2. Academic Validation
  3. DDR1 promotes hepatocellular carcinoma metastasis through recruiting PSD4 to ARF6

DDR1 promotes hepatocellular carcinoma metastasis through recruiting PSD4 to ARF6

  • Oncogene. 2022 Mar;41(12):1821-1834. doi: 10.1038/s41388-022-02212-1.
Xiaochao Zhang  # 1 2 3 4 5 6,  Yabing Hu  # 1 7,  Yonglong Pan 1 2 3 4 5,  Yixiao Xiong 1 2 3 4 5,  Yuxin Zhang 1 2 3 4 5,  Mengzhen Han 1 2 3 4 5,  Keshuai Dong 1 2 3 4 5,  Jia Song 1 2 3 4 5,  Huifang Liang 1 2 3 4 5,  Zeyang Ding 1 2 3 4 5,  Xuewu Zhang 1 2 3 4 5,  He Zhu 1 2 3 4 5,  Qiumeng Liu 1 2 3 4 5,  Xun Lu 1 2 3 4 5,  Yongdong Feng 8,  Xiaoping Chen 1 2 3 4 5,  Zhanguo Zhang 9 10 11 12 13,  Bixiang Zhang 14 15 16 17 18
Affiliations

Affiliations

  • 1 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
  • 3 Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China.
  • 4 Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China.
  • 5 Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
  • 6 Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 7 Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 8 Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
  • 9 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. zhanguo_tjh@hust.edu.cn.
  • 10 Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China. zhanguo_tjh@hust.edu.cn.
  • 11 Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China. zhanguo_tjh@hust.edu.cn.
  • 12 Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China. zhanguo_tjh@hust.edu.cn.
  • 13 Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China. zhanguo_tjh@hust.edu.cn.
  • 14 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. bixiangzhang@163.com.
  • 15 Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China. bixiangzhang@163.com.
  • 16 Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China. bixiangzhang@163.com.
  • 17 Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China. bixiangzhang@163.com.
  • 18 Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China. bixiangzhang@163.com.
  • # Contributed equally.
PMID: 35140331 DOI: 10.1038/s41388-022-02212-1
Abstract

Discoidin Domain Receptor 1 (DDR1) is a member of the receptor tyrosine kinase family, and its ligand is collagen. Previous studies demonstrated that DDR1 is highly expressed in many tumors. However, its role in hepatocellular carcinoma (HCC) remains obscure. In this study, we found that DDR1 was upregulated in HCC tissues, and the expression of DDR1 in TNM stage II-IV was higher than that in TNM stage I in HCC tissues, and high DDR1 expression was associated with poor prognosis. Gene expression analysis showed that DDR1 target genes were functionally involved in HCC metastasis. DDR1 positively regulated the migration and invasion of HCC cells and promoted lung metastasis. Human Phospho-Kinase Array showed that DDR1 activated ERK/MAPK signaling pathway. Mechanically, DDR1 interacted with ARF6 and activated ARF6 through recruiting PSD4. The kinase activity of DDR1 was required for ARF6 activation and its role in metastasis. High expression of PSD4 was associated with poor prognosis in HCC. In summary, our findings indicate that DDR1 promotes HCC metastasis through collagen induced DDR1 signaling mediated PSD4/ARF6 signaling, suggesting that DDR1 and ARF6 may serve as novel prognostic biomarkers and therapeutic targets for metastatic HCC.

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