Protein expression associated with early intrahepatic recurrence of hepatocellular carcinoma after curative surgery

Abstract

The poor prognosis of patients with hepatocellular carcinoma (HCC) is attributed to intrahepatic recurrence. To understand the molecular background of early intrahepatic recurrence, we conducted a global protein expression study. We compared the protein expression profiles of the primary HCC tissues of 12 patients who showed intrahepatic recurrence within 6 months post surgery with those of 15 patients who had no recurrence 2 years post surgery. Two-dimensional difference gel electrophoresis identified 23 protein spots, the intensity of which was highly associated with early intrahepatic recurrence. To validate the prediction performance of the identified proteins, we examined additional HCC tissues from 13 HCC patients; six with early intrahepatic recurrence and seven without recurrence. We found that all but one of the 13 patients were grouped according to their recurrence status based on the intensity of the 23 protein spots. D espite recent progress in early diagnostic modalities and therapeutic management, the prognosis of hepatocellular carcinoma (HCC) patients remains poor, mainly due to intrahepatic recurrence.(1) The incidence of intrahepatic recurrence in the liver remnant ranges from 50% to 100% of HCC patients who undergo curative resection as a result of either intrahepatic metastasis from the primary tumor or multicentric recurrence (2)(3)(4)(5)(6) and the median survival after recurrence is only 11 months. Although various molecular alterations have been correlated with early recurrence of HCC (8)(9)(10)(11)(12)(13) and studies on such events furthered our understanding of HCC biology, the underlying mechanisms remain obscure. Studies focusing on individual candidate genes may be insufficient for precisely understanding the background of the malignant behavior of tumor cells, because the features of cancer cells are defined by multiple genetic alterations in a functionally coordinated manner. With this notion in mind, global mRNA expression analyses have been conducted to identify the gene network associated with early intrahepatic recurrence. (14)(15)(16)(17) Such molecular pathogenesis studies may lead to the development of gene-based biomarkers and novel therapeutic strategies. However, mRNA expression reflects the protein expression of only a small proportion of genes, probably because of post-translational control of protein quantity. (18)(19)(20)(21) To complement gene expression studies, global protein expression profiling, namely a proteomic approach, has been carried out for the study of HCC.(22-28) Conceptually, proteomics reflects the molecular background of cancer phenotypes more directly, as the final product of genetic and epigenetic events is the proteins contained in the cells.In this study we investigated the protein expression of HCC tissues from patients with early intrahepatic recurrence and from patients without recurrence. We used two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) to generate quantitative protein expression profiles, and data-mining methods...

Increased expression of PDIA3 and its association with cancer cell proliferation and poor prognosis in hepatocellular carcinoma

“…Previous studies have reported the upregulation of PDIA3 protein and mRNA levels in HCC (7,10), which is consistent with the results of the current study. However, in previous proteomic studies, PDIA3 was not identified as a candidate biomarker indicating early recurrence and metastasis of HCC (9,11). This may be partially due to patient selection as these studies were conducted with patients in which recurrence and metastasis occurred within 6 months of the treatment, while only 15% of patients in the current study experienced recurrence and metastasis within this same time frame.…”

“…Previous studies have performed proteomic analyses of HCC (7–11) and identified candidate proteins for the early diagnosis (7,10) and rapid progression of HCC (9,11). However, only a limited number of patients were examined in these studies.…”

Translational microarray systems for outcome prediction of hepatocellular carcinoma

“…( 11 ) which applied DNA microarray technology to HCC research for the first time. Thereafter, various class prediction studies, ( 25–31,58,59 ) using DNA microarray or other technologies have been performed (Table 1). Many studies ( 25–27,30,31,58,59 ) have used primary HCC tissues in the search for predictive gene signatures, although two DNA microarray studies used non‐cancerous liver tissues to predict the occurrence of de novo HCC, ( 28 ) and recurrence.…”

“…Thereafter, various class prediction studies, ( 25–31,58,59 ) using DNA microarray or other technologies have been performed (Table 1). Many studies ( 25–27,30,31,58,59 ) have used primary HCC tissues in the search for predictive gene signatures, although two DNA microarray studies used non‐cancerous liver tissues to predict the occurrence of de novo HCC, ( 28 ) and recurrence. ( 29 ) Among nine studies, ( 25–31,58,59 ) four used oligonucleotide arrays, four used cDNA arrays, and one used polymerase chain reaction (PCR)‐based array.…”

Tissue proteomics for cancer biomarker development - Laser microdissection and 2D-DIGE -

“…By monitoring pfetin expression, we may be able to select the patients who may have optimal benefits from adjuvant therapy with imatinib. In liver cancer proteomics, we detected the expression patterns of 23 proteins corresponding to the early intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative surgery (14). Moreover, by focusing on the histological differentiation, we identified APC-binding protein EB1 (EB1) as a novel prognostic biomarker for patients with HCC (15).…”