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Research Article Identification of Differentially Expressed Kinase and Screening Potential Anticancer Drugs in Papillary Thyroid Carcinoma

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Research Article Identification of Differentially Expressed Kinase and Screening Potential Anticancer Drugs in Papillary Thyroid Carcinoma Hindawi Publishing Corporation Disease Markers Volume 2016, Article ID 2832980, 9 pages http://dx.doi.org/10.1155/2016/2832980 Research Article Identification of Differentially Expressed Kinase and Screening Potential Anticancer Drugs in Papillary Thyroid Carcinoma Huairong Zhang,1 Bo Gao,2 and Bingyin Shi1 1 Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China 2Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 15001, China Correspondence should be addressed to Bo Gao; [email protected] and Bingyin Shi; [email protected] Received 30 May 2016; Accepted 8 August 2016 Academic Editor: Stamatios Theocharis Copyright © 2016 Huairong Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aim. We aim to identify protein kinases involved in the pathophysiology of papillary thyroid carcinoma (PTC) in order to provide potential therapeutic targets for kinase inhibitors and unfold possible molecular mechanisms. Materials and Methods.Thegene expression profile of GSE27155 was analyzed to identify differentially expressed genes and mapped onto human protein kinases database. Correlation of kinases with PTC was addressed by systematic literature search, GO and KEGG pathway analysis. Results. The functional enrichment analysis indicated that “mitogen-activated protein kinases pathway” expression was extremely enriched, followed by “neurotrophin signaling pathway,” “focal adhesion,” and “GnRH signaling pathway.” MAPK, SRC, PDGFRa, ErbB, and EGFR were significantly regulated to correct these pathways. Kinases investigated by the literature on carcinoma were considered to be potential novel molecular therapeutic target in PTC and application of corresponding kinase inhibitors could be possible therapeutic tool. Conclusion. SRC, MAPK, and EGFR were the most important differentially expressed kinases in PTC. Combined inhibitors may have high efficacy in PTC treatment by targeting these kinases. 1. Introduction contraindicated to thyroidectomy who suffer from cardiac or respiratory disease, dialysis-dependent renal failure, anti- Thyroid cancer, particularly papillary thyroid carcinoma, is coagulant therapy, obstructive sleep apnea, mental impair- considered to be one of the most common malignancies. ment, thyrotoxicosis, and morbid obesity [6]. The postoper- Its incidence increases in differed geographic regions of the ative complications of surgery are quite common including world in the past decade. Increase in incidence of thyroid can- hypocalcemia (20%–30%) and recurrent laryngeal nerve cerisoneofthetopmalignanciesintheUnitedStates[1].Rise injury (5%–11%) and risk for nerve injury increased signif- in incidence observed may partly be accounted for improve- icantly by reoperation [7]. Due to the limits of traditional ment in diagnosis. It is indicated that papillary thyroid carci- therapy, more efforts are recalled for new drugs develop- nomaisattributedtotheentireincreasesignificantlybysepa- ment with higher efficiency and fewer side effects. Itis rated researches [2, 3]. Although the thyroidectomy, thyroid- protein kinases that function as core in signaling pathways stimulating hormone suppression therapy, and radioiodine participating in tumor proliferation, invasion, metastasis, remnant ablation (RAI) ameliorate the disease-free survival, and tumor microenvironment formation in major types of a group of patients still cannot benefit from the traditional tumors, including thyroid cancer pathogenesis. therapy. 5% of patients with distant metastasis are refractory It has been identified that in papillary thyroid carci- toRAI[4].Itisbelievedthatthetumorcellslosttheir noma several molecular changes exist: rearranged during 131 ability in uptake of the iodide and side effects of I therapy transfection (RET)/papillary thyroid carcinoma gene rear- of salivary gland dysfunction (>40%), abnormally dry eyes rangements, BRAF (B-RAF protooncogene, serine/threonine (25%), and transient fertility reduction (20%) affect the kinase) gene mutations, RAS (rat sarcoma) mutations, and patient living quality seriously [5]. Besides, patients are vascular endothelial growth factor receptor 2 angiogenesis 2 Disease Markers pathways activation. BRAF oncogene mutation occurred in .selleckchem.com/). We than retrieved the number of publi- approximately 45% to 70% of patients with papillary thyroid cations related to each kinase inhibitor and carcinoma. carcinoma and VEGF overexpression is frequently found in tumors that originated in the