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Bioinformatics Analysis of HKDC1 Expression in Non-Small Cell Lung Cancer and Its Relationship to Survival

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Bioinformatics Analysis of HKDC1 Expression in Non-Small Cell Lung Cancer and Its Relationship to Survival Journal of Nutritional Oncology, February 15, 2020, Volume 5, Number 1 DOI: 10.34175/jno202001004 · 31 · Bioinformatics Analysis of HKDC1 Expression in Non-small Cell Lung Cancer and Its Relationship to Survival Lei Wang, Wei Yuan Li, Fang Fang Li, Chun Yan Yang, Deng Cai Mu, Shang Yong Zheng School of Medicine, Yunnan University, Kunming, Yunnan 650091, China Abstract: Lung cancer has become one of the most common types of cancer, and has the highest morbidity and mortality rates. We herein performed a bioinformatic analysis to explore the gene expression of hexokinase domain containing 1 (HKDC1) to further illuminate the molecular mechanisms involved in non-small cell lung cancer (NSCLC). We also examined the relationship between HKDC1 expression and patient survival. The Oncomine and cBioPortal cancer genomics databases were used to investigate the expression of HKDC1 in NSCLC. Then the protein-protein interaction network and protein expression intensity of HKDC1 were examined with the Gene MANIA and The Human Protein Atlas databases. Finally, the prognostic impact of HKDC1 was evaluated via the GEPIA, Oncolnc and Kaplan-Meier Plotter online tools. HKDC1 was significantly up-regulated in NSCLC patients. In addition, the mutation frequency of HKDC1 in NSCLC was high in a large number of studies. Moreover, HKDC1 expression was correlated with a poor prognosis in NSCLC patients. These findings suggest that HKDC1 represents a novel therapeutic target for NSCLC. Key words: HKDC1; NSCLC; Bioinformatics; Expression; Carbohydrate metabolism Introduction genome-scale data source in life science research. Unlike Lung cancer (LC) is a life-threatening disease and the DNA sequence analysis and genotyping, microarrays most prominent cause of cancer morbidity and mortality in analyze mRNA. Genes with meaningful statistically both men and women [1]. Lung cancer is usually classified significant differences can be identified by comparing into two types, non-small cell lung cancer (NSCLC) and expression in adjacent normal tissues and tumor tissues. small cell lung cancer (SCLC). Non-small cell lung cancer We applied mRNA microarray analysis to 15 groups of accounts for about 80% of all lung cancers, and is mainly NSCLC tissues and adjacent non-tumor lung tissues. It composed of three subtypes: lung adenocarcinoma (LUAD), was found that hexokinase domain containing 1 (HKDC1) lung squamous cell carcinoma (LSCC) and large cell lung had relatively high expression in the tumor tissues and cancer (LLCC) [2]. Currently, the most common treatment showed a potential interaction with O-glycan synthesis strategy is chemotherapy [3]. One of the main causes of enzyme glucosaminyl (N-acetyl) transferase 3 (GCNT3) in lung cancer is human epidermal growth factor receptor enriched network diagrams. Previous studies have shown (EGFR) mutation or overexpression/gene amplification. that GCNT3 acts as a NSCLC oncogene [5]. It has also Mutations in EGFR result in sustained activation of the been reported that HKDC1 can effectively cluster LSCC EGFR signal, which drives the growth of tumor cells. patients in gene clustering models, and up-regulation of this This signaling pathway can be effectively blocked using gene may play a role in the adaptive stress response [6]. a tyrosine kinase inhibitor (TKI) that targets EGFR, such Moreover, the HKDC1 protein has enzymatic properties that as erlotinib or gefitinib. However, due to the presence are active in carbohydrate metabolism, and it is considered of intrinsic drug resistance, only a small percentage of to be a hexokinase isoform (REF). patients can benefit from the present treatments. Therefore, The present study was conducted to evaluate the it is necessary to find a more effective therapeutic target. expression of HKDC1 in NSCLC patients by using public Studies have confirmed that one of tyrosine kinase receptor gene expression datasets and bioinformatics platforms (AXL) is a potential therapeutic target, and its inhibition based on the Web. The work accomplished in this study can prevent or overcome the acquired resistance of EGFR provides additional information on the underlying molecular mutant lung cancer to EGFR-TKIs [4]. mechanism in NSCLC. We believe the present findings With the increasing application of genome sequencing, will be helpful in the clinical diagnosis of lung cancer, and DNA microarray analysis has become the most widely used provides new targets for the treatment of NSCLC patients. Materials and Methods Corresponding author: Shang Yong Zheng, MD, PhD, School of Sample collection and human gene expression Medicine, Yunnan University, 2 Cuihu