bims-lorfki 2022-01-30 papers

Front Med (Lausanne). 2021 ;8 777507

Identification of a Three-Glycolysis-Related lncRNA Signature Correlated With Prognosis and Metastasis in Clear Cell Renal Cell Carcinoma.

Tinghao Li, Hang Tong, Junlong Zhu, Zijia Qin, Siwen Yin, Yan Sun, Xudong Liu, Weiyang He.

The clear cell renal cell carcinoma (ccRCC) is not only a malignant disease but also an energy metabolic disease, we aimed to identify a novel prognostic model based on glycolysis-related long non-coding RNA (lncRNAs) and explore its mechanisms. With the use of Pearson correlation analysis between the glycolysis-related differentially expressed genes and lncRNAs from The Cancer Genome Atlas (TCGA) dataset, we identified three glycolysis-related lncRNAs and successfully constructed a prognostic model based on their expression. The diagnostic efficacy and the clinically predictive capacity of the signature were evaluated by univariate and multivariate Cox analyses, Kaplan-Meier survival analysis, and principal component analysis (PCA). The glycolysis-related lncRNA signature was constructed based on the expressions of AC009084.1, AC156455.1, and LINC00342. Patients were grouped into high- or low-risk groups according to risk score demonstrated significant differences in overall survival (OS) period, which were validated by patients with ccRCC from the International Cancer Genome Consortium (ICGC) database. Univariate Cox analyses, multivariate Cox analyses, and constructed nomogram-confirmed risk score based on our signature were independent prognosis predictors. The CIBERSORT algorithms demonstrated significant correlations between three-glycolysis-related lncRNAs and the tumor microenvironment (TME) components. Functional enrichment analysis demonstrated potential pathways and processes correlated with the risk model. Clinical samples validated expression levels of three-glycolysis-related lncRNAs, and LINC00342 demonstrated the most significant aberrant expression. in vitro, the general overexpression of LINC00342 was detected in ccRCC cells. After silencing LINC00342, the aberrant glycolytic levels and migration abilities in 786-O cells were decreased significantly, which might be explained by suppressed Wnt/β-catenin signaling pathway and reversed Epithelial mesenchymal transformation (EMT) process. Collectively, our research identified a novel three-glycolysis-related lncRNA signature as a promising model for generating accurate prognoses for patients with ccRCC, and silencing lncRNA LINC00342 from the signature could partly inhibit the glycolysis level and migration of ccRCC cells.

Keywords: LINC00342; clear cell renal cell carcinoma; glycolysis; lncRNA; prognosis

DOI: https://doi.org/10.3389/fmed.2021.777507

J Cancer. 2022 ;13(2): 691-705

Role of Metabolic Reprogramming of Long non-coding RNA in Clear Cell Renal Cell Carcinoma.

Huijie Zhang, Lei Yu, Jing Chen, Liting Liu, Xudong Yang, Hongwei Cui, Genquan Yue.

Renal cell carcinoma (RCC), one of the most frequent cancers, is a "classical" malignancy characterized by metabolic reprogramming. Clear cell renal cell carcinoma (ccRCC) is its most common histopathological subtype. Long-stranded non-coding ribonucleic acids (LncRNAs) are regulatory RNA molecules with limited protein-coding capacity and evolutionary conservation. Recent studies have revealed that lncRNAs can broadly regulate the metabolic reprogramming of ccRCC and its malignant transformation. However, there are few studies on lncRNAs regulating the metabolism of ccRCC, and the specific mechanisms are unknown. Therefore, this paper summarizes the regulatory mechanisms of lncRNAs in the metabolism of ccRCC, especially in the pathways of glycolysis, mitochondrial function, glutamine and lipid metabolism, cellular mechanisms, interactions with other molecules, specific scientific and clinic implications and applications to provide a basis for early clinical diagnosis, prediction and treatment. We also discuss the clinical application and challenges of targeting lncRNAs in ccRCC metabolism.

Keywords: LncRNAs; metabolic reprogramming; renal clear cell carcinoma

DOI: https://doi.org/10.7150/jca.62683

Biochem Genet. 2022 Jan 27.

LncRNA NEAT2 Modulates Pyroptosis of Renal Tubular Cells Induced by High Glucose in Diabetic Nephropathy (DN) by via miR-206 Regulation.

Amal Ezzat Abd El-Lateef, Adel Galal Ahmed El-Shemi, Mona S Alhammady, Rucui Yuan, Yan Zhang.

