Chen Mengzhu,Wang Xiujie,and Xia Lixin.Comparison of alternative splicing in lung adenocarcinoma and lung squamous carcinoma[J].Journal of Shenzhen University Science and Engineering,2017,34(1):33-45.[doi:10.3724/SP.J.1249.2017.01033]





Comparison of alternative splicing in lung adenocarcinoma and lung squamous carcinoma
1) 深圳大学医学部,呼吸疾病国家重点实验室深圳大学变态反应分室,广东深圳518060
2) 中国科学院遗传与发育生物学研究所,北京100101
Chen Mengzhu1 Wang Xiujie2 and Xia Lixin1
1) State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Health Science Center, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R.China
2) Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, P.R.China
bioinformatics lung adenocarcinoma (LUAD) lung squamous carcinoma (LUSC) alternative splicing (AS) skipping exon (SE) alternative first exon (AF)
R 734.2;Q 811.4
利用SUPPA(a super-fast pipeline for alternative splicing)软件分析癌症基因组数据库癌基因组图谱中肺腺癌和肺鳞癌样本的RNA-Seq数据,发现在鉴定的7种主要可变剪接转录本中外显子跳跃转录本发生频率最高.通过癌组织与癌旁组织的比较,系统地鉴定了肺腺癌和肺鳞癌中差异表达的可变剪接转录本,发现约60%的差异可变剪接转录本是两种肺癌亚型所共有的.功能富集分析表明,癌组织特异的可变剪接转录本主要富集在细胞周期调控、脱氧核糖核酸代谢和核糖核酸代谢等生物过程中,而癌旁组织特异的可变剪接转录本则主要富集在囊泡介导转运、多肽转运和脂质转运等生物过程中.通过肺癌驱动基因可变剪接转录本的比较分析,鉴定了两种肺癌亚型共有或特有的可能具有癌驱动功能的可变剪接转录本.
Lung cancer is a common disease with high morbidity and mortality. Studies have shown that alternative splicing (AS) is closely associated with lung carcinogenesis, but the difference of alternative splicing between lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) remains unclear. Here, we analyze the RNA-Seq data of LUAD and LUSC from TCGA using SUPPA software, and find that skipping exon (SE) is the most frequently occurred AS transcript among seven main AS transcripts identified. By comparing tumor tissues with normal ones, we systematically identify differentially expressed AS transcripts in both LUAD and LUSC, of which around 60% are identical between these two subtypes. Functional analysis reveals that tumor-specific AS transcripts are mainly enriched among genes associated with cell cycle regulation, deoxyribonucleic acid metabolism and RNA metabolism, whereas normal-specific AS transcripts are enriched among genes mainly involved in vesicle-mediated transport, peptide transport and lipid transport. By comparing AS transcripts of cancer-driven genes between LUAD and LUSC, we identify some common and subtype-specific AS transcripts with cancer-driven potentiality.


