bims-lorfki 2020-10-25 papers

bims-lorfki

Biomed News

on Long non-coding RNA functions in the kidney

Issue of 2020‒10‒25
eight papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

Long noncoding RNA SNHG4 promotes renal cell carcinoma tumorigenesis and invasion by acting as ceRNA to sponge miR-204-5p and upregulate RUNX2.
Long non-coding RNA LINC01234 regulates proliferation, migration and invasion via HIF-2α pathways in clear cell renal cell carcinoma cells.
Identification of Cooperative Gene Regulation Among Transcription Factors, LncRNAs, and MicroRNAs in Diabetic Nephropathy Progression.
Long Non-coding RNA CCAT1 Acts as an Oncogene and Promotes Sunitinib Resistance in Renal Cell Carcinoma.
Emerging role of long noncoding RNA-encoded micropeptides in cancer.
Arid2-IR promotes NF-κB-mediated renal inflammation by targeting NLRC5 transcription.
Long non-coding RNA expression profiles in neutrophils revealed potential biomarker for prediction of renal involvement in SLE patients.
LncRNA XIST promotes migration of Wilms' tumor cells through modulation of microRNA-193a-5p.

Cancer Cell Int. 2020 ;20 514

Long noncoding RNA SNHG4 promotes renal cell carcinoma tumorigenesis and invasion by acting as ceRNA to sponge miR-204-5p and upregulate RUNX2.

Jie Wu, Tingting Liu, Lulu Sun, Shaojin Zhang, Gang Dong.

  Background: Long noncoding RNAs (lncRNAs) are involved in the tumorigenesis and progression of human cancers, including renal cell carcinoma (RCC). Small nucleolar RNA host gene 4 (SNHG4) is reported to play an essential role in tumor growth and progression. However, the molecular mechanisms and function of SNHG4 in RCC remain undocumented.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to examine expression levels of SNHG4 in RCC tissue samples and cell lines. Cell counting kit-8, western blotting, activities of caspase-3, -8, and -9, wound-healing, and transwell invasion assays were performed to explore cell proliferation, apoptosis, migration, and invasion. The interaction among SNHG4, miR-204-5p, and RUNX2 was verified by bioinformatic analysis, a luciferase gene report, qRT-PCR, western blot analysis, and RNA immunoprecipitation assays. Xenograft mouse models were carried out to examine the role of SNHG4 in RCC in vivo.
Results: SNHG4 was highly expressed in RCC tissue samples and cell lines, and its upregulation was significantly involved in node involvement, distant metastasis, and reduced overall and relapse-free survival of patients with RCC. SNHG4 acted as an oncogenic lncRNA with promoted RCC cell proliferation, migration, invasion, and inhibited apoptosis. SNHG4 boosted tumor growth in xenograft mouse models. Mechanistically, SNHG4 functioned as a competing endogenous RNA (ceRNA) for sponging miR-204-5p, leading to the upregulation of its target RUNX2 to promote RCC cell proliferation and invasion.
Conclusion: SNHG4 and miR-204-5p might be indicated in RCC progression via RUNX2, suggesting the potential use of SNHG4/miR-204-5p/RUNX2 axis in RCC treatment.

Keywords:  RUNX2; Renal cell carcinoma; SNHG4; ceRNA; miR-204-5p

DOI:  https://doi.org/10.1186/s12935-020-01606-z
PeerJ. 2020 ;8 e10149

Long non-coding RNA LINC01234 regulates proliferation, migration and invasion via HIF-2α pathways in clear cell renal cell carcinoma cells.

Feilong Yang, Cheng Liu, Guojiang Zhao, Liyuan Ge, Yimeng Song, Zhigang Chen, Zhuo Liu, Kai Hong, Lulin Ma.

