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Correlation of Musashi-1, Lgr5, and pEGFR expressions in human small intestinal adenocarcinomas

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Tumor Biology

Abstract

Recent studies have revealed that Musashi-1 and Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5) were putative stem cell genes. The epidermal growth factor receptor (EGFR) has also been extensively studied; it was known as an oncogenic driver in cancers. Overexpressions of Musashi-1, EGFR, and Lgr5 have been reported in some tumor tissues and cell lines. In this study, we used immunohistochemical analysis to investigate the expression pattern of Musashi-1, Lgr5, and pEGFR in 38 small intestinal adenocarcinomas (SIAs) resection specimens, 20 matched normal specimens and tried to analyze the correlations among them. The positive rate of Musashi-1, Lgr5, and pEGFR in SIAs, respectively, was 71 % (27/38), 55 % (21/38), and 45 % (17/38). Compared with the adjacent normal small intestinal mucosa, Musashi-1, Lgr5, and pEGFR protein were overexpressed in SIAs (P< 0.05). Furthermore, Musashi-1 and Lgr5 expressions were significantly correlated with the depth of wall invasion (P = 0.0011, P = 0.0017, respectively). Musashi-1 expression was closely correlated with Lgr5 (P = 0.015, r = 0.392). However, pEGFR expression was not associated with age, gender, tumor size, differentiation, depth of invasion, lymphatic metastasis, TNM stage, and pEGFR expression was not correlated with Musashi-1 or Lgr5 (P > 0.05, r = 0.064; P > 0.05, r = 0.307, respectively). Thus, we suggest that Musashi-1, Lgr5, and pEGFR are overexpressed in human SIAs and may play roles in human SIA carcinogenesis and progression.

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References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.

    Article  PubMed  Google Scholar 

  2. Howe JR, Karnell LH, Menck HR, et al. The American college of surgeons commission on cancer and the American cancer society. Adenocarcinoma of the small bowel: review of the national cancer data base, 1985–1995. Cancer. 1999;86:2693–706.

    Article  CAS  PubMed  Google Scholar 

  3. Lu Y, Frobom R, Lagergren J. Incidence patterns of small bowel cancer in a population-based study in Sweden: increase in duodenal adenocarcinoma. Cancer Epidemiol. 2012;36:e158–63.

    Article  PubMed  Google Scholar 

  4. Dabaja BS, Suki D, Pro B, et al. Adenocarcinoma of the small bowel: presentation, prognostic factors, and outcome of 217 patients. Cancer. 2004;101:518–26.

    Article  PubMed  Google Scholar 

  5. Czaykowski P, Hui D. Chemotherapy in small bowel adenocarcinoma: 10-year experience of the British Columbia cancer agency. Clin Oncol (R Coll Radiol). 2007;19:143–9.

    Article  CAS  Google Scholar 

  6. Koo DH, Yun SC, Hong YS, et al. Systemic chemo-therapy for treatment of advanced small bowel adenocarcinoma with prognostic factor analysis: retrospective study. BMC Cancer. 2011;11:205.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Jigyasu D, Bedikian AY, Stroehlein JR. Chemotherapy for primary adenocarcinoma of the small bowel. Cancer. 1984;53:23–5.

    Article  CAS  PubMed  Google Scholar 

  8. Bobryshev YV, Freeman AK, Botelho NK, et al. Expression of the putative stem cell marker Musashi-1 in Barrett’s esophagus and esophageal adenocarcinoma. Dis Esophagus. 2010;23:580–9.

    Article  CAS  PubMed  Google Scholar 

  9. Kuroda J, Yoshida M, Kitajima M, et al. Utility of preoperative chemoradiotherapy for advanced esophageal carcinoma. J Gastroenterol Hepatol. 2012;27 Suppl 3:88–94.

    Article  PubMed  Google Scholar 

  10. Siebzehnrubl FA, Jeske I, Muller D, et al. Spontaneous in vitro transformation of adult neural precursors into stem-like cancer cells. Brain Pathol. 2009;19:399–408.

