Genome-Wide Transcriptomic Analysis of Non-Tumorigenic Tissues Reveals Aging-Related Prognostic Markers and Drug Targets in Renal Cell Carcinoma

SIMPLE SUMMARY: Few studies have employed expression data of normal tissues to explore the survival of cancer patients. Hence, we identified aging-related genes and microRNAs in normal tissues from patients with various types of cancer and investigated their effects on survival. We built statistical models to predict the survival of cancer patients using the expression levels of aging-related genes and microRNAs. We found that five aging-related genes (DUSP22, MAPK14, MAPKAPK3, STAT1, and VCP) from kidney cancer patients were significantly related to patient survival. We experimentally showed that there is an increase in the five aging-related genes in the macrophages of aged mice and, among these five genes, the invasion of cancer cells is inhibited by downregulating DUSP22. Using the zebrafish model of tumor cell dissemination, it was also confirmed that in vivo treatment with a small molecule inhibitor of DUSP22 blocked the metastasis of cancer cells in the early stage. ABSTRACT: The relationship between expression of aging-related genes in normal tissues and cancer patient survival has not been assessed. We developed a genome-wide transcriptomic analysis approach for normal tissues adjacent to the tumor to identify aging-related transcripts associated with survival outcome, and applied it to 12 cancer types. As a result, five aging-related genes (DUSP22, MAPK14, MAPKAPK3, STAT1, and VCP) in normal tissues were found to be significantly associated with a worse survival outcome in patients with renal cell carcinoma (RCC). This computational approach was investigated using nontumorigenic immune cells purified from young and aged mice. Aged immune cells showed upregulated expression of all five aging-related genes and promoted RCC invasion compared to young immune cells. Further studies revealed DUSP22 as a regulator and druggable target of metastasis. DUSP22 gene knockdown reduced RCC invasion and the small molecule inhibitor BML-260 prevented RCC dissemination in a tumor/immune cell xenograft model. Overall, these results demonstrate that deciphering the relationship between aging-related gene expression in normal tissues and cancer patient survival can provide new prognostic markers, regulators of tumorigenesis and novel targets for drug development.