CLPTM1L promotes growth and enhances aneuploidy in pancreatic cancer cells

Adam Cheuk; Irene Collins; Hemang Parikh; Zhen Xiao; Kris Ylaya; Marta Dzyadyk; Wendy Cozen; Brenda Y Hernandez; Charles F Lynch; Jadranka Loncarek; Sean F Altekruse; Lizhi Zhang; Christopher J Westlake; Valentina M Factor; Snorri Thorgeirsson; William R Bamlet; Jinping Jia; Stephen M Hewitt; Allen D Bosley; Gloria M Petersen; Abbey Thompson; Thorkell Andresson; Jason W Hoskins; Laufey T Amundadottir

doi:10.1158/0008-5472.CAN-13-3176

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CLPTM1L promotes growth and enhances aneuploidy in pancreatic cancer cells

Journal article

Open access

Peer reviewed

CLPTM1L promotes growth and enhances aneuploidy in pancreatic cancer cells

Adam Cheuk, Irene Collins, Hemang Parikh, Zhen Xiao, Kris Ylaya, Marta Dzyadyk, Wendy Cozen, Brenda Y Hernandez, Charles F Lynch, Jadranka Loncarek, …

Cancer research (Chicago, Ill.), Vol.74(10), pp.2785-2795

05/15/2014

DOI: 10.1158/0008-5472.CAN-13-3176

PMCID: PMC4030677

PMID: 24648346

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https://doi.org/10.1158/0008-5472.CAN-13-3176View

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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.

Pancreatic Neoplasms - metabolism

Membrane Proteins - genetics

Neoplasm Proteins - biosynthesis

Humans

Pancreatic Neoplasms - pathology

Carcinoma, Pancreatic Ductal - metabolism

Aneuploidy

Cell Growth Processes - physiology

Pancreatic Neoplasms - genetics

Neoplasm Proteins - metabolism

Carcinoma, Pancreatic Ductal - pathology

Subcellular Fractions - metabolism

Carcinoma, Pancreatic Ductal - genetics

Membrane Proteins - biosynthesis

Animals

Heterografts

Myosin Type II - metabolism

Mice, Nude

HEK293 Cells

Cell Line, Tumor

Female

Membrane Proteins - metabolism

Mice

Neoplasm Proteins - genetics

Details

Title: Subtitle: CLPTM1L promotes growth and enhances aneuploidy in pancreatic cancer cells
Creators: Adam Cheuk - National Cancer Institute
Irene Collins - National Cancer Institute
Hemang Parikh - National Cancer Institute
Zhen Xiao - Frederick National Laboratory for Cancer Research
Kris Ylaya - National Cancer Institute
Marta Dzyadyk - National Cancer Institute
Wendy Cozen - University of Southern California
Brenda Y Hernandez - University of Hawaii Cancer Center
Charles F Lynch - University of Iowa
Jadranka Loncarek - National Cancer Institute
Sean F Altekruse - National Cancer Institute
Lizhi Zhang - Mayo Clinic
Christopher J Westlake - National Cancer Institute
Valentina M Factor - National Cancer Institute
Snorri Thorgeirsson - National Cancer Institute
William R Bamlet - Mayo Clinic
Jinping Jia - National Cancer Institute
Stephen M Hewitt - National Cancer Institute
Allen D Bosley - Frederick National Laboratory for Cancer Research
Gloria M Petersen - Mayo Clinic
Abbey Thompson - National Cancer Institute
Thorkell Andresson - Frederick National Laboratory for Cancer Research
Jason W Hoskins - National Cancer Institute
Laufey T Amundadottir - National Cancer Institute
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.74(10), pp.2785-2795
DOI: 10.1158/0008-5472.CAN-13-3176
PMID: 24648346
PMCID: PMC4030677
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: United States
Grant note: ZIA CP010193-06 / Intramural NIH HHS ZIA CP010193-05 / Intramural NIH HHS T32 HG000044 / NHGRI NIH HHS Z99 CA999999 / Intramural NIH HHS ZIA CP010193-7 / Intramural NIH HHS P30 CA015083 / NCI NIH HHS P50 CA102701 / NCI NIH HHS P30 CA071789 / NCI NIH HHS
Language: English
Date published: 05/15/2014
Academic Unit: Epidemiology
Record Identifier: 9983995113202771

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