Abstract
Granulin-epithelin precursor (GEP) overexpression has been shown in many cancers with functional role on growth, and recently on regulating chemoresistance and cancer stem cell (CSC) properties. Here, we investigate the combined effect of GEP antibody and chemotherapeutic agent. Combination therapy was compared with monotherapy using hepatocellular carcinoma (HCC) cells in vitro and orthotopic liver tumor models in vivo. CD133 and related hepatic CSC marker expressions were investigated by flow cytometry. Antiproliferative and apoptotic effects and signaling mechanisms were examined by immunohistochemistry, flow cytometry, and Western blot analysis. Secretory GEP levels in the serum and culture supernatant samples were measured by ELISA. We demonstrated that HCC cells that survived under chemotherapeutic agents showed upregulation of hepatic CSC markers CD133/GEP/ABCB5, and enhanced colony and spheroid formation abilities. Importantly, GEP antibody sensitized HCC cells to the apoptosis induced by chemotherapy for both HCC cell lines and the chemoresistant subpopulations, and counteracted the chemotherapy-induced GEP/ABCB5 expressions and Akt/Bcl-2 signaling. In human HCC orthotopic xenograft models, GEP antibody treatment alone was consistently capable of inhibiting the tumor growth. Notably, combination of GEP antibody with high dose of cisplatin resulted in the eradication of all established intrahepatic tumor in three weeks. This preclinical study demonstrated that GEP antibody sensitized HCC cells to apoptosis induced by chemotherapeutic agents. Combination treatment with GEP antibody and chemotherapeutic agent has the potential to be an effective therapeutic regimen for GEP-expressing cancers.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world, with an estimation of 748,000 new cases annually [1]
For the HCC cells isolated from the treated xenografts, the residual cells that survived after chemotherapeutic treatment showed enhanced ability on colony formation (Fig. 1D; analysis of variance (ANOVA), P 1⁄4 0.413)
Flow cytometry analysis for hepatic cancer stem cell (CSC) marker demonstrated that the HCC cells selected under chemotherapeutic agents showed increased expression of CD133, Granulin–epithelin precursor (GEP), and ABCB5 (Fig. 1F; ANOVA, P 1⁄4 0.029, 0.058 and 0.298, respectively)
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world, with an estimation of 748,000 new cases annually [1]. Curative treatments, including partial hepatectomy or liver transplantation, are limited to early-stage patients [2, 3]. Patients receiving curative surgery still have high recurrence rate [2, 3]. There is currently no effective treatment for patients with advanced tumors [4]. Chemotherapy is widely used to treat advanced HCC but chemoresistance is observed in the majority of the patients [5, 6]. There is an urgent demand of better therapeutic targets and treatment approaches for this aggressive disease
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