MiR-765 functions as a tumour suppressor and eliminates lipids in clear cell renal cell carcinoma by downregulating PLP2

Abstract

A B S T R A C TBackground: Lipid accumulation has been highlighted in cancer development and progression, but the exact mechanism remains unclear in renal cell carcinoma (RCC). MicroRNAs (miRNAs) have been confirmed to participate in the pathological processes of cancers, including tumour occurrence and inhibition. However, the role and mechanism of miR-765 have not been elucidated in clear cell renal cell carcinoma (ccRCC). Methods: Using The Cancer Genome Atlas (TCGA) database and qRT-PCR, we investigated differences in miR-765 and proteolipid protein 2 (PLP2) expression, as well as their clinical relevance. To investigate the function of miR-765 and PLP2 in ccRCC, we performed in vitro and in vivo experiments to explore their biological functions in ccRCC. Findings: In this study, we showed that miR-765 was upregulated in the plasma of ccRCC patients after tumour resection. Consistently, ccRCC tissues had low expression of miR-765 when compared with corresponding non-cancerous tissues. Overexpression of miR-765 suppressed cell proliferation and metastasis in vitro and in vivo. Mechanistic studies demonstrated that PLP2 was a direct target gene of miR-765. PLP2 was highly expressed in ccRCC tissues, and high PLP2 levels were positively correlated with higher tumour stage and grade and poor prognosis. PLP2 expression was negatively correlated with the miR-765 level in patient samples. We further showed that PLP2 restrained the cell metastasis and proliferation induced by miR-765 and reduced the lipid-eliminating effects of miR-765 in renal cancer cells. Interpretation: Our findings suggest that miR-765 may function as a tumour suppressor and eliminate lipids in clear cell renal cell carcinoma by targeting PLP2. EBioMedicine journal homepage: www.elsevier.com/locate/ebiom that miR-765 inhibits osteosarcoma [23] and tongue squamous cell carcinoma [24]. Nevertheless, to the best of our knowledge, there is still no relevant research about the role of miR-765 in ccRCC. We found that the plasma level of miR-765 was upregulated after tumour resection in ccRCC patients and that ccRCC tissues had a low level of miR-765 compared with corresponding non-ccerous tissues. The present study systematically describes the function and role of miR-765 in ccRCC. Functionally, miR-765 inhibited RCC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, miR-765 serves as a tumour suppressor and eliminates lipids by downregulating PLP2 in ccRCC. Our findings reveal that the miR-765-PLP2 axis may be a biomarker and a therapeutic target for ccRCC. Materials and methods Patient samples and cellsThirty-six clear cell renal cell carcinoma (ccRCC) patient surgical specimens, 18 non-ccRCC (nccRCC) patient surgical specimens and 18 blood plasma samples (preoperative and operational day 7 without chemotherapy or radiotherapy for ccRCC) were obtained from

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