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Cancer Res. 2014 May 15;74(10):2785-95. doi: 10.1158/0008-5472.CAN-13-3176. Epub 2014 Mar 19.

CLPTM1L promotes growth and enhances aneuploidy in pancreatic cancer cells.

Author information

1
Authors' Affiliations: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics; Pediatric Oncology Branch; Laboratory of Pathology; Division of Cancer Control and Population Sciences; Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda; Laboratory of Proteomics and Analytical Technologies, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research; Laboratory of Protein Dynamics and Signaling and Laboratory of Cell & Developmental Signaling, NCI-Frederick, Frederick, Maryland; Keck School of Medicine, University of Southern California, Los Angeles, California; University of Hawaii Cancer Center, Honolulu, Hawaii; Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa; and Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
2
Authors' Affiliations: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics; Pediatric Oncology Branch; Laboratory of Pathology; Division of Cancer Control and Population Sciences; Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda; Laboratory of Proteomics and Analytical Technologies, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research; Laboratory of Protein Dynamics and Signaling and Laboratory of Cell & Developmental Signaling, NCI-Frederick, Frederick, Maryland; Keck School of Medicine, University of Southern California, Los Angeles, California; University of Hawaii Cancer Center, Honolulu, Hawaii; Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa; and Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota amundadottirl@mail.nih.gov.

Abstract

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.

PMID:
24648346
PMCID:
PMC4030677
DOI:
10.1158/0008-5472.CAN-13-3176
[Indexed for MEDLINE]
Free PMC Article

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