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SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling

Wang, Jiangyi, Zou, Yun, Du, Bowen, Li, Wenzhi, Yu, Guopeng, Li, Long, Zhou, Lin, Gu, Xin, Song, Shangqing, Liu, Yushan, Zhou, Wenquan, Xu, Bin, Wang, Zhong·2021·Cell Death & Disease
DOI 10.1038/s41419-021-03958-4PMC PMC8254807
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Abstract

Over the last decade, more than 10 independent SNPs have been discovered to be associated with the risk of renal cell carcinoma among different populations. However, the biological functions of them remain poorly understood. In this study, we performed eQTL analysis, ChIP-PCR, luciferase reporter assay, and Cox regression analysis to identify the functional role and underlying mechanism of rs67311347 in RCC. The ENCORI database, which contains the lncRNA–miRNA–mRNA interactions, was used to explore the possible target miRNA of ENTPD3-AS1. The results showed that the G > A mutation of rs67311347 created a binding motif of ZNF8 and subsequently upregulated ENTPD3-AS1 expression by acting as an enhancer. The TCGA-KIRC and our cohorts both confirmed the downregulation of ENTPD3-AS1 in RCC tissues and demonstrated that increased ENTPD3-AS1 expression was associated with good OS and PFS. Furthermore, ENTPD3-AS1 interacted with miR-155-5p and activated the expression of HIF-1α, which was an important tumor suppressor gene in the development of RCC. The functional experiments revealed that overexpression of ENTPD3-AS1 inhibited cell proliferation in RCC cell lines and the effect could be rescued by knocking down HIF-1α. Our findings reveal that SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling.

