In Silico Transcriptomic Analysis of the Chloride Intracellular Channels (CLIC) Interactome Identifies a Molecular Panel of Seven Prognostic Markers in Patients with Pancreatic Ductal Adenocarcinoma

Author(s): Dimitrios E. Magouliotis, Nikos Sakellaridis, Konstantinos Dimas, Vasiliki S. Tasiopoulou, Konstantina A. Svokos, Alexis A. Svokos, Dimitris Zacharoulis*.

Journal Name: Current Genomics

Volume 21 , Issue 2 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. In this context, the identification of biomarkers regarding the PDAC diagnosis, monitoring, and prognosis is crucial.

Objectives: The purpose of the current study was to investigate the differential gene expression profile of the chloride intracellular channel (CLIC) gene family network in patients with PDAC, in order to suggest novel biomarkers.

Methods: In silico techniques were used to construct the interactome of the CLIC gene family, identify the differentially expressed genes (DEGs) in PDAC as compared to healthy controls, and evaluate their potential prognostic role.

Results: Transcriptomic data of three microarray datasets were included, incorporating 114 tumor and 59 normal pancreatic samples. Twenty DEGs were identified; eight were up-regulated and twelve were downregulated. A molecular signature of seven genes (Chloride Intracellular Channel 1 – CLIC1; Chloride Intracellular Channel 3 – CLIC3; Chloride Intracellular Channel 4 – CLIC4; Ganglioside Induced Differentiation Associated Protein 1 – GDAP1; Ganglioside Induced Differentiation Associated Protein 1 Like 1 – GDAP1L1; Glutathione S-Transferase Pi 1 - GSTP1; Prostaglandin E Synthase 2 – PTGES2) were identified as prognostic markers associated with overall survival. Positive correlations were reported regarding the expression of CLIC1-CLIC3, CLIC4-CLIC5, and CLIC5- CLIC6. Finally, gene set enrichment analysis demonstrated the molecular functions and miRNA families (hsa-miR-122, hsa-miR-618, hsa-miR-425, and hsa-miR-518) relevant to the seven prognostic markers.

Conclusion: These outcomes demonstrate a seven-gene molecular panel that predicts the patients’ prospective survival following pancreatic resection for PDAC.

Keywords: Pancreatic cancer, biomarker, clic, chloride intracellular channel, miRNA, adenocarcinoma.

