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  3. Collagen I-DDR1 signaling promotes hepatocellular carcinoma cell stemness via Hippo signaling repression

Collagen I-DDR1 signaling promotes hepatocellular carcinoma cell stemness via Hippo signaling repression

  • Cell Death Differ. 2023 Apr 28. doi: 10.1038/s41418-023-01166-5.
Yi-Xiao Xiong # 1 2 3,  Xiao-Chao Zhang # 1 2 3 4,  Jing-Han Zhu # 1 2 3,  Yu-Xin Zhang 1 2 3,  Yong-Long Pan 1 2 3,  Yu Wu 1 2 3,  Jian-Ping Zhao 1 2 3,  Jun-Jie Liu 1 2 3,  Yuan-Xiang Lu 1 2 3,  Hui-Fang Liang 5 6 7,  Zhan-Guo Zhang 8 9 10,  Wan-Guang Zhang 11 12 13
Affiliations

Affiliations

  • 1 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 2 Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, Hubei, China.
  • 3 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China.
  • 4 Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 5 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. lianghuifang1997@126.com.
  • 6 Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, Hubei, China. lianghuifang1997@126.com.
  • 7 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China. lianghuifang1997@126.com.
  • 8 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. zhanguo_tjh@hust.edu.cn.
  • 9 Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, Hubei, China. zhanguo_tjh@hust.edu.cn.
  • 10 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China. zhanguo_tjh@hust.edu.cn.
  • 11 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. wgzhang@tjh.tjmu.edu.cn.
  • 12 Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, Hubei, China. wgzhang@tjh.tjmu.edu.cn.
  • 13 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China. wgzhang@tjh.tjmu.edu.cn.
  • # Contributed equally.
PMID: 37117273 DOI: 10.1038/s41418-023-01166-5
Abstract

Cancer Stem Cells (CSCs) are a minority population of Cancer cells with stemness and multiple differentiation potentials, leading to Cancer progression and therapeutic resistance. However, the concrete mechanism of CSCs in hepatocellular carcinoma (HCC) remains obscure. We found that in advanced HCC tissues, collagen I was upregulated, which is consistent with the expression of its receptor DDR1. Accordingly, high collagen I levels accompanied by high DDR1 expression are associated with poor prognoses in patients with HCC. Collagen I-induced DDR1 activation enhanced HCC cell stemness in vitro and in vivo. Mechanistically, DDR1 interacts with CD44, which acts as a co-receptor that amplifies collagen I-induced DDR1 signaling, and collagen I-DDR1 signaling antagonized Hippo signaling by facilitating the recruitment of PP2AA to MST1, leading to exaggerated YAP activation. The combined inhibition of DDR1 and YAP synergistically abrogated HCC cell stemness in vitro and tumorigenesis in vivo. A radiomic model based on T2 weighted images can noninvasively predict collagen I expression. These findings reveal the molecular basis of collagen I-DDR1 signaling inhibiting Hippo signaling and highlight the role of CD44/DDR1/YAP axis in promoting Cancer cell stemness, suggesting that DDR1 and YAP may serve as novel prognostic biomarkers and therapeutic targets in HCC.

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