CLPTM1L Promotes Growth and Enhances Aneuploidy in Pancreatic Cancer Cells
| العنوان: | CLPTM1L Promotes Growth and Enhances Aneuploidy in Pancreatic Cancer Cells |
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| المؤلفون: | Stephen M. Hewitt, Christopher J. Westlake, Marta Dzyadyk, Kris Ylaya, Valentina M. Factor, Wendy Cozen, Adam Cheuk, Irene Collins, Thorkell Andresson, Jadranka Loncarek, Snorri S. Thorgeirsson, Abbey Thompson, Brenda Y. Hernandez, Hemang Parikh, Charles F. Lynch, Gloria M. Petersen, Lizhi Zhang, William R. Bamlet, Jason W. Hoskins, Zhen Xiao, Allen D. Bosley, Laufey T. Amundadottir, Sean F. Altekruse, Jinping Jia |
| المصدر: | Cancer Research. 74:2785-2795 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Cancer Research, Candidate gene, Mice, Nude, Cell Growth Processes, Biology, Article, Mice, Cell Line, Tumor, Pancreatic cancer, medicine, Animals, Humans, Myosin Type II, Endoplasmic reticulum, HEK 293 cells, Membrane Proteins, Aneuploidy, medicine.disease, Molecular biology, Neoplasm Proteins, Pancreatic Neoplasms, HEK293 Cells, medicine.anatomical_structure, Oncology, Membrane protein, Heterografts, Female, CLPTM1L Gene, Pancreas, Cytokinesis, Carcinoma, Pancreatic Ductal, Subcellular Fractions |
| الوصف: | Genome-wide association studies (GWAS) of 10 different cancers have identified pleiotropic cancer predisposition loci across a region of chromosome 5p15.33 that includes the TERT and CLPTM1L genes. Of these, susceptibility alleles for pancreatic cancer have mapped to the CLPTM1L gene, thus prompting an investigation of the function of CLPTM1L in the pancreas. Immunofluorescence analysis indicated that CLPTM1L localized to the endoplasmic reticulum where it is likely embedded in the membrane, in accord with multiple predicted transmembrane domains. Overexpression of CLPTM1L enhanced growth of pancreatic cancer cells in vitro (1.3–1.5–fold; PDAY7 < 0.003) and in vivo (3.46-fold; PDAY68 = 0.039), suggesting a role in tumor growth; this effect was abrogated by deletion of two hydrophilic domains. Affinity purification followed by mass spectrometry identified an interaction between CLPTM1L and non-muscle myosin II (NMM-II), a protein involved in maintaining cell shape, migration, and cytokinesis. The two proteins colocalized in the cytoplasm and, after treatment with a DNA-damaging agent, at the centrosomes. Overexpression of CLPTM1L and depletion of NMM-II induced aneuploidy, indicating that CLPTM1L may interfere with normal NMM-II function in regulating cytokinesis. Immunohistochemical analysis revealed enhanced staining of CLPTM1L in human pancreatic ductal adenocarcinoma (n = 378) as compared with normal pancreatic tissue samples (n = 17; P = 1.7 × 10−4). Our results suggest that CLPTM1L functions as a growth-promoting gene in the pancreas and that overexpression may lead to an abrogation of normal cytokinesis, indicating that it should be considered as a plausible candidate gene that could explain the effect of pancreatic cancer susceptibility alleles on chr5p15.33. Cancer Res; 74(10); 2785–95. ©2014 AACR. |
| تدمد: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-13-3176 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8ee446a11adbfc92455636fddcf4fd64 https://doi.org/10.1158/0008-5472.can-13-3176 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8ee446a11adbfc92455636fddcf4fd64 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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| DOI: | 10.1158/0008-5472.can-13-3176 |