Abstract
Abstract Hepatocellular carcinoma (HCC) is the third most important cause of cancer mortality worldwide. Epithelial-mesenchymal transition (EMT) has been shown to be an important biological process involved in the development and progression of HCC. The factors driving this process, however, are still largely unclear. Glypican-3 (GPC3) is upregulated in HCC and this is associated with poor prognosis. The details of the biological role of GPC3 in HCC are, however, yet to be fully elucidated. We hypothesized that GPC3 may promote HCC progression by inducing EMT. In this study we have examined the effect of human GPC3 in the progression of HCC using a murine HCC cell line (1MEA) derived from Balb/c mouse. We observed that the 1MEA cell line does not express GPC3 and we stably transfected human GPC3 into this cell line. 1MEA cells stably transfected with human glypican-3 (1MEAhGPC3) were then transplanted subcutaneously into 8 Balb/c mice. In comparison, wild type 1MEA was also transplanted into 8 separate Balb/c mice. Further, we performed a comparative analysis of the gene expression of E-cadherin, vimentin, collagen I, fibronectin, twist, slug and snail in both wild type 1MEA and 1MEAhGPC3. 18 days post-transplantation, tumor volume was analyzed. 5 mice transplanted with wild type 1MEA had not yet developed tumors whereas 3 mice transplanted with 1MEAhGPC3 developed tumors that had grown past the allowed tumor volume for the protocol and were sacrificed. Analysis of the remaining mice (3 transplanted with 1MEA and 5 with 1MEAhGPC3 revealed that tumors from 1MEA were 8-fold more voluminous than tumors from 1MEAhGPC3. Comparative analysis of the gene expression profile of 1MEA versus 1MEAhGPC3 revealed that transfection with hGPC3 had resulted in increased expression of mesenchymal markers (collagen I by 27.5-fold, fibronectin by 18-fold, vimentin by 3-fold), loss of epithelial marker (E-cadherin loss by 99%) and increased expression of transcriptional regulators of EMT (twist by 11.7-fold, slug by 148-fold and snail by 8.7-fold).These data clearly show that hGPC3 promotes HCC progression by inducing EMT in HCC cells. To our knowledge, this is the first experimental evidence that hGPC3's role in HCC is associated with induction of EMT and it suggests that therapeutic targeting of GPC3 in human HCC may be an effective approach to the treatment of advanced HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2413. doi:1538-7445.AM2012-2413
Published Version
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