba II, Gazdar AF, Hayward NK, Minna JD (2016) ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. J Clin Invest 126:3219–3235. https://doi.org/10.1172/JCI76725

    Article  PubMed  PubMed Central  Google Scholar 

  68. Inoue K, Fry EA (2015) Aberrant splicing of estrogen receptor, HER2, and CD44 genes in breast cancer. Genet Epigenet 7:19–32. https://doi.org/10.4137/GEG.S35500

    Article  PubMed  PubMed Central  Google Scholar 

  69. Miwa T, Nagata T, Kojima H, Sekine S, Okumura T (2017) Isoform switch of CD44 induces different chemotactic and tumorigenic ability in gallbladder cancer. Int J Oncol 51:771–780. https://doi.org/10.3892/ijo.2017.4063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Li L, Qi L, Qu T, Liu C, Cao L, Huang Q, Song W, Yang L, Qi H, Wang Y, Gao B, Guo Y, Sun B, Meng B, Zhang B, Cao W (2018) Epithelial splicing regulatory protein 1 inhibits the invasion and metastasis of lung adenocarcinoma. Am J Pathol 188:1882–1894. https://doi.org/10.1016/j.ajpath.2018.04.012

    Article  CAS  PubMed  Google Scholar 

  71. Zhang FL, Cao JL, Xie HY, Sun R, Yang LF, Shao ZM, Li DQ (2018) Cancer-associated MORC2-mutant M276I regulates an hnRNPM-mediated CD44 splicing switch to promote invasion and metastasis in triple-negative breast cancer. Cancer Res 78:5780–5792. https://doi.org/10.1158/0008-5472.CAN-17-1394

    Article  CAS  PubMed  Google Scholar 

  72. Preca BT, Bajdak K, Mock K, Sundararajan V, Pfannstiel J, Maurer J, Wellner U, Hopt UT, Brummer T, Brabletz S, Brabletz T, Stemmler MP (2015) A self-enforcing CD 44s/ZEB 1 feedback loop maintains EMT and stemness properties in cancer cells. Int J Cancer 137:2566–2577. https://doi.org/10.1002/ijc.29642

    Article  CAS  PubMed  Google Scholar 

  73. Miyazaki H, Takahashi RU, Prieto-Vila M, Kawamura Y, Kondo S, Shirota T, Ochiya T (2018) CD44 exerts a functional role during EMT induction in cisplatin-resistant head and neck cancer cells. Oncotarget 9:10029–10041. https://doi.org/10.18632/oncotarget.24252

    Article  PubMed  PubMed Central  Google Scholar 

  74. Tsubouchi K, Minami K, Hayashi N, Yokoyama Y, Mori S, Yamamoto H, Koizumi M (2017) The CD44 standard isoform contributes to radioresistance of pancreatic cancer cells. J Radiat Res 58:816–826. https://doi.org/10.1093/jrr/rrx033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Biddle A, Gammon L, Fazil B, Mackenzie IC (2013) CD44 staining of cancer stem-like cells is influenced by down-regulation of CD44 variant isoforms and up-regulation of the standard CD44 isoform in the population of cells that have undergone epithelial-to-mesenchymal transition. PLoS One 8:e57314. https://doi.org/10.1371/journal.pone.0057314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhang H, Brown RL, Wei Y, Zhao P, Liu S, Liu X, Deng Y, Hu X, Zhang J, Gao XD, Kang Y, Mercurio AM, Goel HL, Cheng C (2019) CD44 splice isoform switching determines breast cancer stem cell state. Genes Dev 33:166–179. https://doi.org/10.1101/gad.319889.118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Suwannakul N, Ma N, Thanan R, Pinlaor S, Ungarreevittaya P, Midorikawa K, Hiraku Y, Oikawa S, Kawanishi S, Murata M (2018) Overexpression of CD44 variant 9: a novel cancer stem cell marker in human cholangiocarcinoma in relation to inflammation. Mediat Inflamm 2018:4867234. https://doi.org/10.1155/2018/4867234

    Article  CAS  Google Scholar 

  78. Kiuchi S, Ikeshita S, Miyatake Y, Kasahara M (2015) Pancreatic cancer cells express CD44 variant 9 and multidrug resistance protein 1 during mitosis. Exp Mol Pathol 98:41–46. https://doi.org/10.1016/j.yexmp.2014.12.001

