bims-lorfki Biomed News
on Long non-coding RNA functions in the kidney
Issue of 2021‒08‒29
nine papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

  1. Kaohsiung J Med Sci. 2021 Aug 25.
      Sepsis is characterized by a severe inflammatory response throughout the whole body and can induce acute kidney injury (AKI). This research aimed to investigate the regulatory mechanisms underlying miR-155-5p in sepsis-induced AKI. CLP-treated mice were used as an in vivo model of sepsis-induced AKI, and LPS-treated HK-2 and TCMK-1 cells were used as in vitro models. Bioinformatics analyses and mechanistic assays were utilized to reveal the relationships between molecules. H&E staining was used to reveal morphological changes in kidney tissues. ELISAs were conducted to detect the concentrations of proinflammatory cytokines. We discovered that miR-155-5p was prominently upregulated in sepsis-induced AKI in vivo and in vitro. MiR-155-5p inhibition alleviated kidney injury in mice. Moreover, WWC1 served as a direct target of miR-155-5p and was negatively regulated by miR-155-5p. WWC1 upregulation inhibited the productions of inflammatory cytokines and suppressed apoptosis in vivo and in vitro. In addition, rescue assays demonstrated that WWC1 knockdown counteracted the inhibitory effect of anti-miR-155-5p on inflammation and apoptosis. Moreover, miR-155-5p could bind to XIST. XIST expression was downregulated in LPS-stimulated HK-2 and TCMK-1 cells. XIST could negatively regulate miR-155-5p expression and positively regulate WWC1 expression. Rescue assays revealed that miR-155-5p overexpression significantly reversed the suppressive effects of XIST upregulation on inflammation and apoptosis. In conclusion, our study revealed that the XIST/miR-155-5p/WWC1 axis modulated sepsis-induced AKI progression, providing promising insight into therapeutic targets for sepsis-induced AKI.
    Keywords:  WWC1; XIST; miR-155-5p; sepsis-induced AKI
  2. Diabetol Metab Syndr. 2021 Aug 26. 13(1): 89
      BACKGROUND: Diabetic nephropathy (DN) is a common complication of diabetes. Long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2) is reported to exert a protective role in DN by a previous study. The working mechanism underlying the protective role of CASC2 in DN progression was further explored in this study.METHODS: The expression of CASC2 and microRNA-135a-5p (miR-135a-5p) was determined by real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation ability was assessed by Cell Counting Kit-8 (CCK8) assay and 5-ethynyl-29-deoxyuridine (EDU) assay. Enzyme-linked immunosorbent assay (ELISA) was conducted to analyze the production of inflammatory cytokines in the supernatant. Western blot assay was performed to analyze protein expression. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to verify the target relationship between miR-135a-5p and CASC2 or tissue inhibitors of metalloproteinase 3 (TIMP3).
    RESULTS: High glucose (HG) treatment reduced the expression of CASC2 in human glomerular mesangial cells (HMCs) in a time-dependent manner. CASC2 overexpression suppressed HG-induced proliferation, inflammation and fibrosis in HMCs. miR-135a-5p was validated as a target of CASC2, and CASC2 restrained HG-induced influences in HMCs partly by down-regulating miR-135a-5p. miR-135a-5p bound to the 3' untranslated region (3'UTR) of TIMP3, and CASC2 positively regulated TIMP3 expression by sponging miR-135a-5p in HMCs. miR-135a-5p silencing inhibited HG-induced effects in HMCs partly by up-regulating its target TIMP3. CASC2 overexpression suppressed HG-induced activation of Jun N-terminal Kinase (JNK) signaling partly through mediating miR-135a-5p/TIMP3 signaling.
    CONCLUSIONS: In conclusion, CASC2 alleviated proliferation, inflammation and fibrosis in DN cell model by sponging miR-135a-5p to induce TIMP3 expression.
