Pan-cancer Analysis of NEDD4L and Its Tumor Suppressor Effects in Clear Cell Renal Cell Carcinoma

The expression level of NEDD4L, an E3 ubiquitin ligase, has changed significantly in human cancers. In this study, we aimed to study the expression of NEDD4L in pan-carcinoma and its function in malignant tumors. We analyzed the gene expression level of NEDD4L in pan-cancer from The Cancer Genome Atlas (TCGA) microarray data set, the correlation between gene expression and overall survival, disease-specific survival, and tumor immune microenvironment changes. NEDD4L expression changes in half of the cancer types. Low expression of NEDD4L gene predicts poor overall survival and disease-specific survival (DSS) in renal clear cell carcinoma (KIRC) and renal chromophobe cell carcinoma (KIRP). NEDD4L is negatively related to interstitial cell infiltration and immune cell infiltration in most common cancers. Furthermore, the low expression of NEDD4L was verified in our clear cell renal cell carcinoma (ccRCC) clinical tissues. In ccRCC cells, NEDD4L overexpression significantly reduced cell proliferation and migration. In the functional analysis, we proved that NEDD4L could inhibit ERBB3 and MAPK signaling pathways. When cells are deficient in nutrition, NEDD4L promoted the degradation of the autophagy regulatory protein ULK1. Our study provides novel insights into the role of NEDD4L in pan-cancer. NEDD4L may play a tumor suppressor effect in ccRCC, through tumor immune regulation and ubiquitination of key intracellular kinases.