TIMP-1 mediates TGF-β-dependent crosstalk between hepatic stellate and cancer cells via FAK signaling

Abstract

Transforming growth factor-β (TGF-β) signaling plays a key role in progression and metastasis of HCC. This study was undertaken to gain the proof of concept of a small-molecule inhibitor of TGF-β type I receptor kinase, EW-7197 as a potent anti-cancer therapy for HCC. We identified tissue inhibitors of metalloproteinases-1 (TIMP-1) as one of the secreted proteins of hepatic stellate cells (HSCs) and a key mediator of TGF-β-mediated crosstalk between HSCs and HCC cells. TGF-β signaling led to increased expression of TIMP-1, which activates focal adhesion kinase (FAK) signaling via its interaction with CD63. Inhibition of TGF-β signaling using EW-7197 significantly attenuated the progression and intrahepatic metastasis of HCC in an SK-HEP1-Luc orthotopic-xenograft mouse model. In addition, EW-7197 inhibited TGF-β-stimulated TIMP-1 secretion by HSCs as well as the TIMP-1-induced proliferation, motility, and survival of HCC cells. Further, EW-7197 interrupted TGF-β-mediated epithelial-to-mesenchymal transition and Akt signaling, leading to significant reductions in the motility and anchorage-independent growth of HCC cells. In conclusion, we found that TIMP-1 mediates TGF-β-regulated crosstalk between HSCs and HCC cells via FAK signaling. In addition, EW-7197 demonstrates potent in vivo anti-cancer therapeutic activity and may be a potential new anti-cancer drug of choice to treat patients with liver cancer.

Expression Profile and Function Analysis of LncRNAs during Priming Phase of Rat Liver Regeneration

“…Previous research asserted that hepatocytes were activated at 2 h of LR after PH, and their transition from G0 phase to cell cycle occurred at 2–6 h [ 43 ] ILK pathway could activate the nuclear translocation of β-catenin and enhanced the transcription of LEF-1 through integrin-linked kinase pathway, and then increase the activity of Ap-1 which could promote cell proliferation [ 44 , 45 ], and the expression of critical cytokine IL-6 [ 46 , 47 ] which could affect cell proliferation via Stat3 signal pathway. It has demonstrated that transforming growth factor-β (TGF-β) signaling plays a key role in progression and metastasis of HCC [ 48 , 49 ], and it influences the expression of smad4, smad2/3, and β-catenin proteins and regulates cell activities [ 49 ], which indicates that it is important in liver cells. McCubrey et al pointed out that ERK / MAPK pathway, as the most classic pathway in mitogen-activated protein kinases (MAPKs) pathways [ 50 ], had significant function in cells [ 51 ], and played a key function in tumor cell proliferation, differentiation, survival, migration, and angiogenesis [ 52 ].…”

Inflammatory Mechanisms of HCC Development

“…With positive feed-back loop, the activated HSCs, but also Kupffer cells, macrophages and platelets are responsible for the secretion of TGF-β that in turn activates more HSCs. As a result, the production and the release of ECM molecules, tissue MMPs, such as MMP2, 9, and 13, and MMPs inhibitors, such as TIMP1, are increased [67][68][69]. Tumor cells can induce remodeling by stromal cells through altered signaling pathways.…”

Peer Review #3 of "In silico analyses for potential key genes associated with gastric cancer (v0.1)"

“…TIMP1 is also involved in the cell proliferation, antiapoptotic function, angiogenesis, and oncogenesis (Ries, 2014). Moreover, TIMP1 has been shown to be overexpressed in multiple cancer types and acts as a therapeutic target for GC and other cancers (Omar et al, 2018;Park et al, 2015;Toricelli et al, 2017). The SPARC gene encodes a cysteine-rich acidic matrix-associated protein, which is required for the collagen and is also involved in extracellular matrix synthesis and promotion of changes to cell shape (Morrissey et al, 2016).…”