    Article  CAS  PubMed  Google Scholar 

  79. Omran OM, Ata HS (2012) CD44s and CD44v6 in diagnosis and prognosis of human bladder cancer. Ultrastruct Pathol 36:145–152. https://doi.org/10.3109/01913123.2011.651522

    Article  PubMed  Google Scholar 

  80. Wang Z, Tang Y, Xie L, Huang A, Xue C, Gu Z, Wang K, Zong S (2019) The prognostic and clinical value of CD44 in colorectal Cancer: a Meta-analysis. Front Oncol 9:309. https://doi.org/10.3389/fonc.2019.00309

    Article  PubMed  PubMed Central  Google Scholar 

  81. Tjhay F, Motohara T, Tayama S, Narantuya D, Fujimoto K, Guo J, Sakaguchi I, Honda R, Tashiro H, Katabuchi H (2015) CD 44 variant 6 is correlated with peritoneal dissemination and poor prognosis in patients with advanced epithelial ovarian cancer. Cancer Sci 106:1421–1428. https://doi.org/10.1111/cas.12765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chen L, Fu C, Zhang Q, He C, Zhang F, Wei Q (2020) The role of CD44 in pathological angiogenesis. FASEB J 34:13125–13139. https://doi.org/10.1096/fj.202000380RR

    Article  CAS  PubMed  Google Scholar 

  83. Papadaki C, Manolakou S, Lagoudaki E, Pontikakis S, Ierodiakonou D, Vogiatzoglou K, Messaritakis I, Trypaki M, Giannikaki L, Sfakianaki M, Kalykaki A, Mavroudis D, Tzardi M, Souglakos J (2020) Correlation of PKM2 and CD44 protein expression with poor prognosis in platinum-treated epithelial ovarian Cancer: a retrospective study. Cancers 12:1013. https://doi.org/10.3390/cancers12041013

    Article  CAS  PubMed Central  Google Scholar 

  84. Tamada M, Nagano O, Tateyama S, Ohmura M, Yae T, Ishimoto T, Sugihar E, Onishi N, Yamamoto T, Yanagawa H, Suematsu M, Saya H (2012) Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells. Cancer Res 72:1438–1448. https://doi.org/10.1158/0008-5472.CAN-11-3024

    Article  CAS  PubMed  Google Scholar 

  85. Braeutigam C, Rago L, Rolke A, Waldmeier L, Christofori G, Winter J (2014) The RNA-binding protein Rbfox2: an essential regulator of EMT-driven alternative splicing and a mediator of cellular invasion. Oncogene 33:1082–1092. https://doi.org/10.1038/onc.2013.50

    Article  CAS  PubMed  Google Scholar 

  86. Gordon MA, Babbs B, Cochrane DR, Bitler BG, Richer JK (2019) The long non-coding RNA MALAT1 promotes ovarian cancer progression by regulating RBFOX2-mediated alternative splicing. Mol Carcinog 58:196–205. https://doi.org/10.1002/mc.22919

    Article  CAS  PubMed  Google Scholar 

  87. Wen J, Toomer KH, Chen Z, Cai X (2015) Genome-wide analysis of alternative transcripts in human breast cancer. Breast Cancer Res Treat 151:295–307. https://doi.org/10.1007/s10549-015-3395-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ishii H, Saitoh M, Sakamoto K, Kondo T, Katoh R, Tanaka S, Motizuki M, Masuyama K, Miyazawa K (2014) Epithelial splicing regulatory proteins 1 (ESRP1) and 2 (ESRP2) suppress cancer cell motility via different mechanisms. J Biol Chem 289:27386–27399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yue PJ, Sun YY, Li YH, Xu ZM, Fu WN (2020) MYCT1 inhibits the EMT and migration of laryngeal cancer cells via the SP1/miR-629-3p/ESRP2 pathway. Cell Signal 74:109709. https://doi.org/10.1016/j.cellsig.2020.109709

    Article  CAS  PubMed  Google Scholar 

  90. Mizutani A, Koinuma D, Seimiya H, Miyazono K (2016) The Arkadia-ESRP2 axis suppresses tumor progression: analyses in clear-cell renal cell carcinoma. Oncogene 35:3514–3523. https://doi.org/10.1038/onc.2015.412

    Article  CAS  PubMed  Google Scholar 

  91. Lu ZX, Huang Q, Park JW, Shen S, Lin L, Tokheim CJ, Henry MD, Xing Y (2015) Transcriptome-wide landscape of pre-mRNA alternative splicing associated with metastatic colonization. Mol Cancer Res 13:305–318. https://doi.org/10.1158/1541-7786.MCR-14-0366

