Setayesh Tahereh, Hu Ying, Vaziri Farzam, Wei Dongguang, Wan Yu-Jui Yvonne
Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA.
Biomark Res. 2024 Oct 14;12(1):122. doi: 10.1186/s40364-024-00660-3.
Hepatocellular carcinoma (HCC) arising from metabolic dysfunction-associated steatohepatitis (MASH) presents a significant clinical challenge, particularly given the prevalence of the Western diet (WD). The influence of diet on the tumor microenvironment remains poorly understood. Galectin-1 (Gal-1) is a biomarker for HCC and has a crucial role in liver carcinogenesis. Our previous studies demonstrated that silencing Gal-1 effectively treats mouse HCC. However, the impacts of a WD on Gal-1 signaling on MASH to HCC progression are unknown, and this study addresses these knowledge gaps.
We developed a novel MASH-HCC mouse model. Using spatial transcriptomics and multiplex immunohistochemistry (IHC), we studied the effects of a WD on the liver and tumor microenvironment. By modulating Gal-1 expression through silencing and overexpression, we explored the location-specific impacts of WD on Gal-1 signaling.
Pathways such as Rho signaling, extracellular matrix (ECM) remodeling, and senescence-associated secretory phenotypes (SASP) were prominently activated in WD-induced metabolic dysfunction-associated fatty liver disease (MAFLD) and MASH-HCC, compared to healthy livers controls. Furthermore, Rho GTPase effectors, ECM remodeling, neutrophil degranulation, cellular stress, and cell cycle pathways were consistently enriched in human and mouse MASH-HCC. Spatially, these pathways were enriched in the tumor and tumor margins of mouse MASH-HCC. Additionally, there was a notable increase in CD11c and PD-L1-positive cells from non-tumor tissues to the tumor margin and inside the tumor of MASH-HCC, suggesting compromised immune surveillance due to WD intake. Moreover, MASH-HCC exhibited significant Gal-1 induction in N-Cadherin-positive cells, indicating enhanced epithelial-to-mesenchymal transition (EMT). Modulating Gal-1 expression in MASH-HCC further established its specific roles in regulating Rho signaling and SASP in the tumor margin and non-tumor tissues in MASH-HCC.
WD intake significantly influences vital cellular processes involved in Gal-1-mediated signaling, including Rho signaling and ECM remodeling, in the tumor microenvironment, thereby contributing to the development of MASH-HCC.
由代谢功能障碍相关脂肪性肝炎（MASH）引发的肝细胞癌（HCC）带来了重大的临床挑战，尤其是考虑到西方饮食（WD）的流行情况。饮食对肿瘤微环境的影响仍知之甚少。半乳糖凝集素-1（Gal-1）是HCC的一种生物标志物，在肝癌发生过程中起关键作用。我们之前的研究表明，沉默Gal-1可有效治疗小鼠HCC。然而，WD对Gal-1信号传导在MASH向HCC进展过程中的影响尚不清楚，本研究填补了这些知识空白。
我们建立了一种新型的MASH-HCC小鼠模型。利用空间转录组学和多重免疫组织化学（IHC），我们研究了WD对肝脏和肿瘤微环境的影响。通过沉默和过表达来调节Gal-1表达，我们探索了WD对Gal-1信号传导的位置特异性影响。
与健康肝脏对照相比，Rho信号传导通路、细胞外基质（ECM）重塑和衰老相关分泌表型（SASP）等通路在WD诱导的代谢功能障碍相关脂肪性肝病（MAFLD）和MASH-HCC中显著激活。此外，Rho GTPase效应器、ECM重塑、中性粒细胞脱颗粒、细胞应激和细胞周期通路在人和小鼠MASH-HCC中持续富集。在空间上，这些通路在小鼠MASH-HCC的肿瘤和肿瘤边缘富集。此外，从非肿瘤组织到MASH-HCC的肿瘤边缘和肿瘤内部，CD11c和PD-L1阳性细胞显著增加，这表明由于摄入WD导致免疫监视受损。此外，MASH-HCC在N-钙黏蛋白阳性细胞中表现出显著的Gal-1诱导，表明上皮-间质转化（EMT）增强。在MASH-HCC中调节Gal-1表达进一步确定了其在调节MASH-HCC肿瘤边缘和非肿瘤组织中的Rho信号传导和SASP方面的特定作用。
摄入WD显著影响肿瘤微环境中Gal-1介导的信号传导所涉及的重要细胞过程，包括Rho信号传导和ECM重塑，从而促进MASH-HCC的发展。