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Figures

Fig. 1 RCC-associated SNP rs67311347 regulated the expression of ENPTD3-AS1. A The Manhattan Plot of RCC-associated SNPs in GWAS. B eQTL analysis of rs67311347 using data from the GTEx Project. C The expression of ENPTD3-AS1 in normal kidney tissues with different genotypes of SNP rs67311347 in Cohort 1. D The expression of ENPTD3-AS1 in RCC cell lines with different genotypes of SNP rs67311347.
Fig. 1 RCC-associated SNP rs67311347 regulated the expression of ENPTD3-AS1. A The Manhattan Plot of RCC-associated SNPs in GWAS. B eQTL analysis of rs67311347 using data from the GTEx Project. C The expression of ENPTD3-AS1 in normal kidney tissues with different genotypes of SNP rs67311347 in Cohort 1. D The expression of ENPTD3-AS1 in RCC cell lines with different genotypes of SNP rs67311347.CC BY · PubMed Central
Fig. 2 SNP rs67311347 regulated the expression of lncRNA ENTPD3-AS1 as an enhancer. A The genomic location of rs67311347 and ENTPD3-AS1. B Epigenetic tracks obtained from ENCODE database showed the enrichment of enhancer marks (H3K27ac peaks, H3K4me1 peaks) and transcription marks (H3K4me3 peaks) in the rs67311347 region. C The Polymerase II ChIP-PCR showed that Polymerase II occupied the rs67311347 region. D Relative reporter gene activity of the constructs containing the WT or Mut allele of rs67311347 in forward orientation in A498 cells. E The altered allele A of rs67311347 created a ZNF8 binding motif. F ChIP-qPCR of ZNF8 in RCC cell lines carrying different genotypes of rs67311347.
Fig. 2 SNP rs67311347 regulated the expression of lncRNA ENTPD3-AS1 as an enhancer. A The genomic location of rs67311347 and ENTPD3-AS1. B Epigenetic tracks obtained from ENCODE database showed the enrichment of enhancer marks (H3K27ac peaks, H3K4me1 peaks) and transcription marks (H3K4me3 peaks) in the rs67311347 region. C The Polymerase II ChIP-PCR showed that Polymerase II occupied the rs67311347 region. D Relative reporter gene activity of the constructs containing the WT or Mut allele of rs67311347 in forward orientation in A498 cells. E The altered allele A of rs67311347 created a ZNF8 binding motif. F ChIP-qPCR of ZNF8 in RCC cell lines carrying different genotypes of rs67311347.CC BY · PubMed Central
Fig. 3 ENTPD3-AS1 was a protective lncRNA in RCC development. A ENTPD3-AS1 expression in the tumor and normal tissues in TCGA-KIRC. B The Kaplan–Meier analyses of overall survival between patients with high and low expression of ENTPD3-AS1 in TCGA-KIRC, n = 527. C ENTPD3-AS1 expression in RCC tissues and adjacent normal tissues in Cohort 1. D The Kaplan–Meier analyses of overall survival between patients with high and low expression of ENTPD3-AS1 in Cohort 1, n = 105. E Clinical and pathological features between ENTPD3-AS1 high and low-expression groups in Cohort 1. The heatmap demonstrated the association of different characters with ENTPD3-AS1 expression. The χ2 test was used. F The AUC of overall survival for ENTPD3-AS1 expression, AJCC stage, and combined group in Cohort 1. G Multivariate cox regression analysis of ENTPD3-AS1 expression in Cohort 1.
Fig. 3 ENTPD3-AS1 was a protective lncRNA in RCC development. A ENTPD3-AS1 expression in the tumor and normal tissues in TCGA-KIRC. B The Kaplan–Meier analyses of overall survival between patients with high and low expression of ENTPD3-AS1 in TCGA-KIRC, n = 527. C ENTPD3-AS1 expression in RCC tissues and adjacent normal tissues in Cohort 1. D The Kaplan–Meier analyses of overall survival between patients with high and low expression of ENTPD3-AS1 in Cohort 1, n = 105. E Clinical and pathological features between ENTPD3-AS1 high and low-expression groups in Cohort 1. The heatmap demonstrated the association of different characters with ENTPD3-AS1 expression. The χ2 test was used. F The AUC of overall survival for ENTPD3-AS1 expression, AJCC stage, and combined group in Cohort 1. G Multivariate cox regression analysis of ENTPD3-AS1 expression in Cohort 1.CC BY · PubMed Central
Fig. 4 The in vitro functional assays of ENTPD3-AS1. A, B Cell proliferation was measured in 786-O and A498 cells after being transfected with ENTPD3-AS1 overexpression plasmid. C, D Colony formation was measured in 786-O and A498 cells after being transfected with ENTPD3-AS1 overexpression plasmid.
Fig. 4 The in vitro functional assays of ENTPD3-AS1. A, B Cell proliferation was measured in 786-O and A498 cells after being transfected with ENTPD3-AS1 overexpression plasmid. C, D Colony formation was measured in 786-O and A498 cells after being transfected with ENTPD3-AS1 overexpression plasmid.CC BY · PubMed Central
Fig. 5 ENTPD3-AS1 suppressed RCC development through miR-155-5p. A The predicted target of ENTPD3-AS1 in the ENCORI database. B The direct interaction between ENTPD3-AS1 and miR-155-5p was confirmed by luciferase reporter assay. C, D Overexpression of ENTPD3-AS1 decreased miR-155-5p expression in 786-O and A498 cells. E The correlation between ENTPD3-AS1 and miR-155-5p expression in TCGA-KIRC. F The correlation between ENTPD3-AS1 and miR-155-5p expression in Cohort 1. G The expression of miR-155-5p in RCC tissues and corresponding normal tissues in Cohort1. H The Kaplan–Meier analyses of overall survival between patients with high and low expression of miR-155-5p in Cohort 1. I Multivariate cox regression analysis of miR-155-5p expression in Cohort 1.
Fig. 5 ENTPD3-AS1 suppressed RCC development through miR-155-5p. A The predicted target of ENTPD3-AS1 in the ENCORI database. B The direct interaction between ENTPD3-AS1 and miR-155-5p was confirmed by luciferase reporter assay. C, D Overexpression of ENTPD3-AS1 decreased miR-155-5p expression in 786-O and A498 cells. E The correlation between ENTPD3-AS1 and miR-155-5p expression in TCGA-KIRC. F The correlation between ENTPD3-AS1 and miR-155-5p expression in Cohort 1. G The expression of miR-155-5p in RCC tissues and corresponding normal tissues in Cohort1. H The Kaplan–Meier analyses of overall survival between patients with high and low expression of miR-155-5p in Cohort 1. I Multivariate cox regression analysis of miR-155-5p expression in Cohort 1.CC BY · PubMed Central
Fig. 6 miR-155-5p promoted RCC development by regulating HIF-1α. A The potential target gene of miR-155-5p in TargetScanHuman database. B The direct interaction between miR-155-5p and HIF-1α by luciferase assays. C The expression of HIF-1α after overexpression of miR-155-5p. D The expression of HIF-1α after overexpression of ENTPD3-AS1. E, F Knockdown of HIF-1α rescued ENTPD3-AS1 overexpression inducing a decrease in cell proliferation. G SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling.
Fig. 6 miR-155-5p promoted RCC development by regulating HIF-1α. A The potential target gene of miR-155-5p in TargetScanHuman database. B The direct interaction between miR-155-5p and HIF-1α by luciferase assays. C The expression of HIF-1α after overexpression of miR-155-5p. D The expression of HIF-1α after overexpression of ENTPD3-AS1. E, F Knockdown of HIF-1α rescued ENTPD3-AS1 overexpression inducing a decrease in cell proliferation. G SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling.CC BY · PubMed Central

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Metadata

Authors
Wang, J., Zou, Y., Du, B., Li, W., Yu, G., Li, L., Zhou, L., Gu, X., Song, S., Liu, Y., Zhou, W., Xu, B., & Wang, Z.
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2021-07-03
Volume
12
Issue
7
ISSN
2041-4889
DOI
10.1038/s41419-021-03958-4
PMC
PMC8254807
Cited by
51
References
4
Language
en
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