Circular RNA circPPP6R3 upregulates CD44 to promote the progression of clear cell renal cell carcinoma via sponging miR-1238-3p

Chen, Zhiliang; Zheng, Zijie; Xie, Yingwei; Zhong, Qiyu; Shangguan, Wentai; Zhang, Yishan; Zhu, Dingjun; Xie, Wenlian

doi:10.1038/s41419-021-04462-5

Cited by 17 publications

(10 citation statements)

References 46 publications

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“…In cRCC, most researchers have reported the functions of circRNAs as miRNA sponges [15][16][17]70]. In our study, we validated that circPOLR2A acted as an oncogene not via the ceRNA mechanism, but through interacting with the PEBP1 and UBE3C proteins and further inhibiting the stability of the PEBP1 protein.…”

Section: Discussionsupporting

confidence: 74%

Circular RNA circPOLR2A promotes clear cell renal cell carcinoma progression by facilitating the UBE3C-induced ubiquitination of PEBP1 and, thereby, activating the ERK signaling pathway

Chen

Liu

et al. 2022

Mol Cancer

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Background Increasing evidence has demonstrated that circular RNAs (circRNAs) are implicated in cancer progression. However, the aberrant expression and biological functions of circRNAs in clear cell renal cell carcinoma (cRCC) remain largely elusive. Method Differentially expressed circRNAs in cRCC were filtered via bioinformatics analysis. Aberrant circPOLR2A expression was validated in cRCC tissues and cell lines via qRT-PCR. Sanger sequencing was used to identify the backsplicing site of circPOLR2A. In vitro and in vivo functional experiments were performed to evaluate the role of circPOLR2A in cRCC malignancy. RNA pull-down, mass spectrometry, RIP, FISH and immunofluorescence assays were used to identify and validate the circPOLR2A-interacting proteins. Ubiquitination modification and interaction between proteins were detected via Co-IP and western blotting. The m6A modification in circPOLR2A was validated by the meRIP assay. Results Bioinformatics analysis revealed that circPOLR2A was highly expressed in cRCC tissues and metastatic cRCC tissues. CircPOLR2A expression was associated with tumor size and TNM stage in cRCC patients. In vitro and in vivo functional assays revealed that circPOLR2A accelerated cRCC cell proliferation, migration, invasion and angiogenesis, while inhibiting apoptosis. Further mechanistic research suggested that circPOLR2A could interact with UBE3C and PEBP1 proteins, and that UBE3C could act as a specific ubiquitin E3 ligase for the PEBP1 protein. The UBE3C/circPOLR2A/PEBP1 protein-RNA ternary complex enhanced the UBE3C-mediated ubiquitination and degradation of the PEBP1 protein which could inactivate the ERK signaling pathway. Rescue experiments revealed that the PEBP1 protein was the functional downstream target of circPOLR2A. Furthermore, m6A modification in circPOLR2A was confirmed, and the m6A reader YTHDF2 could regulate circPOLR2A expression. Conclusion Our study demonstrated that circPOLR2A modulated the UBE3C-mediated ubiquitination and degradation of the PEBP1 protein, and further activated the ERK pathway during cRCC progression and metastasis. The m6A reader, YTHDF2, regulated circPOLR2A expression in cRCC. Hence, circPOLR2A could be a potential target for the diagnosis and treatment of cRCC.

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Section: Discussionsupporting

confidence: 74%

Circular RNA circPOLR2A promotes clear cell renal cell carcinoma progression by facilitating the UBE3C-induced ubiquitination of PEBP1 and, thereby, activating the ERK signaling pathway

Chen

Liu

et al. 2022

Mol Cancer

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“…Among 26 studies with a total of 2048 patients, the expression of six circRNAs (circ‐0001451, circ‐RAPGEF5, circ‐AMOTL1L, circ‐ESRP1, circ‐CYP24A1, and circ‐DVL1) was downregulated, 34,43,57,58,62,63 whereas 18 circRNAs (circ‐001895, circ‐001287, circ‐HIPK3, circ‐PDK1, circ‐MYLK, circ‐0085576, circ‐PTCH1, circ‐400,068, circ‐NUP98, circ‐001842, circ‐RS‐7 (two studies), circ‐AKT1, circ‐SDHC (two studies), circ‐TLK1, circ‐SNX6, circ‐0054537, circ‐CHST15, and circ‐PPP6R3) were upregulated in the RCC tissue 37–39,42,44,46–56,59–61,64 (Table S1). The tumor suppressor (downregulated) circRNAs were associated with smaller tumor size (OR = 0.71 [95% CI 0.58–0.87]; p = 0.001), lower T stage (OR = 0.45 [95% CI 0.27–0.75]; p = 0.002), less lymph node metastasis (OR = 0.29 [95% CI 0.12–0.72]; p = 0.008), less distant metastasis (OR = 0.24 [95% CI 0.14–0.41]; p < 0.001), and lower TNM stage (OR = 0.36 [95% CI 0.24–0.56]; p < 0.001).…”

