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Updated: Aug 8, 2026
A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
System analysis based on the pyroptosis-related genes identifes GSDMD as a novel therapy target for skin cutaneous
Shixin Zhao1,2, Yongkang Zhu1,2, Hengdeng Liu1,2
1Department of Burns, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
Background:
Skin cutaneous melanoma (SKCM) is the most aggressive skin cancer, accounting for more than 75% mortality rate of skin-related cancers. As a newly identified programmed cell death, pyroptosis has been found to be closely associated with tumor progression. Nevertheless, the prognostic significance of pyroptosis in SKCM remains elusive.
Methods:
A total of 469 SKCM samples and 812 normal samples were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Firstly, differentially expressed pyroptosis-related genes (PRGs) between normal samples and SKCM samples were identified. Secondly, we established a prognostic model based on univariate Cox and LASSO Cox regression analyses, which was validated in the test cohort from GSE65904. Thirdly, a nomogram was used to predict the survival probability of SKCM patients. The R package "pRRophetic" was utilized to identify the drug sensitivity between the low- and high-risk groups. Tumor immune infiltration was evaluated using "immuneeconv" R package. Finally, the function of GSDMD and SB525334 was explored in A375 and A2058 cells.
Results:
Based on univariate Cox and LASSO regression analyses, we established a prognostic model with identified eight PRGs (AIM2, CASP3, GSDMA, GSDMC, GSDMD, IL18, NLRP3, and NOD2), which was validated in the test cohort. SKCM patients were divided into low- and high-risk groups based on the median of risk score. Kaplan-Meier survival analysis showed that high-risk patients had shorter overall survival than low-risk patients. Additionally, time-dependent ROC curves validated the accuracy of the risk model in predicting the prognosis of SKCM. More importantly, 4 small molecular compounds (SB525334, SR8278, Gemcitabine, AT13387) were identified, which might be potential drugs for patients in different risk groups. Finally, overexpression of GSDMD and SB525334 treatment inhibit the proliferation, migration, and invasion of SKCM cells.
Conclusion:
In this study, we constructed a prognostic model based on PRGs and identified GSDMD as a potential therapeutic target, which provide new insights into SKCM treatment.
Insights
This study developed a prognostic model for cutaneous melanoma using pyroptosis-related genes (PRGs). The model identifies high-risk patients and suggests GSDMD as a potential therapeutic target for improved skin cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Skin cutaneous melanoma (SKCM) is an aggressive skin cancer with high mortality.
- Pyroptosis, a programmed cell death pathway, is implicated in tumor progression, but its prognostic role in SKCM is unclear.
Purpose of the Study:
- To investigate the prognostic significance of pyroptosis-related genes (PRGs) in SKCM.
- To establish a predictive model for SKCM patient survival.
- To identify potential therapeutic targets and drug sensitivities in different risk groups.
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases for gene expression analysis.
- Developed a prognostic model using univariate Cox and LASSO Cox regression analyses, validated with external data (GSE65904).
- Assessed drug sensitivity and tumor immune infiltration; explored GSDMD and SB525334 functions in SKCM cell lines.
Main Results:
- An eight-gene PRG prognostic model was established and validated, showing high-risk SKCM patients have poorer overall survival.
- The model accurately predicted prognosis, with potential therapeutic compounds (SB525334, SR8278, Gemcitabine, AT13387) identified for different risk groups.
- Overexpression of GSDMD and SB525334 treatment inhibited SKCM cell proliferation, migration, and invasion.
Conclusions:
- A novel prognostic model based on PRGs was constructed for SKCM.
- GSDMD is identified as a potential therapeutic target, offering new insights for SKCM treatment strategies.
