Title:USP3 inhibition is Active Against Chemo-resistant Hepatocellular
Carcinoma Anchorage-independent Growth via Suppressing
Wnt/β-catenin
Volume: 24
Issue: 5
Author(s): Jianguo Xu, Ge Sang Wang Gui, Chao Yang, Shuchen Zhu, Zemin Chen, Suo Lang Bai Ma, Ci Yang, Ci Ren Luo Bu, Ying Zhu*Wen Xu*
Affiliation:
- Medical Department, Chayu County People’s Hospital, Chayu, Xizang, China
- Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen,
Guangdong, China
- Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen,
Guangdong, China
Keywords:
USP3, HCC, chemoresistance, β-catenin, USPs, sensitizing target.
Abstract:
Background: USPs are a family of enzymes that regulate protein
degradation, and their dysregulation has been implicated in the development and
progression of cancer.
Aims: This study aimed to determine whether ubiquitin-specific proteases 3 (USP3)
could be a potential target for therapy in hepatocellular carcinoma (HCC), particularly in
resistant HCC. This study systematically investigated the role of USP3 in HCC, with a
focus on chemo-resistant HCC cells.
Methods: The level of USP3 from clinical samples was measured using an ELISA assay.
Cell proliferation, apoptosis, migration, and anchorage-independent colony formation
assays were performed. Transfection was performed to knock down USP3 expression
and measure β-catenin activity, and real-time PCR was used to measure levels of MYC
and CYCLIN D1 genes.
Results: USP3 protein was upregulated in HCC tissues, but its upregulation was not
associated with clinicopathology. USP3 knockdown had a similar inhibitory effect on
growth in both sensitive and resistant HCC cells, did not affect migration, and induced
apoptosis in sensitive but not resistant HCC cells. Furthermore, USP3 knockdown was
more effective in suppressing anchorage-independent colony formation in chemoresistant
HCC cells compared to their chemo-sensitive counterparts. Pearson
correlation coefficient analysis revealed a strong positive correlation between USP3
and CTNNB1, and consistently, USP3 knockdown reduced the levels and activities of
β-catenin in HCC cells. Using a Wnt activator (lithium) in rescue studies significantly
reversed the inhibitory effects of USP3 knockdown.
Conclusion: The findings suggest that inhibiting USP3 is an effective strategy against
cancer stem cells and chemo-resistant HCC cells.
