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Arsenic trioxide inhibits liver cancer stem cells and metastasis by targeting SRF/MCM7 complex
Hai-Yang Wang1,2, Biao Zhang1,2, Jun-Nian Zhou3,4,5
1Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China.
Abstract:
Hepatocellular carcinoma (HCC) has a high mortality rate due to the lack of effective treatments and drugs. Arsenic trioxide (ATO), which has been proved to successfully treat acute promyelocytic leukemia (APL), was recently reported to show therapeutic potential in solid tumors including HCC. However, its anticancer mechanisms in HCC still need further investigation. In this study, we demonstrated that ATO inhibits tumorigenesis and distant metastasis in mouse models, corresponding with a prolonged mice survival time. Also, ATO was found to significantly decrease the cancer stem cell (CSC)-associated traits. Minichromosome maintenance protein (MCM) 7 was further identified to be a potential target suppressed dramatically by ATO, of which protein expression is increased in patients and significantly correlated with tumor size, cellular differentiation, portal venous emboli, and poor patient survival. Moreover, MCM7 knockdown recapitulates the effects of ATO on CSCs and metastasis, while ectopic expression of MCM7 abolishes them. Mechanistically, our results suggested that ATO suppresses MCM7 transcription by targeting serum response factor (SRF)/MCM7 complex, which functions as an important transcriptional regulator modulating MCM7 expression. Taken together, our findings highlight the importance of ATO in the treatment of solid tumors. The identification of SRF/MCM7 complex as a target of ATO provides new insights into ATO's mechanism, which may benefit the appropriate use of this agent in the treatment of HCC.
Insights
Arsenic trioxide (ATO) effectively treats hepatocellular carcinoma (HCC) by inhibiting tumor growth and metastasis. It targets the SRF/MCM7 complex, offering new therapeutic strategies for this deadly cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) presents a significant global health challenge with high mortality rates due to limited effective treatments.
- Arsenic trioxide (ATO), a drug successful in treating acute promyelocytic leukemia (APL), shows emerging potential against solid tumors like HCC, but its precise mechanisms remain unclear.
Purpose of the Study:
- To investigate the anticancer mechanisms of arsenic trioxide (ATO) in hepatocellular carcinoma (HCC).
- To identify molecular targets of ATO and evaluate its therapeutic potential in preclinical HCC models.
Main Methods:
- Utilized mouse models to assess the effects of ATO on HCC tumorigenesis, metastasis, and survival.
- Investigated ATO's impact on cancer stem cell (CSC) traits and identified Minichromosome maintenance protein 7 (MCM7) as a key target.
- Performed gene knockdown and ectopic expression studies to validate MCM7's role and explored the regulatory mechanism involving serum response factor (SRF).
Main Results:
- ATO significantly inhibited HCC tumor growth and distant metastasis in vivo, prolonging mouse survival.
- ATO treatment reduced CSC-associated traits and suppressed MCM7 expression, which is upregulated in HCC patients and correlates with poor prognosis.
- Knockdown of MCM7 mimicked ATO's effects, while MCM7 overexpression counteracted them, confirming MCM7 as a critical mediator. ATO was found to suppress MCM7 transcription via the SRF/MCM7 complex.
Conclusions:
- Arsenic trioxide demonstrates significant therapeutic potential against hepatocellular carcinoma by targeting cancer stem cells and metastasis.
- The SRF/MCM7 signaling pathway is identified as a novel molecular target of ATO in HCC, providing mechanistic insights for its clinical application.
- These findings support the further investigation and potential use of ATO as a treatment for solid tumors, particularly HCC.
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