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Genome‑Wide Investigation of the Clinical Implications and Molecular Mechanism of Long Noncoding RNA LINC00668 and Protein‑Coding Genes in Hepatocellular Carcinoma

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Genome‑Wide Investigation of the Clinical Implications and Molecular Mechanism of Long Noncoding RNA LINC00668 and Protein‑Coding Genes in Hepatocellular Carcinoma 860 INTERNATIONAL JOURNAL OF ONCOLOGY 55: 860-878 2019 Genome‑wide investigation of the clinical implications and molecular mechanism of long noncoding RNA LINC00668 and protein‑coding genes in hepatocellular carcinoma XIANGKUN WANG1, XIN ZHOU1, JUNQI LIU1, ZHENGQIAN LIU1, LINBO ZHANG2, YIZHEN GONG3, JIANLU HUANG4, LONG YU1,5, QIAOQI WANG6, CHENGKUN YANG1, XIWEN LIAO1, TINGDONG YU1, CHUANGYE HAN1, GUANGZHI ZHU1, XINPING YE1 and TAO PENG1 Department of 1Hepatobiliary Surgery, 2Health Management and Division of Physical Examination and 3Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021; 4Department of Hepatobiliary Surgery, Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530031; 5Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000; 6Department of Medical Cosmetology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530000, P.R. China Received April 12, 2019; Accepted July 31, 2019 DOI: 10.3892/ijo.2019.4858 Abstract. Hepatocellular carcinoma (HCC) is one of the clinical factors and PCGs were used to construct a nomo- leading causes of tumor-related mortalities worldwide. gram for predicting prognosis in HCC. A Connectivity Map Long noncoding RNAs have been reported to be associ- was constructed to identify candidate target drugs for HCC. ated with tumor initiation, progression and prognosis. The The top 10 PCGs identified were: Pyrimidineregic receptor present study aimed to explore the association between long P2Y4 (P2RY4), signal peptidase complex subunit 2 (SPCS2), noncoding RNA LINC00668 and its co-expression correlated family with sequence similarity 86 member C1 (FAM86C1), protein-coding genes (PCGs) in HCC. Data of 370 HCC tudor domain containing 5 (TDRD5), ferritin light chain patients from The Cancer Genome Atlas database were used (FTL), stratifin (SFN), nucleolar complex associated 2 for analysis. LINC00668 and its top 10 PCGs were selected homolog (NOC2L), peroxiredoxin 1 (PRDX1), cancer/testis to determine their diagnostic and prognostic value. Molecular antigen 2 CTAG2 and leucine zipper and CTNNBIP1 domain mechanisms were explored to identify metabolic processes that containing (LZIC). FAM86C1, CTAG2 and SFN had signifi- LINC00668 and its PCGs are involved in. Prognosis-related cant diagnostic value for HCC (total area under the curve ≥0.7, P≤0.05); LINC00668, FAM86C1, TDRD5, FTL and SFN were of significant prognostic value for HCC (all P≤0.05). Investigation into the molecular mechanism indicated that Correspondence to: Professor Tao Peng, Department of LINC00668 affects cell division, cell cycle, mitotic nuclear Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi division, and drug metabolism cytochrome P450 (all P≤0.05). Medical University, Nanning, Guangxi 530021, P.R. China The Connectivity Map identified seven candidate target drugs E-mail: [email protected] for the treatment of HCC, which were: Indolylheptylamine, mimosine, disopyramide, lidocaine, NU-1025, bumetanide, Abbreviations: HCC, hepatocellular carcinoma; HBV, hepatitis and DQNLAOWBTJPFKL‑PKZXCIMASA‑N (all P≤0.05). B virus; LSCC, laryngeal squamous cell carcinoma; GC, gastric Our findings indicated that LINC00668 may function as an cancer; OSCC, oral squamous cell carcinoma; DEG, differentially oncogene and its overexpression indicates poor prognosis expressed gene; PCG, protein‑coding gene; AUC, area under curve; of HCC. FAM86C1, CTAG2 and SFN are of diagnostic TCGA, The Cancer Genome Atlas; KEGG, Kyoto Encyclopedia significance, while FAM86C1, TDRD5, FTL and SFN are of of Genes and Genomes; GSEA, gene set enrichment analysis; BP, biological process; CC, cellular component; MF, molecular function; prognostic significance for HCC. GO, gene ontology; OS, overall survival; ROC, receiver operating characteristic; GGI, gene‑gene interaction; DAVID, database for Introduction annotation, visualization and integrated discovery Liver cancer ranked in the top 10 among estimated new cases Key words: hepatocellular carcinoma, molecular mechanism, of cancer and associated worldwide in 2018, across 20 world long-noncoding RNA, LINC00668, protein-coding gene regions, with 841,080 (4.7%) new cases and 781,631 (8.2%) mortalities (1). Hepatocellular carcinoma (HCC) is not only the predominant histological type of liver cancer, but also WANG et al: CLINICAL SIGNIFICANCE OF LNCRNA00668 AND GENES IN HEPATOCELLULAR CARCINOMA 861 accounts for the highest proportion of ~80% of all primary the correlation between LINC00668 