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PSMC2 knockdown suppressed tumor progression of skin cutaneous melanoma

ABSTRACT: Skin cutaneous melanoma (SKCM) is the most lethal tumor among three of the major malignant cancers of the skin. The mechanism underlying the malignant biological behaviors of SKCM is not fully clear. Our study intended to verify the molecular mechanism of proteasome 26 S subunit ATPase 2 (PSMC2) in malignant biological behaviors of SKCM. The Cancer Genome Atlas (TCGA) database was used to analyze the expression of PSMC2 in SKCM and its impact on prognosis. PSMC2 expression in 105 paired SKCM tissues was investigated by immunohistochemistry (IHC), its functional roles were verified using a series of cell experiments, and the underlying pathway was detected by protein-chip technology and gene set enrichment analysis. We found that PSMC2 was significantly upregulated in SKCN patients from TCGA datasets and verified in clinical SKCM tissues. Moreover, high PSMC2 was shown to closely correlate with the pathological stages and lymphatic metastasis of SKCM patients. Functionally, knockdown of PSMC2 suppressed the progression of SKCM through inhibiting cell proliferation, migration, and DNA damage in vitro as well as cell growth in vivo, whereas inducing apoptosis, cycle arrest in G2 phase. Similarly, pharmaceutical inhibition of proteasome with MG132 mimicked the PSMC2 knockdown induced defects in cell cycle arrest, apoptosis and proliferation, while overexpression of PSMC2 has the opposite effects. Mechanistically, the silence of PSMC2 remarkably elevated the pro-apoptotic proteins DR6, IGFBP-4, p21, and p53, while inhibited the anti-apoptosis protein TRAILR-3 and the proteins related to the Wnt signaling pathway. The present study revealed that PSMC2 participated in a positive regulation to promote the progression of SKCM through regulating the Wnt signaling pathway. Our findings may offer a new mechanism underlying the development and progression of SKCM, and a deeper understanding of PSMC2 may contribute to SKCM treatment.

SUBMITTER: Yang Y

PROVIDER: S-EPMC8556233 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Necroptosis has been identified recently as a newly recognized programmed cell death that has an impact on tumor progression and prognosis, although the necroptosis-related gene (NRGs) potential prognostic value in skin cutaneous melanoma (SKCM) has not been identified. The aim of this study was to construct a prognostic model of SKCM through NRGs in order to help SKCM patients obtain precise clinical treatment strategies. Methods: RNA sequencing data collected from The Cancer Genome Atlas (TCGA) were used to identify differentially expressed and prognostic NRGs in SKCM. Depending on 10 NRGs via the univariate Cox regression analysis usage and LASSO algorithm, the prognostic risk model had been built. It was further validated by the Gene Expression Omnibus (GEO) database. The prognostic model performance had been assessed using receiver operating characteristic (ROC) curves. We evaluated the predictive power of the prognostic model for tumor microenvironment (TME) and immunotherapy response. Results: We constructed a prognostic model based on 10 NRGs (FASLG, TLR3, ZBP1, TNFRSF1B, USP22, PLK1, GATA3, EGFR, TARDBP, and TNFRSF21) and classified patients into two high- and low-risk groups based on risk scores. The risk score was considered a predictive factor in the two risk groups regarding the Cox regression analysis. A predictive nomogram had been built for providing a more beneficial prognostic indicator for the clinic. Functional enrichment analysis showed significant enrichment of immune-related signaling pathways, a higher degree of immune cell infiltration in the low-risk group than in the high-risk group, a negative correlation between risk scores and most immune checkpoint inhibitors (ICIs), anticancer immunity steps, and a more sensitive response to immunotherapy in the low-risk group. Conclusions: This risk score signature could be applied to assess the prognosis and classify low- and high-risk SKCM patients and help make the immunotherapeutic strategy decision.

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PSMC2 knockdown suppressed tumor progression of skin cutaneous melanoma

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