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UTRN inhibits melanoma growth by suppressing p38 and JNK/c-Jun signaling pathways
Sitong Zhou1, Wen Ouyang2, Xi Zhang3
1Department of Dermatology, The First People's Hospital of Foshan, 81 Lingnan Avenue North, Foshan, 528000, Guangdong, China.
Background:
Utrophin (UTRN), as a tumor suppressor gene, is involved in various cancer progression. The function of UTRN in the melanoma process and the related molecular mechanisms are still unclear. Herein, we studied the function of UTRN in melanoma growth and the relevant molecular mechanisms.
Methods:
Using the GEO database and UCSC Xena project, we compared the expression of UTRN in non-cancerous and melanoma tissues. Immunohistochemistry (IHC) staining, qRT-PCR and Western Blot (WB) were performed to evaluate UTRN expression in clinical samples. A total of 447 cases with UTRN expression data, patient characteristics and survival data were extracted from TCGA database and analyzed. After stable transduction and single cell cloning, the proliferation ability of A375 human melanoma cells was analyzed by Cell Counting Kit‑8 (CCK) and 5‑ethynyl‑2'‑deoxyuridine (EdU) incorporation assays. GSEA was performed to predict the mechanism by which UTRN regulated melanoma growth. Then WB analysis was used to assess the protein expression levels of pathway signaling in overexpression (EXP) melanoma cells. Epac activator 8-pCPT-2'-O-Me-cAMP was then used to evaluate the proliferation ability by activation of p38 and JNK/c-Jun signaling pathways.
Results:
Data from GEO and UCSC Xena project indicated that UTRN expression was decreased in melanoma. Experiment on clinical samples further confirmed our finding. TCGA results showed that a reduced expression of UTRN in 447 melanoma samples was associated with advanced clinical characteristics (T stage, Clark level, ulceration), shorter survival time and poorer prognosis. In addition, up-regulated UTRN expression inhibited melanoma cell proliferation when compared to control group. MAPK signaling pathway was presented in both KEGG and BioCarta databases by using GSEA tool. WB results confirmed the down-regulated expression of p38, JNK1 and c-Jun in EXP group when compared to control group. Epac activator 8-pCPT-2'-O-Me-cAMP treatment could partially rescue proliferation of tumor cells.
Conclusion:
We have demonstrated that reduced UTRN predicted poorer prognosis and UTRN inhibited melanoma growth via p38 and JNK1/c-Jun pathways. Therefore, UTRN could serve as a tumor suppressor and novel prognostic biomarker for melanoma patients.
Insights
Reduced Utrophin (UTRN) expression is linked to poorer melanoma prognosis. Utrophin suppresses melanoma growth by inhibiting p38 and JNK1/c-Jun pathways, suggesting its potential as a prognostic biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Utrophin (UTRN) is implicated in cancer progression, but its role in melanoma remains unclear.
- This study investigates the function and molecular mechanisms of UTRN in melanoma growth.
Purpose of the Study:
- To determine the role of Utrophin (UTRN) in melanoma development and progression.
- To elucidate the molecular pathways through which UTRN influences melanoma growth.
Main Methods:
- Comparative analysis of UTRN expression in non-cancerous and melanoma tissues using GEO and UCSC Xena.
- Validation of UTRN expression in clinical samples via immunohistochemistry, qRT-PCR, and Western Blot.
- Functional assays (CCK, EdU) and pathway analysis (GSEA, Western Blot) in A375 melanoma cells to assess UTRN's impact on proliferation and signaling pathways (p38, JNK/c-Jun).
Main Results:
- Decreased UTRN expression was observed in melanoma tissues and correlated with advanced clinical characteristics and poorer prognosis in 447 TCGA samples.
- Upregulated UTRN significantly inhibited melanoma cell proliferation.
- GSEA and Western Blot analysis revealed that UTRN suppresses melanoma growth via the p38 and JNK1/c-Jun signaling pathways.
Conclusions:
- Reduced Utrophin (UTRN) expression is a predictor of poor prognosis in melanoma patients.
- UTRN acts as a tumor suppressor in melanoma by inhibiting the p38 and JNK1/c-Jun pathways.
- UTRN holds potential as a novel prognostic biomarker for melanoma.
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