J Cancer 2020; 11(16):4917-4932. doi:10.7150/jca.40673

Research Paper

EXO1 Plays a Carcinogenic Role in Hepatocellular Carcinoma and is related to the regulation of FOXP3

Guang Yang1, Keshuai Dong2, Zunyi Zhang1, Erlei Zhang1, Binyong Liang1, Xiaoping Chen1, Zhiyong Huang1✉

1. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2. Department of Hepatobiliary and Laparoscopic Surgery, Renmin Hospital, Wuhan University, Hubei Key Laboratory of Digestive System Disease, Wuhan, China.

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Citation:
Yang G, Dong K, Zhang Z, Zhang E, Liang B, Chen X, Huang Z. EXO1 Plays a Carcinogenic Role in Hepatocellular Carcinoma and is related to the regulation of FOXP3. J Cancer 2020; 11(16):4917-4932. doi:10.7150/jca.40673. Available from http://www.jcancer.org/v11p4917.htm

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Abstract

Exonuclease 1 (EXO1), a member of the RAD2 nuclease family, was first described as possessing 5' to 3' nuclease activity and 5' structure-specific endonuclease activity. Here, we show that EXO1 is significantly upregulated in HCC tumor tissues and that high EXO1 expression is significantly correlated with liver cirrhosis. We further demonstrate that EXO1 knockdown decreases proliferation and colony forming abilities of HCC cells in vitro and tumorigenicity in vivo, as well as decreases migration and invasive capabilities of HCC cells. Alternatively, EXO1 overexpression significantly increases the proliferation, colony forming ability, and migration and invasive capabilities of HCC cells in vitro. Additionally, we truncated a region upstream of the transcription start site (TSS) of EXO1 and used the region with the strongest transcriptional activity to predict that the transcription factor FOXP3 can bind to the EXO1 promoter. Bioinformatics analysis found that FOXP3 was positively correlated with EXO1 and luciferase reporter assays and RT-PCR confirmed that FOXP3 could enhance the transcriptional activity of EXO1. CCK-8 assays showed that depletion of FOXP3 further reduces cell proliferation ability after knocking down of EXO1 in vitro. Taken together, our findings indicate that EXO1 acts as an oncogene in HCC and its expression level is related to FOXP3 activity.

Keywords: EXO1, FOXP3, Hepatocellular carcinoma, Metastasis, Transcriptional regulation