Sharpin (Shank-associated RH domain-interacting
protein, also known as SIPL1) is a multifunctional molecule that participates in various biological settings, including nuclear factor-κB signaling activation and tumor suppressor gene inhibition.
Sharpin is upregulated in various types of
cancers, including
hepatocellular carcinoma (HCC), and is implicated in
tumor progression. However, the exact roles of
Sharpin in
tumorigenesis and
tumor progression remain largely unknown. Here we report novel mechanisms of HCC progression through
Sharpin overexpression. In our study,
Sharpin was upregulated in human HCC tissues. Increased
Sharpin expression enhanced
hepatoma cell invasion, whereas decrease in
Sharpin expression by RNA interference inhibited invasion. Microarray analysis identified that
Versican, a
chondroitin sulfate proteoglycan that plays crucial roles in
tumor progression and invasion, was also upregulated in
Sharpin-expressing stable cells.
Versican expression increased in the majority of HCC tissues and knocking down of
Versican greatly attenuated
hepatoma cell invasion.
Sharpin expression resulted in a significant induction of
Versican transcription synergistically with Wnt/β-
catenin pathway activation. Furthermore,
Sharpin-overexpressing cells had high tumorigenic properties in vivo. These results demonstrate that
Sharpin promotes
Versican expression synergistically with the Wnt/β-
catenin pathway, potentially contributing to HCC development. A
Sharpin/
Versican axis could be an attractive therapeutic target for this currently untreatable
cancer.