What question did this study set out to answer?

To evaluate the role of TMEM72 in renal cell carcinoma and its potential as a prognostic biomarker.

May 6, 20260 citations

TMEM72 Inhibits the proliferation by promoting cellular senescence through the activation of the P38/MAPK signaling pathway in renal cell carcinoma.

FDFang DaiPeking University Shenzhen Hospital HWHuming WangAnhui Medical University WCWenhao ChuPeking University Shenzhen Hospital

Puntos clave

To evaluate the role of TMEM72 in renal cell carcinoma and its potential as a prognostic biomarker.
Proteomic profiling of RCC and adjacent tissues to identify differentially expressed proteins.
Validation of TMEM72 expression using TCGA-KIRC cohort and independent patient cohort.
Functional assays including proliferation, cell cycle, and senescence analyses in RCC models.
In vivo effects evaluated using a xenograft model.
RNA sequencing and immune infiltration analysis to explore underlying mechanisms.
TMEM72 expression was significantly downregulated in RCC, associated with poor prognosis.
Overexpression of TMEM72 suppressed RCC cell proliferation and tumor growth; silencing promoted tumor progression.
TMEM72 induced G1/S cell cycle arrest and promoted cellular senescence via the p38/MAPK pathway.
TMEM72 expression correlated with anti-tumor immune cell infiltration, while negatively associated with immunosuppressive cells.

Resumen

BACKGROUND: Renal cell carcinoma (RCC) is a highly heterogeneous malignancy lacking reliable prognostic biomarkers and effective therapeutic targets. TMEM72, a kidney-enriched protein, is dysregulated in RCC, yet its biological function and underlying mechanisms remain unclear. METHODS: Proteomic profiling of paired RCC and adjacent tissues was performed to identify differentially expressed proteins. TMEM72 expression and clinical relevance were validated using the TCGA-KIRC cohort and an independent patient cohort. Functional assays, including proliferation, cell cycle, and senescence analyses, were conducted in gain- and loss-of-function RCC models, and in vivo effects were evaluated using a xenograft model. RNA sequencing, single-cell analysis, and immune infiltration analysis were performed to explore underlying mechanisms. RESULTS: TMEM72 was significantly downregulated in RCC and its low expression was associated with poor prognosis. TMEM72 overexpression suppressed RCC cell proliferation and tumor growth, whereas its silencing promoted tumor progression. Mechanistically, TMEM72 induced G1/S cell cycle arrest and promoted cellular senescence. Further analyses revealed that TMEM72 activated the p38/MAPK signaling pathway, leading to enhanced phosphorylation of p38 and p53, while pharmacological inhibition of p38 partially reversed these effects. Immune microenvironment analysis showed that TMEM72 was predominantly expressed in epithelial and malignant cells and was positively associated with infiltration of anti-tumor immune cells, including M1 macrophages, monocytes, and NK cells, but negatively correlated with immunosuppressive populations such as regulatory T cells and M0 macrophages. CONCLUSIONS: TMEM72 suppresses RCC progression by promoting p38/MAPK-dependent cellular senescence and may contribute to tumor immune microenvironment remodeling, highlighting its potential as a prognostic biomarker and therapeutic target.

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