Coordination of SLC39A1 and DRP1 facilitates HCC recurrence by impairing mitochondrial quality control
Rui Li
Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
Search for more papers by this authorZhe Wang
Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
Search for more papers by this authorLixin Cheng
Department of Critical Care Medicine, Shenzhen People's Hospital, the First Affiliated Hospital of Southern University of Science and Technology, the Second Clinical Medical College of Jinan University, Shenzhen, China
Search for more papers by this authorZhiqiang Cheng
Department of Pathology, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
Search for more papers by this authorQiong Wu
School of Basic Medicine, North Sichuan Medical College, Nanchong, China
Search for more papers by this authorFengjuan Chen
Department of Hepatopathy, The Eighth Affiliated Hospital of the Guangzhou Medical University, Guangzhou, China
Search for more papers by this authorCorresponding Author
Dong Ji
Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
Correspondence
Yijin Wang, School of Medicine, Southern University of Science and Technology, No. 1088, Xueyuan Road, Nanshan District 518055, Shenzhen, Guangdong, China.
Email: [email protected]
Qingxian Cai, Department of Hepatopathy, the Third People's Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, No. 29, Buji Bulan Road, Longgang District 518038, Shenzhen, China.
Email: [email protected]
Dong Ji, Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, No. 100, West Fourth Ring Road, Fengtai District 100039, Beijing, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Qingxian Cai
Department of Hepatopathy, the Third People's Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
Correspondence
Yijin Wang, School of Medicine, Southern University of Science and Technology, No. 1088, Xueyuan Road, Nanshan District 518055, Shenzhen, Guangdong, China.
Email: [email protected]
Qingxian Cai, Department of Hepatopathy, the Third People's Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, No. 29, Buji Bulan Road, Longgang District 518038, Shenzhen, China.
Email: [email protected]
Dong Ji, Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, No. 100, West Fourth Ring Road, Fengtai District 100039, Beijing, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Yijin Wang
Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
Correspondence
Yijin Wang, School of Medicine, Southern University of Science and Technology, No. 1088, Xueyuan Road, Nanshan District 518055, Shenzhen, Guangdong, China.
Email: [email protected]
Qingxian Cai, Department of Hepatopathy, the Third People's Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, No. 29, Buji Bulan Road, Longgang District 518038, Shenzhen, China.
Email: [email protected]
Dong Ji, Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, No. 100, West Fourth Ring Road, Fengtai District 100039, Beijing, China.
Email: [email protected]
Search for more papers by this authorRui Li
Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
Search for more papers by this authorZhe Wang
Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
Search for more papers by this authorLixin Cheng
Department of Critical Care Medicine, Shenzhen People's Hospital, the First Affiliated Hospital of Southern University of Science and Technology, the Second Clinical Medical College of Jinan University, Shenzhen, China
Search for more papers by this authorZhiqiang Cheng
Department of Pathology, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
Search for more papers by this authorQiong Wu
School of Basic Medicine, North Sichuan Medical College, Nanchong, China
Search for more papers by this authorFengjuan Chen
Department of Hepatopathy, The Eighth Affiliated Hospital of the Guangzhou Medical University, Guangzhou, China
Search for more papers by this authorCorresponding Author
Dong Ji
Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
Correspondence
Yijin Wang, School of Medicine, Southern University of Science and Technology, No. 1088, Xueyuan Road, Nanshan District 518055, Shenzhen, Guangdong, China.
Email: [email protected]
Qingxian Cai, Department of Hepatopathy, the Third People's Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, No. 29, Buji Bulan Road, Longgang District 518038, Shenzhen, China.
Email: [email protected]
Dong Ji, Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, No. 100, West Fourth Ring Road, Fengtai District 100039, Beijing, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Qingxian Cai
Department of Hepatopathy, the Third People's Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
Correspondence
Yijin Wang, School of Medicine, Southern University of Science and Technology, No. 1088, Xueyuan Road, Nanshan District 518055, Shenzhen, Guangdong, China.
Email: [email protected]
Qingxian Cai, Department of Hepatopathy, the Third People's Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, No. 29, Buji Bulan Road, Longgang District 518038, Shenzhen, China.
Email: [email protected]
Dong Ji, Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, No. 100, West Fourth Ring Road, Fengtai District 100039, Beijing, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Yijin Wang
Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
Correspondence
Yijin Wang, School of Medicine, Southern University of Science and Technology, No. 1088, Xueyuan Road, Nanshan District 518055, Shenzhen, Guangdong, China.
Email: [email protected]
Qingxian Cai, Department of Hepatopathy, the Third People's Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, No. 29, Buji Bulan Road, Longgang District 518038, Shenzhen, China.
Email: [email protected]
Dong Ji, Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, No. 100, West Fourth Ring Road, Fengtai District 100039, Beijing, China.
Email: [email protected]
Search for more papers by this authorRui Li and Zhe Wang contributed equally to this work.
Abstract
Background
Despite rapid advances in HCC therapy, surgical resection is still the most effective treatment. However, postoperative relapse develops in a large population and the mechanism remains to be explored.
Methods
HCC resection samples were retrospectively collected from 12 nonrelapsed and 15 relapsed HCC patients for RNA sequencing. Liver-specific solute carrier family 39 member 1 (SLC39A1) knockout mice were generated by crossing Alb-Cre mice and SLC39A1flox/flox mice. Liver samples were examined for inflammation, fibrosis, proliferation, and apoptosis. Mitochondrial mass, autophagy, ROS, and mitochondrial membrane potential (MMP), were detected. Co-immunoprecipitation and molecular docking were used to identify protein interactions.
Results
SLC39A1 is highly expressed in relapsed HCC patients and negatively correlated with overall survival. Knockdown of SLC39A1 inhibited cell proliferation by arresting the cell cycle and promoted cell apoptosis, accompanied by suppressing autophagic flux. Mechanistically, SLC39A1 interacts with a member of the dynamin superfamily of GTPases dynamin-related protein 1 (DRP1), followed by facilitating mitochondrial fission and MMP reduction. Inhibition of DRP1 abolished SLC39A1-induced mitochondrial division and MMP depolarization, while overexpression of DRP1 reversed mitochondrial fusion and MMP hyperpolarization in SLC39A1 silenced cells, accompanied by recuperative cell proliferative ability. SLC39A1flox/flox,Alb-Cre mice displayed fewer tumour numbers and less liver damage compared with SLC39A1flox/flox mice. A specific peptide targeting SLC39A1 to disturb the combination of full-length SLC39A1 and DRP1 efficiently suppressed HCC progression.
Conclusions
Our findings reveal a key role of SLC39A1-DRP1 interaction in HCC progression by disturbing mitochondrial quality control and providing a competitive peptide as a potential anti-tumour therapy.
Key points
- SLC39A1 correlates with HCC recurrence and HCC mortality.
- Interaction of SLC39A1 and DRP1 facilitates HCC by regulating mitochondrial quality control.
- Specific peptide targeting SLC39A1 efficiently prevents HCC progression.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
All data generated or analysed during this study are included in this article. The data from the RNA sequencing analysis used in this research can be found in the National Genomics Data Center (PRJCA004993) and the GEO database (GSE268875).
Supporting Information
| Filename | Description |
|---|---|
| ctm270362-sup-0001-SuppMat.docx41.9 MB | Supporting information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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