Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third 
leading cause of cancer-related death worldwide. Current treatments are 
extremely disappointing. SPARC (Secreted protein, acidic and rich in cysteine) 
is a matricellular glycoprotein with differential expression in several tumors, 
including HCC, which significance remains unclear. We infected HCC cells (HepG2, 
Hep3B and Huh7) with an adenovirus expressing SPARC (AdsSPARC) to examine the 
role of SPARC expression on HCC cells and its effect on tumor aggressiveness. 
The in vitro HCC cells substrate-dependent proliferation and cell cycle profile 
were unaffected; however, SPARC overexpression reduced HCC proliferation when 
cells were grown in spheroids. A mild induction of cellular apoptosis was 
observed upon SPARC overexpression. SPARC overexpression resulted in spheroid 
growth inhibition in vitro while no effects were found when recombinant SPARC 
was exogenously applied. Moreover, the clonogenic and migratory capabilities 
were largely decreased in SPARC-overexpressing HCC cells, altogether suggesting 
a less aggressive HCC cell phenotype. Consistently, AdsSPARC-transduced cells 
showed increased E-cadherin expression and a concomitant decrease in N-cadherin 
expression. Furthermore, SPARC overexpression was found to reduce HCC cell 
viability in response to 5-FU-based chemotherapy in vitro, partially through 
induction of apoptosis. In vivo experiments revealed that SPARC overexpression 
in HCC cells inhibited their tumorigenic capacity and increased animal survival 
through a mechanism that partially involves host macrophages. Our data suggest 
that SPARC overexpression in HCC cells results in a reduced tumorigenicity 
partially through the induction of mesenchymal-to-epithelial transition (MET). 
These evidences point to SPARC as a novel target for HCC treatment.