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Identification of genes highly downregulated in pancreatic cancer through a meta-analysis of microarray datasets: implications for discovery of novel tumor-suppressor genes and therapeutic targets

  • Original Article – Cancer Research
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Abstract

Purpose

The lack of specific symptoms at early tumor stages, together with a high biological aggressiveness of the tumor contribute to the high mortality rate for pancreatic cancer (PC), which has a 5-year survival rate of about 7%. Recent failures of targeted therapies inhibiting kinase activity in clinical trials have highlighted the need for new approaches towards combating this deadly disease.

Methods

In this study, we have identified genes that are significantly downregulated in PC, through a meta-analysis of large number of microarray datasets. We have used qRT-PCR to confirm the downregulation of selected genes in a panel of PC cell lines.

Results

This study has yielded several novel candidate tumor-suppressor genes (TSGs) including GNMT, CEL, PLA2G1B and SERPINI2. We highlight the role of GNMT, a methyl transferase associated with the methylation potential of the cell, and CEL, a lipase, as potential therapeutic targets. We have uncovered genetic links to risk factors associated with PC such as smoking and obesity. Genes important for patient survival and prognosis are also discussed, and we confirm the dysregulation of metabolic pathways previously observed in PC.

Conclusions

While many of the genes downregulated in our dataset are associated with protein products normally produced by the pancreas for excretion, we have uncovered some genes whose downregulation appear to play a more causal role in PC. These genes will assist in providing a better understanding of the disease etiology of PC, and in the search for new therapeutic targets and biomarkers.

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Acknowledgements

We are grateful to Dr. Kavita Dhanwada (Department of Biology, University of Northern Iowa) for providing us access to tissue culture facilities, and to Mr. Connor Schmidt (Department of Chemistry and Biochemistry, University of Northern Iowa) for technical assistance.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of Northern Iowa, 1227 W. 27th Street, Cedar Falls, IA, 50613-0423, USA

    Nalin C. W. Goonesekere, Wyatt Andersen & Alex Smith

  2. Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China

    Xiaosheng Wang

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  1. Nalin C. W. Goonesekere
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  2. Wyatt Andersen
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Correspondence to Nalin C. W. Goonesekere or Xiaosheng Wang.

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Funding

Nalin Goonesekere received funding from an NSF-EPSCoR Grant (6052.00.24201.0000.21.0122) and a CHAS creative grant from the University of Northern Iowa. Xiaosheng Wang received start-up funds from China Pharmaceutical University. Wyatt Anderson and Alex Smith received SURP and SOAR Grants from the University of Northern Iowa.

Conflict of interest

The authors, Nalin Goonesekere, Xiaosheng Wang, Wyatt Anderson and Alex Smith declare no conflicts of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Supplementary Fig. 1

Molecular function classes of genes downregulated in PC as determined by the PANTHER Classification System (Mi et al. 2013). (EPS 916 KB)

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Goonesekere, N.C.W., Andersen, W., Smith, A. et al. Identification of genes highly downregulated in pancreatic cancer through a meta-analysis of microarray datasets: implications for discovery of novel tumor-suppressor genes and therapeutic targets. J Cancer Res Clin Oncol 144, 309–320 (2018). https://doi.org/10.1007/s00432-017-2558-4

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