    Keywords:  CASC2; Diabetic nephropathy; High glucose; TIMP3; miR-135a-5p
  3. Int J Mol Sci. 2021 Aug 17. pii: 8846. [Epub ahead of print]22(16):
      Renal cell carcinomas (RCC) account for 2-3% of the global cancer burden and are characterized by the highest mortality rate among all genitourinary cancers. However, excluding conventional imagining approaches, there are no reliable diagnostic and prognostic tools available for clinical use at present. Liquid biopsies, such as urine, serum, and plasma, contain a significant amount of tumor-derived nucleic acids, which may serve as non-invasive biomarkers that are particularly useful for early cancer detection, follow-up, and personalization of treatment. Changes in epigenetic phenomena, such as DNA methylation level, expression of microRNAs (miRNAs), and long noncoding RNAs (lncRNAs), are observed early during cancer development and are easily detectable in biofluids when morphological changes are still undetermined by conventional diagnostic tools. Here, we reviewed recent advances made in the development of liquid biopsy-derived DNA methylation-, miRNAs- and lncRNAs-based biomarkers for RCC, with an emphasis on the performance characteristics. In the last two decades, a mass of circulating epigenetic biomarkers of RCC were suggested, however, most of the studies done thus far analyzed biomarkers selected from the literature, used relatively miniature, local, and heterogeneous cohorts, and suffered from a lack of sufficient validations. In summary, for improved translation into the clinical setting, there is considerable demand for the validation of the existing pool of RCC biomarkers and the discovery of novel ones with better performance and clinical utility.
    Keywords:  DNA methylation; epigenetic alterations; liquid biopsy; lncRNAs; miRNAs; non-invasive detection; renal cell carcinoma
  4. Cancer Manag Res. 2021 ;13 6489-6497
      Purpose: Long noncoding RNAs have been studied more and more as potential prognostic markers. However, the prognostic of LINC00460 in clear cell renal cell carcinoma (ccRCC) has not been explored. In this study, the potential role of LINC00460 was investigated in ccRCC.Patients and Methods: One hundred thirteen pairs of ccRCC tissues and para-normal tissues were collected. The expressions of LINC00460 in these tissues and ccRCC cells were evaluated via qRT-PCR. The prognostic value of LINC00460 was accessed with the use of Kaplan-Meier analysis and Cox proportional hazards model analysis. The influence of LINC00460 on ccRCC cell proliferation, migration, and invasion was determined via cell counting kit-8 (CCK-8) and Transwell assays.
    Results: The results revealed that LINC00460 was significantly enhanced in ccRCC tissues, as well as in ccRCC cell lines. The overexpression of LINC00460 was significantly associated with lymph node metastasis and TNM stage, and lead to poor overall survival. Knockdown of LINC00460 reduces the cell ability of proliferation, migration, and invasion. LINC00460 could sponge to miR-149-5p.
    Conclusion: LINC00460 may be developed as a prognostic biomarker and molecular therapy target for ccRCC.
    Keywords:  LINC00460; clear cell renal cell carcinoma; miR-149-5p; prognosis
  5. Immun Inflamm Dis. 2021 Aug 25.
      BACKGROUND: Patients with advanced clear cell renal cell carcinoma (ccRCC) have a poor prognosis and lack effective prognostic biomarkers. N6-methyladenosine-related lncRNAs (m6A-related long noncoding RNAs [lncRNAs]) have been confirmed to be associated with the development of multiple tumors, but its role in ccRCC is not clear.METHODS: Gene expression data and clinical information of ccRCC patients were extracted from The Cancer Genome Atlas Database. The prognostic m6A-related lncRNAs were obtained by Pearson's correlation analysis and univariate Cox regression analysis. Afterward, the cluster classification and its correlation with prognosis, clinical characteristics, and immunity were analyzed. LASSO regression was used to establish the prognostic risk model. The predictive performance of the prognostic model was evaluated and validated by survival analysis and receiver operating characteristic curve analysis, et al. The expression of immune checkpoints and immune cell infiltration in patients with different risks were systematically analyzed.
