Tim-1-mediated extracellular matrix promotes the development of hepatocellular carcinoma

Abstract

Tim-1 (T-cell immunoglobulin and mucin domain 1), also known as Kim-1 (kidney injury molecule 1) or hepatitis A virus cellular receptor 1 (HAVCR1), is a transmembrane protein expressed on various immune and epithelial cells. It plays a role in modulating inflammatory and immune responses. In this study, we find that Tim-1 is overexpressed in hepatocellular carcinoma (HCC) samples and that its expression is significantly correlated with postoperative survival. Bulk RNA sequencing reveals a general upregulation of extracellular matrix-related genes in HCC tissues with Tim-1 overexpression. The results of the cell and in vivo experiments reveal that Tim-1 in HCC not only affects biological processes such as the proliferation, migration, and invasion of HCC cells but also broadly promotes extracellular matrix processes by influencing cytokine secretion. Further studies demonstrate that Tim-1 mediates the activation of hepatic stellate cells and upregulates Th1 and Th2 cytokines, thereby promoting HCC progression. Thus, Tim-1 may represent a novel target for future interventions in HCC and liver fibrosis.

1. Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is characterized by high morbidity and mortality, with multiple predisposing factors contributing to its onset. Research indicates that approximately 90% of patients with HCC have pre-existing liver fibrosis or cirrhosis [1]. As liver fibrosis progresses, the extracellular matrix (ECM) is gradually accumulated in liver tissue, leading to mechanical changes and increased stiffness. These ECM alterations contribute to the progression of HCC within a cirrhotic liver environment [2,3].

In an inflammatory environment, studies have shown that Kupffer cells, natural killer cells, and liver sinusoidal endothelial cells secrete significant levels of cytokines such as IL-13, IL-21, and TGF-β. These cytokines stimulate and activate hepatic stellate cells (HSCs), resident fibroblasts, and mesenchymal cells, prompting them to produce increased amounts of type I, III, and IV collagen and laminin [4‒7]. This process leads to ECM accumulation, supporting the invasion and metastasis of HSCs and liver cancer cells and further promoting the development of HCC [8,9]. Additionally, the ECM serves as the primary structural component of the tumor barrier, significantly hindering the efficacy of chemotherapy drugs against liver cancer cells [10,11].

Tim-1, a member of the human T-cell immunoglobulin and mucin domain (Tim) family, plays a significant role in regulating the tumor microenvironment [12‒14]. Tim-1 can suppress B-cell activation, antigen presentation, and T-cell activation, negatively impacting antitumor immunity [15,16]. Conversely, blocking Tim-1 reduces IFN-γ production in T cells and effectively decreases the expressions of TNF-α and IL-6, thereby improving the inflammatory tumor microenvironment (TME). Both inflammatory responses and cytokine secretion play crucial roles in the development of HCC and in tumor-related ECM processes [17]. Therefore, investigating and elucidating the impact of Tim-1 on HCC progression, particularly its regulatory influence on the ECM process, is essential for developing novel therapeutic approaches.