1. Academic Validation
  2. Matrix stiffness-upregulated LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation

Matrix stiffness-upregulated LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation

  • J Exp Clin Cancer Res. 2018 May 4;37(1):99. doi: 10.1186/s13046-018-0761-z.
Sifan Wu 1 Qiongdan Zheng 1 Xiaoxia Xing 1 Yinying Dong 1 Yaohui Wang 2 Yang You 1 Rongxin Chen 1 Chao Hu 3 Jie Chen 1 Dongmei Gao 1 Yan Zhao 1 Zhiming Wang 4 Tongchun Xue 1 Zhenggang Ren 1 Jiefeng Cui 5
Affiliations

Affiliations

  • 1 Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
  • 2 Department of Radiology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China.
  • 3 Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.
  • 4 Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.
  • 5 Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China. [email protected].
Abstract

Background: Higher matrix stiffness affects biological behavior of tumor cells, regulates tumor-associated gene/miRNA expression and stemness characteristic, and contributes to tumor invasion and metastasis. However, the linkage between higher matrix stiffness and pre-metastatic niche in hepatocellular carcinoma (HCC) is still largely unknown.

Methods: We comparatively analyzed the expressions of LOX family members in HCC cells grown on different stiffness substrates, and speculated that the secreted LOXL2 may mediate the linkage between higher matrix stiffness and pre-metastatic niche. Subsequently, we investigated the underlying molecular mechanism by which matrix stiffness induced LOXL2 expression in HCC cells, and explored the effects of LOXL2 on pre-metastatic niche formation, such as BMCs recruitment, fibronectin production, MMPs and CXCL12 expression, cell adhesion, etc. RESULTS: Higher matrix stiffness significantly upregulated LOXL2 expression in HCC cells, and activated JNK/c-JUN signaling pathway. Knockdown of Integrin β1 and α5 suppressed LOXL2 expression and reversed the activation of above signaling pathway. Additionally, JNK Inhibitor attenuated the expressions of p-JNK, p-c-JUN, c-JUN and LOXL2, and shRNA-c-JUN also decreased LOXL2 expression. CM-LV-LOXL2-OE and rhLOXL2 upregulated MMP9 expression and fibronectin production obviously in lung fibroblasts. Moreover, activation of Akt pathway contributed to LOXL2-induced fibronectin upregulation. LOXL2 in CM as chemoattractant increased motility and invasion of BMCs, implicating a significant role of LOXL2 in BMCs recruitment. Except that, CM-LV-LOXL2-OE as chemoattractant also increased the number of migrated HCC cells, and improved chemokine CXCL12 expression in lung fibroblasts. The number of HCC cells adhered to surface of lung fibroblasts treated with CM-LV-LOXL2-OE was remarkably higher than that of the control cells. These results indicated that the secreted LOXL2 facilitated the motility of HCC cells and strengthened CTCs settlement on the remodeled matrix "soil".

Conclusion: Integrin β1/α5/JNK/c-JUN signaling pathway participates in higher matrix stiffness-induced LOXL2 upregulation in HCC cells. The secreted LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation.

Keywords

Hepatocellular carcinoma; LOXL2; Matrix stiffness; Pre-metastatic niche.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13319
    99.67%, JNK Inhibitor
    JNK