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Journal of Cancer Research and Clinical Oncology

Erschienen in:

13.06.2019 | Original Article – Cancer Research

Aberrant expression of Sec61α in esophageal cancers

verfasst von: Kai Bachmann, Maximillian Bockhorn, Oliver Mann, Florian Gebauer, Marco Blessmann, Jakob Robert Izbicki, Katharina Grupp

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 8/2019

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Abstract

Introduction

The heterotrimeric Sec61α translocon complex is topological located in the membrane of the endoplasmic reticulum (ER) and allows protein transport and calcium across the membrane. Recently, aberrant expression of Sec proteins was linked to carcinogenesis and prognosis of patients.

Materials and methods

Here, we analysed the role of Sec61α in esophageal cancer, and we analysed Sec61α staining on a tissue microarray containing more than 600 esophageal cancer specimens by immunohistochemistry.

Results

Sec61α staining was always strong in benign esophagus, but was only found in 5% of interpretable esophageal adenocarcinomas (EACs) and 14.5% of squamous cell carcinomas (ESCCs). Reduced Sec61α staining was not strongly linked to tumor phenotype in both subgroups of esophageal cancers and was unrelated to clinical outcome of patients (EACs: p = 0.8051 and ESCCs: p = 0.2751).

Conclusions

Thus, Sec61α measurement has not an additional prognostic benefit for the patients.

Becker T, Bhushan S, Jarasch A, Armache J-P, Funes S, Jossinet F, Gumbart J, Mielke T, Berninghausen O, Schulten K, Westhof E, Gilmore R, Mandon EC, Beckmann R (2009) Structure of monomeric yeast and mammalian Sec61 complexes interacting with the translating ribosome. Science 326:1369–1373. https://doi.org/10.1126/science.1178535 CrossRefPubMedPubMedCentral

Casper M, Weber SN, Kloor M, Müllenbach R, Grobholz R, Lammert F, Zimmer V (2013) Hepatocellular carcinoma as extracolonic manifestation of Lynch syndrome indicates SEC63 as potential target gene in hepatocarcinogenesis. Scand J Gastroenterol 48:344–351. https://doi.org/10.3109/00365521.2012.752030 CrossRefPubMed

Conti BJ, Devaraneni PK, Yang Z, David LL, Skach WR (2015) Cotranslational stabilization of Sec62/63 within the er Sec61 translocon is controlled by distinct substrate-driven translocation events. Mol Cell 58:269–283. https://doi.org/10.1016/j.molcel.2015.02.018 CrossRefPubMedPubMedCentral

Flourakis M, van Coppenolle F, Lehen’kyi VY, Beck B, Skryma R, Prevarskaya N (2006) Passive calcium leak via translocon is a first step for iPLA2-pathway regulated store operated channels activation. FASEB J 20:1215–1217. https://doi.org/10.1096/fj.05-5254fje CrossRefPubMed

Giunti R, Gamberucci A, Fulceri R, Bánhegyi G, Benedetti A (2007) Both translocon and a cation channel are involved in the passive Ca²⁺ leak from the endoplasmic reticulum: a mechanistic study on rat liver microsomes. Arch Biochem Biophys 462:115–121. https://doi.org/10.1016/j.abb.2007.03.039 CrossRefPubMed

Görlich D, Prehn S, Hartmann E, Kalies KU, Rapoport TA (1992) A mammalian homolog of SEC61p and SECYp is associated with ribosomes and nascent polypeptides during translocation. Cell 71:489–503CrossRefPubMed

Kaiser M-L, Römisch K (2015) Proteasome 19S RP binding to the Sec61 channel plays a key role in ERAD. PLoS One 10:e0117260. https://doi.org/10.1371/journal.pone.0117260 CrossRefPubMedPubMedCentral

Kim H, Bhattacharya A, Qi L (2015) Endoplasmic reticulum quality control in cancer: friend or foe. Semin Cancer Biol 33:25–33. https://doi.org/10.1016/j.semcancer.2015.02.003 CrossRefPubMedPubMedCentral

Linxweiler M, Schick B, Zimmermann R (2017) Let’s talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine. Signal Transduct Target Ther 2:17002. https://doi.org/10.1038/sigtrans.2017.2 CrossRefPubMedPubMedCentral

Lomax RB, Camello C, van Coppenolle F, Petersen OH, Tepikin AV (2002) Basal and physiological Ca(2+) leak from the endoplasmic reticulum of pancreatic acinar cells. Second messenger-activated channels and translocons. J Biol Chem 277:26479–26485. https://doi.org/10.1074/jbc.M201845200 CrossRefPubMed

Lu Z, Zhou L, Killela P, Rasheed AB, Di C, Poe WE, McLendon RE, Bigner DD, Nicchitta C, Yan H (2009) Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress. Cancer Res 69:9105–9111. https://doi.org/10.1158/0008-5472.CAN-09-2775 CrossRefPubMedPubMedCentral

Mirlacher M, Simon R (2010) Recipient block TMA technique. Methods Mol Biol 664:37–44. https://doi.org/10.1007/978-1-60761-806-5_4 CrossRefPubMed

Mori Y, Sato F, Selaru FM, Olaru A, Perry K, Kimos MC, Tamura G, Matsubara N, Wang S, Xu Y, Yin J, Zou T-T, Leggett B, Young J, Nukiwa T, Stine OC, Abraham JM, Shibata D, Meltzer SJ (2002) Instabilotyping reveals unique mutational spectra in microsatellite-unstable gastric cancers. Cancer Res 62:3641–3645PubMed

