Genetic Ablation of LAT1 Inhibits Growth of Liver Cancer Cells and Downregulates mTORC1 Signaling

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Hepatocellular carcinoma (HCC) is a major global health concern.
• Identifying novel therapeutic targets is crucial for improving HCC treatment outcomes.
• Amino acid transporters play a significant role in cancer cell metabolism and growth.

Purpose of the Study:

• To investigate the role of the amino acid transporter LAT1 in hepatocellular carcinoma (HCC) tumorigenesis.
• To evaluate LAT1 as a potential therapeutic target for HCC.
• To elucidate the molecular mechanisms by which LAT1 influences HCC cell proliferation.

Main Methods:

• Comprehensive analysis of gene expression and dependency in HCC patients and cell lines.
• CRISPR/Cas9 gene editing to knockout (KO) LAT1 in the Huh7 HCC cell line.
• Assessment of branched-chain amino acid (BCAA) transport activity, cell proliferation, and tumor growth in xenograft models.
• RNA-sequencing analysis to investigate changes in the mTORC1 signaling pathway.

Main Results:

• LAT1 was identified as a key amino acid transporter supporting HCC tumorigenesis.
• LAT1 knockout significantly reduced BCAA transport and cell proliferation in Huh7 cells.
• LAT1 ablation suppressed tumor growth in a xenograft model.
• LAT1 knockout led to reduced phosphorylation of p70S6K and S6RP, indicating impaired mTORC1 signaling.
• Overexpression of LAT1 rescued reduced cell proliferation and mTORC1 activity.

Conclusions:

• LAT1 is essential for maintaining HCC cell growth and tumorigenesis.
• Targeting LAT1 represents a promising therapeutic strategy for liver cancer.
• LAT1 influences HCC progression through the mTORC1 signaling pathway.