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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common solid tumors; more than 700,000 cases are diagnosed worldwide per year[1]
Arsenic trioxide (ATO) inhibits distant metastasis and prolongs survival of intrahepatic metastasis model mice To minimize the toxicity of ATO on normal cells, we used various dosages of ATO to explore their effects on proliferation of normal human fetal liver L02 cells (Fig. S1A and B) and found that ATO at 3.6 μM or less had little effect on L02 cell apoptosis (Fig. S1C)
We used 3.6 μM for further assays in HCC cells and found that ATO at 3.6 μM had significant inhibitory effects on the proliferation (Fig. S1D), G0/G1 population (Fig. S1E), and the invasion of cells (Fig. S1F) but little effects on cell apoptosis (Fig. S1G). These results suggested that low dose of ATO inhibits HCC cell proliferation and invasion without inducing apoptosis
Summary
Hepatocellular carcinoma (HCC) is one of the most common solid tumors; more than 700,000 cases are diagnosed worldwide per year[1]. HCC has a high mortality rate due to the high metastatic potential and lack of effective treatments and drugs[2]. Researchers have been making efforts to investigate more effective treatment options. Arsenic trioxide (ATO), an FDA-approved drug as the first line treatment of acute promyelocytic leukemia (APL), is showing promising therapeutic potential in advanced liver cancers. As demonstrated by multiple clinical trials, HCC patients received ATO as a therapeutic agent or a chemosensitizer showed less extrahepatic metastasis and prolonged survival[3,4,5]. Its anticancer mechanisms of action in HCC remain unclear
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