Genome‑wide investigation of the clinical implications and molecular mechanism of long noncoding RNA LINC00668 and protein‑coding genes in hepatocellular carcinoma

Wang,Xiangkun; Wang,Xiangkun; Zhou,Xin; Zhou,Xin; Liu,Junqi; Liu,Junqi; Liu,Zhengqian; Liu,Zhengqian; Zhang,Linbo; Zhang,Linbo; Gong,Yizhen; Gong,Yizhen; Huang,Jianlu; Huang,Jianlu; Yu,Long; Yu,Long; Wang,Qiaoqi; Wang,Qiaoqi; Yang,Chengkun; Yang,Chengkun; Liao,Xiwen; Liao,Xiwen; Yu,Tingdong; Yu,Tingdong; Han,Chuangye; Han,Chuangye; Zhu,Guangzhi; Zhu,Guangzhi; Ye,Xinping; Ye,Xinping; Peng,Tao; Peng,Tao

doi:10.3892/ijo.2019.4858

Genome‑wide investigation of the clinical implications and molecular mechanism of long noncoding RNA LINC00668 and protein‑coding genes in hepatocellular carcinoma

Authors:
- Xiangkun Wang
- Xin Zhou
- Junqi Liu
- Zhengqian Liu
- Linbo Zhang
- Yizhen Gong
- Jianlu Huang
- Long Yu
- Qiaoqi Wang
- Chengkun Yang
- Xiwen Liao
- Tingdong Yu
- Chuangye Han
- Guangzhi Zhu
- Xinping Ye
- Tao Peng
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China, Health Management and Division of Physical Examination, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China, Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China, Department of Hepatobiliary Surgery, Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530031, P.R. China, Department of Medical Cosmetology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530000, P.R. China
Published online on: August 14, 2019 https://doi.org/10.3892/ijo.2019.4858
Pages: 860-878
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of tumor‑related mortalities worldwide. Long noncoding RNAs have been reported to be associated with tumor initiation, progression and prognosis. The present study aimed to explore the association between long noncoding RNA LINC00668 and its co‑expression correlated protein‑coding genes (PCGs) in HCC. Data of 370 HCC patients from The Cancer Genome Atlas database were used for analysis. LINC00668 and its top 10 PCGs were selected to determine their diagnostic and prognostic value. Molecular mechanisms were explored to identify metabolic processes that LINC00668 and its PCGs are involved in. Prognosis‑related clinical factors and PCGs were used to construct a nomogram for predicting prognosis in HCC. A Connectivity Map was constructed to identify candidate target drugs for HCC. The top 10 PCGs identified were: Pyrimidineregic receptor P2Y4 (P2RY4), signal peptidase complex subunit 2 (SPCS2), family with sequence similarity 86 member C1 (FAM86C1), tudor domain containing 5 (TDRD5), ferritin light chain (FTL), stratifin (SFN), nucleolar complex associated 2 homolog (NOC2L), peroxiredoxin 1 (PRDX1), cancer/testis antigen 2 CTAG2 and leucine zipper and CTNNBIP1 domain containing (LZIC). FAM86C1, CTAG2 and SFN had significant 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 LINC00668 affects cell division, cell cycle, mitotic nuclear division, and drug metabolism cytochrome P450 (all P≤0.05). The Connectivity Map identified seven candidate target drugs for the treatment of HCC, which were: Indolylheptylamine, mimosine, disopyramide, lidocaine, NU‑1025, bumetanide, and DQNLAOWBTJPFKL‑PKZXCIMASA‑N (all P≤0.05). Our findings indicated that LINC00668 may function as an oncogene and its overexpression indicates poor prognosis of HCC. FAM86C1, CTAG2 and SFN are of diagnostic significance, while FAM86C1, TDRD5, FTL and SFN are of prognostic significance for HCC.