    Article  CAS  PubMed  Google Scholar 

  11. McDonald T, Wang R, Bailey W, et al. Identification and cloning of an orphan G protein-coupled receptor of the glycoprotein hormone receptor subfamily. Biochem Biophys Res Commun. 1998;247:266–70.

    Article  CAS  PubMed  Google Scholar 

  12. Barker N, Clevers H. Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells. Gastroenterology. 2010;138:1681–96.

    Article  CAS  PubMed  Google Scholar 

  13. Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449:1003–7.

    Article  CAS  PubMed  Google Scholar 

  14. Rezza A, Skah S, Roche C, et al. The overexpression of the putative gut stem cell marker Musashi-1 induces tumorigenesis through Wnt and Notch activation. J Cell Sci. 2010;123:3256–65.

    Article  CAS  PubMed  Google Scholar 

  15. Walker F, Zhang HH, Odorizzi A, et al. LGR5 is a negative regulator of tumourigenicity, antagonizes Wnt signalling and regulates cell adhesion in colorectal cancer cell lines. PLoS ONE. 2011;6:e22733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Potten CS, Booth C, Tudor GL, et al. Identification of a putative intestinal stem cell and early lineage marker, Musashi-1. Differentiation. 2003;71:28–41.

    Article  CAS  PubMed  Google Scholar 

  17. Montgomery RK, Breault DT. Small intestinal stem cell markers. J Anat. 2008;213:52–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nishimura S, Wakabayashi N, Toyoda K, et al. Expression of Musashi-1 in human normal colon crypt cells: a possible stem cell marker of human colon epithelium. Dig Dis Sci. 2003;48:1523–9.

    Article  CAS  PubMed  Google Scholar 

  19. Hirsch D, Barker N, McNeil N, et al. LGR5 positivity defines stem-like cells in colorectal cancer. Carcinogenesis. 2014;35:849–58.

    Article  CAS  PubMed  Google Scholar 

  20. Schulenburg A, Cech P, Herbacek I, et al. CD44-positive colorectal adenoma cells express the potential stem cell markers Musashi antigen (msi1) and ephrin B2 receptor (EphB2). J Pathol. 2007;213:152–60.

    Article  CAS  PubMed  Google Scholar 

  21. Fan LF, Dong WG, Jiang CQ, et al. Expression of putative stem cell genes musashi-1, and β1-integrin in human colorectal adenomas and adenocarcinoma. Int J Color Dis. 2010;25:17–23.

    Article  Google Scholar 

  22. Uchida H, Yamazaki K, Fukuma M, et al. Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 in colorectal cancer. Cancer Sci. 2010;101:1731–7.

    Article  CAS  PubMed  Google Scholar 

  23. Toda M, Iizuka Y, Yu W, et al. Expression of the neural RNA-binding protein Musashi1 in human gliomas. Glia. 2001;34:1–7.

    Article  CAS  PubMed  Google Scholar 

  24. Shu HJ, Saito T, Watanabe H, et al. Expression of the Musashi1 gene encoding the RNA-binding protein in human hepatoma cell lines. Biochem Biophys Res Commun. 2002;293:150–4.

    Article  CAS  PubMed  Google Scholar 

  25. Ye F, Zhou C, Cheng Q, et al. Stem-cell-abundant proteins Nanog, Nucleostemin and Musashi1 are highly expressed in malignant cervical epithelial cells. BMC Cancer. 2008;8:108.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Yamanoi K, Fukuma M, Uchida H, et al. Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 in gastric cancer. Pathol Int. 2013;63:13–9.

    Article  CAS  PubMed  Google Scholar 

  27. Becker L, Huang Q, Mashimo Q. Lgr5, an intestinal stem cell marker, is abnormally expressed in Barrett’s esophagus and esophageal adenocarcinoma. Dis Esophagus. 2010;23:168–74.

    Article  CAS  PubMed  Google Scholar 

  28. Wu XS, Xi HQ, Chen L. Lgr5 is a potential marker of colorectal carcinoma stem cells that correlates with patient survival. World J Surg Oncol. 2012;10:244.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Todaro M, Francipane MG, Medema JP, Stassi G. Colon cancer stem cells: promise of targeted therapy. Gastroenterology. 2010;138:2151–62.

