記住我
Research ArticleCell biologyTherapeutics
Open Access | 
10.1172/JCI178428
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Zhang, H. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Lin, J. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Zheng, S. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Ma, L. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Pang, Z. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Yin, H. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Meng, C. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Wang, Y. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Han, Q. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Zhang, X. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Li, Z. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Cao, L. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Liu, L. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Fei, T. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Gao, D. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Yang, L. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Peng, X. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Ding, C. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by Wang, S. in: JCI | PubMed | Google Scholar
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
2Department of Pathology, the Fourth People’s Hospital of Shenyang, Shenyang, China.
3College of Sciences, Northeastern University, Shenyang, China.
4College of Basic Medical Science, China Medical University, Shenyang, China.
5State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China.
7CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
Address correspondence to: Ren Sheng, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13944806789; Email: shengren@mail.neu.edu.cn. Or to: Shixue Wang, 5625 Renmin Street, Chaoyang District, Changchun, 130022 Jilin, China. Phone: 86.13756116863; Email: wangsx@ciac.ac.cn. Or to: Chen Ding, 195 Chuangxin Road, Hunnan District, Shenyang, 110819 Liaoning, China. Phone: 86.13644079688; Email: dingchen@mail.neu.edu.cn.
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Find articles by
Sheng, R.
in:
JCI
|
PubMed
|
Google Scholar
|
Authorship note: HZ and JL contributed equally to this work as co–first authors.
Published July 4, 2024 - More info
Published in Volume 134, Issue 16 on August 15, 2024
AbstractCell cycle regulation is largely abnormal in cancers. Molecular understanding and therapeutic targeting of the aberrant cell cycle are essential. Here, we identified that an underappreciated serine/threonine kinase, cyclin-dependent kinase–like 3 (CDKL3), crucially drives rapid cell cycle progression and cell growth in cancers. With regard to mechanism, CDKL3 localizes in the nucleus and associates with specific cyclin to directly phosphorylate retinoblastoma (Rb) for quiescence exit. In parallel, CDKL3 prevents the ubiquitin-proteasomal degradation of cyclin-dependent kinase 4 (CDK4) by direct phosphorylation on T172 to sustain G1 phase advancement. The crucial function of CDKL3 in cancers was demonstrated both in vitro and in vivo. We also designed, synthesized, and characterized a first-in-class CDKL3-specific inhibitor, HZ1. HZ1 exhibits greater potency than CDK4/6 inhibitor in pan-cancer treatment by causing cell cycle arrest and overcomes acquired resistance to CDK4/6 inhibitor. In particular, CDKL3 has significant clinical relevance in colon cancer, and the effectiveness of HZ1 was demonstrated by murine and patient-derived cancer models. Collectively, this work presents an integrated paradigm of cancer cell cycle regulation and suggests CDKL3 targeting as a feasible approach in cancer treatment.
Graphical Abstract
Introduction
The cell cycle consists of multiple modules and machineries to regulate cell division in a precise manner (1, 2). A complete cell cycle is composed of G1, S, G2, and M phases sequentially. The progression of the cell cycle is primarily governed by cyclins and cyclin-dependent kinases (CDKs) at various stages (2, 3). For instance, the pair of CDK4/6–cyclin D is known to maintain the G1 phase progression (4). At the G1/S phase checkpoint, the combination of CDK1/2–cyclin E/A takes over the responsibility for G1-to-S transition (4, 5). In both processes, the phosphorylation of retinoblastoma (Rb) protein by CDKs is essentially required (3, 4). The phosphorylated Rb (i.e., on S807/S811) can dissociate with the transcription factor E2F, leading to the expression of multiple cell cycle–related genes that are required in the ensuing phases (6).
Besides active cycling, cells can exit the cell cycle and stay in a resting/quiescent state called G0 phase. Cells in this state are generally found nondividing and nongrowing (7). The regulation of G0 entry and exit remains obscure. Earlier literature suggested CDK3–cyclin C to support the G0-to-G1 transition by phosphorylation of Rb (8). However, CDK3 in most laboratory mice harbors the natural loss-of-function mutation with no phenotypic defects (2, 4). Hence, the biological importance of CDK3 in G0 phase exit was undermined by this phenomenon. Even though new factors have been reported to regulate this transition in recent years (9, 10), the understanding of this process is still largely lacking (7).
