ACTG1 and TLR3 are biomarkers for alcohol‑associated hepatocellular carcinoma

Gao,Bing; Li,Shicheng; Tan,Zhen; Ma,Leina; Liu,Jia

doi:10.3892/ol.2018.9757

ACTG1 and TLR3 are biomarkers for alcohol‑associated hepatocellular carcinoma

Authors:
- Bing Gao
- Shicheng Li
- Zhen Tan
- Leina Ma
- Jia Liu
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Affiliations: School of Pharmacy, Qingdao University, Qingdao, Shandong 266021, P.R. China, Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China, Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China, Cancer Institute, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266021, P.R. China
Published online on: November 26, 2018 https://doi.org/10.3892/ol.2018.9757
Pages: 1714-1722
Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Alcohol consumption is a risk factor for the development of hepatocellular carcinoma (HCC); however, the association between alcohol and HCC remains unknown. The present study aimed to identify key genes related to alcohol‑associated HCC to improve the current understanding of the pathology of this disease. Alcohol‑associated and non‑alcohol‑associated HCC samples in the GSE50579 dataset of the Gene Omnibus Database were analyzed to investigate altered gene expression. Integrated bioinformatics methods were employed to clarify the biological functions of the differentially expressed genes (DEGs), including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein‑protein interactions (PPIs). The present study reported that candidate biomarker micro (mi)RNAs via TargetScan Human 7.1. DEGs and their associated miRNAs (according to bioinformatics analysis) were validated using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). Additionally, 284 EGs from the GSE50579 dataset were revealed. In GO term analysis, DEGs were closely associated with the ‘regulation of nucleic acid metabolism’. KEGG pathway analysis indicated that the DEGs were tightly engaged in the ‘VEGF and VEGF receptor signaling network’, ‘proteoglycan syndecan‑mediated signaling events’, ‘erbB receptor signaling’ and ‘β1 integrin cell surface interactions’. According to the results of PPI and heat map analysis, the main hub genes were centrin 3 (CETN3), Toll‑like receptor 3 (TLR3), receptor tyrosine‑protein kinase (ERBB4), heat shock protein family member 8, actin γ1 (ACTG1) and α‑smooth muscle actin. it was demonstrated that the ACTG1, TLR3, miR‑6819‑3p and miRΝΑ (miR)‑6877‑3P had undefined associations. Furthermore, RT‑qPCR analysis revealed that miR‑6819‑3p and miR‑6877‑3P may enhance the expression levels of ACTG1 and inhibit the expression levels of TLR3 in alcohol‑associated HCC tissues. TLR3 and ACTG1 were proposed as potential biomarkers of alcohol‑associated HCC. Investigation into the regulatory functions of miR‑6819‑3p and miR‑6877‑3P may provide novel insights into the treatment of alcohol‑associated HCC.