  Long non-coding RNAs (lncRNAs) have been proved to have an important role in different malignancies including clear cell renal cell carcinoma (ccRCC). However, their role in disease progression is still not clear. The objective of the study was to identify lncRNA-based prognostic biomarkers and further to investigate the role of one lncRNA LINC01234 in progression of ccRCC cells. We found that six adverse prognostic lncRNA biomarkers including LINC01234 were identified in ccRCC patients by bioinformatic analysis using The Cancer Genome Atlas database. LINC01234 knockdown impaired cell proliferation, migration and invasion in vitro as compared to negative control. Furthermore, the epithelial-mesenchymal transition was inhibited after LINC01234 knockdown. Additionally, LINC01234 knockdown impaired hypoxia-inducible factor-2a (HIF-2α) pathways, including a suppression of the expression of HIF-2α, vascular endothelial growth factor A, epidermal growth factor receptor, c-Myc, Cyclin D1 and MET. Together, these datas showed that LINC01234 was likely to regulate the progression of ccRCC by HIF-2α pathways, and LINC01234 was both a promising prognostic biomarker and a potential therapeutic target for ccRCC.

Keywords:  Bioinformatics; Cell Invasion; Cell migration; Cell proliferation; Clear cell renal cell carcinoma; EMT; HIF-2α pathways; LINC01234; lncRNA

DOI:  https://doi.org/10.7717/peerj.10149
Front Genet. 2020 ;11 1008

Identification of Cooperative Gene Regulation Among Transcription Factors, LncRNAs, and MicroRNAs in Diabetic Nephropathy Progression.

Ling Chen, Binbin Wu, Shaobin Wang, Yu Xiong, Boya Zhou, Xianyi Cheng, Tao Zhou, Ruibang Luo, Tak-Wah Lam, Bin Yan, Junhui Chen.

  The pathogenesis of diabetic nephropathy (DN) is accompanied by alterations in biological function and signaling pathways regulated through complex molecular mechanisms. A number of regulatory factors, including transcription factors (TFs) and non-coding RNAs (ncRNAs, including lncRNAs and miRNAs), have been implicated in DN; however, it is unclear how the interactions among these regulatory factors contribute to the development of DN pathogenesis. In this study, we developed a network-based analysis to decipher interplays between TFs and ncRNAs regulating progression of DN by combining omics data with regulatory factor-target information. To accomplish this, we identified differential expression programs of mRNAs and miRNAs during early DN (EDN) and established DN. We then uncovered putative interactive connections among miRNA-mRNA, lncRNA-miRNA, and lncRNA-mRNA implicated in transcriptional control. This led to the identification of two lncRNAs (MALAT1 and NEAT1) and the three TFs (NF-κB, NFE2L2, and PPARG) that likely cooperate with a set of miRNAs to modulate EDN and DN target genes. The results highlight how crosstalk among TFs, lncRNAs, and miRNAs regulate the expression of genes both transcriptionally and post-transcriptionally, and our findings provide new insights into the molecular basis and pathogenesis of progressive DN.

Keywords:  diabetic nephropathy; long non-coding RNAs; microRNAs; regulatory interactions; transcription factors

DOI:  https://doi.org/10.3389/fgene.2020.01008
Front Oncol. 2020 ;10 516552

Long Non-coding RNA CCAT1 Acts as an Oncogene and Promotes Sunitinib Resistance in Renal Cell Carcinoma.

Liping Shan, Wei Liu, Yunhong Zhan.

  Although sunitinib contributes to prolonging the progression-free survival of metastatic renal cell carcinoma significantly, the universal presence of resistance limits the initial response rate and restricts durable responses. The mechanisms involved in sunitinib resistance vary and need further investigation. We found long non-coding RNA (lncRNA) colon cancer-associated transcript-1 (CCAT1) overexpressed in sunitinib-resistant cells while declined in the parental cells. Moreover, lncRNA CCAT1 increased significantly in samples with resistance to sunitinib compared with those with responses to sunitinib. The reduction of CCAT1 suppressed cell growth and colony formation while triggering apoptosis. Inversely, the ectopic expression of c-Myc reversed the inhibition of cell growth and enhancement of apoptosis by the knockdown of CCAT1. We also verified that anti-apoptosis protein B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia 1 (Mcl-1) decreased along with the deregulation of CCAT1, whereas the expression of Bcl-2 and Mcl-1 restored in cells that were transfected sh-CCAT1 and c-Myc simultaneously. Apart from the in vitro experiments, we demonstrated that knockdown of CCAT1 boosted response to sunitinib by performing sunitinib-resistant ACHN mouse models. Briefly, lncRNA CCAT1 conferred renal cell carcinoma resistance to sunitinib in a c-Myc-dependent manner, providing a novel target for improvement of sunitinib therapy.

