CircAMOTL1L Suppresses Renal Cell Carcinoma Growth by Modulating the miR-92a-2-5p/KLLN Pathway.

Ling Gao,Xiaolei He,Xian Shao,Qingqing Yue,Fujun Hou,Ruonan Zhang,Weifei Wu,Xuejuan Yang,Limin Li

doi:10.1155/2021/9970272

Abstract

Accumulating evidence indicates that the dysregulation of circular RNAs (circRNAs) contributes to tumor progression; however, the regulatory functions of circRNAs in renal cell carcinoma (RCC) remain largely unknown. In this study, the function and underlying mechanism of circAMOTL1L in RCC progression were explored. qRT-PCR showed the downregulation of circAMOTL1L in RCC tissues and cell lines. The decrease in circAMOTL1L expression correlated with the tumor stage, metastasis, and poor prognosis in patients with RCC. Functional experiments revealed that circAMOTL1L inhibited cell proliferation and increased apoptosis in RCC cells. Subcutaneous implantation with circAMOTL1L-overexpressing cells in nude mice decreased the growth ability of the xenograft tumors. Mechanistically, circAMOTL1L served as a sponge for miR-92a-2-5p in upregulating KLLN (killin, p53-regulated DNA replication inhibitor) expression validated by bioinformatics analysis, oligo pull-down, and luciferase assays. Further, reinforcing the circAMOTL1L–miR-92a-2-5p–KLLN axis greatly reduced the growth of RCC in vivo. Conclusively, our findings demonstrate that circAMOTL1L has an antioncogenic role in RCC growth by modulating the miR-92a-2-5p–KLLN pathway. Thus, targeting the novel circAMOTL1L–miR-92a-2-5p–KLLN regulatory axis might provide a therapeutic strategy for RCC.

Highlights

Renal cell carcinoma (RCC) is a common malignant tumor of the human urinary system and the second leading cause of death among patients with urologic tumors, accounting for approximately 3% of all adult malignancies [1,2,3]
We investigated the involvement of the circAMOTL1L–miR-92a-2-5p–KLLN axis in the RCC growth in vivo. 786-O cells stably transfected with LV-circAMOTL1L, LV-anti-miR-92a-2-5p, or both were injected into nude mice for establishing a xenograft model
These results demonstrate that the circAMOTL1L–miR-92a-2-5p–KLLN axis is involved in RCC growth through regulation of the proliferation and apoptosis of RCC cells

Summary

Introduction

Renal cell carcinoma (RCC) is a common malignant tumor of the human urinary system and the second leading cause of death among patients with urologic tumors, accounting for approximately 3% of all adult malignancies [1,2,3]. Accumulating studies have confirmed that circRNAs perform different critical regulatory activities in gene expression, including sponging miRNA [12], modulating alternative splicing [8], interacting with RNA binding proteins [13], and regulating gene transcription and protein-encoding ability [14]. Accumulating evidence suggests that circRNAs play critical roles in tumor progression by regulating the proliferation, apoptosis, invasion, and metastasis of tumor cells [19,20,21] and are gradually being expected to become valuable prognostic biomarkers and therapeutic targets for malignant tumors. CircPVT1 promotes progression of ccRCC by sponging miR-145-5p and regulating TBX15 expression [23]. CircAMOTL1L served as a sponge of miR-92a-2-5p, thereby upregulating KLLN expression and inducing RCC growth inhibition. CircAMOTL1L may serve as an antioncogene in RCC progression, and a novel regulatory network involving the circAMOTL1L–miR-92a-2-5p–KLLN axis might serve as a therapeutic strategy for RCC

Materials and Methods

Results

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Discussion