Original ArticlesCircRNA cRAPGEF5 inhibits the growth and metastasis of renal cell carcinoma via the miR-27a-3p/TXNIP pathway
Introduction
The incidence of renal cell carcinoma (RCC) has been increasing, with more than 400,000 estimated new cases and more than 170,000 deaths in 2018 worldwide [1]. As the most common type of kidney cancer, clear cell RCC (ccRCC) accounts for approximately 70–75% of cases [2]. Previous studies have reported that approximately 20–30% of RCC patients present with distant metastases at primary diagnosis, and nearly 25% of primary nonmetastatic cases treated with nephrectomy developed metastasis [3,4]. Although considerable improvements in the 5-year relative survival rates have been reported, the overall prognosis is far from satisfactory, particularly for metastatic RCC [5]. Thus, the potential mechanisms related to the development and progression of RCC still need to be further explored, and novel reliable therapeutic targets and predictive biomarkers are also needed to improve the survival rate of RCC patients.
Circular RNA (circRNA) is a novel class of endogenous RNA and uniquely presents with covalently closed loop structures [6], which is different from linear mRNA or long noncoding RNA. circRNAs are derived from precursor mRNAs through backsplicing and lack 5′ caps and 3’ polyadenylated tails [6,7]. Many studies have reported that circRNAs are widely expressed in a variety of mammalian tissues or cells and display specific expression patterns according to different cell types, tissues and developmental stages [[8], [9], [10], [11]]. Recently, a series of studies demonstrated that circRNAs were not byproducts of error splicing but were functional regulators [8] and were associated with many cancer types [12], including lung cancer [13], prostate cancer [14], breast cancer [15], glioma [16], hepatocellular carcinoma (HCC) [17,18], and renal cell carcinoma [19].
miRNAs are small noncoding RNAs and function mainly by regulating the expression of target genes [20,21]. Considerable miRNAs have been reported to be involved in the carcinogenesis and progression of RCC [22,23]. Recent studies found that circRNAs could function as sponges of miRNAs and regulate gene expression by blocking the activities of miRNAs [24]. Previous sequencing data show that hsa_circ_0001681 (derived from the RAPGEF5 gene, termed cRAPGEF5) is abnormally expressed in various cancers, including glioblastoma [25], liver cancer [26] and thyroid cancer [27]. A recent study reported that cRAPGEF5 could promote the proliferation and metastasis of papillary thyroid cancer through the miR-198/FGFR1 pathway [28]. However, whether cRAPGEF5 is abnormally expressed and plays a regulatory role in RCC remains unclear.
In the present study, we examined cRAPGEF5 expression in RCC tissues and identified that cRAPGEF5 is downregulated in RCC tissues and related to RCC prognosis. We further explored the functions and mechanisms of cRAPGEF5 in RCC. Functionally, silencing cRAPGEF5 enhances the growth, migration, and invasion abilities of RCC cells. Mechanistically, cRAPGEF5 could inhibit the progression of RCC by acting as a sponge of oncogenic miR-27a-3p to upregulate TXNIP. Therefore, cRAPGEF5 may serve as a novel therapeutic target and predictive biomarker for RCC patients.
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Patients and samples
A total of 42 pairs of RCC and adjacent nontumor tissues and a cohort of 245 RCC tumor tissues were obtained from surgical resection specimens of RCC patients at Changzheng Hospital (Shanghai, China). The samples were quickly frozen in liquid nitrogen after surgery and then stored at the Biobank of Shanghai Changzheng Hospital until use. All samples were diagnosed by two pathologists independently. None of the patients underwent preoperative treatment. Written informed consent was obtained from
Expression and circRNA characterization of cRAPGEF5 in RCC
Bioinformatics analysis showed that cRAPGEF5 is an exonic circRNA that is cyclized with the second through sixth exons of the RAPGEF5 gene (Fig. 1A) [29]. A previous study found that cRAPGEF5 is associated with the progression of papillary thyroid carcinoma [28]; however, the role of cRAPGEF5 in RCC remains unclear. To measure the expression level of cRAPGEF5 in RCC tissues, we first designed specific PCR primers for cRAPGEF5, which were verified through Sanger sequencing and agarose gel
Discussion
The function of circRNA in tumors has received increasing attention, but its role in RCC tumorigenesis and progression remains unclear. In our study, the level of cRAPGEF5 in RCC was found to be relatively low; however, this result is different from the results in thyroid cancer [28], probably due to the tissue-specific expression of cRAPGEF5. Moreover, due to the limitation of the number of cases in this study, more cases may be required to fully support this conclusion.
The regulatory
Declaration of competing interest
All of the contributors in this work declared no conflicts of interest.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (81730073, 81874093, 81874093 and 81902560) and the Shanghai Sailing Program (19YF1448300).
References (54)
- et al.
Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biologic complexity
Eur. Urol.
(2015) - et al.
Exon circularization requires canonical splice signals
Cell Rep.
(2015) - et al.
Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed
Mol. Cell
(2015) - et al.
hsa_circ_0091570 acts as a ceRNA to suppress hepatocellular cancer progression by sponging hsa-miR-1307
Cancer Lett.
(2019) - et al.
Androgen receptor (AR) promotes clear cell renal cell carcinoma (ccRCC) migration and invasion via altering the circHIAT1/miR-195-5p/29a-3p/29c-3p/CDC42 signals
Cancer Lett.
(2017) - et al.
Origins and Mechanisms of miRNAs and siRNAs
Cell
(2009) - et al.
Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma
J. Hepatol.
(2018) - et al.
circRAPGEF5 contributes to papillary thyroid proliferation and metastatis by regulation miR-198/FGFR1, molecular therapy
Nucleic acids
(2019) - et al.
Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis, Laboratory investigation
J. Tech. Methods Pathol.
(2005) - et al.
Circular RNAs: a novel class of functional RNA molecules with a therapeutic perspective, molecular therapy
J. Am. Soc Gene Ther.
(2019)
Circular intronic long noncoding RNAs
Mol. Cell
Repression of protein synthesis by miRNAs: how many mechanisms?
Trends Cell Biol.
MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation
Mol. Cell
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
CA A Cancer J. Clin.
Systemic therapy for metastatic renal-cell carcinoma
N. Engl. J. Med.
Renal cell carcinoma recurrences and metastases in primary non-metastatic patients: a population-based study
World J. Urol.
Treatment of renal cell carcinoma: current status and future directions
CA A Cancer J. Clin.
The biogenesis and emerging roles of circular RNAs
Nat. Rev. Mol. Cell Biol.
Detecting and characterizing circular RNAs
Nat. Biotechnol.
Circular RNAs are a large class of animal RNAs with regulatory potency
Nature
Cell-type specific features of circular RNA expression
PLoS Genet.
The landscape of circular RNA in cancer
Cell
circTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1
Nat. Commun.
Widespread and functional RNA circularization in localized prostate cancer
Cell
The circular RNome of primary breast cancer
Genome Res.
Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis
J. Natl. Cancer Inst.
A noncoding regulatory RNAs network driven by circ-CDYL acts specifically in the early stages hepatocellular carcinoma
Hepatology
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These authors contributed equally to this work.