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1	Park JW, Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ, Kudo M, Johnson P, Wagner S, Orsini LS and Sherman M: Global patterns of hepatocellular carcinoma management from diagnosis to death: The BRIDGE Study. Liver Int. 35:2155–2166. 2015. View Article : Google Scholar : PubMed/NCBI
2	Nahon P and Nault JC: Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma. Liver Int. 37:1591–1601. 2017. View Article : Google Scholar : PubMed/NCBI
3	Li DK, Yan P, Abou-Samra AB, Chung RT and Butt AA: Proton pump inhibitors are associated with accelerated development of cirrhosis, hepatic decompensation and hepatocellular carcinoma in noncirrhotic patients with chronic hepatitis C infection: Results from ERCHIVES. Aliment pharmacol Ther. 47:246–258. 2018. View Article : Google Scholar : PubMed/NCBI
4	David D, Raghavendran A, Goel A Bharath, Kumar C, Kodiatte TA, Burad D, Abraham P, Ramakrishna B, Joseph P, Ramachandran J and Eapen CE: Risk factors for non-alcoholic fatty liver disease are common in patients with non-B non-C hepatocellular carcinoma in India. Indian J Gastroenterol. 36:373–379. 2017. View Article : Google Scholar : PubMed/NCBI
5	Xin B, Cui Y, Wang Y, Wang L, Yin J, Zhang L, Pang H, Zhang H and Wang RA: Combined use of alcohol in conventional chemical-induced mouse liver cancer model improves the simulation of clinical characteristics of human hepatocellular carcinoma. Oncol Lett. 14:4722–4728. 2017. View Article : Google Scholar : PubMed/NCBI
6	Ramadori P, Cubero FJ, Liedtke C, Trautwein C and Nevzorova YA: Alcohol and hepatocellular carcinoma: Adding fuel to the flame. Cancers (Basel). 9:E1302017. View Article : Google Scholar : PubMed/NCBI
7	Neumann O, Kesselmeier M, Geffers R, Pellegrino R, Radlwimmer B, Hoffmann K, Ehemann V, Schemmer P, Schirmacher P, Lorenzo Bermejo J and Longerich T: Methylome analysis and integrative profiling of human HCCs identify novel protumorigenic factors. Hepatology. 56:1817–1827. 2012. View Article : Google Scholar : PubMed/NCBI
8	Harbig J, Sprinkle R and Enkemann SA: A sequence-based identification of the genes detected by probesets on the Affymetrix U133 plus 2.0 array. Nucleic Acids Res. 33:e312005. View Article : Google Scholar : PubMed/NCBI
9	Wettenhall JM, Simpson KM, Satterley K and Smyth GK: affylmGUI: A graphical user interface for linear modeling of single channel microarray data. Bioinformatics. 22:897–899. 2006. View Article : Google Scholar : PubMed/NCBI
10	Han L, Suzek TO, Wang Y and Bryant SH: The text-mining based pubchem bioassay neighboring analysis. BMC Bioinformatics. 11:5492010. View Article : Google Scholar : PubMed/NCBI
11	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
12	Cho E, Lee JE, Rimm EB, Fuchs CS and Giovannucci EL: Alcohol consumption and the risk of colon cancer by family history of colorectal cancer. Am J Clin Nut. 95:413–419. 2012. View Article : Google Scholar
13	Murugan S, Boyadjieva N and Sarkar DK: Protective effects of hypothalamic beta-endorphin neurons against alcohol-induced liver injuries and liver cancers in rat animal models. Alcohol Clin Exp Res. 38:2988–2997. 2014. View Article : Google Scholar : PubMed/NCBI
14	Hidaka A, Sasazuki S, Matsuo K, Ito H, Sawada N, Shimazu T, Yamaji T, Iwasaki M, Inoue M and Tsugane S: JPHC Study Group: Genetic polymorphisms of ADH1B, ADH1C and ALDH2, alcohol consumption, and the risk of gastric cancer: The Japan Public Health Center-based prospective study. Carcinogenesis. 36:223–231. 2015. View Article : Google Scholar : PubMed/NCBI
15	Xu M, Wang S, Qi Y, Chen L, Frank JA, Yang XH, Zhang Z, Shi X and Luo J: Role of MCP-1 in alcohol-induced aggressiveness of colorectal cancer cells. Mol Carcinog. 55:1002–1011. 2016. View Article : Google Scholar : PubMed/NCBI
16	Brooks PJ and Zakhari S: Moderate alcohol consumption and breast cancer in women: From epidemiology to mechanisms and interventions. Alcohol Clin Exp Res. 37:23–30. 2013. View Article : Google Scholar : PubMed/NCBI
17	Rendtorff ND, Zhu M, Fagerheim T, Antal TL, Jones M, Teslovich TM, Gillanders EM, Barmada M, Teig E, Trent JM, et al: A novel missense mutation in ACTG1 causes dominant deafness in a Norwegian DFNA20/26 family, but ACTG1 mutations are not frequent among families with hereditary hearing impairment. Eur J Hum Genet. 14:1097–1105. 2006. View Article : Google Scholar : PubMed/NCBI
18	van Wijk E, Krieger E, Kemperman MH, De Leenheer EM, Huygen PL, Cremers CW, Cremers FP and Kremer H: A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26). J Med Genet. 40:879–884. 2003. View Article : Google Scholar : PubMed/NCBI
19	Morín M, Bryan KE, Mayo-Merino F, Goodyear R, Mencía A, Modamio-Høybjør S, del Castillo I, Cabalka JM, Richardson G, Moreno F, et al: In vivo and in vitro effects of two novel gamma-actin (ACTG1) mutations that cause DFNA20/26 hearing impairment. Hum Mol Genet. 18:3075–3089. 2009. View Article : Google Scholar : PubMed/NCBI
20	Park G, Gim J, Kim AR, Han KH, Kim HS, Oh SH, Park T, Park WY and Choi BY: Multiphasic analysis of whole exome sequencing data identifies a novel mutation of ACTG1 in a nonsyndromic hearing loss family. BMC Genomics. 14:1912013. View Article : Google Scholar : PubMed/NCBI
