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Digestive Diseases and Sciences

, Volume 57, Issue 4, pp 905–912 | Cite as

SEL1L, an UPR Response Protein, a Potential Marker of Colonic Cell Transformation

  • Hassan AshktorabEmail author
  • William Green
  • Giovanna Finzi
  • Fausto Sessa
  • Mehdi Nouraie
  • Edward L. Lee
  • Annalisa Morgano
  • Antonio Moschetta
  • Monica Cattaneo
  • Renato Mariani-Costantini
  • Hassan Brim
  • Ida BiunnoEmail author
Original Article

Abstract

Background

SEL1L gene product is implicated in the endoplasmic reticulum (ER)-associated protein degradation and Unfolded Protein Response pathways. This gene and associated miRNAs have been indicated as predictive and prognostic markers of pancreatic cancer.

Aim

Explore the role of SEL1L in colorectal cancer (CRC) progression.

Methods

SEL1L expression was analysed immunohistochemically in 153 adenomas and 71 CRCs from African American and North Italian patients. The distribution of stained cells was determined by computing median and inter quartile range. The receiver operating characteristics plot was used as discriminate power of SEL1L expression, CRC diagnosis and the effects on patient survival.

Results

SEL1L was low in normal mucosa and confined to few scattered cells at the base crypt of the villi and in the foveolar glandular compartment. The highest levels were in Paneth cells within the lysosomes. The enterocytic progenitor cells and mature enterocytes showed less cytoplasmic staining. In CRCs, SEL1L expression significantly correlated with the progression from adenoma to carcinoma (P = 0.0001) being stronger in well-to-moderately differentiated cancers. No correlation was found with other clinicopathological characteristics or ethnicity.

Conclusions

SEL1L expression is a potential CRC tissue biomarker since its expression is significantly higher in adenoma cells with respect to normal mucosa. The levels of expression decrease sensibly in undifferentiated CRC cancers. Interestingly, Paneth cells contain high levels of SEL1L protein that could indicate pre-neoplastic mucosa undergoing neoplastic transformation. Since SEL1L’s major function lies within ER stress and active ERAD response, it may identify CRCs with differentiated secretory phenotype and acute cellular stress.

Keywords

SEL1L expression Colorectal cancers Paneth’s cells 

Notes

Acknowledgments

This work was supported in part by Grants #CA102681 and CA90890 funded by the National Cancer Institute, NIH, by the RCMI, by the Italian Government MIUR-FIRB grant nRBIP064CRT to IB, by Italian Government MIUR 60% grants to RMC for 2008 and 2009 and by a grant from “Associazione Italiana per la Ricerca sul Cancro” (AIRC) to AM. Dr. A. Morgano is a PhD student in the Oncology program at G. d’Annunzio University, Chieti, Italy.

