机构：[1]Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China四川大学华西医院[2]Department of Hepatobiliary Surgery, Guizhou Provincial People’s Hospital, Guiyang 550000, Guizhou Province, China[3]The First Department of General Surgery, The First People’s Hospital of Qujing, Qujing, Yunnan Province, China云南省第一人民医院[4]Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China四川大学华西医院[5]Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China四川大学华西医院[6]Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China[7]Department of General Surgery, Mianzhu Hospital of West China Hospital, Sichuan University, Mianzhu City, Sichuan Province, China
A previous study reported that histone methy transferase SETD3 is up-regulated in tumor tissues of hepatocellular carcinoma (HCC) and is associated with the growth of HCC. However, the clinical significance and the effect of SETD3 on HCC metastasis remain unclear. In the present study, both the protein and mRNA expression levels of SETD3 were measured in a larger cohort of HCC patients. The results showed that the protein level of SETD3 in HCC tissues was significantly higher than that in non-tumorous tissues, which was inconsistent with the mRNA expression level of SETD3. The high protein level of SETD3 in HCC tissues was significantly associated with male gender. poor pathological differentiation, liver cirrhosis and unfavorable prognosis of HCC patients. Subsequently, we demonstrated that SETD3 could be regulated at post-transcriptional step by a couple of miRNAs (miR-16, miR-195 and miR-497). Additionally, in vitro and in vivo experiments revealed that SETD3 played opposing roles in proliferation and metastasis of HCC: promoting proliferation but inhibiting metastasis. Mechanistic experiments revealed that doublecortin-like kinase 1 (DCLK1) was a downstream target of SETD3. SETD3 could increase the DNA methylation level of DCLK1 promoter to inhibit the transcription of DCLK1. Further study revealed that DCLK1/P13K/rriatrix metalloproteinase (MMP) 2 (MMP-2) was an important pathway that mediated the effect of SETD3 on HCC metastasis. In conclusion, the present study revealed that SETD3 is associated with tumorigenesis and is a promising biomarker for predicting the prognosis of HCC patients after surgical resection. In addition, SETD3 plays inhibitory role in HCC metastasis partly through DCLK1/P13K/MMP-2 pathway.
基金：
This work was supported by the Key Technology Research and Development Program of the Sichuan Province [grant numbers
2019YFS0208, 2017FZ0082, 2015SZ0131]; the National Natural Science Foundation of China [grant number 71673193];
the Chinese Foundation for Hepatitis Prevention and Control–TianQing Liver Disease Research Fund Subject [grant number
TQGB20190202]; and the Natural Science Foundation for Young Scientists and the Science and Technology Planning Project
of Gansu Province [grant number 18JR3RA058].
第一作者机构：[1]Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China[7]Department of General Surgery, Mianzhu Hospital of West China Hospital, Sichuan University, Mianzhu City, Sichuan Province, China
推荐引用方式(GB/T 7714)：
Xu Liangliang,Wang Peng,Feng Xinfu,et al.SETD3 is regulated by a couple of microRNAs and plays opposing roles in proliferation and metastasis of hepatocellular carcinoma[J].CLINICAL SCIENCE.2019,133(20):2085-2105.doi:10.1042/CS20190666.
APA：
Xu, Liangliang,Wang, Peng,Feng, Xinfu,Tang, Jianwei,Li, Lian...&Xu, Mingqing.(2019).SETD3 is regulated by a couple of microRNAs and plays opposing roles in proliferation and metastasis of hepatocellular carcinoma.CLINICAL SCIENCE,133,(20)
MLA：
Xu, Liangliang,et al."SETD3 is regulated by a couple of microRNAs and plays opposing roles in proliferation and metastasis of hepatocellular carcinoma".CLINICAL SCIENCE 133..20(2019):2085-2105