[1]
Ferlay, J.; Soerjomataram, I.; Ervik, M. GLOBOCAN 2012: Estimated, Cancer Incidence and Mortality Worldwide in 2012 v1.0: IARC Cancer Base No. 11. International Agency for Research on Cancer., http://globocan.iarc.fr
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin., 2015, 65(1), 5-29.
[http://dx.doi.org/10.3322/caac.21254] [PMID: 25559415]
[3]
Wong, H.H.; Chu, P. Immunohistochemical features of the gastrointestinal tract tumors. J. Gastrointest. Oncol., 2012, 3(3), 262-284.
[PMID: 22943017]
[4]
Neoptolemos, J.P.; Urrutia, R.; Abbruzzese, J.; Büchler, M.W., Eds.; Pancreatic Cancer; Springer-Verlag: New York, 2010. LVIII, 1390
[http://dx.doi.org/10.1007/978-0-387-77498-5]
[5]
Yeo, T.P. Demographics, epidemiology, and inheritance of pancreatic ductal adenocarcinoma. Semin. Oncol., 2015, 42(1), 8-18.
[http://dx.doi.org/10.1053/j.seminoncol.2014.12.002] [PMID: 25726048]
[6]
Rahib, L.; Smith, B.D.; Aizenberg, R.; Rosenzweig, A.B.; Fleshman, J.M.; Matrisian, L.M. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res., 2014, 74(11), 2913-2921.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0155] [PMID: 24840647]
[7]
Videira, M.; Reis, R.L.; Brito, M.A. Deconstructing breast cancer cell biology and the mechanisms of multidrug resistance. Biochim. Biophys. Acta, 2014, 1846(2), 312-325.
[PMID: 25080053]
[8]
Tasiopoulou, V.; Magouliotis, D.; Solenov, E.I. Transcriptional over-expression of chloride intracellular channels 3 and 4 in malignant pleural mesothelioma. Comput. Biol. Chem., 2015, 59, 111-116.
[http://dx.doi.org/10.1016/j.compbiolchem.2015.09.012]
[9]
Peretti, M.; Angelini, M.; Savalli, N.; Florio, T.; Yuspa, S.H.; Mazzanti, M. Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets. Biochim. Biophys. Acta, 2015, 1848(10 Pt B), 2523-2531.
[http://dx.doi.org/10.1016/j.bbamem.2014.12.012] [PMID: 25546839]
[10]
Jia, N.; Dong, S.; Zhao, G.; Gao, H.; Li, X.; Zhang, H. CLIC1 overexpression is associated with poor prognosis in pancreatic ductal adenocarcinomas. J. Cancer Res. Ther., 2016, 12(2), 892-896.
[http://dx.doi.org/10.4103/0973-1482.154057] [PMID: 27461670]
[11]
Warde-Farley, D.; Donaldson, S.L.; Comes, O.; Zuberi, K.; Badrawi, R.; Chao, P.; Franz, M.; Grouios, C.; Kazi, F.; Lopes, C.T.; Maitland, A.; Mostafavi, S.; Montojo, J.; Shao, Q.; Wright, G.; Bader, G.D.; Morris, Q. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res., 2010, 38(Web Server issue), W214-W220.
[http://dx.doi.org/10.1093/nar/gkq537 ] [PMID: 20576703]
[12]
Goswami, C.P.; Nakshatri, H. PROGgene: gene expression based survival analysis web application for multiple cancers. J. Clin. Bioinforma., 2013, 3(1), 22.
[http://dx.doi.org/10.1186/2043-9113-3-22] [PMID: 24165311]
[13]
Goswami, C.P.; Nakshatri, H. PROGgeneV2: enhancements on the existing database. BMC Cancer, 2014, 14, 970.
[http://dx.doi.org/10.1186/1471-2407-14-970] [PMID: 25518851]
[14]
Chen, J.; Bardes, E.E.; Aronow, B.J.; Jegga, A.G. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res., 2009, 37(Web Server issue), W305-W311.
[http://dx.doi.org/10.1093/nar/gkp427 ] [PMID: 19465376]
[15]
Prevarskaya, N.; Skryma, R.; Shuba, Y. Ion channels and the hallmarks of cancer. Trends Mol. Med., 2010, 16(3), 107-121.
[http://dx.doi.org/10.1016/j.molmed.2010.01.005] [PMID: 20167536]
[16]
Macpherson, I.R.; Rainero, E.; Mitchell, L.E.; van den Berghe, P.V.; Speirs, C.; Dozynkiewicz, M.A.; Chaudhary, S.; Kalna, G.; Edwards, J.; Timpson, P.; Norman, J.C. CLIC3 controls recycling of late endosomal MT1-MMP and dictates invasion and metastasis in breast cancer. J. Cell Sci., 2014, 127(Pt 18), 3893-3901.
[http://dx.doi.org/10.1242/jcs.135947] [PMID: 25015290]
[17]
Dozynkiewicz, M.A.; Jamieson, N.B.; Macpherson, I.; Grindlay, J.; van den Berghe, P.V.; von Thun, A.; Morton, J.P.; Gourley, C.; Timpson, P.; Nixon, C.; McKay, C.J.; Carter, R.; Strachan, D.; Anderson, K.; Sansom, O.J.; Caswell, P.T.; Norman, J.C. Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression. Dev. Cell, 2012, 22(1), 131-145.
[http://dx.doi.org/10.1016/j.devcel.2011.11.008] [PMID: 22197222]
[18]
Zou, Q.; Yang, Z.; Li, D.; Liu, Z.; Yuan, Y. Association of chloride intracellular channel 4 and Indian hedgehog proteins with survival of patients with pancreatic ductal adenocarcinoma. Int. J. Exp. Pathol., 2016, 97(6), 422-429.
[http://dx.doi.org/10.1111/iep.12213] [PMID: 28205343]
[19]
Chen, Y.C.; Tzeng, C.H.; Chen, P.M.; Lin, J.K.; Lin, T.C.; Chen, W.S.; Jiang, J.K.; Wang, H.S.; Wang, W.S. Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX-4 treatment in Asian patients with colorectal carcinoma. Cancer Sci., 2010, 101(2), 530-535.
[http://dx.doi.org/10.1111/j.1349-7006.2009.01418.x] [PMID: 19922504]
[20]
Chen, Y.L.; Tseng, H.S.; Kuo, W.H.; Yang, S.F.; Chen, D.R.; Tsai, H.T. Glutathione S-Transferase P1 (GSTP1) gene polymorphism increases age-related susceptibility to hepatocellular carcinoma. BMC Med. Genet., 2010, 11, 46.
[http://dx.doi.org/10.1186/1471-2350-11-46] [PMID: 20331903]
[21]
Shield, A.J.; Murray, T.P.; Board, P.G. Functional characterisation of ganglioside-induced differentiation-associated protein 1 as a glutathione transferase. Biochem. Biophys. Res. Commun., 2006, 347(4), 859-866.
[http://dx.doi.org/10.1016/j.bbrc.2006.06.189] [PMID: 16857173]
[22]
Ke, J.; Shen, Z.; Li, M.; Peng, C.; Xu, P.; Wang, M.; Zhu, Y.; Zhang, X.; Wu, D. Prostaglandin E2 triggers cytochrome P450 17α hydroxylase overexpression via signal transducer and activator of transcription 3 phosphorylation and promotes invasion in endometrial cancer. Oncol. Lett., 2018, 16(4), 4577-4585.
[http://dx.doi.org/10.3892/ol.2018.9165] [PMID: 30214592]
[23]
Camacho, M.; León, X.; Fernández-Figueras, M.T.; Quer, M.; Vila, L. Prostaglandin E(2) pathway in head and neck squamous cell carcinoma. Head Neck, 2008, 30(9), 1175-1181.
[http://dx.doi.org/10.1002/hed.20850] [PMID: 18642283]
[24]
Tesfaye, A.A.; Azmi, A.S.; Philip, P.A. miRNA and gene expression in pancreatic ductal adenocarcinoma. Am. J. Pathol., 2019, 189(1), 58-70.
[http://dx.doi.org/10.1016/j.ajpath.2018.10.005] [PMID: 30558723]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 21
ISSUE: 2
Year: 2020
Page: [119 - 127]
Pages: 9
DOI: 10.2174/1389202921666200316115631
Price: $65

Article Metrics

PDF: 11