Low Expression Levels of SLC22A12 Indicates a Poor Prognosis and Progresses Clear Cell Renal Cell Carcinoma.

Jiaju Xu,Xiong Yang,Jingchong Liu,Hairong Xiong,Di Liu,Qi Wang,Yuenan Liu,Tianbo Xu,Huageng Liang,Zhiyong Xiong,Hongmei Yang,Xiaoping Zhang,Yi Shou

doi:10.3389/fonc.2021.659208

Abstract

Clear cell renal cell carcinoma (ccRCC) accounts for approximately 4/5 of all kidney cancers. Accumulation of minor changes in the cellular homeostasis may be one cause of ccRCC. Therefore, we downloaded the RNA sequencing and survival data of the kidney renal cell carcinoma (KIRC) cohort from the Cancer Genome Atlas (TCGA) database. After the univariate and multivariate Cox regression analyses, 19 kidney-specific differentially expressed genes (DEGs) were found. Solute Carrier Family 22 Member 12 (SLC22A12) resulted in an independent prognostic predictor for both overall survival (OS) and disease-free survival (DFS). SLC22A12 expression was lower in tumoral tissue compared to normal tissue. Moreover, patients in the SLC22A12 low expression group had a higher pathological stage and worse survival than the high expression group. Additionally, qRT-PCR assay, immunoblotting test (IBT), and immunohistochemical (IHC) analyses of cancer tissues/cells and the corresponding normal controls verified that SLC22A12 is downregulated in ccRCC. Receiver operator characteristic (ROC) curves showed that the low expression level of SLC22A12 could be a good diagnostic marker for ccRCC (AUC=0.7258; p <0.0001). Gene set enrichment analysis (GSEA) showed that SLC22A12 expression levels are related to metabolism, cell cycle, and tumor-related signaling pathways. GO and KEGG analyses revealed that SLC22A12 transports multiple organic compounds, ions, and hormones and participates in the extracellular structure organization. Furthermore, SLC22A12 over-expression in vitro inhibited the proliferation, migration, and invasion of renal cancer cells by regulating PI3K/Akt pathways. Such effects were reversed when knocking out SLC22A12. In summary, as a transporter for many vital metabolites, SLC22A12 may affect tumor cell survival through its impacts on the mentioned metabolites. In conclusion, this study uncovered that SLC22A12 is a promising prognostic and diagnostic biomarker for ccRCC.

Highlights

Kidney cancer, called renal cancer, represents a significant threat to human health, as it develops fatal metastasis in the lung or brain
One of the aims of this work was to identify the critical genes for cellular homeostasis in Clear cell renal cell carcinoma (ccRCC)
We screened three independent gene sets: differently expressed gene (DEG) set in the Cancer Genome Atlas (TCGA) datasets, kidney-specific gene sets, and cellular homeostasis gene sets

Summary

Introduction

Called renal cancer, represents a significant threat to human health, as it develops fatal metastasis in the lung or brain. Kidney cancer mainly includes renal cell cancer (RCC), transitional cell cancer (TCC), and Wilms tumor. RCC accounts for roughly 4/5 of kidney cancers, while most of the other renal cancer are TCC [1,2,3]. According to the American Cancer Society, 73,750 new kidney and renal pelvis cancer cases were estimated in the United States in 2020. The five-year survival rate is 93% for patients with localized kidney cancer, 70% with surrounding lymph nodes spread, and 12% with distant metastasis [5]. It is crucial to investigate the biological functions and molecular mechanisms involved in kidney cancer in order to find new therapeutic targets

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