Keywords:  CCAT1; apoptosis; renal cell carcinoma; resistance; sunitinib

DOI:  https://doi.org/10.3389/fonc.2020.516552
Cancer Cell Int. 2020 ;20 506

Emerging role of long noncoding RNA-encoded micropeptides in cancer.

Mujie Ye, Jingjing Zhang, Meng Wei, Baihui Liu, Kuiran Dong.

  Increasing evidence has indicated that long noncoding RNAs (lncRNAs) play various important roles in the development of cancers. The widespread applications of ribosome profiling and ribosome nascent chain complex sequencing revealed that some short open reading frames of lncRNAs have micropeptide-coding potential. The resulting micropeptides have been shown to participate in N6-methyladenosine modification, tumor angiogenesis, cancer metabolism, and signal transduction. This review summarizes current information regarding the reported roles of lncRNA-encoded micropeptides in cancer, and explores the potential clinical value of these micropeptides in the development of anti-cancer drugs and prognostic tumor biomarkers.

Keywords:  Cancer; Coding potential; Micropeptide; Open reading frame; lncRNA

DOI:  https://doi.org/10.1186/s12935-020-01589-x
Cell Mol Life Sci. 2020 Oct 22.

Arid2-IR promotes NF-κB-mediated renal inflammation by targeting NLRC5 transcription.

Puhua Zhang, Chaolun Yu, Jianwen Yu, Zhijian Li, Hui-Yao Lan, Qin Zhou.

  Increasing evidence shows that long non-coding RNAs (lncRNAs) play an important role in a variety of disorders including kidney diseases. It is well recognized that inflammation is the initial step of kidney injury and is largely mediated by nuclear factor Kappa B (NF-κB) signaling. We had previously identified lncRNA-Arid2-IR is an inflammatory lncRNA associated with NF-κB-mediated renal injury. In this study, we examined the regulatory mechanism through which Arid2-IR activates NF-κB signaling. We found that Arid2-IR was differentially expressed in response to various kidney injuries and was induced by transforming growth factor beta 1(TGF-β1). Using RNA sequencing and luciferase assays, we found that Arid2-IR regulated the activity of NF-κB signal via NLRC5-dependent mechanism. Arid2-IR masked the promoter motifs of NLRC5 to inhibit its transcription. In addition, during inflammatory response, Filamin A (Flna) was increased and functioned to trap Arid2-IR in cytoplasm, thereby preventing its nuclear translocation and inhibition of NLRC5 transcription. Thus, lncRNA Arid2-IR mediates NF-κB-driven renal inflammation via a NLRC5-dependent mechanism and targeting Arid2-IR may be a novel therapeutic strategy for inflammatory diseases in general.

Keywords:  Arid2-IR; Flna; Inflammation; NF-κB; NLRC5

DOI:  https://doi.org/10.1007/s00018-020-03659-9
Rheumatology (Oxford). 2020 Oct 17. pii: keaa575. [Epub ahead of print]

Long non-coding RNA expression profiles in neutrophils revealed potential biomarker for prediction of renal involvement in SLE patients.

Bin Cai, Jingyi Cai, Zhihua Yin, Xiaoyue Jiang, Chao Yao, Jianyang Ma, Zhixin Xue, Ping Miao, Qingqing Xiao, Yijun Cheng, Jialin Qin, Qiang Guo, Nan Shen, Zhizhong Ye, Bo Qu, Huihua Ding.

