Abstract
AimTo screen novel markers for hepatocellular carcinoma (HCC) by a combination of expression profile, interaction network analysis and clinical validation.MethodsHCC significant molecules which are differentially expressed or had genetic variations in HCC tissues were obtained from five existing HCC related databases (OncoDB.HCC, HCC.net, dbHCCvar, EHCO and Liverome). Then, the protein-protein interaction (PPI) network of these molecules was constructed. Three topological features of the network ('Degree', 'Betweenness', and 'Closeness') and the k-core algorithm were used to screen candidate HCC markers which play crucial roles in tumorigenesis of HCC. Furthermore, the clinical significance of two candidate HCC markers growth factor receptor-bound 2 (GRB2) and GRB2-associated-binding protein 1 (GAB1) was validated.ResultsIn total, 6179 HCC significant genes and 977 HCC significant proteins were collected from existing HCC related databases. After network analysis, 331 candidate HCC markers were identified. Especially, GAB1 has the highest k-coreness suggesting its central localization in HCC related network, and the interaction between GRB2 and GAB1 has the largest edge-betweenness implying it may be biologically important to the function of HCC related network. As the results of clinical validation, the expression levels of both GRB2 and GAB1 proteins were significantly higher in HCC tissues than those in their adjacent nonneoplastic tissues. More importantly, the combined GRB2 and GAB1 protein expression was significantly associated with aggressive tumor progression and poor prognosis in patients with HCC.ConclusionThis study provided an integrative analysis by combining expression profile and interaction network analysis to identify a list of biologically significant HCC related markers and pathways. Further experimental validation indicated that the aberrant expression of GRB2 and GAB1 proteins may be strongly related to tumor progression and prognosis in patients with HCC. The overexpression of GRB2 in combination with upregulation of GAB1 may be an unfavorable prognostic factor for HCC.
Highlights
Hepatocellular carcinoma (HCC) accounts for one of the most common malignant tumors and the third leading cause of cancer-related deaths worldwide [1]
Identification of candidate HCC markers In total, 6179 HCC significant genes and 977 HCC significant proteins which were differentially expressed or had genetic variations in HCC tissues relative to their corresponding normal tissues were collected from five existing HCC related databases (OncoDB.HCC, HCC.net, dbHCCvar, EHCO and Liverome) after removing redundancy
Since multiple biological processes or pathways are implicated in tumorigenesis and tumor progression of HCC, we constructed HCC related network using protein-protein interaction (PPI) information of HCC significant proteins
Summary
Hepatocellular carcinoma (HCC) accounts for one of the most common malignant tumors and the third leading cause of cancer-related deaths worldwide [1]. The overall 5-year survival rate for HCC patients is still only 5% [2]. Several attempts have been made to predict the occurrence and prognosis of HCC based on single or multiple clinicopathologic features such as the severity of the liver function, age, tumor size, grade, microvascular invasion, portal vein thrombosis, and the presence of microsatellite regions [5,6]. HCC patients with the same clinicopathologic features often display different outcome, suggesting that there may be several complex molecular and cellular events involved in the development and aggressive progression of HCC. Elucidating the molecular mechanisms underlying tumor progression and identifying the key markers that differentiate the occurrence and the various stages of HCC are essential for developing novel prognostic factors and improve therapeutic strategies
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