Identification of Lung-Cancer-Related Genes with the Shortest Path Approach in a Protein-Protein Interaction Network

Lung cancer is one of the leading causes of cancer mortality worldwide. The main types of lung cancer are small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC). In this work, a computational method was proposed for identifying lung-cancer-related genes with a shortest path approach in a protein-protein interaction (PPI) network. Based on the PPI data from STRING, a weighted PPI network was constructed. 54 NSCLC- and 84 SCLC-related genes were retrieved from associated KEGG pathways. Then the shortest paths between each pair of these 54 NSCLC genes and 84 SCLC genes were obtained with Dijkstra's algorithm. Finally, all the genes on the shortest paths were extracted, and 25 and 38 shortest genes with a permutation P value less than 0.05 for NSCLC and SCLC were selected for further analysis. Some of the shortest path genes have been reported to be related to lung cancer. Intriguingly, the candidate genes we identified from the PPI network contained more cancer genes than those identified from the gene expression profiles. Furthermore, these genes possessed more functional similarity with the known cancer genes than those identified from the gene expression profiles. This study proved the efficiency of the proposed method and showed promising results.

[1]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[2]  S. Lindquist,et al.  HSP90 and the chaperoning of cancer , 2005, Nature Reviews Cancer.

[3]  Minoru Kanehisa,et al.  The KEGG database. , 2002, Novartis Foundation symposium.

[4]  A. Cheung,et al.  Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c , 2005, Journal of Cell Science.

[5]  Mona Singh,et al.  Whole-proteome prediction of protein function via graph-theoretic analysis of interaction maps , 2005, ISMB.

[6]  Shunpu Zhang,et al.  A comprehensive evaluation of SAM, the SAM R-package and a simple modification to improve its performance , 2007, BMC Bioinformatics.

[7]  Hao Li,et al.  Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression , 2008, Nature Cell Biology.

[8]  A. Gregor,et al.  Small cell lung cancer. , 1997, Lung cancer.

[9]  Damian Szklarczyk,et al.  The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored , 2010, Nucleic Acids Res..

[10]  Luonan Chen,et al.  Network‐Based Prediction of Protein Function , 2009 .

[11]  J. Zhao,et al.  α4 is highly expressed in carcinogen-transformed human cells and primary human cancers , 2011, Oncogene.

[12]  H. Land,et al.  Anticancer activity of the cholesterol exporter ABCA1 gene. , 2012, Cell reports.

[13]  M. Noguchi,et al.  Binding of lactoferrin to IGBP1 triggers apoptosis in a lung adenocarcinoma cell line. , 2011, Anticancer research.

[14]  R. Rintoul,et al.  ECM overrides DNA damage-induced cell cycle arrest and apoptosis in small-cell lung cancer cells through β1 integrin-dependent activation of PI3-kinase , 2006, Cell Death and Differentiation.

[15]  Gábor Csárdi,et al.  The igraph software package for complex network research , 2006 .

[16]  D. Klionsky,et al.  Tap42-associated protein phosphatase type 2A negatively regulates induction of autophagy , 2009, Autophagy.

[17]  G. Borisy,et al.  Cell Migration: Integrating Signals from Front to Back , 2003, Science.

[18]  Ambuj K. Singh,et al.  Molecular Function Prediction Using Neighborhood Features , 2010, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[19]  G. Giaccone,et al.  Targeting the dynamic HSP90 complex in cancer , 2010, Nature Reviews Cancer.

[20]  N. Cho,et al.  Targeting ILK and β4 integrin abrogates the invasive potential of ovarian cancer. , 2012, Biochemical and biophysical research communications.

[21]  M. Tretiakova,et al.  The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer. , 2006, Cancer research.

[22]  Barry Komm,et al.  Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. , 2003, Endocrinology.

[23]  W. Sommergruber,et al.  Expression of G Protein-Coupled Receptor 19 in Human Lung Cancer Cells Is Triggered by Entry into S-Phase and Supports G2–M Cell-Cycle Progression , 2012, Molecular Cancer Research.

[24]  Yiannis Kourmpetis,et al.  Bayesian Markov Random Field Analysis for Protein Function Prediction Based on Network Data , 2010, PloS one.

[25]  V. Janssens,et al.  Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. , 2001, The Biochemical journal.

[26]  K. Kinzler,et al.  Ferredoxin reductase affects p53-dependent, 5-fluorouracil–induced apoptosis in colorectal cancer cells , 2001, Nature Medicine.

[27]  Josef Stoer,et al.  Numerische Mathematik 1 , 1989 .

[28]  Y. Sakao,et al.  Hsp90 inhibitors cause G2/M arrest associated with the reduction of Cdc25C and Cdc2 in lung cancer cell lines , 2006, Journal of Cancer Research and Clinical Oncology.