Road, Kunming, Yunnan 650091, China; Tel: +86 182 0889 0689; Fax: +86 871 65034358; microarrays Email: [email protected] The genes studied were the same as in a previous · 32 · Journal of Nutritional Oncology, February 15, 2020, Volume 5, Number 1 article [5]. Fifteen pairs of lung tissue samples (including in NSCLC was conducted in the Oncomine database cancerous tissue and para-cancerous tissues) for gene chip (http://www.oncomine.org/) with the following filter analysis were collected from lung cancer patients who conditions on datasets: (HKDC1, cancer vs. normal underwent thoracic surgery at the Yunnan Cancer Hospital analysis, lung cancer, mRNA, clinical specimen). The in 2014-2015. Each patient’s condition had been confirmed mRNA expression in NSCLC and adjacent non-tumor before the resection, and none of the patients had received lung tissues (ANT) or normal tissues was downloaded treatment or had other tumors that might have metastasized from the Oncomine database. Then, raw data were to the lung. The surgeon removed the excised tissue from normalized to transform them to log2 values. The the operating room and placed it in a cell cryotube, then cBioPortal database provides a portal that simplifies immediately put the tissue cryotube into liquid nitrogen the molecular analysis of cancer tissues and cell lines for cryopreservation (the tissue was frozen within 30 min into readily understandable genetic, epigenetic, gene of resection). The sample information was recorded, and expression, and proteomic events [10]. The cBioPortal the sample was stored in an ultra-low temperature freezer for the Cancer Genomics database was used to view the at -80°C until analysis. All of the above processes were proportion of genetic alterations in NSCLC patients and approved by the patients and their families, as well as the the results of mutation analyses of the mRNA. Ethics Committee of Yunnan Cancer Hospital and the Ethics Committee of Yunnan University, and met the clinical Protein expression of HKDC1 in NSCLC norms and medical ethics regulations. The samples were The Human Protein Atlas (HPA) aims to map all human analyzed using an oligonucleotide microarray (Affymetrix proteins in cells, tissues and organs using the integration GeneChip Human Transcriptome Array 2.0, Thermo Fisher of various -omics technologies with online bioinformatics Scientific) to determine the expression profile of NSCLC- tools. The HPA currently facilitates the systematic related genes, and the original data were normalized to investigation of the transcriptome of the protein-coding obtain the expression levels of different genes, which were genes for more than 17 tumor types [11]. It also contains statistically analyzed. images of histological sections from normal and cancer tissues obtained by immunohistochemistry. Antibodies were Functional analysis for promising up-regulated genes labeled with 3,3’-diaminobenzidine (DAB) and the resulting The Metascape (http://metascape.org/gp/), an online brown staining indicates where an antibody had bound to bioinformatics resource platform, includes gene annotation, its corresponding antigen. The intensity of antibody staining enrichment summaries, and pathway and process indicates the extent of protein expression. We verified the enrichment analyses [7]. We uploaded 174 genes that were protein expression of HKDC1 in NSCLC samples using this identified as being up-regulated into the object box of platform. Metascape. The functional annotation of those genes was then elucidated by enrichment analysis on the Metascape Evaluation of the prognostic value of HKDC1 in tool. A clustering network was also constructed to identify NSCLC the valuable genes with a potential interaction with GCNT3. We evaluated the clinical prognostic significance of the HKDC1 gene using the GEPIA [12], Oncolnc [13] Construction of a protein-protein interaction (PPI) and Kaplan-Meier Plotter [14] online tools. The GEPIA network database was used to assess the disease-free survival GeneMANIA is an open online tool that can be used to (DFS) of NSCLC patients. We set a 50:50 ratio collecting construct biomolecular interaction networks [8]. This makes survival data of NSCLC patients on the Oncolnc databases. it possible to explore the protein-protein, protein-DNA and In addition, the best probe was selected in Kaplan- genetic interactions, pathways, reactions, gene and protein Meier Plotter to obtain the prognostic information of LC expression data for any given gene. We downloaded a patients. P-values < 0.05 were considered to be statistically chart that identifies the most co-expressed and pathway- significant. associated genes or proteins. Information was collected on several genes, and the most interesting were selected for Results further study. Human gene expression microarray analysis We performed human gene expression microarray Evaluation of the mRNA expression
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