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Chimeric RNA-binding protein-based killing switch targeting hepatocellular carcinoma cells.

ABSTRACT: Cancer cell-specific killing switches are synthetic circuits developed as an intelligent weapon to specifically eliminate malignant cells. RNA-delivered synthetic circuits provide safer means to control oncolytic functions, in which proteolysis-responding capsid-cNOT7 is developed to enable logic computation and modular design. Unfortunately, although circuits containing these capsid-cNOT7s exhibited good performance when introduced as replicons, in modified mRNA (modRNA) delivery, the performance was not quite as good. To improve this situation, alternative modules suitable for modRNA delivery need to be developed. An attractive option is RNA-binding protein (RBP)/riboswitches. In this study, RBPs were engineered by fusing with degron and cleavage sites. The compatibility of these chimeric RBPs with proteolysis-based sensing units were tested. Eight two-input logic gates and four three-input logic gates were implemented. After building this chimeric RBP-based system, we constructed a hepatocellular carcinoma (HCC) cell-specific killing circuit using two proteolysis-based sensing units, a two-input logic OR gate, and a leakproof apoptosis-inducing actuator, which distinguished HCC cells and induced apoptosis in a mixed IMR90-PLC/PRF/5 population.

SUBMITTER: Yang J

PROVIDER: S-EPMC8463442 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAlthough the expression of RNA-binding protein (RBP) genes in hepatocellular carcinoma (HCC) varies and is associated with tumor progression, there has been no overview study with multiple cohorts and large samples. The HCC-associated RBP genes need to be more accurately identified, and their clinical application value needs to be further explored.MethodsFirst, we used the robust rank aggregation (RRA) algorithm to extract HCC-associated RBP genes from nine HCC microarray datasets and verified them in The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and International Cancer Genome Consortium (ICGC) Japanese liver cancer (ICGC-LIRI-JP) cohort. In addition, the copy number variation (CNV), single-nucleotide variant (SNV), and promoter-region methylation data of HCC-associated RBP genes were analyzed. Using the random forest algorithm, we constructed an RBP gene-based prognostic score system (RBP-score). We then evaluated the ability of RBP-score to predict the prognosis of patients. The relationships between RBP-score and other clinical characteristics of patients were analyzed.ResultsThe RRA algorithm identified 30 RBP mRNAs with consistent expression patterns across the nine HCC microarray datasets. These 30 RBP genes were defined as HCC-associated RBP genes. Their mRNA expression patterns were further verified in the TCGA-LIHC and ICGC-LIRI-JP cohorts. Among these 30 RBP genes, some showed significant copy number gain or loss, while others showed differences in the methylation levels of their promoter regions. Some RBP genes were risk factors or protective factors for the prognosis of patients. We extracted 10 key HCC-associated RBP genes using the random forest algorithm and constructed an RBP-score system. RBP-score effectively predicted the overall survival (OS) and disease-free survival (DFS) of HCC patients and was associated with the tumor, node, metastasis (TNM) stage, α-fetoprotein (AFP), and metastasis risk. The clinical value of RBP-score was validated in datasets from different platforms. Cox analysis suggested that a high RBP-score was an independent risk factor for poor prognosis in HCC patients. We also successfully established a combined RBP-score+TNM LASSO-Cox model that more accurately predicted the prognosis.ConclusionThe RBP-score system constructed based on HCC-associated RBP genes is a simple and highly effective prognostic evaluation tool. It is suitable for different subgroups of HCC patients and has cross-platform characteristics. Combining RBP-score with the TNM staging system or other clinical parameters can lead to an even greater clinical benefit. In addition, the identified HCC-associated RBP genes may serve as novel targets for HCC treatment.

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Chimeric RNA-binding protein-based killing switch targeting hepatocellular carcinoma cells.

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