View Figures

View References

1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Testino G, Leone S, Patussi V, Scafato E and Borro P: Hepatocellular carcinoma: Diagnosis and proposal of treatment. Minerva Med. 107:413–426. 2016.PubMed/NCBI
3	Li S, Huang Y, Huang Y, Fu Y, Tang D, Kang R, Zhou R and Fan XG: The long non-coding RNA TP73-AS1 modulates HCC cell proliferation through miR-200a-dependent HMGB1/RAGE regulation. J Exp Clin Cancer Res. 36:512017. View Article : Google Scholar : PubMed/NCBI
4	Gomaa AI, Khan SA, Toledano MB, Waked I and Taylor-Robinson SD: Hepatocellular carcinoma: Epidemiology, risk factors and pathogenesis. World J Gastroenterol. 14:4300–4308. 2008. View Article : Google Scholar : PubMed/NCBI
5	Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, Dienes HP and Odenthal M: MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology. 47:1223–1232. 2008. View Article : Google Scholar : PubMed/NCBI
6	Farazi PA and DePinho RA: Hepatocellular carcinoma pathogenesis: From genes to environment. Nat Rev Cancer. 6:674–687. 2006. View Article : Google Scholar : PubMed/NCBI
7	Llovet JM: Liver cancer: Time to evolve trial design after everolimus failure. Nat Rev Clin Oncol. 11:506–507. 2014. View Article : Google Scholar : PubMed/NCBI
8	Forner A, Llovet JM and Bruix J: Hepatocellular carcinoma. Lancet. 379:1245–1255. 2012. View Article : Google Scholar : PubMed/NCBI
9	Tanaka S and Arii S: Molecular targeted therapy for hepatocellular carcinoma in the current and potential next strategies. J Gastroenterol. 46:289–296. 2011. View Article : Google Scholar : PubMed/NCBI
10	St Laurent G, Wahlestedt C and Kapranov P: The Landscape of long noncoding RNA classification. Trends Genet. 31:239–251. 2015. View Article : Google Scholar : PubMed/NCBI
11	Devaux Y, Zangrando J, Schroen B, Creemers EE, Pedrazzini T, Chang CP, Dorn GW II, Thum T and Heymans S; Cardiolinc network: Long noncoding RNAs in cardiac development and ageing. Nat Rev Cardiol. 12:415–425. 2015. View Article : Google Scholar : PubMed/NCBI
12	Ma L, Bajic VB and Zhang Z: On the classification of long non-coding RNAs. RNA Biol. 10:925–933. 2013. View Article : Google Scholar : PubMed/NCBI
13	Penny GD, Kay GF, Sheardown SA, Rastan S and Brockdorff N: Requirement for Xist in X chromosome inactivation. Nature. 379:131–137. 1996. View Article : Google Scholar : PubMed/NCBI
14	Mourtada-Maarabouni M, Hedge VL, Kirkham L, Farzaneh F and Williams GT: Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5). J Cell Sci. 121:939–946. 2008. View Article : Google Scholar : PubMed/NCBI
15	Huo X, Han S, Wu G, Latchoumanin O, Zhou G, Hebbard L, George J and Qiao L: Dysregulated long noncoding RNAs (lncRNAs) in hepatocellular carcinoma: Implications for tumori-genesis, disease progression, and liver cancer stem cells. Mol Cancer. 16:1652017. View Article : Google Scholar
16	Pickard MR and Williams GT: Regulation of apoptosis by long non-coding RNA GAS5 in breast cancer cells: Implications for chemotherapy. Breast Cancer Res Treat. 145:359–370. 2014. View Article : Google Scholar : PubMed/NCBI
17	Pickard MR, Mourtada-Maarabouni M and Williams GT: Long non-coding RNA GAS5 regulates apoptosis in prostate cancer cell lines. Biochim Biophys Acta. 1832:1613–1623. 2013. View Article : Google Scholar : PubMed/NCBI
18	Xiaoguang Z, Meirong L, Jingjing Z, Ruishen Z, Qing Z and Xiaofeng T: Long noncoding RNA CPS1-IT1 suppresses cell proliferation and metastasis in human lung cancer. Oncol Res. 25:373–380. 2017. View Article : Google Scholar
19	Zhang M, Wang W, Li T, Yu X, Zhu Y, Ding F, Li D and Yang T: Long noncoding RNA SNHG1 predicts a poor prognosis and promotes hepatocellular carcinoma tumorigenesis. Biomed Pharmacother. 80:73–79. 2016. View Article : Google Scholar : PubMed/NCBI
