Oncogenic Wnt3a is a promising sensitive biomarker for monitoring hepatocarcinogenesis

Background: The effective treatment for hepatocellular carcinoma(HCC) depends on early diagnosis. Previously, the abnormal expression of Wnt3a as the key signaling molecule in the Wnt/β-catenin pathway was found in HCC cells and could be released into the circulation. In this study, we used rat model of hepatocarcinogenesis to dynamically investigate the alteration of oncogenic Wnt3a and to explore its early monitor value for HCC. Methods: Sprague-Dawley rats(SD) were fed with diet 2-fluorenylacetamide(2-FAA, 0.05%) for inducing hepatocarcinogenesis, and grouped based on liver morphological alteration by Hematoxylin & Eosin(H&E) staining; rats fed with normal chow were used as normal control(NC). Total RNA and protein were purified from rat livers. Differently expressed genes(DEGs) or Wnt3a m RNA, cellular distribution, and Wnt3a protein levels were analyzed by whole genome microarray with signal logarithm ratio(SLR log 2 cy5/cy3), immunohistochemistry, and enzyme-linked immunosorbent assay, respectively. Results: Models of rat hepatocarcinogenesis were successfully established based on liver histopathological H&E staining. Rats were divided into the cell degeneration(r Deg), precancerosis(r Pre-C) and HCC(r HCC) groups. Total numbers of the up-and down-regulated DEGs with SLR ≥ 8 were 55 and 48 in the r Deg group, 268 and 57 in the r Pre-C group, and 312 and 201 in the r HCC group, respectively. Significantly altered genes were involved in cell proliferation, signal transduction, tumor metastasis, and apoptosis. Compared with the NC group, Wnt3a m RNA was increased by 4.6 folds( P < 0.001) in the r Deg group, 7.4 folds( P < 0.001) in the r Pre-C group, and 10.4 folds( P < 0.001) in the r HCC group; the positive rates of liver Wnt3a were 66.7%( P = 0.001) in the r Deg group, 10 0%( P < 0.0 01) in the r Pre-C group, and 100%( P < 0.001) in the r HCC group, respectively. Also, there were significant differences of liver Wnt3a( P < 0.001) or serum Wnt3a( P < 0.001) among different groups. Conclusions: Overexpression of Wnt3a was associated with rat hepatocarcinogenesis and it should be expected to be a promising monitoring biomarker for HCC occurrence at early stage.