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1、http:/ - 1 - Effective Hierarchical Clustering Methods for Establishing Theoretical p38 MAPK Signaling Pathway in Head and neck squamous cell carcinoma gene expression profiles of Head and neck squamous cell carcinoma Jiang Lili，Lu Yinghua Biomedical Engineering Beijing University of Posts and Telec
2、ommunications，Beijing（100876） E-mail：， Abstract Signaling pathway analysis and interpretation of the massive gene expression data is a challenging task. Clustering technology is one of the useful and popular methods to obtain these patterns inherent in the data. In order to find the best way to esta
3、blish theoretical p38 MAPK signaling pathway based on Head and neck squamous cell carcinoma expression profiles, we use and compare common hierarchical clustering algorithms, such as Pearsons correlation, Euclidean distance, Euclidean distance harmonic, spearman rank correlation, kendalls tau, City-
4、block distance etc, The algorithm constructs a hierarchy from top to bottom based on a self-organizing tree. It dynamically finds the number of clusters at each level.We find that,Spearman rank correlation, kendalls tau, City-block distance, and Euclidean Distance are all fit to the analysis of the
5、cascade composed from a MAP3K11(MLK3), a MAP2K3(MKK3), a MAPK11(P38 MAPK/) toMEF2A in head and neck squamous cell carcinoma expression profiles. The result is consistent with the biological experimental p38 MAPK signaling pathway. Keywords：p38 MAPK，gene expression，clustering，signaling patheway , 1 I
6、ntroduction The invention of Genechips paves the way of large-scale analysis of genes. However, to efficiently find out the hidden patterns in the flood of data remains to be a heavy task for biologists. Techniques of data mining or knowledge discovery from database (KDD) can facilitate the progress
7、 greatly in its ability to handle large scale data. The method proposed by Eisen et al. (1998)1 uses clustering analysis to process the data from DNA microarray experiments, or other genomic datasets, and attaches a graphical display of the original data to the dendrogram to help biologists finding
8、out the genes with similar functions in a naturalistic way. In this paper we use the program and choose different hierarchical clustering ways, such as Pearsons correlation, Euclidean distance, Euclidean distance harmonic, spearman rank correlation, kendalls tau, City-block distance etc, and use Tre
9、eView to find effective method for establishing theoretical p38 MAPK signaling pathway of Head and neck squamous cell carcinoma expression profiles. p38 MAPK is a member of the MAPK family of kinases that is potently and preferentially activated by a variety of environmental stresses including ioniz
10、ing radiation, heat shock oxidative stress, and osmotic shock; inflammatory cytokines and rceptor systems of the TNF family;and vasoactive stresses associated with the response to ischemia2. As with other MAPKs, the core signaling unit is composed of a MAPKKK, typically an MEKK, or a member of the m
11、ixed lineage kinases(MLK) that would phosphorylate and activate MKK3 and MKK6 occurs through phosphorylation of serine and threonine residues at sites Ser189 and Thr193 for MKK3 and Ser207 and Thr211 for MKK6.Ser189 of MKK3/6 can also be directly phosphorylated by ASK2,which is regulatd by apoptotic
12、 stimuli345. Stress signals are delivered to this cascade by small GTPases of the Rho family (Rac,Rho,cdc42).Both Rac2 and cdc42 mediate the stimulation of MEKKs and MLKs67.MKK3 and SEK activate p38 MAP kinase by phosphorylation at Thr180 and Tyr182.Four p38 genes have been identified to date in mam
13、malian cells, with the and isoforms associated with activation of the proteins Hsp25,Hsp27,and MAPKAPK-2.Hsp27 is phosphorylated at serines 15,78,and 82 by MAPKAP kinase pathway48910. http:/ - 2 - Phosphorylation at Thr222,Ser272 and Th334 by p38 in an in vitro kinase assay seems to be essential for
14、 the activate ATF-2 by phosphorylation at Thr69 and Thr71111213. p38 MAPK has also been shown to regulate other transcription factors such as STAT1,the Max/Myc complex,MEF-2,Elk-1 and indirectly CREB via activation of MSK1. as shown in figure 1141516. In this paper, the signaling pathway MAP3K11(MLK
15、3), MAP2K3(MKK3), MAPK11(P38 MAPK/), MEF2A is verified using hierarchical clustering, based on the Gene Expression Omnibus (GEO) database17. The macroarry data is about Head and neck squamous cell carcinoma expression profiles, which is available at http:/www.ncbi.nlm.nih.gov/geo. It gives the Class
16、ification of 55 primary and 5 recurrent tumors from 60 patients with head and neck squamous cell carcinoma (HNSCC). Pathological diagnosis of 38 patients indicated that 26 were positive for lymph node metastasis. Results identify 4 subtypes of HNSCC with different clinical outcomes. The dataset platform organism is Hom
