Speaker
Description
Background: Valine‑tRNA synthetase (VARS), a key member of aminoacyl‑tRNA synthetases, catalyzes valine‑tRNA formation and maintains translational fidelity. Our preliminary TCGA analysis demonstrated that VARS is significantly upregulated in hepatocellular carcinoma (HCC) tissues, and high VARS expression correlates with poorer overall and disease‑free survival, suggesting VARS functions as an oncogene in HCC progression.
Methods: Spontaneous and orthotopic HCC mouse models were established to evaluate tumor growth and lung metastasis following Vars knockdown. CCK‑8 and Transwell assays were used to assess the proliferation and migration of mouse HCC cells. Proteomic analysis was performed to enrich VARS-regulated signaling pathways; mitochondrial staining and immunohistochemical staining detected relevant indicators in Vars knockdown stable cells and mouse liver tumors, respectively. Additionally, spontaneous HCC mice were treated with subcutaneous GalNAc-siRNA or a valine-restricted diet.
Results: Vars knockdown significantly suppressed the proliferation and migration of mouse HCC cells in vitro, as well as tumor growth and metastasis in vivo, whereas restoration of VARS promoted tumor growth and metastasis. Proteomic profiling identified key involved signaling pathways, and combined with functional verification, the results showed that VARS regulates mitochondrial function and T cell-mediated immune response. Therapeutically, both GalNAc-siRNA treatment and valine-restricted diet markedly inhibited HCC growth and metastasis in the spontaneous mouse model.
Conclusions: Targeting VARS effectively inhibits HCC progression by regulating mitochondrial function and T cell-mediated immune response, providing a novel insight and experimental basis for the clinical treatment of HCC.
