Proteomic profiling reveals the prognostic value of adenomatous polyposis coli–end-binding protein 1 in hepatocellular carcinoma

Abstract

Histological differentiation is a major pathological parameter associated with poor prognosis in patients with hepatocellular carcinoma (HCC) and the molecular signature underlying HCC differentiation may involve key proteins potentially affecting the malignant characters of HCC. To develop prognostic biomarkers for HCC, we examined the global protein expression profiles of 45 surgically resected tissues, including 27 HCCs with different degree of histological differentiation, 11 adjacent nontumor tissues, and seven normal liver tissues. Unsupervised classification grouped the 45 samples according to their histological classification based on the protein expression profiles created by laser microdissection and two-dimensional difference gel electrophoresis (2D-DIGE). Statistical analysis and mass spectrometry identified 26 proteins with differential expression, of which 14 were functionally linked to c-Myc, AP-1, HIF1A, hepatocyte nuclear factor 4 alpha, or the Ras superfamily (RhoA, CDC42, and Rac1). Among the proteins identified, we focused on APC-binding protein EB1 (EB1) because it was dominantly expressed in poorly differentiated HCCs, which generally correlate with the poor prognosis in patients with HCC. In addition, EB1 is controlled by c-Myc, RhoA, and CDC42, which have all been linked to HCC malignancy. Immunohistochemistry in a further 145 HCC cases revealed that EB1 significantly correlated with the degree of histological differentiation (P < 0.001), and univariate and multivariate analyses indicated that EB1 is an independent prognostic factor for recurrence (hazard ratio, 2.740; 95% confidence interval, 1.771-4.239; P < 0.001) and survival (hazard ratio, 2.256; 95% confidence interval, 1.337-3.807; P ‫؍‬ 0.002) of patients with HCC after curative surgery. Conclusion: Proteomic profiling revealed the molecular signature behind the progression of HCC, and the prognostic value of EB1 in HCC. (HEPATOLOGY 2008;48:1851-1863 H epatocellular carcinoma (HCC) is one of the most common and aggressive malignancies world-wide and is the third leading cause of cancer death. 1 HCC is a major health problem with high prevalence in Asia and Africa, 2,3 and recent studies indicated that the incidence of HCC has increased substantially in the United States and the United Kingdom over the last decades. 4,5

Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver

“…Many of these dysregulated genes are known to exhibit altered expression in HCC and, in some cases, functionally contribute to hepatocarcinogenesis. Such genes include components of insulin-like growth factor 2 (Igf2), Ras, and β-catenin (Ctnnb1) signaling pathways (Supplemental Figure 4A), as well as other genes known to play a role in HCC such as Epcam (21), c-Myc (23), and Rhoa (24). Real-time RT-PCR validated the upregulation of several of these transcripts in LKO livers ( Figure 2E and Supplemental Table 4), and Western blotting documented the increased expression of the majority of these proteins in KO livers ( Figure 2F).…”

Proteomic Differences Between Hepatocellular Carcinoma and Nontumorous Liver Tissue Investigated by a Combined Gel-based and Label-free Quantitative Proteomics Study

“…In particular, the proteomics-based approach has turned out to be a promising one, offering several quantification techniques to reveal differences in protein expression that are caused by a particular disease. In most studies, the well-established 2D-DIGE technique has been applied for protein quantification followed by identification via mass spectrometry (7)(8)(9)(10)(11)(12)(13)(14)(15). Even if the quantification is very accurate and sensitive in this gel-based approach, the relatively high amount of protein sample necessary for protein identification is the major disadvantage of this technique.…”

Post-translational Modifications Regulate Assembly of Early Spindle Orientation Complex in Yeast

“…In humans, mutations in APC are responsible for development of familial adenomatous polyposis and resulting colorectal cancer (7). Its binding partner EB1 has been identified as a prognostic marker for recurrence and survival of hepatocellular carcinoma (8) and as an oncogenic factor (9).…”