Mechanism of tumor‑derived extracellular vesicles in regulating renal cell carcinoma progression by the delivery of MALAT1.

Abstract

Renal cell carcinoma (RCC) is a major healthcare burden globally. Tumor-derived extracellular vesicles (EVs) contribute to the formation of a pro-metastatic microenvironment. In the present study, we explored the role and mechanism of RCC cell 786-O-derived EVs (786-O-EVs) in RCC. First, 786-O-EVs were extracted and identified, and EV internalization of RCC cells was observed. RCC cell malignant behaviors and long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression patterns were detected before and after 786-O-EV treatment. MALAT1 was intervened to evaluate RCC cell behaviors. The downstream mechanism involving MALAT1 was predicted. In addition, the relationship among MALAT1, transcription factor CP2 like 1 (TFCP2L1) and ETS proto-oncogene 1, transcription factor (ETS1) was analyzed. TFCP2L1 expression patterns were measured after 786-O-EV exposure. Tumor xenograft formation assay and lung metastasis model were adopted to verify the role of 786-O-EVs in vivo in RCC. It was found that 786-O-EVs could be internalized by RCC cells. 786-O-EVs promoted RCC cell malignant behaviors, accompanied by elevated MALAT1 expression levels. The 786-O-EVs with MALAT1 knockdown attenuated the promotive effect of sole 786-O-EVs on RCC cells. MALAT1 located ETS1 in the TFCP2L1 promoter and negatively regulated TFCP2L1, and ETS1 protein could specifically bind to MALAT1. 786-O-EVs enhanced the binding of ETS1 and the TFCP2L1 promoter and decreased TFCP2L1 expression. In vivo, 786-O-EVs promoted tumor growth and RCC lung metastasis, which was suppressed following inhibition of MALAT1. Our findings indicated that 786-O-EVs promoted RCC invasion and metastasis by transporting MALAT1 to promote the binding of transcription factor ETS1 and TFCP2L1 promoter.