Abstract
Runt-related transcription factor 3 (RUNX3) is a tumor suppressor in many human solid tumors. In this study, renal cell carcinoma (RCC) microarray analysis showed that the level of RUNX3 expression was lower in RCC tissue than in adjacent normal renal tissues, and was correlated with depth of invasion (pT stage) (P<0.001) and Tumor Node Metastasis (TNM) stage (P<0.001). RUNX3 expression was negatively correlated with poor 5-year overall and disease-free patient survival. RUNX3 suppressed RCC metastasis and invasion and increased levels of E-cadherin, an important marker of epithelial-mesenchymal transition, in vitro and in vivo. RUNX3 also inhibited microRNA-6780a-5p, which directly targeted the E-cadherin 3’untranslated region and decreased its expression. We confirmed that miR-6780a-5p mimics abrogated RUNX3-mediated E-cadherin upregulation and RCC metastasis/invasion inhibition. Thus, RUNX3 targeted the miR-6780a-5p/E-cadherin/EMT signaling axis to suppress renal carcinoma cell migration and invasion. This pathway illustrates a new RUNX3 function and provides potential targets for the treatment of RUNX3 mutant and loss-of-function RCC tumors. RUNX3 may also act as an effective prognostic indicator in RCC.
Highlights
Renal cell carcinoma (RCC), the most prevalent malignancies of the adult kidney, reportedly accounts for approximately 90% of renal cancer patients [1]
RUNX3 expression was negatively related with depth of invasion (P
To determine whether RUNX3-mediated renal cell carcinoma (RCC) metastasis inhibition was controlled by miR-6780a-5p induction, we upregulated miR-6780a-5p using mimics in RUNX3-overexpressing RCC cells. miR-6780a-5p upregulation attenuated RUNX3-induced E-cadherin expression (Figure 6A–6B) and abrogated RUNX3mediated migration and invasion repression (Figure 6C– 6F). These results suggested that the effects of RUNX3 on E-cadherin and cell metastasis were largely dependent on miR-6780a-5p inhibition
Summary
Renal cell carcinoma (RCC), the most prevalent malignancies of the adult kidney, reportedly accounts for approximately 90% of renal cancer patients [1]. About 30% of patients have metastasic disease. A higher percentage of patients develop metachronous metastases after nephrectomy [3]. Appropriate RCC biomarkers, which are critical to disease prediction, evaluation and therapy development, are urgently needed. All three RUNX family members regulate gene expression in cell proliferation and differentiation pathways in humans [5] through binding to gene promoters or enhancers [6]. RUNX3 is localized on chromosome 1p.13-p36.11, where loss of heterozygosity (LOH) is frequently observed in multiple cancers, demonstrating its potential role as a tumor suppressor [7]. The mechanisms of RUNX3 tumorigenesis and metastasis promotion are as yet unclear
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