DDR1 promotes hepatocellular carcinoma metastasis through recruiting PSD4 to ARF6

Xiaochao Zhang,Yixiao Xiong,Zhanguo Zhang,Xun Lu,Bixiang Zhang,He Zhu,Jia Song,Zeyang Ding,Huifang Liang,Yabing Hu,Yongdong Feng,Yonglong Pan,Qiumeng Liu,Xuewu Zhang,Xiaoping Chen,Keshuai Dong,Mengzhen Han,Yuxin Zhang

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.

Highlights

Hepatocellular Carcinoma (HCC) is the fourth leading cause of cancer-related mortality worldwide [1]
We found that Discoidin domain receptor 1 (DDR1) was upregulated in hepatocellular carcinoma (HCC) tissues, and the expression of DDR1 in TNM stage II-IV was higher than that in TNM stage I in HCC tissues
High DDR1 expression was associated with poor prognosis

Summary

INTRODUCTION

Hepatocellular Carcinoma (HCC) is the fourth leading cause of cancer-related mortality worldwide [1]. Previous studies showed that DDR1 is involved in key cellular processes, including cell proliferation, migration, survival, and differentiation [13]. Nilotinib inhibited DDR1 kinase activity and reduced the invasion and metastasis of colorectal cancer cells [14]. Other studies suggest that the kinase activity is not necessary for the function of DDR1 in the cancer development. DDR1 promoted collective cancer-cell migration through DDR1–Par3/Par complex independent of its kinase activity or collagen binding [16]. DDR1 regulates multi-organ site metastatic reactivation of breast cancer by non-canonical signaling independent of its kinase activity [18]. The knockdown of DDR1 significantly inhibited the migration and invasion of HLE and HLF cells induced by collagen I

RESULTS

DISCUSSION

MATERIALS AND METHODS

Findings

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