Conflict of Interest

None

References

  1. 1.
    Vembar SS, Brodsky JL. One step at a time: Endoplasmic reticulum-associated degradation. Natl Rev Mol Cell Biol. 2008;9:944–957. doi: 10.1038/nrm2546.CrossRefGoogle Scholar
  2. 2.
    Cattaneo M, Lotti LV, Martino S, et al. Secretion of novel SEL1L endogenous variants is promoted by ER stress/UPR via endosomes and shed vesicles in human cancer cells. PLoS One. 2011;6:e17206. doi: 10.1371/journal.pone.0017206.PubMedCrossRefGoogle Scholar
  3. 3.
    Ma J, Stampfer MJ, Giovannucci E, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res. 1997;57:1098–1102.PubMedGoogle Scholar
  4. 4.
    Ma Y, Hendershot LM. ER chaperone functions during normal and stress conditions. J Chem Neuroanat. 2004;28:51–65. doi: 10.1016/j.jchemneu.2003.08.007.PubMedCrossRefGoogle Scholar
  5. 5.
    Orlowski RZ, Zeger EL. Targeting the proteasome as a therapeutic strategy against haematological malignancies. Expert Opin Investig Drugs. 2006;15:117–130. doi: 10.1517/13543784.15.2.117.PubMedCrossRefGoogle Scholar
  6. 6.
    Scriven P, Brown NJ, Pockley AG, Wyld L. The unfolded protein response and cancer: A brighter future unfolding? J Mol Med. 2007;85:331–341. doi: 10.1007/s00109-006-0150-5.PubMedCrossRefGoogle Scholar
  7. 7.
    Voorhees PM, Dees EC, O’Neil B, Orlowski RZ. The proteasome as a target for cancer therapy. Clin Cancer Res. 2003;9:6316–6325.PubMedGoogle Scholar
  8. 8.
    Zhang F, Hamanaka RB, Bobrovnikova-Marjon E, et al. Ribosomal stress couples the unfolded protein response to p53-dependent cell cycle arrest. J Biol Chem. 2006;281:30036–30045. doi: 10.1074/jbc.M604674200.PubMedCrossRefGoogle Scholar
  9. 9.
    Wang J, Hua H, Ran Y, et al. Derlin-1 is overexpressed in human breast carcinoma and protects cancer cells from endoplasmic reticulum stress-induced apoptosis. Breast Cancer Res. 2008;10:R7. doi: 10.1186/bcr1849.PubMedCrossRefGoogle Scholar
  10. 10.
    Cattaneo M, Orlandini S, Beghelli S, et al. SEL1L expression in pancreatic adenocarcinoma parallels SMAD4 expression and delays tumor growth in vitro and in vivo. Oncogene. 2003;22:6359–6368. doi: 10.1038/sj.onc.1206665.PubMedCrossRefGoogle Scholar
  11. 11.
    Orlandi R, Cattaneo M, Troglio F, et al. SEL1L expression decreases breast tumor cell aggressiveness in vivo and in vitro. Cancer Res. 2002;62:567–574.PubMedGoogle Scholar
  12. 12.
    Granelli P, Cattaneo M, Ferrero S, et al. SEL1L and squamous cell carcinoma of the esophagus. Clin Cancer Res. 2004;10:5857–5861. doi: 10.1158/1078-0432.CCR-04-0075.PubMedCrossRefGoogle Scholar
  13. 13.
    Barberis MC, Roz E, Biunno I. SEL1L expression in prostatic intraepithelial neoplasia and adenocarcinoma: An immunohistochemical study. Histopathology. 2006;48:614–616. doi: 10.1111/j.1365-2559.2005.02274.x.PubMedCrossRefGoogle Scholar
  14. 14.
    Ferrero S, Falleni M, Cattaneo M, et al. SEL1L expression in non-small cell lung cancer. Hum Pathol. 2006;37:505–512. doi: 10.1016/j.humpath.2005.12.012.PubMedCrossRefGoogle Scholar
  15. 15.
    Greene FL, Sobin LH. A worldwide approach to the TNM staging system: Collaborative efforts of the AJCC and UICC. J Surg Oncol. 2009;99:269–272. doi: 10.1002/jso.21237.PubMedCrossRefGoogle Scholar
  16. 16.
    Ashktorab H, Belgrave K, Hosseinkhah F, et al. Global histone H4 acetylation and HDAC2 expression in colon adenoma and carcinoma. Dig Dis Sci. 2009;54:2109–2117. doi: 10.1007/s10620-008-0601-7.PubMedCrossRefGoogle Scholar
  17. 17.
    Hewitt SM. The application of tissue microarrays in the validation of microarray results. Methods Enzymol. 2006;410:400–415.PubMedCrossRefGoogle Scholar
  18. 18.
    Cattaneo M, Lotti LV, Martino S, et al. Functional characterization of two secreted SEL1L isoforms capable of exporting unassembled substrate. J Biol Chem. 2009;284:11405–11415. doi: 10.1074/jbc.M805408200.PubMedCrossRefGoogle Scholar
  19. 19.
    Cattaneo M, Otsu M, Fagioli C, et al. SEL1L and HRD1 are involved in the degradation of unassembled secretory Ig-mu chains. J Cell Physiol. 2008;215:794–802. doi: 10.1002/jcp.21364.PubMedCrossRefGoogle Scholar
  20. 20.
    Christianson JC, Shaler TA, Tyler RE, Kopito RR. OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD. Nat Cell Biol. 2008;10:272–282. doi: 10.1038/ncb1689.PubMedCrossRefGoogle Scholar
  21. 21.
    Mueller B, Klemm EJ, Spooner E, Claessen JH, Ploegh HL. SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins. Proc Natl Acad Sci USA. 2008;105:12325–12330. doi: 10.1073/pnas.0805371105.PubMedCrossRefGoogle Scholar
  22. 22.
    Mueller B, Lilley BN, Ploegh HL. SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER. J Cell Biol. 2006;175:261–270. doi: 10.1083/jcb.200605196.PubMedCrossRefGoogle Scholar
  23. 23.
    Cattaneo M, Fontanella E, Canton C, Delia D, Biunno I. SEL1L affects human pancreatic cancer cell cycle and invasiveness through modulation of PTEN and genes related to cell-matrix interactions. Neoplasia. 2005;7:1030–1038.PubMedCrossRefGoogle Scholar
  24. 24.
    Liu Q, Chen J, Mai B, et al. A single-nucleotide polymorphism in tumor suppressor gene SEL1L as a predictive and prognostic marker for pancreatic ductal adenocarcinoma in caucasians. Mol Carcinog. 2011. (Epub ahead of print). doi: 10.1002/mc.20808.
  25. 25.
    Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843–850. doi: 10.1038/nature03319.PubMedCrossRefGoogle Scholar
  26. 26.
    Fribley AM, Evenchik B, Zeng Q, et al. Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa. J Biol Chem. 2006;281:31440–31447. doi: 10.1074/jbc.M604356200.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Hassan Ashktorab
    • 1
    • 2
    Email author
  • William Green
    • 1
    • 2
  • Giovanna Finzi
    • 3
  • Fausto Sessa
    • 4
    • 5
  • Mehdi Nouraie
    • 1
    • 2
  • Edward L. Lee
    • 1
    • 2
  • Annalisa Morgano
    • 6
    • 7
    • 8
  • Antonio Moschetta
    • 8
  • Monica Cattaneo
    • 9
  • Renato Mariani-Costantini
    • 6
    • 7
  • Hassan Brim
    • 1
    • 2
  • Ida Biunno
    • 9
    Email author
  1. 1.Department of Medicine and Cancer CenterHoward University College of MedicineWashington, DCUSA
  2. 2.Department of PathologyHoward University College of MedicineWashington, DCUSA
  3. 3.Department of PathologyOspedale di CircoloVareseItaly
  4. 4.Department of Human MorphologyUniversity of InsubriaVareseItaly
  5. 5.Department of PathologyMultimedica IRCCSMilanItaly
  6. 6.Department of Oncology and Neuroscience“G. d’Annunzio” UniversityChietiItaly
  7. 7.Center of Excellence on Ageing, G. d’Annunzio University FoundationChieti-PescaraItaly
  8. 8.Laboratory of Lipid Metabolism and Cancer, Department of Translational Pharmacology (DTP)Consorzio Mario Negri SudS. Maria ImbaroItaly
  9. 9.Institute of Genetics and Biomedical Research-National Research CouncilMilanoItaly

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