Glypican-3-Mediates Autophagy and Promotes Self-Renewal and Tumor Initiation of Hepatocellular Carcinoma CellsSun CK, Chua MS*, Wei W and So SK
Asian Liver Center, Department of Surgery, Stanford University Medical Center, Stanford, CA 94305, USA
- *Corresponding Author:
- Mei-Sze Chua, Ph.D.
Department of Surgery, Stanford University School of Medicine
Stanford University, 1201 Welch Road, MSLS Building
P228, Stanford, CA 94305-5655, USA
E-mail: [email protected]
Received date: May 22, 2014; Accepted date: September 03, 2014; Published date: September 05, 2014
Citation: Sun CK, Chua MS, Wei W, So SK (2014) Glypican-3-Mediates Autophagy and Promotes Self-Renewal and Tumor Initiation of Hepatocellular Carcinoma Cells. J Stem Cell Res Ther 4:229. doi:10.4172/2157-7633.1000229
Copyright: © 2014 Sun CK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Objective: Understanding the biological functions of cancer stem cells (CSCs) provide new avenues for therapeutic interventions, which is especially important in hepatocellular carcinoma (HCC), an often fatal malignancy. We aim to determine whether glypican-3 (GPC3), an over-expressed membrane protein in HCC, mediates CSC properties in HCC cells.
Design: We determined the cell surface expression of GPC3 in HCC patients and HCC cell lines, and isolated GPC3-high/low sub-populations to study their abilities to self-renew. Additionally, we used HCC cell-based systems where GPC3 expression was either suppressed or induced, to validate the stem-like properties (spheroid formation, cell cycle progression, tumor initiation) that may be mediated by GPC3.
Results: We observed highly specific cell surface expression of GPC3 in HCC cells only (and not in normal hepatocytes or tumor-associated fibroblasts). The GPC3-high sub-populations isolated from HCC cells possess higher levels of self-renewing ability, have lower percentages of cells in the G0/G1 phase, and promoted tumor formation in vivo. These observations were confirmed in HCC cell-based systems where GPC3 expression was either suppressed or induced. The effects of GPC3 (and EpCAM and CD133) on spheroid formation and cell cycle were nullified by the starvation-induced autophagy inhibitor, 3-methyladenine (3-MA), indicating that these processes are partially regulated by autophagy.
Conclusion: We provide first evidence that GPC3 is a novel CSC marker in HCC, and that it mediates selfrenewal, cell cycle progression, and tumor formation partly via autophagy induction. We also suggest that autophagy inhibition may be a general approach for intervening with liver CSC functions, regardless of cell surface marker expression.