CircCYP24A1 hampered malignant phenotype of renal cancer carcinoma through modulating CMTM-4 expression via sponging miR-421

Xiaorong Wu,Wei Xue,Chen Yang,Yonghui Chen,Ling Zhao,Jiale Zhou,Zhaolin Yang

doi:10.1038/s41419-022-04623-0

Xiaorong Wu, Wei Xue + Show 5 more

Open Access

https://doi.org/10.1038/s41419-022-04623-0

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Abstract

Renal cell carcinoma (RCC) is a lethal urinary malignancy. Circular RNAs (circRNAs) contribute to the malignant phenotype and progression of several types of human cancers, including RCC. In this study, we identified relatively low hsa_circ_0060927 (circCYP24A1) expression in RCC tissue through high-throughput sequencing and RT–qPCR. Fluorescence in situ hybridization (FISH) was used to validate the expression and subcellular localization of circCYP24A1 in RCC tissues. CCK-8, Transwell, EdU, and wound-healing assays indicated that circCYP24A1 overexpression inhibited the proliferation, invasion, and migration of RCC cells. Dual-luciferase reporter, RNA immunoprecipitation (RIP), FISH, and RNA-pulldown assays verified that circCYP24A1 inhibited RCC progression by sponging miR-421, thus inducing CMTM-4 expression. Xenograft assays and metastasis models further indicated that circCYP24A1 significantly inhibited the metastasis and proliferation of RCC cells in vivo. Taken together, circCYP24A1 is a prognosis-related circRNA in RCC that functions through the circCYP24A1/miR-421/CMTM-4 axis to modulate RCC progression.

Highlights

Renal cell carcinoma (RCC) is the 7th most common tumor worldwide [1] and is related to approximately 140,000 deaths per year
Twelve circRNAs were upregulated, while 19 circRNAs were downregulated in RCC tissues compared with normal tissues according to our analysis of the sequencing data (Fig. 1A)
CircCYP24A1 overexpression in RCC cells leads to reduced lung metastasis As RCC shows a relatively high metastasis rate, we further explored whether circCYP24A1 overexpression correlates with the metastatic ability of RCC cells. 786-O-luc cells transfected with LVNC, LV-circCYP24A1, LV-circCYP24A1 plus miR-421 mimic, and LVcircCYP24A1 plus sh-CMTM4 were injected into the tail vein of nude mice to explore the lung metastasis ability of RCC cells

Summary

Introduction

Renal cell carcinoma (RCC) is the 7th most common tumor worldwide [1] and is related to approximately 140,000 deaths per year. Surgery remains the main treatment for RCC [2]. Recurrence still occurs in 30% of patients with RCC after radical nephrectomy. Resistance to radiation therapy and conventional chemotherapy leads to an unsatisfactory clinical outcome of RCC [3]. The high recurrence rate and unclear pathogenesis still intrigue us and prompt explorations to improve the therapeutic and diagnostic strategies for RCC. CircRNA was first explored using electron microscopy 50 years ago; circRNA is generated by backsplicing to form a circular configuration and is more stable than linear RNA [4]. The competitive endogenous RNA hypothesis is a conventional and well-recognized mechanism by which circRNAs regulate biological processes. Acting as ceRNAs, circRNAs interact with their miRNA targets and function as miRNA sponges, modulating expression at the posttranscriptional level [5]

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