[29]  Ka-Lok Ng,et al.  Prediction of protein functions based on function-function correlation relations , 2010, Comput. Biol. Medicine.

[30]  R. Costa,et al.  Chk2 Mediates Stabilization of the FoxM1 Transcription Factor To Stimulate Expression of DNA Repair Genes , 2006, Molecular and Cellular Biology.

[31]  K. Chou,et al.  Identification of Colorectal Cancer Related Genes with mRMR and Shortest Path in Protein-Protein Interaction Network , 2012, PloS one.

[32]  K. Kinzler,et al.  Ferredoxin reductase affects p53-dependent, 5-fluorouracil–induced apoptosis in colorectal cancer cells , 2001, Nature Medicine.

[33]  D. Yee,et al.  Targeting insulin-like growth factor pathways , 2006, British Journal of Cancer.

[34]  Stanley Letovsky,et al.  Predicting protein function from protein/protein interaction data: a probabilistic approach , 2003, ISMB.

[35]  M. Teh,et al.  FOXM1 is a downstream target of Gli1 in basal cell carcinomas. , 2002, Cancer research.

[36]  R. Sharan,et al.  Network-based prediction of protein function , 2007, Molecular systems biology.

[37]  Edsger W. Dijkstra,et al.  A note on two problems in connexion with graphs , 1959, Numerische Mathematik.

[38]  M. Follettie,et al.  Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. , 2005, Cancer research.

[39]  Christopher Haslett,et al.  Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: A mechanism for small cell lung cancer growth and drug resistance in vivo , 1999, Nature Medicine.

[40]  Jun Wu,et al.  B cell receptor-associated protein α4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A , 1997 .

[41]  C. Pilarsky,et al.  Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data. , 2004, Neoplasia.

[42]  Lei Zhang,et al.  Identification of retinoblastoma related genes with shortest path in a protein-protein interaction network. , 2012, Biochimie.

[43]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[44]  Yusuke Nakamura,et al.  Genome‐wide analysis of gene expression in human intrahepatic cholangiocarcinoma , 2005, Hepatology.

[45]  W. Hahn,et al.  Involvement of PP2A in viral and cellular transformation , 2005, Oncogene.

[46]  Y. Chang,et al.  Clinical significance of insulin receptor substrate-I down-regulation in non-small cell lung cancer. , 2006, Oncology reports.

[47]  Philippe Dessen,et al.  Atlas of Genetics and Cytogenetics in Oncology and Haematology, year 2003 , 2003, Nucleic Acids Res..

[48]  R. Costa,et al.  Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice. , 2006, Cancer research.

[49]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[50]  C. Thompson,et al.  Alpha4 is an essential regulator of PP2A phosphatase activity. , 2009, Molecular cell.

[51]  J. Sasaki,et al.  Quantitation by 1H‐NMR of dolichol, cholesterol and choline‐containing lipids in extracts of normal and phathological thyroid tissue , 2000, NMR in biomedicine.

[52]  Xinbin Chen,et al.  The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis , 2002, Oncogene.

[53]  Antonio Reverter,et al.  A Boolean-based systems biology approach to predict novel genes associated with cancer: Application to colorectal cancer , 2011, BMC Systems Biology.

[54]  A. M. Houghton,et al.  Neutrophil Elastase-Mediated Degradation of IRS-1 Accelerates Lung Tumor Growth , 2010, Nature Medicine.

[55]  C. R. Ramachandran,et al.  Biochemical changes in tumor tissues of oral cancer patients. , 2003, Clinical biochemistry.

[56]  M. Noguchi,et al.  Overexpression of immunoglobulin (CD79a) binding protein1 (IGBP‐1) in small lung adenocarcinomas and its clinicopathological significance , 2011, Pathology international.

[57]  A. Jemal,et al.  Cancer statistics, 2012 , 2012, CA: a cancer journal for clinicians.

[58]  Ya‐Wen Cheng,et al.  Gender difference in estrogen receptor alpha promoter hypermethylation and its prognostic value in non‐small cell lung cancer , 2005, International journal of cancer.

[59]  Sandhya Rani,et al.  Human Protein Reference Database—2009 update , 2008, Nucleic Acids Res..

[60]  M. Teh,et al.  FOXM 1 Is a Downstream Target of Gli 1 in Basal Cell Carcinomas 1 , 2002 .

[61]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[62]  Y. Benjamini,et al.  THE CONTROL OF THE FALSE DISCOVERY RATE IN MULTIPLE TESTING UNDER DEPENDENCY , 2001 .

[63]  Jan P van Meerbeeck,et al.  Small-cell lung cancer , 1980, The Lancet.

[64]  S. Kasif,et al.  Whole-genome annotation by using evidence integration in functional-linkage networks. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[65]  R. Costa,et al.  New and unexpected: forkhead meets ARF. , 2005, Current opinion in genetics & development.