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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
A systems biology-based approach to screen key splicing factors in hepatocellular carcinoma
1Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
Abstract:
A splicing factor is as an important upstream regulator of the alternative splicing process. Hence, it is considered to be a therapeutic target for hepatocellular carcinoma (HCC) tissues. In this study, a systems biology-based methodology was used to screen the essential splicing factors precisely and efficiently. A more comprehensive set of alternative splicing events, which were linked to patient survival, was constructed by performing the bivariate Cox regression and receiver operating characteristic (ROC) analyses. Then, the expression data was obtained from The Cancer Genome Altas (TCGA) data set and the three Gene Expression Omnibus (GEO) datasets. It was used to obtain the survival-related splicing factors, which showed a significantly differential expression in the tumor and normal tissues. Using the topological properties of the bipartite graph association network of the alternative splicing events and the splicing factors, we identified the five key splicing factors. Among them, four factors were found to play a prominent role in the development of HCC. The remaining factor was Survival Motor Neuron Domain Containing 1(SMNDC1), which showed a positive correlation with the immune cell infiltration, the biomarkers of immune cells, and the immune checkpoint genes. By performing quantitative real-time polymerase chain reaction analyses, we proved that SMNDC1 was overexpressed in tumor cells. Following the knockdown of its expression, the proliferation and the migration of HCC cells could be suppressed. These results confirmed that the screening method of this study was reliable and accurate. It provided new insights into the mechanism through which splicing factors elicit tumor development.
Insights
Researchers identified key splicing factors, including SMNDC1, crucial for hepatocellular carcinoma (HCC) development. Targeting these factors, particularly SMNDC1, offers a promising therapeutic strategy for HCC by inhibiting tumor cell proliferation and migration.
Area of Science:
- Molecular Biology
- Cancer Research
- Systems Biology
Background:
- Splicing factors regulate alternative splicing and are potential therapeutic targets in hepatocellular carcinoma (HCC).
- Identifying essential splicing factors in HCC is crucial for developing targeted therapies.
Purpose of the Study:
- To screen and identify essential splicing factors involved in hepatocellular carcinoma (HCC) using a systems biology approach.
- To investigate the role of identified splicing factors, particularly SMNDC1, in HCC progression and immune interactions.
Main Methods:
- Utilized a systems biology methodology to screen splicing factors.
- Performed bivariate Cox regression and receiver operating characteristic (ROC) analyses on TCGA and GEO datasets to identify survival-related splicing factors.
- Analyzed topological properties of a bipartite graph association network to identify key splicing factors.
- Validated SMNDC1 overexpression and functional role in HCC cells via quantitative real-time polymerase chain reaction (qRT-PCR) and gene knockdown experiments.
Main Results:
- Identified five key splicing factors, with four implicated in HCC development.
- SMNDC1 demonstrated a positive correlation with immune cell infiltration, immune cell biomarkers, and immune checkpoint genes.
- SMNDC1 was significantly overexpressed in HCC tumor tissues.
- Knockdown of SMNDC1 suppressed HCC cell proliferation and migration.
Conclusions:
- The study successfully identified key splicing factors, including SMNDC1, critical for HCC pathogenesis.
- SMNDC1 plays a significant role in promoting HCC progression and is associated with the tumor immune microenvironment.
- The findings provide novel insights into splicing factor-mediated mechanisms in HCC and suggest SMNDC1 as a potential therapeutic target.
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