Single-Cell Study Identifies RNA Linked to Drug Resistance in Liver Cancer
Summary
The authors used single cell RNA sequencing (scRNA-seq) to identify a noncoding RNA (ncRNA) called LINC00968 that mediates resistance to sorafenib treatment in hepatocellular carcinoma (HCC) cells. Sorafenib is a drug that inhibits multiple kinases involved in cancer growth and survival, but most HCC patients develop resistance to it after an initial response. The authors of the paper found that LINC00968 was highly expressed in sorafenib-resistant HCC cells and that knocking down LINC00968 sensitized them to sorafenib-induced apoptosis. They also showed that LINC00968 interacted with a protein called YBX1 and regulated its nuclear localization and transcriptional activity. YBX1 is known to be involved in various aspects of cancer biology, such as proliferation, invasion, metastasis, and drug resistance. The authors suggested that LINC00968 could be a potential biomarker and therapeutic target for overcoming sorafenib resistance in HCC patients.
Research Criteria
This study used single-cell RNA sequencing analysis to look at the mechanisms of intra-tumoral diversity that affect treatment responses as well as the genetic heterogeneity of the tumoral microenvironment. The researchers were able to pinpoint individual cells or genes with particular genetic modifications or expression profiles that may contribute to the emergence of therapeutic resistance thanks to this technology, which enabled a deeper investigation into hundreds of cancer drivers.
Sample Type
HCC cell lines.
Result—Single Cell Enrichment of Stemness/EMT Gene Signatures in Sorafenib Resistant Cells
The authors of the study first cultivated Hep3B and Huh7 cells that were resistant to the drug sorafenib (designated as Hep3B-P and Huh7-R, respectively). The prevalence of stemness/EMT phenotypes at the population level led the authors to postulate that the induction of these phenotypes could be a substantial factor in the development of sorafenib resistance. In order to test this hypothesis, the authors conducted single-cell RNA sequencing using the 10x system on both Huh7-P and Huh7-R cells. After applying strict criteria for the elimination of low-quality cells, a total of 4,776 cells were selected for subsequent analysis of single-cell sequencing data. The results revealed marked differences in gene expression between Huh7-P and Huh7-R cells, which were visualized through the use of heatmaps and a two-dimensional tSNE plot. Although the data indicated an upregulation of stemness/EMT genes in Huh7-R cells, there was a simultaneous downregulation of proliferative markers and genes related to the cell cycle, suggesting that sorafenib treatment may selectively enrich a subset of resistant cells that possess a slow cell cycle or exist in a quiescent state.
Fig.1 Single-cell enrichment of stemness/EMT gene signatures in sorafenib-resistant cells. (Zhou, 2022)
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Reference
- Zhou, K.; et al. Single cell RNA-seq analysis identifies a noncoding RNA mediating resistance to sorafenib treatment in HCC. Molecular Cancer. 2022, 21(1): 1-5.