The cell cycle is often dysregulated in cancer (2, 7). The cell cycle entry and exit of normal cells occur on a clear schedule. However, various types of (epi)genetic changes allow the cancer cells to bypass the resting phase (7). Thereby, in cancers, an accelerated and uncontrolled cell cycle is widely seen, which favors infinite mitogenic proliferation (7). Targeting of cell cycle progression has been shown to be effective in cancer therapy (11, 12). Given the central role of CDKs in cell cycle regulation and their enzymatic nature, multiple small-molecule inhibitors of CDKs have been designed and tested in clinical trials or have been clinically approved in cancer treatment (11, 12). However, clinical feedback pointed out the challenge of acquired drug resistance to these inhibitors (13). The discovery of new targets to overcome such resistance is hence of greater necessity and value.
CDKL3 belongs to the cyclin-dependent kinase–like (CDKL) kinase subfamily, which is part of the CMGC Ser/Thr protein kinase superfamily. CDKL kinases share the conserved α-helix on the kinase domain of CDK as the putative cyclin-binding site (14–16). However, whether CDKL could bind cyclins or function via cyclins is unknown. In fact, the CDKL family is overall underexplored in terms of both function and mechanism. CDKL5 has been shown to be related to neurological disorders, whereas CDKL1 was reported to regulate cilia formation (17–19). Though CDKL3 was reported to associate with cancer progression (20–22), the mechanism requires further scrutiny with rigorous evidence.
Here, we report that CDKL3 directly promotes cell cycle progression in cancer. Two parallel regulatory paths exist molecularly. First, CDKL3 couples with cyclin A2 to directly lead to Rb phosphorylation and G0-to-G1 transition. Ablation of CDKL3 results in cell cycle exit and growth retardation in cancers. Also, CDKL3 can phosphorylate CDK4 on T172 with the assistance of cyclin A2. This leads to the consequence that CDK4 avoids ubiquitin-proteasome–dependent degradation, thereby sustaining G1 phase progression. E3 ubiquitin ligases such as Trim28 cause CDK4 ubiquitination in the absence of T172 phosphorylation. Moreover, we rationally designed and characterized the small-molecule inhibitor HZ1 specifically against CDKL3. HZ1 showed strong tumor-suppressing effect with IC50 at nanomolar range and the potential to overcome resistance to CDK4/6 inhibitor, and manifested satisfactory tumor clearance in laboratory animals and patient-derived samples. Taken together, we have discovered a series of mechanistic findings on the critical role of CDKL3 in cell cycle regulation and revealed the cyclin-dependent function of the CDKL kinase subfamily. Besides its value for basic biomedical research, this work also presents and proposes an alternative cancer therapeutic approach by targeting of CDKL3-mediated cancer cell cycle progression.
ResultsCDKL3 loss abrogates cancer cell growth by impeding G0-to-G1 transition. Similarly to CDK family kinases, CDKL kinases contain the conserved putative cyclin-binding α-helix (14–16, 19) (Figure 1A). CDKL3 also has a potential nucleus localization sequence (NLS) conserved among different species (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/JCI178428DS1). We speculated that CDKL3 might be ready to localize in the nucleus and regulate the cell cycle in a manner reminiscent of CDKs. CDKL3’s subcellular location was inspected to test this assumption. Immunofluorescence has demonstrated that endogenous CDKL3 localizes largely in the nucleus with a small amount in the cytoplasm (Figure 1B and Supplemental Figure 1, B and C). This nuclear localization was largely independent of cell cycle phase (Supplemental Figure 1D). We found that CDKL3 could no longer effectively dwell in the nucleus after internal deletion of the putative NLS (Figure 1C). After the insertion of the NLS of CDKL3, tandem green fluorescent proteins (GFPs), which could only stay in the cytosol, became able to translocate into the nucleus (Figure 1C).
留言 (0)