    RESULTS: A total of 27 prognostic m6A-related lncRNAs were identified. These m6A-related lncRNAs were differentially expressed between tumor and normal tissues. Among them, 24 high-risk m6A-related lncRNAs were overexpressed in Cluster 2 and correlated with poor prognosis, low stromal score, high expression of immune checkpoints, and immunosuppressive cells infiltration. Based upon, a prognostic risk model composed of seven m6A-related lncRNAs was constructed. After a series of analyses, it was proved that this model had good sensitivity and specificity, and could predict the prognosis of patients with different clinical stratification. The expression of PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, and TIGIT were significantly increased in the high-risk patients, and there was a correlation between the risk score and immune cell infiltration.
    CONCLUSIONS: The seven m6A-related lncRNAs prognostic risk signature showed reliable prognostic predictive power for ccRCC and was associated with the expression of immune checkpoints and immune cell infiltration. This seven m6A-related lncRNAs signature will be helpful in managing ccRCC and guiding individualized immunotherapy.
    Keywords:  N6-methyladenosine; clear cell renal cell carcinoma; immune cell infiltration; immune checkpoint; long noncoding RNA; prognosis
  6. BMC Nephrol. 2021 Aug 24. 22(1): 288
      OBJECTIVE: Long noncoding RNA (lncRNA) taurine upregulated gene 1 (TUG1) is increased under the condition of ischemia. This study intended to identify the mechanism of TUG1 in renal ischemia-reperfusion (I/R).METHODS: First, a rat model of acute renal injury induced by I/R was established, followed by the measurement of blood urea nitrogen (BUN), serum creatine (SCr), methylenedioxyphetamine (MDA) and superoxide dismutase (SOD) in the serum of rats. TUG1 was knocked down in I/R rats (ko-TUG1 group). Next, histological staining was used to evaluate the pathological damage and apoptosis of rat kidney. Western blot analysis was used to detect the levels of apoptosis- and autophagy-related proteins and transmission electron microscope was used to observe autophagosomes. Autophagy and apoptosis were evaluated after inhibition of the autophagy pathway using the inhibitor 3-MA. The targeting relation among TUG1, microRNA (miR)-29 and phosphatase and tensin homolog (PTEN) were validated. Lastly, the effects of TUG1 on biological behaviors of renal tubular cells were evaluated in vitro.
    RESULTS: In vivo, the levels of BUN, SCr and MDA in the serum of I/R-treated rats were increased while SOD level and autophagosomes were reduced, tubule epithelial cells were necrotic, and TUG1 was upregulated in renal tissues of I/R-treated rats, which were all reversed in rats in the ko-TUG1 group. Autophagy inhibition (ko-TUG1 + 3-MA group) averted the protective effect of TUG1 knockdown on I/R-treated rats. TUG1 could competitively bind to miR-29 to promote PTEN expression. In vitro, silencing TUG1 (sh-TUG1 group) promoted viability and autophagy of renal tubular cells and inhibited apoptosis.
    CONCLUSIONS: LncRNA TUG can promote PTEN expression by competitively binding to miR-29 to promote autophagy and inhibited apoptosis, thus aggravating acute renal injury in I/R-treated rats.
    Keywords:  Apoptosis; Autophagy; Long noncoding RNA TUG1; PTEN; Renal ischemia-reperfusion; mcroRNA-29
  7. Oncol Lett. 2021 Oct;22(4): 727
      The role of GAS6 antisense RNA 1 (GAS6-AS1) in clear cell renal cell carcinoma (ccRCC) remains unclear. The aim of the present study was to investigate the role and molecular mechanisms of GAS6-AS1 in the progression of ccRCC. GAS6-AS1 was found to be upregulated in ccRCC tissues and cell lines, and patients with high GAS6-AS1 expression levels exhibited a poor prognosis. Small interfering (si)RNA GAS6-AS1 inhibited the activity, colony formation, invasiveness and glycolysis of OSRC-2 and SW839 cells, while GAS6-AS1 overexpression promoted these functions. Moreover, si-GAS6-AS1 increased the phosphorylation level of AMP-activated protein kinase (AMPK) and decreased that of mTOR, as well as decreasing proliferating cell nuclear antigen (PCNA), MMP-2 and hexokinase-2 (HK2) expression, which were reversed by inhibiting AMPK or mTOR. In addition, the silencing of GAS6-AS1 suppressed the growth of xenografted tumors and attenuated the expression of PCNA, MMP-2 and HK2 in tumor tissues. These findings conclude that GAS6-AS1 regulated the proliferation, invasiveness and glycolysis of ccRCC cells by regulating the AMPK/mTOR signaling pathway, and suggest that GAS6-AS1 may be a potential therapeutic target for ccRCC.