21	Wei Q, Zhu H, Qian X, Chen Z, Yao J, Lu Y, Cao X and Xing G: Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss. J Transl Med. 12:3112014. View Article : Google Scholar : PubMed/NCBI
22	Bunnell TM and Ervasti JM: Delayed embryonic development and impaired cell growth and survival in Actg1 null mice. Cytoskeleton (Hoboken). 67:564–572. 2010. View Article : Google Scholar : PubMed/NCBI
23	Mutai H, Suzuki N, Shimizu A, Torii C, Namba K, Morimoto N, Kudoh J, Kaga K, Kosaki K and Matsunaga T: Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: A cross-sectional, multi-center next-generation sequencing study. Orphanet J Rare Dis. 8:1722013. View Article : Google Scholar : PubMed/NCBI
24	Huang S, Cai M, Zheng Y, Zhou L, Wang Q and Chen L: miR-888 in MCF-7 side population sphere cells directly targets E-cadherin. J Genet Genomics. 41:35–42. 2014. View Article : Google Scholar : PubMed/NCBI
25	Dong X, Han Y, Sun Z and Xu J: Actin Gamma 1, a new skin cancer pathogenic gene, identified by the biological feature-based classification. J Cell Biochem. 119:1406–1419. 2017. View Article : Google Scholar : PubMed/NCBI
26	Gan TQ, Xie ZC, Tang RX, Zhang TT, Li DY, Li ZY and Chen G: Clinical value of miR-145-5p in NSCLC and potential molecular mechanism exploration: A retrospective study based on GEO, qRT-PCR, and TCGA data. Tumour Biol. 39:10104283176916832017. View Article : Google Scholar : PubMed/NCBI
27	Liu Y, Zhang Y, Wu H, Li Y, Zhang Y, Liu M, Li X and Tang H: miR-10a suppresses colorectal cancer metastasis by modulating the epithelial-to-mesenchymal transition and anoikis. Cell Death Dis. 8:e27392017. View Article : Google Scholar : PubMed/NCBI
28	Sun Q, Wang Y, Zhang Y, Liu F, Cheng X, Hou N, Zhao X and Yang X: Expression profiling reveals dysregulation of cellular cytoskeletal genes in HBx–induced hepatocarcinogenesis. Cancer Biol Ther. 6:668–674. 2007. View Article : Google Scholar : PubMed/NCBI
29	Xu YY, Chen L, Wang GL, Zhou JM, Zhang YX, Wei YZ, Zhu YY and Qin J: A synthetic dsRNA, as a TLR3 pathwaysynergist, combined with sorafenib suppresses HCC in vitro and in vivo. BMC Cancer. 13:5272013. View Article : Google Scholar : PubMed/NCBI
30	Zhang SY, Herman M, Ciancanelli MJ, Pérez de Diego R, Sancho-Shimizu V, Abel L and Casanova JL: TLR3 immunity to infection in mice and humans. Curr Opin Immunol. 25:19–33. 2013. View Article : Google Scholar : PubMed/NCBI
31	Chen C, Feng Y, Zou L, Wang L, Chen HH, Cai JY, Xu JM, Sosnovik DE and Chao W: Role of extracellular RNA and TLR3-Trif signaling in myocardial ischemia-reperfusion injury. J Am Heart Assoc. 3:e0006832014. View Article : Google Scholar : PubMed/NCBI
32	Chen XL, Xu YY, Chen L, Wang GL and Shen Y: TLR3 plays significant roles against HBV-associated HCC. Gastroenterol Res Prac. 2015:5721712015.
33	Das A, Chai JC, Kim SH, Lee YS, Park KS, Jung KH and Chai YG: Transcriptome sequencing of microglial cells stimulated with TLR3 and TLR4 ligands. BMC Genomics. 16:5172015. View Article : Google Scholar : PubMed/NCBI
34	Szeles L, Meissner F, Dunand-Sauthier I, Thelemann C, Hersch M, Singovski S, Haller S, Gobet F, Fuertes Marraco SA, Mann M, et al: TLR3-mediated CD8+ dendritic cell activation is coupled with establishment of a cell-intrinsic antiviral state. J Immunol. 195:1025–1033. 2015. View Article : Google Scholar : PubMed/NCBI
35	Qiu X, Dong Y, Cao Y and Luo Y: Correlation between TLR2, TLR3, TLR4, and TLR9 polymorphisms and susceptibility to and prognosis of severe hepatitis among the newborns. J Clin Lab Anal. 32:2018. View Article : Google Scholar
36	Yuan MM, Xu YY, Chen L, Li XY, Qin J and Shen Y: TLR3 expression correlates with apoptosis, proliferation and angiogenesis in hepatocellular carcinoma and predicts prognosis. BMC Cancer. 15:2452015. View Article : Google Scholar : PubMed/NCBI
37	Kar P, Kumar D, Gumma PK, Chowdhury SJ and Karra VK: Down regulation of TRIF TLR3, and MAVS in HCV infected liver correlates with the outcome of infection. J Med Virol. 89:2165–2172. 2017. View Article : Google Scholar : PubMed/NCBI
38	Hu X, Ye J, Qin A, Zou H, Shao H and Qian K: Both microRNA-155 and virus-encoded MiR-155 ortholog regulate TLR3 expression. PLoS One. 10:e01260122015. View Article : Google Scholar : PubMed/NCBI
39	Ho V, Lim TS, Lee J, Steinberg J, Szmyd R, Tham M, Yaligar J, Kaldis P, Abastado JP and Chew V: TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression. Oncotarget. 6:27252–27266. 2015. View Article : Google Scholar : PubMed/NCBI
40	Guo Z, Chen L, Zhu Y, Zhang Y, He S, Qin J, Tang X, Zhou J and Wei Y: Double-stranded RNA-induced TLR3 activation inhibits angiogenesis and triggers apoptosis of human hepatocellular carcinoma cells. Oncol Rep. 27:396–402. 2012.PubMed/NCBI
41	Yoneda K, Sugimoto K, Shiraki K, Tanaka J, Beppu T, Fuke H, Yamamoto N, Masuya M, Horie R, Uchida K and Takei Y: Dual topology of functional Toll-like receptor 3 expression in human hepatocellular carcinoma: Differential signaling mechanisms of TLR3-induced NF-kappaB activation and apoptosis. Int J Oncol. 33:929–936. 2008.PubMed/NCBI