    Article  CAS  PubMed  Google Scholar 

  30. Al-Hajj M. Cancer stem cells and oncology therapeutics. Curr Opin Oncol. 2007;19:61–4.

    PubMed  Google Scholar 

  31. Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006;366:2–16.

    Article  CAS  PubMed  Google Scholar 

  32. Lurje G, Lenz HJ. EGFR signaling and drug discovery. Oncol-Basel. 2009;77:400–10.

    Article  CAS  Google Scholar 

  33. Bianco R, Gelardi T, Damiano V, Ciardiello F, Tortora G. Rational bases for the development of EGFR inhibitors for cancer treatment. Int J Biochem Cell Biol. 2007;39:1416–31.

    Article  CAS  PubMed  Google Scholar 

  34. Sebastian S, Settleman J, Reshkin SJ, et al. The complexity of targeting EGFR signalling in cancer: from expression to turnover. Biochim Biophys Acta. 2006;1766:120–39.

    CAS  PubMed  Google Scholar 

  35. Zhang H, Berezov A, Wang Q, et al. ErbB receptors: from oncogenes to targeted cancer therapies. J Clin Invest. 2007;117:2051–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Arteaga CL. ErbB-targeted therapeutic approaches in human cancer. Exp Cell Res. 2003;284:122–30.

    Article  CAS  PubMed  Google Scholar 

  37. Li S, Li Q. Cancer stem cells and tumor metastasis (Review). Int J Oncol. 2014;44:1806–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. O’Brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445:106–10.

    Article  PubMed  Google Scholar 

  39. Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445:111–5.

    Article  CAS  PubMed  Google Scholar 

  40. Levin TG, Powell AE, Davies PS, et al. Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastrointestinal tract. Gastroenterology. 2010;139:2072–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chu P, Clanton DJ, Snipas TS, et al. Characterization of a subpopulation of colon cancer cells with stem cell-like properties. Int J Cancer. 2009;124:1312–21.

    Article  CAS  PubMed  Google Scholar 

  42. Carpentino JE, Hynes MJ, Appelman HD, et al. Aldehyde dehydrogenase expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer. Cancer Res. 2009;69:8208–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Becker L, Huang Q, Mashimo H. Immunostaining of Lgr5, an intestinal stem cell marker, in normal and premalignant human gastrointestinal tissue. Sci World J. 2008;8:1168–76.

    Article  CAS  Google Scholar 

  44. Garcia MI, Ghiani M, Lefort A, et al. LGR5 deficiency deregulates Wnt signaling and leads to precocious Paneth cell differentiation in the fetal intestine. Dev Biol. 2009;331:58–67.

    Article  CAS  PubMed  Google Scholar 

  45. Sureban SM, May R, George RJ, et al. Knockdown of RNA binding protein Musashi-1 leads to tumor regression in vivo. Gastroenterology. 2008;134:1448–58.

    Article  CAS  PubMed  Google Scholar 

  46. Morita H, Mazerbourg S, Bouley DM, et al. Neonatal lethality of LGR5 null mice is associated with ankyloglossia and gastrointestinal distension. Mol Cell Biol. 2004;24:9736–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Aguirre A, Rubio ME, Gallo V. Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature. 2010;467:323–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu X, Qin J, Luo Q, et al. Cross-talk between EGF and BMP9 signalling pathways regulates the osteogenic differentiation of mesenchymal stem cells. J Cell Mol Med. 2013;17:1160–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Perez A, Neskey DM, Wen J, et al. CD44 interacts with EGFR and promotes head and neck squamous cell carcinoma initiation and progression. Oral Oncol. 2013;49:306–13.

    Article  CAS  PubMed  Google Scholar 

  50. Feng Y, Dai X, Li X, et al. EGF signalling pathway regulates colon cancer stem cell proliferation and apoptosis. Cell Prolif. 2012;45:413–9.

    Article  CAS  PubMed  Google Scholar 

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Wang, Y., Jiang, CQ. & Fan, LF. Correlation of Musashi-1, Lgr5, and pEGFR expressions in human small intestinal adenocarcinomas. Tumor Biol. 36, 6075–6082 (2015). https://doi.org/10.1007/s13277-015-3288-3

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