Shc3 promotes hepatocellular carcinoma stemness and drug resistance by interacting with β-catenin to inhibit its ubiquitin degradation pathway.

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers with an insidious onset, strong invasiveness, insensitivity to chemotherapy, and poor prognosis, thus makes clinical treatment challenging. The mechanisms require further elucidation for developing novel therapies and targeting drug resistance. Here, we observed high Shc3 expression in patients with chemoresistant and recurrent HCCs. Shc3 overexpression induced a significant increase in MDR1/P-glycoprotein expression, whereas Shc3 knockdown impaired this expression. Further, Shc3 inhibition significantly restored HCC cell sensitivity to doxorubicin and sorafenib. Mechanistically, Shc3 interacted with β-catenin, inhibited destruction complex stability, promoted β-catenin release, and dampened β-catenin ubiquitination. Shc3 bound β-catenin and facilitated its nuclear translocation, prompting the β-catenin/TCF pathway to elevate MDR1 transcription. β-catenin blockage abolished the discrepancy in drug resistance between Shc3-depleted HCC cells and control cells, which further validating that β-catenin is required for Shc3-mediated liver chemotherapy. We also determined the effect of Shc3 on the sensitivity of HCC to chemotherapy in vivo. Collectively, this study provides a potential strategy to target these pathways concurrently with systemic chemotherapy that can improve the clinical treatment of HCC.

• Authors: Yun Liu, Hao Zhuang, Fang Cao, Jie Li, Yan Guo, Jun Zhang, Qiang Zhao, Yuanyuan Liu
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 3 Pg. 278 (03 15 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 33723262 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Antineoplastic Agents
• CTNNB1 protein, human
• SHC3 protein, human
• Src Homology 2 Domain-Containing, Transforming Protein 3
• TCF Transcription Factors
• beta Catenin
• Doxorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics, metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism, pathology)
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm
• Female
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Humans
• Liver Neoplasms (drug therapy, genetics, metabolism, pathology)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Proteolysis
• Signal Transduction
• Src Homology 2 Domain-Containing, Transforming Protein 3 (genetics, metabolism)
• TCF Transcription Factors (genetics, metabolism)
• Ubiquitination
• Xenograft Model Antitumor Assays
• beta Catenin (metabolism)
• Mice