20	Zhao B, Xu H, Ai X, Adalat Y, Tong Y, Zhang J and Yang S: Expression profiles of long noncoding RNAs in lung adenocarcinoma. Onco Targets Ther. 11:5383–5390. 2018. View Article : Google Scholar : PubMed/NCBI
21	Zhao L, Cao H, Chi W, Meng W, Cui W, Guo W and Wang B: Expression profile analysis identifies the long non-coding RNA landscape and the potential carcinogenic functions of LINC00668 in laryngeal squamous cell carcinoma. Gene. 687:47–55. 2019. View Article : Google Scholar
22	Zhang E, Yin D, Han L, He X, Si X, Chen W, Xia R, Xu T, Gu D, De W, et al: E2F1-induced upregulation of long noncoding RNA LINC00668 predicts a poor prognosis of gastric cancer and promotes cell proliferation through epigenetically silencing of CKIs. Oncotarget. 7:23212–23226. 2016.PubMed/NCBI
23	Paci P, Colombo T and Farina L: Computational analysis identifies a sponge interaction network between long non-coding RNAs and messenger RNAs in human breast cancer. BMC Syst Biol. 8:832014. View Article : Google Scholar : PubMed/NCBI
24	Liao Q, Liu C, Yuan X, Kang S, Miao R, Xiao H, Zhao G, Luo H, Bu D, Zhao H, et al: Large-scale prediction of long non-coding RNA functions in a coding-non-coding gene co-expression network. Nucleic Acids Res. 39:3864–3878. 2011. View Article : Google Scholar : PubMed/NCBI
25	Shaul YD, Yuan B, Thiru P, Nutter-Upham A, McCallum S, Lanzkron C, Bell GW and Sabatini DM: MERAV: A tool for comparing gene expression across human tissues and cell types. Nucleic Acids Res. 44:D560–D566. 2016. View Article : Google Scholar :
26	Montojo J, Zuberi K, Rodriguez H, Kazi F, Wright G, Donaldson SL, Morris Q and Bader GD: GeneMANIA Cytoscape plugin: Fast gene function predictions on the desktop. Bioinformatics. 26:2927–2928. 2010. View Article : Google Scholar : PubMed/NCBI
27	Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B and Ideker T: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498–2504. 2003. View Article : Google Scholar : PubMed/NCBI
28	Maere S, Heymans K and Kuiper M: BiNGO: A Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics. 21:3448–3449. 2005. View Article : Google Scholar : PubMed/NCBI
29	Robinson MD, McCarthy DJ and Smyth GK: edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 26:139–140. 2010. View Article : Google Scholar
30	Huang da W, Sherman BT and Lempicki RA: Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37:1–13. 2009. View Article : Google Scholar
31	Huang da W, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009. View Article : Google Scholar : PubMed/NCBI
32	Maass PG, Luft FC and Bähring S: Long non-coding RNA in health and disease. J Mol Med (Berl). 92:337–346. 2014. View Article : Google Scholar
33	Yang G, Lu X and Yuan L: LncRNA: A link between RNA and cancer. Biochim Biophys Acta. 1839:1097–1109. 2014. View Article : Google Scholar : PubMed/NCBI
34	Wong CM, Kai AK, Tsang FH and Ng IO: Regulation of hepato-carcinogenesis by microRNAs. Front Biosci (Elite Ed). 5:49–60. 2013. View Article : Google Scholar
35	Ulitsky I and Bartel DP: lincRNAs: Genomics, evolution, and mechanisms. Cell. 154:26–46. 2013. View Article : Google Scholar : PubMed/NCBI
36	Nagano T and Fraser P: No-nonsense functions for long noncoding RNAs. Cell. 145:178–181. 2011. View Article : Google Scholar : PubMed/NCBI
37	Tsai MC, Spitale RC and Chang HY: Long intergenic noncoding RNAs: New links in cancer progression. Cancer Res. 71:3–7. 2011. View Article : Google Scholar : PubMed/NCBI
38	Spizzo R, Almeida MI, Colombatti A and Calin GA: Long non-coding RNAs and cancer: A new frontier of translational research? Oncogene. 31:4577–4587. 2012. View Article : Google Scholar : PubMed/NCBI