Section: Resultsmentioning

confidence: 99%

“…Among these, 54 studies were excluded due to the following reasons: non-original articles (n = 19), conference abstracts (n = 3), and studies without available data for any of the defined outcomes (n = 32). Ultimately, 41 studies consisting of 3485 patients with RCC were included in this study, among which 26 studies investigated clinicopathological features, 34,37-39,42-4 4,46-6 4 31 studies evaluated prognostic outcomes, 23,25,[34][35][36][37][38][39][40][41][42][43][44]46,48,50,51,[53][54][55][56][57][63][64][65][66][67][68][69][70][71] and eight studies assessed the diagnosis of RCC. 34,[40][41][42]48,58,72,73 The studies were published between 2017 and 2022 and were conducted in China (n = 38), Germany (n = 2), and Canada (n = 1).…”

Section: Search Results and Study Selectionmentioning

confidence: 99%

Circular RNAs as prognostic and diagnostic biomarkers in renal cell carcinoma

Rashedi

Mardani

Rafati

et al. 2022

Clinical Laboratory Analysis

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Background Circular RNAs (circRNAs) play pivotal roles in proliferation, apoptosis, migration, and invasion of renal cell carcinoma (RCC) cells. This study is aimed to systematically summarize the current evidence regarding the clinical implications of circRNAs in RCC patients. Methods A systematic search in PubMed, Embase, and Web of Science was performed until January 1, 2022. The correlation between the expression of circRNAs and clinicopathological, prognostic, and diagnostic features of RCC was evaluated using the meta‐analysis. Results Ultimately, 41 studies with 3485 RCC patients were included in this study: 26 studies for clinicopathological features, 31 studies for prognosis, and eight studies for diagnosis. Altered expression of circRNAs was significantly associated with clinicopathological characteristics of RCC, including tumor size, tumor stage, lymph node metastasis, distant metastasis, and TNM stage. The tumor promoter circRNAs were associated with reduced overall survival (OS) (Hazard Ratio (HR) = 1.98, 95% confidence interval [CI] 1.68–2.34) and disease/progression/recurrence‐free survival (DFS/PFS/RFS) (HR = 2.34, 95% CI 1.85–2.97). Contrarily, the tumor suppressor circRNAs were linked with better OS (HR = 0.49, 95% CI 0.40–0.60) and DFS/PFS/RFS (HR = 0.40, 95% CI 0.28–0.59). The pooled sensitivity and specificity of circRNAs for RCC diagnosis in tissue samples were both 0.84. These results in fluid samples (serum and urine) were 0.78 and 0.69, respectively. Conclusion CircRNAs can serve as promising diagnostic and prognostic biomarkers for RCC.

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“…Moreover, inhibition of circKIF4A caused the suppression of proliferation and metastasis, suggesting a vital role of circKIF4A in NSCLC progression (Figure 2). miR-1238 is reported as a suppressor in multiple cancers [18][19][20]. CircRNAs has the ability to sponge miR-1238 to enhance tumor progressions.…”

Section: Discussionmentioning

confidence: 99%

“…miR-1238 is reported as a suppressor in multiple cancers [ 18 – 20 ]. CircRNAs has the ability to sponge miR-1238 to enhance tumor progressions.…”

Section: Discussionmentioning

confidence: 99%

CircKIF4A promotes non-small cell lung cancer proliferation and metastasis through MiR-1238/CLDN14 axis

Luo

Liu

et al. 2022

Aging

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As the leading cause of cancer-related death worldwide, non-small-cell lung cancer (NSCLC) is still in need of improved therapeutic strategies. CircKIF4A has been found to be involved in the progression of multiple cancers while its role in NSCLC remains unclear. To investigate the functions of circKIF4A, we assessed the expression of circKIF4A in NSCLC cells and tissues and performed experiments to determine the detailed functions of circKIF4A in NSCLC, including migration and proliferation. We found CircKIF4A expressed more heavily in the cells and tissues of NSCLC patients, and functional studies showed that inhibition of circKIF4A reduced NSCLC cells metastasis and proliferation. Furthermore, we seek to identify the underlying regulatory effect of circKIF4A in NSCLC. Studies revealed that circKIF4A sponged miR-1238 to promote NSCLC progression by upregulating claudin14 (CLDN14) expression. In conclusion, circKIF4A is a potential diagnostic and therapeutic target in the circKIF4A/miR-1238/CLDN14 axis that plays an important role in NSCLC progression.

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Circular RNA circPPP6R3 upregulates CD44 to promote the progression of clear cell renal cell carcinoma via sponging miR-1238-3p

Cited by 17 publications

References 46 publications

Circular RNA circPOLR2A promotes clear cell renal cell carcinoma progression by facilitating the UBE3C-induced ubiquitination of PEBP1 and, thereby, activating the ERK signaling pathway

Circular RNA circPOLR2A promotes clear cell renal cell carcinoma progression by facilitating the UBE3C-induced ubiquitination of PEBP1 and, thereby, activating the ERK signaling pathway

Circular RNAs as prognostic and diagnostic biomarkers in renal cell carcinoma

CircKIF4A promotes non-small cell lung cancer proliferation and metastasis through MiR-1238/CLDN14 axis

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