  OBJECTIVE: The long non-coding RNA plays an important role in inflammation and autoimmune diseases. The aim of this study is to screen and identify abnormally expressed lncRNAs in peripheral blood neutrophils of SLE patients as novel biomarkers and to explore the relationship between lncRNAs levels and clinical features, disease activity and organ damage.METHODS: RNA-seq technology was used to screen differentially expressed lncRNAs in neutrophils from SLE patients and healthy donors. Based on the results of screening, candidate lncRNA levels in neutrophils of 88 SLE patients, 35 other connective disease controls, and 78 healthy controls were qualified by real-time quantitative polymerase chain reaction.
RESULTS: LncRNA expression profiling revealed 360 up-regulated lncRNAs and 224 down-regulated lncRNAs in neutrophils of SLE patients when compared with healthy controls. qPCR assay validated that the expression of Lnc-FOSB-1:1 was significantly decreased in neutrophils of SLE patients when compared with other CTD patients or healthy controls. It correlated negatively with SLE Disease Activity Index 2000 (SLEDAI-2K) score (r = -0.541, P < 0.001) and IFN scores (r = -0.337, P = 0.001). More importantly, decreased Lnc-FOSB-1:1 expression was associated with lupus nephritis. Lower baseline Lnc-FOSB-1:1 level was associated with higher risk of future renal involvement (within an average of 2.6 years) in patients without renal disease at baseline (P = 0.019).
CONCLUSION: LncRNA expression profile in neutrophils of SLE patients revealed differentially expressed lncRNAs. Validation study on Lnc-FOSB-1:1 suggest that it is a potential biomarker for prediction of near future renal involvement.

Keywords:  biomarkers; long non-coding RNA; lupus nephritis; systemic lupus erythematosus

DOI:  https://doi.org/10.1093/rheumatology/keaa575
Eur Rev Med Pharmacol Sci. 2020 Oct;pii: 23199. [Epub ahead of print]24(19): 9889-9898

LncRNA XIST promotes migration of Wilms' tumor cells through modulation of microRNA-193a-5p.

F-Z Yao, R He, Y-C Jiang, Y Hou, D Qian.

OBJECTIVE: The aim of this study was to investigate long non-coding RNA (lncRNA) XIST expression in Wilms' tumor (WT) and to further explore its relationship with clinical features and prognosis of WT patients.PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was carried out to examine the expression level of XIST in tumor tissue samples and paracancerous ones collected from 43 patients with renal cell carcinoma, and the interplay between XIST expression and clinical indicators, as well as prognosis of patients was analyzed. Meanwhile, XIST level in the nephroblast cancer cell line was further confirmed by qRT-PCR. In addition, XIST knockdown model was constructed using lentivirus in the WT cell lines, including HFWT and 17-94, and the influence of XIST on WT cell functions was analyzed through transwell assay. Finally, we investigated whether lncRNA XIST plays a role in the progression of WT by modulating microRNA-193a-5p.
RESULTS: In this research, qRT-PCR results revealed a significantly higher expression of lncRNA XIST in tumor tissue specimens of patients with renal cell carcinoma than that in adjacent ones. Compared with patients with low expression of lncRNA XIST, those with high XIST expression had a higher incidence of distant metastasis and a lower overall survival rate. Compared with the negative control group, the metastatic ability of WT cells in the lncRNA XIST knockdown group was markedly weakened. In addition, the results of qPCR showed that mRNA expression of lncRNA XIST and microRNA-193a-5p were negatively correlated in renal cell carcinoma tissue specimens. At the same time, silencing microRNA-193a-5p reversed the reduced metastasis ability of WT cells induced by knockdown of XIST.
CONCLUSIONS: LncRNA XIST expression is dramatically enhanced in WT tissues and cell lines, which is closely associated with the incidence of distant metastasis and patients' poor prognosis. In addition, we demonstrated that lncRNA XIST may accelerate the malignant progression of WT via inhibiting microRNA-193a-5p.

DOI: https://doi.org/10.26355/eurrev_202010_23199