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Targeting leucyl-tRNA synthetase 1 with leucine restores N-glycosylation and overcomes chemoresistance in ICC

ABSTRACT: Chemotherapy shows limited efficacy in intrahepatic cholangiocarcinoma (ICC). Selective mRNA translation enables tumour cells to redistribute resources and withstand chemical stress, but the underlying mechanisms remain poorly understood. Here, we demonstrate that leucyl-tRNA synthetase 1 (LARS1) is significantly decreased in ICC and correlates with poor prognosis. Using overexpression and knockout mouse models, we establish the crucial role of LARS1 in ICC chemoresistance. Mechanistically, LARS1 knockdown selectively suppresses the mRNA translation of N-glycan biosynthesis enzymes in a leucine codon frequency-dependent manner, reducing the N-glycosylation of ABCC1 at the N929 site and promoting ICC chemoresistance. Notably, exogenous leucine supplementation emerges effectively restore LARS1 expression and enhance chemotherapy efficacy in ICC. Our findings provide new insights into the selective mRNA hypotranslation underlying ICC chemoresistance and propose a promising diet-drug combination strategy to improve therapeutic outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296606 | GEO | 2026/05/01

REPOSITORIES: GEO

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Project description:Interstitial cells of Cajal (ICC) are electrical pacemakers and mediators of neuromuscular neurotransmission in the gastrointestinal tract. Studies in organotypic cultures of intact gastric muscular wall tissues identified Kit(low)Cd44(+)Cd34(+)Insr(+)Igf1r(+) cells as local ICC progenitors (Lorincz et al., Gastroenterology 2008;134:1083-1093). Subsequently, conditionally immortalized Kit(low)Cd34(+) cells were isolated by immunomagnetic and fluorescent cell sorting and serial cloning from the gastric muscular wall of homozygous, 14-day-old H-2Kb-tsA58 mice and shown to share other phenotypic characteristics with in-situ ICC precursors (2xSCS70 cells; Bardsley et al., Gastroenterology 2010;139:942-952). 2xSCS70 cells were also found to express the ICC marker Ano1, to be able to extensively self-renew in the absence of the SV40 tsA58-TAg when cultured in NeuroCultÂ® Neural Stem Cell Proliferation Medium (NSCPM; STEMCELL Technologies) and to differentiate into Kit(+) ICC both in vitro and in vivo. Wild-type cells with Kit(low)Ano1(+)Cd44(+)Cd34(+)Insr(+)Igf1r(+) phenotype (2xSCS2F10 cells) were prospectively isolated from primary cultures of dissociated gastric muscular wall tissues from 7-day-old C57BL/6J mice by serial cloning following 150-day expansion in NSCPM containing 5% cell-free chick embryo extract (CEE; Accurate Chemical). Long-term culturing of both cell lines was associated with further decline in Kit expression while expression of Ano1 and other markers of ICC precursors was maintained. Following spontaneous transformation, both 2xSCS70 and 2xSCS2F10 cells grafted into nude mice gave rise to tumors containing Kit(+)cells and otherwise resembling gastrointestinal stromal tumors (GIST), which originate from the ICC lineage (Bardsley et al., Gastroenterology 2010;139:942-952). This study utilized RNA-sequencing to complement the companion microarray study in non-transformed 2xSCS70 and 2xSCS2F10 cells. Libraries were made from total RNA isolated from ICC progenitor cell lines using the Illumina TruSeq mRNA Sample Preparation Kit v2 and sequenced on the Illumina HiSeq 2000 platform.

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Targeting leucyl-tRNA synthetase 1 with leucine restores N-glycosylation and overcomes chemoresistance in ICC

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