Diabetes and extracellular matrix in NASH

非酒精性脂肪性肝炎（NASH）是肝细胞癌（HCC）的危险因素，通常发生在肝硬化前阶段。由于这些患者没有经过筛查，这些肿瘤通常在晚期才被诊断出来。我们试图了解不同的途径如何在非肝硬化NASH中创造促致癌环境。我们之前在一个动物模型中发现，肝硬化前T2DM/NASH患者的晚期糖基化终产物（AGEs）是坏死性炎症和氧化性肝损伤的关键。AGE清除受体AGER1在NASH中下调，加速AGE沉积，在体内纠正AGER1可改善肝损伤。为了研究高AGE环境如何为转化细胞创造有利条件，我们在水动力注射hMET/突变体β-catenin之前调节饮食/AGE含量。高AGE背景诱导早期和更具侵袭性的HCC， AGE积累与基质动力学的显著变化有关。我们发现AGE抑制逆转了体内基质粘弹性的变化，降低了肿瘤负荷。我们将验证在非肝硬化T2DM/NASH患者中，AGEs有助于增加基质粘弹性和基质细胞改变，从而创造一个有利于侵入的环境。在Aim 1中，我们将建立并研究一种新的NASH模型，以研究饮食/AGE含量、基质粘弹性、性别与HCC特征和预后之间的关系。在目标2中，我们建议开发一种具有可调粘弹性的3D水凝胶系统来研究细胞形状/细胞骨架的变化、侵袭和迁移。利用RNAseq数据，我们将探索赋予侵袭和迁移特性的关键基质细胞信号。这些研究将首次概述粘弹性如何引发一个促侵袭的生态位，并确定驱动HCC侵袭的关键基质细胞信号。

Non-alcoholic steatohepatitis (NASH) is a risk factor for hepatocellular carcinoma (HCC) that often arises at a pre-cirrhotic stage. As this patient population is not screened, often these tumors are diagnosed at a late stage. We seek to understand how distinct pathways could create a pro-carcinogenic environment in non-cirrhotic NASH. We previously showed that advanced glycation end products (AGEs) in patients with pre-cirrhotic T2DM/NASH and in an animal model, are key to necroinflammation and oxidative liver injury. The AGE clearance receptor AGER1 was downregulated in NASH, accelerating AGE deposition, and correcting AGER1 in vivo improved liver injury. To study how high AGE environment creates permissive conditions for transformed cells, we modulated the diet/AGE content prior to hydrodynamic injection of hMET/mutant β-catenin. High AGE background induced an earlier and more invasive HCC, and AGE accumulation was linked to significant changes in matrix dynamics. We found that AGE inhibition reversed changes in matrix viscoelasticity in vivo and lowered the tumor burden. We will test the hypothesis that in non-cirrhotic T2DM/NASH AGEs contribute to an increase in matrix viscoelasticity and matricellular changes creating a pro-invasive environment. In Aim 1, we will establish and investigate a novel NASH model to study the association between diet/AGE content, matrix viscoelasticity, gender and HCC characteristics as well as outcomes. In Aim 2 we propose to develop a 3D hydrogel system with tunable viscoelasticity to study cellular shape/cytoskeletal changes, invasion and migration. Using RNAseq data we will explore the key matricellular signals that confer invasive and migratory properties. These studies will for the first time outline how viscoelasticity elicits a pro-invasive niche, and identify the key matricellular signals that drive invasion of HCC.