Nyathi Y, Wilkinson BM, Pool MR (2013) Co-translational targeting and translocation of proteins to the endoplasmic reticulum. Biochim Biophys Acta 1833:2392–2402. https://doi.org/10.1016/j.bbamcr.2013.02.021 CrossRefPubMed

Ong HL, Liu X, Sharma A, Hegde RS, Ambudkar IS (2007) Intracellular Ca(2+) release via the ER translocon activates store-operated calcium entry. Pflugers Arch 453:797–808. https://doi.org/10.1007/s00424-006-0163-5 CrossRefPubMed

Park E, Rapoport TA (2012) Mechanisms of Sec61/SecY-mediated protein translocation across membranes. Annu Rev Biophys 41:21–40. https://doi.org/10.1146/annurev-biophys-050511-102312 CrossRefPubMed

Pfeffer S, Dudek J, Gogala M, Schorr S, Linxweiler J, Lang S, Becker T, Beckmann R, Zimmermann R, Förster F (2014) Structure of the mammalian oligosaccharyl-transferase complex in the native ER protein translocon. Nat Commun 5:3072. https://doi.org/10.1038/ncomms4072 CrossRefPubMed

Pfeffer S, Burbaum L, Unverdorben P, Pech M, Chen Y, Zimmermann R, Beckmann R, Förster F (2015) Structure of the native Sec61 protein-conducting channel. Nat Commun 6:8403. https://doi.org/10.1038/ncomms9403 CrossRefPubMed

Roy A, Wonderlin WF (2003) The permeability of the endoplasmic reticulum is dynamically coupled to protein synthesis. J Biol Chem 278:4397–4403. https://doi.org/10.1074/jbc.M207295200 CrossRefPubMed

Schulmann K, Brasch FE, Kunstmann E, Engel C, Pagenstecher C, Vogelsang H, Krüger S, Vogel T, Knaebel H-P, Rüschoff J, Hahn SA, Knebel-Doeberitz MV, Moeslein G, Meltzer SJ, Schackert HK, Tympner C, Mangold E, Schmiegel W (2005) HNPCC-associated small bowel cancer: clinical and molecular characteristics. Gastroenterology 128:590–599CrossRefPubMed

Shao S, Hegde RS (2011) Membrane protein insertion at the endoplasmic reticulum. Annu Rev Cell Dev Biol 27:25–56. https://doi.org/10.1146/annurev-cellbio-092910-154125 CrossRefPubMedPubMedCentral

Simon SM, Blobel G (1991) A protein-conducting channel in the endoplasmic reticulum. Cell 65:371–380CrossRefPubMed

Skach WR (2009) Cellular mechanisms of membrane protein folding. Nat Struct Mol Biol 16:606–612. https://doi.org/10.1038/nsmb.1600 CrossRefPubMedPubMedCentral

Smith MH, Ploegh HL, Weissman JS (2011) Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science 334:1086–1090. https://doi.org/10.1126/science.1209235 CrossRefPubMed

Song Y, Li L, Ou Y, Gao Z, Li E, Li X, Zhang W, Wang J, Xu L, Zhou Y, Ma X, Liu L, Zhao Z, Huang X, Fan J, Dong L, Chen G, Ma L, Yang J, Chen L, He M, Li M, Zhuang X, Huang K, Qiu K, Yin G, Guo G, Feng Q, Chen P, Wu Z, Wu J, Ma L, Zhao J, Luo L, Fu M, Xu B, Chen B, Li Y, Tong T, Wang M, Liu Z, Lin D, Zhang X, Yang H, Wang J, Zhan Q (2014) Identification of genomic alterations in oesophageal squamous cell cancer. Nature 509:91–95. https://doi.org/10.1038/nature13176 CrossRefPubMed

van Coppenolle F, Vanden Abeele F, Slomianny C, Flourakis M, Hesketh J, Dewailly E, Prevarskaya N (2004) Ribosome-translocon complex mediates calcium leakage from endoplasmic reticulum stores. J Cell Sci 117:4135–4142. https://doi.org/10.1242/jcs.01274 CrossRefPubMed

Van den Berg B, Clemons WM, Collinson I, Modis Y, Hartmann E, Harrison SC, Rapoport TA (2004) X-ray structure of a protein-conducting channel. Nature 427:36–44. https://doi.org/10.1038/nature02218 CrossRefPubMed

Watanabe G, Kaganoi J, Imamura M, Shimada Y, Itami A, Uchida S, Sato F, Kitagawa M (2001) Progression of esophageal carcinoma by loss of EGF-STAT1 pathway. Cancer J 7:132–139PubMed

Wirth A, Jung M, Bies C, Frien M, Tyedmers J, Zimmermann R, Wagner R (2003) The Sec61p complex is a dynamic precursor activated channel. Mol Cell 12:261–268CrossRefPubMed

Wonderlin WF (2009) Constitutive, translation-independent opening of the protein-conducting channel in the endoplasmic reticulum. Pflugers Arch 457:917–930. https://doi.org/10.1007/s00424-008-0545-y CrossRefPubMed

Titel: Aberrant expression of Sec61α in esophageal cancers
verfasst von: Kai Bachmann
Maximillian Bockhorn
Oliver Mann
Florian Gebauer
Marco Blessmann
Jakob Robert Izbicki
Katharina Grupp
Publikationsdatum: 13.06.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 8/2019
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-019-02955-7

Springer Medizin

Aberrant expression of Sec61α in esophageal cancers