Open Access

ARTICLE

Macrophage-derived exosomal miR-342-3p promotes the progression of renal cell carcinoma through the NEDD4L/CEP55 axis

by JIAFU FENG^1,2,#,*, BEI XU^1,2,#, CHUNMEI DAI^1,2,#, YAODONG WANG^1,4, GANG XIE^1,5, WENYU YANG^1,2, BIN ZHANG^1,2, XIAOHAN LI⁶, JUN WANG³

1 NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang, 621000, China
2 Departments of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, China
3 Medical Technology Institute, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
4 Departments of Urology Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, China
5 Departments of Pathology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, China
6 Department of Medical Laboratory, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China

* Corresponding Author: JIAFU FENG. Email:
# These authors contributed equally to this work and should be all considered as the first authors

Oncology Research 2021, 29(5), 331-349. https://doi.org/10.32604/or.2022.03554

Received 18 March 2022; Accepted 19 September 2022; Issue published 10 October 2022

Abstract

Due to its difficulty in early diagnosis and lack of sensitivity to chemotherapy and radiotherapy, renal cell carcinoma (RCC) remains to be a frequent cause of cancer-related death. Here, we probed into new targets for its early diagnosis and treatment for RCC. microRNA (miRNA) data of M2-EVs and RCC were searched on the Gene Expression Omnibus database, followed by the prediction of the potential downstream target. Expression of target genes was measured via RT-qPCR and Western blot, respectively. M2 macrophage was obtained via flow cytometry with M2-EVs extracted. The binding ability of miR-342-3p to NEDD4L and to CEP55 ubiquitination was studied with their roles in the physical abilities of RCC cells assayed. Subcutaneous tumor-bearing mouse models and lung metastasis models were prepared to observe in vivo role of target genes. M2-EVs induced RCC growth and metastasis. miR-342-3p showed high expression in both M2-EVs and RCC cells. M2-EVs carrying miR-342-3p promoted RCC cell abilities to proliferate, invade and migrate. In RCC cells, M2-EV-derived miR-342-3p could specifically bind to NEDD4L and consequently elevate CEP55 protein expression via suppressing NEDD4L, thereby exerting tumor-promoting effects. CEP55 could be degraded by ubiquitination under the function of NEDD4L, and miR-342-3p delivered by M2-EVs facilitated the RCC occurrence and development by activating the PI3K/AKT/mTOR signaling pathway. In conclusion, M2-EVs promote RCC growth and metastasis by delivering miR-342-3p to suppress NEDD4L and subsequently inhibit CEP55 ubiquitination and degradation via activation of the PI3K/AKT/mTOR signaling pathway, strongly driving the proliferative, migratory and invasive of RCC cells.

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