Augmenting the Antitumor Effect of TRAIL by SOCS3 with Double-Regulated Replicating Oncolytic Adenovirus in Hepatocellular Carcinoma

Abstract

Aberrant JAK/STAT3 pathway has been reported to be related to hepatocellular carcinoma (HCC) in many cell lines. In this study, a double-regulated oncolytic adenovirus vector that can replicate and induce a cytopathic effect in alpha-fetoprotein (AFP)-positive HCC cell lines with p53 dysfunction was successfully constructed. Two therapeutic genes, suppressor of cytokine signaling 3 (SOCS3) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were chosen and incorporated into this vector system, respectively. The combined treatment of AFP-D55-SOCS3 and AFP-D55-TRAIL (2:3 ratio) exhibited potent antitumor activity in AFP-positive HCC cell lines compared with any other treatment both in vitro and in vivo. Specific replication and low progeny yield in AFP-positive HCC cell lines rendered these double-regulated oncolytic adenoviruses remarkably safe. Our data demonstrated that restoration of SOCS3, which inhibits the JAK/STAT3 pathway, by AFP-D55-SOCS3 not only could antagonize HCC therapeutic resistance to TRAIL and adenoviruses, but could also induce cell cycle arrest in HCC cell lines. SOCS3 could down-regulate Cyclin D1 and anti-apoptotic proteins such as XIAP, Survivin, Bcl-xL, and Mcl-1, which are responsible for the synergistic inhibitory effects of AFP-D55-SOCS3 and AFP-D55-TRAIL. Dual gene and double-regulated oncolytic adenoviruses may provide safety and excellent antitumor effects for liver cancer, which is the advantage of a cancer-targeting gene virotherapy strategy.

Integrated Analysis of Mutation Data from Various Sources Identifies Key Genes and Signaling Pathways in Hepatocellular Carcinoma

“…Specifically, among the top 50 mutated genes with the highest betweenness coefficients, 11 well-known and emerging cancer genes (TP53, CTNNB1, PIK3CA, EGFR, IGF1R, JAK2, STAT1, NFKB1, LEPR, SOCS3, and HRAS) were observed in HCC [2], [15], [28], [29], [30]. For the remaining 12 genes (RAF1, TRAF6, PPARA, MAPK8, MAPK9, RHOA, MDM2, GNAS, PTK2, PLAU, VEGFB, and CCL5), there is some but not sufficient evidence to support their roles in liver tumorigenesis [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], which warrants further investigation.…”

Tumor suppressor in lung cancer-1 (TSLC1) mediated by dual-regulated oncolytic adenovirus exerts specific antitumor actions in a mouse model

“…Moreover, the use of a tumor-specific promoter as a replacement for the E1A endogenous promoter improves the targeting of the oncolytic virus. The human telomerase reverse transcriptase (hTERT) promoter [31] , the α-fetoprotein (AFP) promoter [32,33] and the differential display code 3 (DD3) promoter [34] have been extensively utilized in targeted cancer therapy. Survivin is a cancer gene and could potentially be useful for cancer diagnosis and therapy [20,21,35] .…”

Progress in clinical oncolytic virus-based therapy for hepatocellular carcinoma

“…Infection of a malignant hepatocyte (illustrated by the large blue rectangular cell) by replication-competent adenovirus results in the expression of engineered therapeutic genes. Suppressor of cytokine signalling (SOCS)-1 and SOCS3 inhibit JAK phosphorylation of STAT, thus attenuating cytokine signal transduction and suppressing tumour growth (Wei et al, 2011;Liu et al, 2013). Tumour suppressor in lung cancer 1 (TSLC1) is a cell adhesion molecule whose overexpression inhibits cell growth and migration, and induces apoptosis (He et al, 2012).…”