thyroid [8–11]. In the land- 3. Results mark DECISION study, Sorafenib, a multikinase inhibitor of RET/RAS/RAF pathway, VEGF receptors 2 and 3, improved 3.1. Establishment of Differentially Expressed Protein Kinases. the progression-free survival by 3 months, from 5.8 months Thereare518humanproteinkinasesintotalintheprotein to 10.8 months, compared with placebo [12]. It emerged as a kinase database. Amongst them, 110 kinases were predicted potentially effective option and approved by Food and Drug to be related to papillary thyroid carcinoma in our network. Administration (FDA) as a receptor tyrosine kinase inhibitor We tried to delineate a network of protein kinases engaged as treatment of differentiated thyroid cancer refractory to in PTC. Several kinase families exhibited correlation to RAI. pathophysiological process of PTC via the GO database. We aimed to investigate the protein kinase expression Here, we presented a map of these kinases to visualize their difference between papillary thyroid carcinoma and normal relationship in biological process. thyroid and possible molecular mechanisms underlying PTC. We try to provide valuable information on PTC associated 3.2. Functional Analysis and Literature Review. GO and protein kinases for potential therapeutic targets. KEGG enrichment analyses were conducted in the differen- tially expressed kinases. Kinases with a result of less than 0.05 2. Method in GO terms and pathways with FDR-value were considered tobethemostvaluablepossibletargetsandwereappliedfor 2.1. Identify Differentially Expressed Protein Kinases in PTC. further analysis. Study in different kinds of cancer mainly We searched in the NCBI (National Center for Biotechnology focused on the roles of SRC (v-src sarcoma (Schmidt-Ruppin Information) Gene Expression Omnibus (GEO) database A-2) viral oncogene homolog (avian)), MAPK (mitogen- (https://www.ncbi.nlm.nih.gov/geo/) to retrieve the genome- activated protein kinase), MET (met protooncogene (hepa- wide expression profile of human papillary thyroid carci- tocyte growth factor receptor)), ATM (ataxia telangiectasia noma. The original dataset from GSE27155 including 51 mutated), PDGFRa (platelet-derived growth factor receptor, human specimens of PTC and 4 specimens of normal thyroid alpha polypeptide), ErbB (v-erb-a erythroblastic leukemia tissues was downloaded and array from the Affymetrix plat- viral oncogene homolog), MAP2 K1 (bromodomain contain- form was processed. To discover the differential gene expres- ing 4), TGFbR1 (transforming growth factor, beta receptor 1), sion the significance analysis of microarrays (SAM) was and CDK6 (cyclin-dependent kinase 6) (shown in Figure 1). applied. False discovery rate (FDR) less than 0.05 was con- Coincidently, the above-predicted kinases were confirmed sidered to present significant difference. All the differentially with differentially protein kinases expression investigated in expressedgenesweremappedontoTheHumanPro- PTC patients (Figure 2). 39 GO terms were annotated and tein Kinase Reference Database to establish differentially presented as common biological process among all these expressed kinases in PTC. Then we conducted systematic kinases (Table 1). Finally, we built networks to investigate screening of the literature in PubMed for researches concern- the relationship among kinases, signaling pathways, and GO ing the association between papillary thyroid carcinoma and terms(Figures3and4). protein kinases. 3.3. Potential Novel Kinase Inhibitors for PTC. To investi- 2.2. Database-Based GO and Pathway Enrichment Analysis gate novel kinase inhibitors for the treatment of PTC, we and Literature Review. Each protein kinase’s corresponding conducted a literature review of the cancer-related research GO term or ID in the GO database was validated by AmiGO including 20 focused kinases involved in our network. The search engine. Gene ontology (GO) enrichment analysis was publication number could indicate the extent of the research used to evaluate the potential function for the differentially on kinase inhibitor use in cancer treatment (Table 2). expressed genes. The pathway was analyzed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. To 4. Discussion obtain putatively valuable new kinase targets for the treat- ment of PTC, we conducted a systematic literature screening Tyrosine kinases, classified as receptor tyrosine kinase (RTK) of all the protein kinases. The keywords in the title and and nonreceptor tyrosine kinase (nRTK), are essential medi- abstracts “each protein kinase,” “cancer,” and “papillary ators of signaling pathways through catalyzing phosphory- thyroid carcinoma” were used. Finally, we drew the picture lation of selecting tyrosine residues with ATP, leading to of interactions among kinases, signaling
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