and genome-wide genes, liver cancer incidences (2). In China, HCC is a common type of using R 3.5.0 (https://www.r-project.org/). LncRNAs do not tumor and is the second leading cause of cancer mortality (3). encode proteins alone, and their function has been associ- Approximately 80-90% of all HCC cases are a result of liver ated with co-expressed protein coding genes (PCGs) (23,24). cirrhosis, while the second highest percentage is a result of LINC00668 and its top 10 correlated genes, known as PCGs, persistent hepatitis B or C virus (HBV) infection (4). Other risk were employed for further analysis based on the median levels factors for HCC include obesity, iron overload, alcohol abuse, of expression which served as the cut‑off value; they were environmental pollutants and aflatoxin contaminations (5,6). further divided as low and high expression PCGs. Early-stage HCC can be diagnosed and effectively treated through curative resection and liver transplantation, but treat- Expression of LINC00668 and genes in tumor and non‑tumor ments for advanced HCC are limited and have unsatisfactory tissue. The expression of LINC00668 and its top 10 PCGs in outcomes (7,8). HCC tumor recurrence, drug resistance, and tumor and non-tumor tissues were obtained from the Metabolic disease relapse after therapy are critical issues that result in gEne RApid Visualizer (http://merav.wi.mit.edu/) (25). poor prognosis (8,9). Scatter plots were then created in TCGA database using these Long noncoding RNAs (lncRNAs), of >200 nucleotides data and were visualized using GraphPad 7.0 (GraphPad in length, are a subclass of functional noncoding RNAs Software, Inc.). that are capable affecting protein expression (10,11). These lncRNAs share several characteristics of mRNAs: LncRNAs Diagnostic, prognostic and joint‑effect analysis of LINC00668 are 5'capped, equipped with a 3'polyadenylate tail, are and its PCGs. The diagnostic value of LINC00668 and its top made up of a variety of exons and are transcribed by RNA 10 PCGs were visualized in GraphPad 7.0, using receiver oper- polymerase II (11,12). Previous studies have indicated that ating characteristic (ROC) curves. An area under curve (AUC) lncRNAs play a pivotal role in many biological processes, value of <0.7 was considered significant for HCC diagnosis. including cell cycle regulation, cardiac development and X Then, joint‑effect analysis was performed between significant chromosome inactivation (11-14). In addition, lncRNAs are genes and LINC0068. involved in several diseases (15). Microarray technology has Thereafter, their prognostic value for overall survival (OS) identified both upregulated and downregulated lncRNAs in were analyzed using SPSS 16.0 (SPSS, Inc.) and the results were a large number of malignancies, such as breast cancer (16), presented using Kaplan-Meier plots visualized using GraphPad prostate cancer (17), lung cancer (18) and HCC (19). 7.0. Joint-effect analysis with LINC00668 was performed on LncRNA LINC00668 has been identified to be associ- genes that were of prognostic significance for HCC. ated with tumor progression and prognosis: LINC00668, along with LINC00710 and LINC00607, are the three most Gene set enrichment analysis (GSEA). GSEA (http://software. significantly downregulated lncRNAs in lung adenocarci- broadinstitute.org/gsea/index.jsp.), which includes Gene noma (20). LINC00668 has been identified as a potentially Ontology (GO): Biological process (BP), cellular component carcinogenic lncRNA and its knockdown can inhibit the (CC), molecular function (MF) and Kyoto Encyclopedia of proliferation, invasion and migration abilities of laryngeal Genes and Genomes (KEGG) metabolic pathway analyses, squamous cell carcinoma (LSCC) cell lines (21). Induced was performed to explore the potential molecular mechanisms by E2F transcription factor 1, upregulated LINC00668 can of LINC00668 and genes that are responsible for the develop- predict poor prognosis of gastric cancer (GC) and promote ment and progression of HCC. Then, the KEGG set (c2.cp.kegg. cell proliferation by epigenetically silencing cyclin-dependent v6.1.symbols.gmt) and GO sets (c5.bp.v6.1.symbols.gmt, c5.cc. protein kinase inhibitors (22). However, the aforementioned v6.1.symbols.gmt, c5.mf.v6.1.symbols.gmt) obtained were studies did not report the tissues specificities of LINC00668 used for analysis. in tumor cells. Databases (https://portals.broadinstitute. org/ccle/page?gene=LINC00668) indicate that tumor cells of Nomogram, co‑expression matrix, gene‑gene interaction these organs expressing LINC00668 highly are meningioma, (GGI) and GO interaction network. Prognosis-related colorectal, stomach, bile duct and liver. In addition, the genes, LINC00668 and clinical factors were included in the association between LINC00668 and HCC remains unclear. nomogram.
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