    Article  CAS  PubMed  Google Scholar 

  92. Fici P, Gallerani G, Morel AP, Mercatali L, Ibrahim T, Scarpi E, Amadori D, Puisieux A, Rigaud M, Fabbri F (2017) Splicing factor ratio as an index of epithelial-mesenchymal transition and tumor aggressiveness in breast cancer. Oncotarget 8:2423–2436. https://doi.org/10.18632/oncotarget.13682

    Article  PubMed  Google Scholar 

  93. Fagoonee S, Bearzi C, Di Cunto F, Clohessy JG, Rizzi R, Reschke M, Tolosano E, Provero P, Pandolfi PP, Silengo L, Altruda F (2013) The RNA binding protein ESRP1 fine-tunes the expression of pluripotency-related factors in mouse embryonic stem cells. PLoS One 8:e72300. https://doi.org/10.1371/journal.pone.0072300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Xu Y, Gao XD, Lee JH, Huang H, Tan H, Ahn J, Reinke LM, Peter ME, Feng Y, Gius D, Siziopikou KP, Peng J, Xiao X, Cheng C (2014) Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing. Genes Dev 28:1191–1203. https://doi.org/10.1101/gad.241968.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sun H, Liu T, Zhu D, Dong X, Liu F, Liang X, Chen C, Shao B, Wang M, Wang Y (2017) HnRNPM and CD44s expression affects tumor aggressiveness and predicts poor prognosis in breast cancer with axillary lymph node metastases. Genes Chromosomes Cancer 56:598–607. https://doi.org/10.1002/gcc.22463

    Article  CAS  PubMed  Google Scholar 

  96. Harvey SE, Xu Y, Lin X, Gao XD, Qiu Y, Ahn J, Xiao X, Cheng C (2018) Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT. RNA 24:1326–1338. https://doi.org/10.1261/rna.066712.118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hayes GM, Carrigan PE, Miller LJ (2007) Serine-arginine protein kinase 1 overexpression is associated with tumorigenic imbalance in mitogen-activated protein kinase pathways in breast, colonic, and pancreatic carcinomas. Cancer Res 67:2072–2080. https://doi.org/10.1158/0008-5472.CAN-06-2969

    Article  CAS  PubMed  Google Scholar 

  98. Gökmen-Polar Y, Neelamraju Y, Goswami CP, Gu X, Nallamothu G, Janga SC, Badve S (2015) Expression levels of SF3B3 correlate with prognosis and endocrine resistance in estrogen receptor-positive breast cancer. Mod Pathol 28:677–685. https://doi.org/10.1038/modpathol.2014.146

    Article  CAS  PubMed  Google Scholar 

  99. Gökmen-Polar Y, Neelamraju Y, Goswami CP, Gu Y, Gu X, Nallamothu G, Vieth E, Janga SC, Ryan M, Badve SS (2019) Splicing factor ESRP1 controls ER-positive breast cancer by altering metabolic pathways. EMBO Rep 20:e46078. https://doi.org/10.15252/embr.201846078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Vengoji R, Macha MA, Nimmakayala RK, Rachagani S, Siddiqui JA, Mallya K, Gorantla S, Jain M, Ponnusamy MP, Batra SK, Shonka N (2019) Afatinib and Temozolomide combination inhibits tumorigenesis by targeting EGFRvIII-cMet signaling in glioblastoma cells. J Exp Clin Cancer Res 38:266. https://doi.org/10.1186/s13046-019-1264-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hagen RM, Ladomery MR (2012) Role of splice variants in the metastatic progression of prostate cancer. Biochem Soc Trans 40:870–874. https://doi.org/10.1042/BST20120026

    Article  CAS  PubMed  Google Scholar 

  102. Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK (2012) Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets 16:15–31. https://doi.org/10.1517/14728222.2011.648617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Urbanski LM, Leclair N, Anczuków O (2018) Alternative-splicing defects in cancer: splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics. Wiley Interdiscip Rev RNA 9:e1476. https://doi.org/10.1002/wrna.1476