    Keywords:  AMP-activated protein kinase/mTOR signaling pathway; GAS6 antisense RNA 1; clear cell renal cell carcinoma; glycolysis; proliferation
  8. Int J Mol Sci. 2021 Aug 06. pii: 8477. [Epub ahead of print]22(16):
      The amount of human long noncoding RNA (lncRNA) genes is comparable to protein-coding; however, only a small number of lncRNAs are functionally annotated. Previously, it was shown that lncRNAs can participate in many key cellular processes, including regulation of gene expression at transcriptional and post-transcriptional levels. The lncRNA genes can contain small open reading frames (sORFs), and recent studies demonstrated that some of the resulting short proteins could play an important biological role. In the present study, we investigate the widely expressed lncRNA LINC00493. We determine the structure of the LINC00493 transcript, its cell localization and influence on cell physiology. Our data demonstrate that LINC00493 has an influence on cell viability in a cell-type-specific manner. Furthermore, it was recently shown that LINC00493 has a sORF that is translated into small protein SMIM26. The results of our knockdown and overexpression experiments suggest that both LINC00493/SMIM26 transcript and protein affect cell viability, but in the opposite manner.
    Keywords:  LINC00493; MTT; SMIM26; lncRNA; long noncoding RNA; sORF; wound healing
  9. Thorac Cancer. 2021 Aug 28.
      BACKGROUND: GPRIN1 may be a novel tumor regulator, but its role and mechanism in tumors are still unclear.METHODS: First, a pan-cancer correlation analysis was conducted on the expression and prognosis of GPRIN1 based on the data downloaded from The Cancer Genome Atlas (TCGA) database. Second, the Starbase database was used to predict the upstream miRNAs and lncRNAs of GPRIN1, and the expression analysis, survival analysis, and correlation analysis were performed to screen the microRNA (miRNAs)/long non-coding RNAs (lncRNAs) that had a correlation with kidney renal papillary cell carcinoma (KIRP) or lung adenocarcinoma (LUAD). Third, the CIBERSORT algorithm was employed to calculate the proportion of various types of immune cells, and then the R packages were used for evaluating the relation between GPRIN1 expression and tumor immune cell infiltration as well as between GPRIN1 and the immune cell biomarker. Finally, the correlation analysis was made on GPRIN1 and immune checkpoints (CD274, CTLA4, and PDCD1).
    RESULTS: The pan-cancer analysis suggested that GPRIN1 was up-expressed in KIRP and LUAD, and it correlated with poor prognosis. LINC00894/MMP25-AS1/SNHG1/LINC02298/MIR193BHG-miR-140-3p was likely to be the most promising upstream regulation pathway of GPRIN1. Upexpression of LINC00894/MMP25-AS1/SNHG1/LINC02298/MIR193BHG and downexpression of miR-140-3p were found relevant with poor outcomes of KIRP and LUAD. GPRIN1 expression was significantly correlated with tumor immune cell infiltration, immune cell biomarkers, and immune checkpoints.
    CONCLUSIONS: The competitive endogenous (ceRNA) of miR-140-3p-GPRIN1 axis and its upstream lncRNAs are closely related to KIRP and LUAD, and might affect the prognosis and therapeutic effect of KIRP and LUAD.
    Keywords:  GPRIN1; Kidney renal papillary cell carcinoma; Lung adenocarcinoma; competing endogenous RNAs; miR-140-3p