Systems analysis utilising pathway interactions identifies sonic hedgehog pathway as a primary biomarker and oncogenic target in hepatocellular carcinoma.
The development and progression of cancer is associated with disruption of biological networks. Historically studies have identified sets of signature genes involved in events ultimately leading to the development of cancer. Identification of such sets does not indicate which biologic processes are oncogenic drivers and makes it difficult to identify key networks to target for interventions. Using a comprehensive, integrated computational approach, the authors identify the sonic hedgehog (SHH) pathway as the gene network that most significantly distinguishes tumour and tumour-adjacent samples in human hepatocellular carcinoma (HCC). The analysis reveals that the SHH pathway is commonly activated in the tumour samples and its activity most significantly differentiates tumour from the non-tumour samples. The authors experimentally validate these in silico findings in the same biologic material using Western blot analysis. This analysis reveals that the expression levels of SHH, phosphorylated cyclin B1, and CDK7 levels are much higher in most tumour tissues as compared to normal tissue. It is also shown that siRNA-mediated silencing of SHH gene expression resulted in a significant reduction of cell proliferation in a liver cancer cell line, SNU449 indicating that SHH plays a major role in promoting cell proliferation in liver cancer. The SHH pathway is a key network underpinning HCC aetiology which may guide the development of interventions for this most common form of human liver cancer.
Sol
S
Efroni
Daoud
D
Meerzaman
Carl F
CF
Schaefer
Sharon
S
Greenblum
Myung
M
Soo-Lyu
Ying
Y
Hu
Constance
C
Cultraro
Eran
E
Meshorer
Kenneth H
KH
Buetow
D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056744:Cyclin B1 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D013597:Systems Analysis; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D014408:Biomarkers, Tumor; C534699:CCNB1 protein, human; D056744:Cyclin B1; D053823:Hedgehog Proteins; D034741:RNA, Small Interfering; C509239:SHH protein, human; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human