Transcription factor ASCL1 targets SLC6A13 to inhibit the progression of hepatocellular carcinoma via the glycine-inflammasome signaling

• Published in: Biomolecules & biomedicine Vol. 24; no. 6; pp. 1606 - 1619
• Main Authors: Zhang, Hongyan, Zong, Ruiqing, Wu, Huiqi, Jiang, Jun, Liu, Chuanyong, Liu, Suiyi
• Format: Journal Article
• Language: English
• Published: Bosnia and Herzegovina Association of Basic Medical Sciences of Federation of Bosnia and Herzegovina 17-10-2024
• Subjects: Amino Acid Transport Systems - genetics; Amino Acid Transport Systems - metabolism; ASCL1; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Disease Progression; Gene Expression Regulation, Neoplastic; Glycine - analogs & derivatives; Glycine - pharmacology; glycine-inflammasome signaling; hepatocellular carcinoma; Humans; Inflammasomes - genetics; Inflammasomes - metabolism; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Prognosis; Signal Transduction - drug effects; SLC6A13; transcription factor
• ISSN: 2831-0896; 2831-090X; 2831-090X
• DOI: 10.17305/bb.2024.10328

Hepatocellular carcinoma (HCC), the most common primary liver cancer, typically arises from chronic liver conditions such as hepatitis, cirrhosis, or other chronic liver diseases, and is characterized by its aggressive nature and poor prognosis. The purpose of this research was to clarify the function of achaete-scute family bHLH transcription factor 1 (ASCL1) and solute carrier family 6 member 13 (SLC6A13) in influencing tumor cell behavior, inflammatory responses, and the regulation of inflammasomes. We analyzed the differentially expressed genes (DEGs) in the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) database, as well as in the GSE14520 and GSE67764 datasets, to identify the expression changes of SLC6A13 in liver cancer. The prognostic significance of SLC6A13 in LIHC was assessed through Kaplan-Meier survival curve analysis. Transcriptional regulation of SLC6A13 by ASCL1 was explored using the Joint Annotation of the Human Genome and other species by the Systematic Pipeline for the Annotation of Regulatory Regions (JASPAR) database and dual-luciferase assays. In vitro experiments investigated the impact of ASCL1 and SLC6A13 overexpression on HCC cell growth. Additionally, the effects of ethanol treatment and glycine modulation on the inflammatory response in HCC cell lines were evaluated. HCC samples showed reduced levels of SLC6A13, which correlates with a better prognosis for liver metastases. Elevated SLC6A13 expression correlated with improved overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), and disease-specific survival (DSS). ASCL1 upregulated SLC6A13 and inhibited proliferation, migration, and invasion of HCC cells. Ethanol induced the production of inflammatory cytokines, which was enhanced by overexpression of SLC6A13 but counteracted by glycine. This study highlighted elevated expression of SLC6A13 in LIHC which has been correlated with improved OS, PFS, RFS, and DSS. Overexpression of SLC6A13 and ASCL1 in HCC cells enhanced inflammasome activation, which was exacerbated by ethanol and attenuated by glycine.