[1] Siegel R L, Miller K D, Jemal A. Cancer statistics, 2015[J]. CA: A Cancer Journal for Clinicians, 2015, 65(1): 5-29.
[2] Chen Wanqing, Zheng Rongshou, Baade P D, et al. Cancer statistics in China, 2015[J]. CA: A Cancer Journal for Clinicians, 2016, 66(2): 115-132.
[3] Chang J T H, Lee Y M, Huang R S. The impact of the Cancer Genome Atlas on lung cancer[J]. Translational Research, 2015, 166(6): 568-585.
[4] Subramanian J, Govindan R. Lung cancer in never smokers: a review[J]. Journal of Clinical Oncology, 2007, 25(5): 561-570.
[5] Hammerman P S, Lawrence M S, Voet D, et al. Comprehensive genomic characterization of squamous cell lung cancers[J]. Nature, 2012, 489(7417): 519-525.
[6] Collisson E A, Campbell J D, Brooks A N, et al. Comprehensive molecular profiling of lung adenocarcinoma[J]. Nature, 2014, 511(7511): 543-550.
[7] Paez J G, Jnne P A, Lee J C, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy[J]. Science, 2004, 304(5676): 1497-1500.
[8] Antonicelli A, Cafarotti S, Indini A, et al. EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation[J]. International Journal of Medical Sciences, 2013, 10(3): 320-330.
[9] Rekhtman N, Paik P K, Arcila M E, et al. Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations[J]. Clinical Cancer Research, 2012, 18(4): 1167-1176.
[10] Pan Qun, Shai O, Lee L J, et al. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing[J]. Nature Genetics, 2008, 40(12): 1413-1415.
[11] Chen Mo, Manley J L. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches[J]. Nature Reviews Molecular Cell Biology, 2009, 10(11): 741-754.
[12] Wahl M C, Will C L, Lührmann R. The spliceosome: design principles of a dynamic RNP machine[J]. Cell, 2009, 136(4): 701-718.
[13] Venables J P, Klinck R, Koh C, et al. Cancer-associated regulation of alternative splicing[J]. Nature Structural & Molecular Biology, 2009, 16(6): 670-676.
[14] Chen J, Weiss W A. Alternative splicing in cancer: implications for biology and therapy[J]. Oncogene, 2015, 34(1): 1-14.
[15] Takehara T, Liu Xiaolong, Fujimoto J, et al. Expression and role of Bcl-xL in human hepatocellular carcinomas[J]. Hepatology, 2001, 34(1): 55-61.
[16] Alamancos GP, Pagès A, Trincado JL, et al. Leveraging transcript quantification for fast computation of alternative splicing profiles[J]. RNA, 2015, 21(9): 1521-1531.
[17] Huang Dawei, Sherman B T, Lempicki R A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources[J]. Nature Protocols, 2009, 4(1): 44-57.
[18] Supek F, Bonjak M, kunca N, et al. REVIGO summarizes and visualizes long lists of gene ontology terms[J]. PLoS One, 2011, 6(7): e21800.
[19] Finn R D, Coggill P, Eberhardt R Y, et al. The Pfam protein families database: towards a more sustainable future[J]. Nucleic Acids Research, 2016, 44(D1): D279-D285.
[20] Wamg Z N, Lo H S, Yang H, et al. Computational analysis and experimental validation of tumor-associated alternative RNA splicing in human cancer[J]. Cancer Research, 2003, 63(3): 655-657.
[21] Pio R, Blanco D, Pajares M J, et al. Development of a novel splice array platform and its application in the identification of alternative splice variants in lung cancer[J]. BMC Genomics, 2010, 11: 352.
[22] Planque C, Choi Y H, Guyetant S, et al. Alternative splicing variant of kallikrein-related peptidase 8 as an independent predictor of unfavorable prognosis in lung cancer[J]. Clinical Chemistry, 2010, 56(6): 987-997.
[23] Fan Y C, Min L, Chen H, et al. Alternative splicing isoform of T cell factor 4 K suppresses the proliferation and metastasis of non-small cell lung cancer cells[J]. Genetics and Molecular Research : GMR, 2015, 14(4): 14009-14018.
[24] Misquitta-Ali CM, Cheng E, O’Hanlon D, et al. Global profiling and molecular characterization of alternative splicing events misregulated in lung cancer[J]. Molecular and Cellular Biology, 2011, 31(1): 138-150.
[25] Pelosi G, Schianchi E, Dell’orto P, et al. Detecting cell-free circulating hTERT mRNA in the plasma may identify a subset of nonsmall cell lung cancer patients[J]. Laboratory Investigation, 2006, 448(1): 7-15.
[26] Fujiwara M, Kamma H, Wu W, et al. Expression and alternative splicing pattern of human telomerase reverse transcriptase in human lung cancer cells[J]. International Journal of Oncology, 2004, 24(4): 925-930.


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 TANG Yu-lin,CAO Yan,OU Zhong-hua,et al.Regulatable gene expression controlled by the promoter of Sali3-2 under different abiotic stresses[J].Journal of Shenzhen University Science and Engineering,2012,29(1):73.[doi:10.3724/SP.J.1249.2012.01073]
 BI De,XIAO Hua-jun,ZHOU Cui-hong,et al.Bioinformatic analysis of ?cardiac and pulmonary hypoxia[J].Journal of Shenzhen University Science and Engineering,2012,29(1):541.[doi:10.3724/SP.J.1249.2012.06541]
 LOU Sulin,ZHU Xiulan,ZENG Zhiyong,et al.Bioinformatics analysis of Dunaliella microRNAs by high-throughput sequencing[J].Journal of Shenzhen University Science and Engineering,2018,35(1):331.[doi:10.3724/SP.J.1249.2018.04331]
[5]张尉欣,刘阳,刘 帅,等.镉胁迫下菜心的转录组分析[J].深圳大学学报理工版,2018,35(5):543.[doi:10.3724/SP.J.1249.2018.05543]
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Foundation:National High-Tech Research and Development Program (2012AA020409); Shenzhen Science and Technology Basic Research Foundation(JCYJ20150525092941055)
Corresponding author:Professor Wang Xiujie. E-mail: xjwang@genetics.ac.cn; Professor Xia Lixin. E-mail:xialixin@126.com
Citation:Chen Mengzhu, Wang Xiujie, Xia Lixin. Comparison of alternative splicing in lung adenocarcinoma and lung squamous carcinoma[J]. Journal of Shenzhen University Science and Engineering, 2017, 34(1): 33-45.(in Chinese)
引文:陈梦竹,王秀杰,夏立新.肺腺癌和肺鳞癌中mRNA可变剪接特征的比较[J]. 深圳大学学报理工版,2017,34(1):33-45.
更新日期/Last Update: 2016-12-30