    Article  PubMed  PubMed Central  Google Scholar 

  104. Silden E, Hjelle SM, Wergeland L, Sulen A, Andresen V, Bourdon JC, Micklem DR, McCormack E, Gjertsen BT (2013) Expression of TP53 isoforms p53β or p53γ enhances chemosensitivity in TP53null cell lines. PLoS One 8:e56276. https://doi.org/10.1371/journal.pone.0056276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Surget S, Khoury MP, Bourdon JC (2013) Uncovering the role of p53 splice variants in human malignancy: a clinical perspective. Onco Targets Ther 7:57–68. https://doi.org/10.2147/OTT.S53876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Arsic N, Gadéa G, Lagerqvist EL, Busson M, Cahuzac N, Brock C, Hollande F, Gire V, Pannequin J, Roux P (2015) The p53 isoform Δ133p53β promotes cancer stem cell potential. Stem Cell Reports 4:531–540. https://doi.org/10.1016/j.stemcr.2015.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kourtidis A, Ngok SP, Anastasiadis PZ (2013) p120 catenin: an essential regulator of cadherin stability, adhesion-induced signaling, and cancer progression. Prog Mol Biol Transl Sci 116:409–432. https://doi.org/10.1016/B978-0-12-394311-8.00018-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Yanagisawa M, Huveldt D, Kreinest P, Lohse CM, Cheville JC, Parker AS, Copland JA, Anastasiadis PZ (2008) A p120 catenin isoform switch affects rho activity, induces tumor cell invasion, and predicts metastatic disease. J Biol Chem 283:18344–18354. https://doi.org/10.1074/jbc.M801192200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lin JC (2017) Therapeutic applications of targeted alternative splicing to cancer treatment. Int J Mol Sci 19:75. https://doi.org/10.3390/ijms19010075

    Article  CAS  PubMed Central  Google Scholar 

  110. Orian-Rousseau V, Ponta H (2015) Perspectives of CD44 targeting therapies. Arch Toxicol 89:3–14. https://doi.org/10.1007/s00204-014-1424-2

    Article  CAS  PubMed  Google Scholar 

  111. Li L, Hao X, Qin J, Tang W, He F, Smith A, Zhang M, Simeone DM, Qiao XT, Chen ZN, Lawrence TS, Xu L (2014) Antibody against CD44s inhibits pancreatic tumor initiation and postradiation recurrence in mice. Gastroenterology 146:1108–1118. https://doi.org/10.1053/j.gastro.2013.12.035

    Article  CAS  PubMed  Google Scholar 

  112. Gunia S, Hussein S, Radu DL, Pütz KM, Breyer R, Hecker H, Samii M, Walter GF, Stan AC (1999) CD44s-targeted treatment with monoclonal antibody blocks intracerebral invasion and growth of 9L gliosarcoma. Clin Exp Metastasis 17:221–230. https://doi.org/10.1023/a:1006699203287

    Article  CAS  PubMed  Google Scholar 

  113. Chen J, Lee BH, Williams IR, Kutok JL, Mitsiades CS, Duclos N, Cohen S, Adelsperger J, Okabe R, Coburn A, Moore S, Huntly BJP, Fabbro D, Anderson KC, Griffin JD, Gilliland DG (2005) FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies. Oncogene 24:8259–8267. https://doi.org/10.1038/sj.onc.1208989

    Article  CAS  PubMed  Google Scholar 

  114. Bruno IG, Jin W, Cote GJ (2004) Correction of aberrant FGFR1 alternative RNA splicing through targeting of intronic regulatory elements. Hum Mol Genet 13:2409–2420. https://doi.org/10.1093/hmg/ddh272

    Article  CAS  PubMed  Google Scholar 

  115. Yadav S, Bhagat SD, Gupta A, Samaiya A, Srivastava A, Shukla S (2019) Dietary-phytochemical mediated reversion of cancer-specific splicing inhibits Warburg effect in head and neck cancer. BMC Cancer 19:1031. https://doi.org/10.1186/s12885-019-6257-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The authors do not have any funding agency to acknowledge for this review article.

Author information

Author notes

  1. Debanwita Roy Burman, Shalini Das and Rahul Bhattacharya contributed equally to this work.

Authors and Affiliations

  1. Amity Institute of Biotechnology, Amity University, Kolkata, Major Arterial Road (South-East), AA II, Newtown, Kolkata, West Bengal, 700135, India

    Debanwita Roy Burman, Shalini Das, Chandrima Das & Rahul Bhattacharya

Authors
  1. Debanwita Roy Burman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shalini Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chandrima Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rahul Bhattacharya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rahul Bhattacharya.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roy Burman, D., Das, S., Das, C. et al. Alternative splicing modulates cancer aggressiveness: role in EMT/metastasis and chemoresistance. Mol Biol Rep 48, 897–914 (2021). https://doi.org/10.1007/s11033-020-06094-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-06094-y

Keywords

Search

Navigation