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Eurycomalactone switches hepatocellular carcinoma cells into a quiescence state through 5'tRFAla&5'tiRNAAla/DVL/β-catenin pathway inhibition

ABSTRACT: Although tsRNA was reported to have the ability to modulate a variety of physiological processes analogous to miRNA, the possible regulatory functions and mechanisms of tsRNAs related to the pharmacological effects of small molecules are still obscure. Herein it is shown that the natural product eurycomalactone (ELT) can reversibly switch hepatocellular carcinoma (HCC) PLC/PEF/5 and HUH7 cells into a quiescence state characterized by cell proliferation inhibition without cell death, cell cycle arrest at G0/G1 phase and cell reactivation after drug withdrawal. On the basis that β-catenin activity might mediate the proliferation or quiescence of cancer cells, the total, cytoplasmic and nuclear β-catenin, as well as its target proteins, c-myc, CD44 and cyclin D1, are all shown to be significantly weakened by ELT. Subsequently, two new tsRNAs, namely 5'tRFAla and 5'tiRNAAla, which match well with the mRNAs of Dishevelled proteins DVL2 and DVL3, two vital upstream regulators of β-catenin, are found to be decreased significantly in ELT-treated PLC/PEF/5 cells. The concentrations of the DVL2 and DVL3 proteins are similarly reduced. Accordingly, it is suggested that ELT decreases 5'tRFAla and 5'tiRNAAla levels and so suppressing the translation of their matched DVL2 and DVL3 mRNAs that thereby inhibits the β-catenin pathway and so reversibly switching HCC cells into a quiescence state. As such, this study suggests that, like miRNAs, tsRNAs might activate the translation of their matched mRNAs in non-dividing cells and so providing a possible means for suppressing tumor cell growth

ORGANISM(S): Homo sapiens

PROVIDER: GSE236560 | GEO | 2023/07/10

REPOSITORIES: GEO

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Project description:For developing a accurate prognostic signature for “pan-driver-gene-negative” LUAD, we employed whole genome microarray expression profiling as a discovery platform to identify candidate genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “pan-driver-gene-negative” LUAD. Furthermore, the Wnt/β-catenin-pathway-based gene expression profiles revealed 39 transcripts differentially expressed by diagnostic status, with 30 genes being upregulated and 9 downregulated. Finally, a Wnt/β-catenin-pathway-based signature (CSDW) comprising 4 genes (β-catenin, Wnt2b, DVL3 and SOX9) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival (hazard ratio [HR] 10·42, 6·46–16·79; p<0·001) than patients with low-risk scores. The CSDW performance was further validated in an internal cohort and two external cohorts. The protein expression levels of several hub genes, including β-catenin, SOX9, DVL3 and Wnt2b, were strongly correlated with lymphatic metastasis and distant organ metastasis. Furthermore, a nomogram comprising CSDW and other variables was generated to predict progression-free survival and overall survival in the training cohort and performed well in the three independent validation cohorts (C-index: 0·725, 0·697 and 0·693, respectively). For developing a accurate prognostic signature for “pan-driver-gene-negative” LUAD, we employed whole genome microarray expression profiling as a discovery platform to identify candidate genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “pan-driver-gene-negative” LUAD. Furthermore, the Wnt/β-catenin-pathway-based gene expression profiles revealed 39 transcripts differentially expressed by diagnostic status, with 30 genes being upregulated and 9 downregulated. Finally, a Wnt/β-catenin-pathway-based signature (CSDW) comprising 4 genes (β-catenin, Wnt2b, DVL3 and SOX9) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival (hazard ratio [HR] 10·42, 6·46–16·79; p<0·001) than patients with low-risk scores. The CSDW performance was further validated in an internal cohort and two external cohorts. The protein expression levels of several hub genes, including β-catenin, SOX9, DVL3 and Wnt2b, were strongly correlated with lymphatic metastasis and distant organ metastasis. Furthermore, a nomogram comprising CSDW and other variables was generated to predict progression-free survival and overall survival in the training cohort and performed well in the three independent validation cohorts (C-index: 0·725, 0·697 and 0·693, respectively).

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Eurycomalactone switches hepatocellular carcinoma cells into a quiescence state through 5'tRFAla&5'tiRNAAla/DVL/β-catenin pathway inhibition

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