39	Zhang H, Chen Z, Wang X, Huang Z, He Z and Chen Y: Long non-coding RNA: A new player in cancer. J Hematol Oncol. 6:372013. View Article : Google Scholar : PubMed/NCBI
40	Li J, Zhuang C, Liu Y, Chen M, Chen Y, Chen Z, He A, Lin J, Zhan Y, Liu L, et al: Synthetic tetracycline-controllable shRNA targeting long non-coding RNA HOXD-AS1 inhibits the progression of bladder cancer. J Exp Clin Cancer Res. 35:992016. View Article : Google Scholar : PubMed/NCBI
41	Hu Y, Wang J, Qian J, Kong X, Tang J, Wang Y, Chen H, Hong J, Zou W, Chen Y, et al: Long noncoding RNA GAPLINC regulates CD44-dependent cell invasiveness and associates with poor prognosis of gastric cancer. Cancer Res. 74:6890–6902. 2014. View Article : Google Scholar : PubMed/NCBI
42	Hu X, Feng Y, Zhang D, Zhao SD, Hu Z, Greshock J, Zhang Y, Yang L, Zhong X, Wang LP, et al: A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell. 26:344–357. 2014. View Article : Google Scholar : PubMed/NCBI
43	Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, Liu F, Pan W, Wang TT, Zhou CC, et al: A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 25:666–681. 2014. View Article : Google Scholar : PubMed/NCBI
44	Cui M, Xiao Z, Wang Y, Zheng M, Song T, Cai X, Sun B, Ye L and Zhang X: Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway. Cancer Res. 75:846–857. 2015. View Article : Google Scholar : PubMed/NCBI
45	Tang J, Zhuo H, Zhang X, Jiang R, Ji J, Deng L, Qian X, Zhang F and Sun B: A novel biomarker Linc00974 interacting with KRT19 promotes proliferation and metastasis in hepatocellular carcinoma. Cell Death Dis. 5:e15492014. View Article : Google Scholar : PubMed/NCBI
46	Zhang CZ: Long intergenic non-coding RNA 668 regulates VEGFA signaling through inhibition of miR-297 in oral squamous cell carcinoma. Biochem Biophys Res Commun. 489:404–412. 2017. View Article : Google Scholar : PubMed/NCBI
47	Ding D, Liu J, Midic U, Wu Y, Dong K, Melnick A, Latham KE and Chen C: TDRD5 binds piRNA precursors and selectively enhances pachytene piRNA processing in mice. Nat Commun. 9:1272018. View Article : Google Scholar : PubMed/NCBI
48	Shen Y, Li X, Zhao B, Xue Y, Wang S, Chen X, Yang J, Lv H and Shang P: Iron metabolism gene expression and prognostic features of hepatocellular carcinoma. J Cell Biochem. 119:9178–9204. 2018. View Article : Google Scholar : PubMed/NCBI
49	Liu Y, Zhu X, Zhu J, Liao S, Tang Q, Liu K, Guan X, Zhang J and Feng Z: Identification of differential expression of genes in hepatocellular carcinoma by suppression subtractive hybridization combined cDNA microarray. Oncol Rep. 18:943–951. 2007.PubMed/NCBI
50	Wang K, Xu X, Nie Y, Dai L, Wang P and Zhang J: Identification of tumor-associated antigens by using SEREX in hepatocellular carcinoma. Cancer Lett. 281:144–150. 2009. View Article : Google Scholar : PubMed/NCBI
51	Brum AM, van de Peppel J, Nguyen L, Aliev A, Schreuders-Koedam M, Gajadien T, van der Leije CS, van Kerkwijk A, Eijken M, van Leeuwen JPTM and van der Eerden BCJ: Using the Connectivity Map to discover compounds influencing human osteoblast differentiation. J Cell Physiol. 233:4895–4906. 2018. View Article : Google Scholar
52	Busby J, Murray L, Mills K, Zhang SD, Liberante F and Cardwell CR: A combined connectivity mapping and pharmacoepidemiology approach to identify existing medications with breast cancer causing or preventing properties. Pharmacoepidemiol Drug Saf. 27:78–86. 2018. View Article : Google Scholar
53	Xiao SJ, Zhu XC, Deng H, Zhou WP, Yang WY, Yuan LK, Zhang JY, Tian S, Xu L, Zhang L and Xia HM: Gene expression profiling coupled with Connectivity Map database mining reveals potential therapeutic drugs for Hirschsprung disease. J Pediatr Surg. 53:1716–1721. 2018. View Article : Google Scholar : PubMed/NCBI