Patients suffering from terminal-stage diabetic nephropathy (DN) are commonly diagnosed with kidney failure. The condition of DN patients gets generally improved by long-chain noncoding RNA (LncRNA) since it regulates microRNA (miR). The current study analyzes the role played by NEAT2/miR-206 upon cell death of renal tubular epithelial cells (RTECs), high glucose (HG)-induced inflammation and oxidative stress in diabetic nephropathy (DN). The researcher used high glucose (HG) to treat HK-2 cells in in vitro conditions to establish the DN cell model. qRT-PCR was used to confirm the transfection effect whereas the researcher also tested NEAT2, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing (NLRP3), caspase-1, interleukin IL-1β, gasdermin D (GSMDD)-N, and miR-206. To analyze the proteins in caspase-1, IL-1β, GSMDD-N, and NLRP3, Western blot technique was performed. The technique is also used to observe the pyroptosis. To identify TNF-α, IL-6, MCP-9, NEAT2, miR-206, and NLRP3, dual-luciferase reporter assay was conducted through ELISA kit to emphasize the correlation that exists among the above-mentioned factors. NEAT2 has been confirmed to have bound with miR-206 through double luciferase report experiments as well as RNA immunoprecipitation (RIP). NEAT2, present in HK-2 cells, was induced by HG. So, if NEAT2 is knocked down, it would mitigate TNF-α, IL-6, and MCP-9 as well. Among the HK-2 cells intervened with HG, the overexpressed miR-206 that was transfected into cells was in alignment with the modifications introduced in inflammatory factors and cytokines after NEAT2 is knocked down. The current study concludes that if NEAT2 is upregulated, it has the potential to retreat the inhibition of miR-206 on inflammatory response as well pyroptosis. Further, by targeting miR-206, NEAT2 has the potential to enhance HG-induced HK-2 pyroptosis. This miR-206 is predicted to be a latent target in the clinical treatment of DN.

Keywords: Diabetic nephropathy (DN); High glucose; NEAT2; Pyroptosis; Renal tubular cells; miR-206

DOI: https://doi.org/10.1007/s10528-021-10164-6

Immunobiology. 2022 Jan 11. pii: S0171-2985(22)00005-5. [Epub ahead of print]227(2): 152179

Effects of total glucosides of paeony on acute renal injury following ischemia-reperfusion via the lncRNA HCG18/miR-16-5p/Bcl-2 axis.

Wei Zhao, Yuan Zhang, Mingzhu Zhang, Yong Zhi, Xiaohan Li, Xuezheng Liu.

Renal ischemia-reperfusion injury (I/RI) has been classified as a detrimental health concern that always exacerbates acute kidney injury (AKI). Previously, total glucosides of paeony (TGP) have been reported to relieve AKI. This study sought to analyze the effect of TGP on AKI. The TCMSP database was used to predict the potential targets of TGP. Bilateral renal I/RI-induced AKI models and HK-2 cell hypoxia/reoxygenation (H/R) models were subsequently established. HLA complex group 18 (HCG18) expression was detected using RT-qPCR and overexpressed in the H/R cells, followed by the examination of cell viability, autophagosomes, and apoptosis. Subcellular localization of HCG18 was detected using the nuclear/cytosol fractionation assay. The binding relationships between HCG18 and miR-16-5p, and miR-16-5p and Bcl-2 were verified using a combination of dual-luciferase assay, RNA immunoprecipitation assay, and RNA pull-down. Serum creatinine (S-Cr), blood urea nitrogen (BUN), and KIM-1 contents in AKI mice were examined using ELISA, and the pathological modifications in renal tissue and apoptosis were assessed using hematoxylin and eosin staining and TUNEL staining. HCG18 was downregulated in the in vitro and in vivo models. Our findings denoted that TGP promoted HK-2 cell autophagy and proliferation and inhibited inflammation and apoptosis by upregulating HCG18, thus alleviating AKI. HCG18 was predominantly localized in the cytoplasm. HCG18 could competitively bind to miR-16-5p. Additionally, miR-16-5p overexpression reversed the stimulative effect of HCG18 on HK-2 cell autophagy. miR-16-5p targeted Bcl-2. Bcl-2 overexpression reversed the inhibitory effect of miR-16-5p on HK-2 cell autophagy. TGP treatment reduced the S-Cr, BUN, and KIM-1 contents, and alleviated renal tubular injury and apoptosis in I/RI mice by upregulating HCG18. Briefly, our study elicited that TGP inhibited miR-16-5p and promoted Bcl-2 by upregulating HCG18, thus promoting autophagy and alleviating AKI in I/RI mice.

Keywords: Acute kidney injury; Autophagy; Bcl-2; LncRNA HCG18; Renal ischemia–reperfusion injury; Total glucosides of paeony; ceRNA; miR-16-5p

DOI: https://doi.org/10.1016/j.imbio.2022.152179

Nat Rev Mol Cell Biol. 2022 Jan 25.

Mechanisms of lncRNA biogenesis as revealed by nascent transcriptomics.

Takayuki Nojima, Nick J Proudfoot.

Mammalian genomes express two principal gene categories through RNA polymerase II-mediated transcription: protein-coding transcription units and non-coding RNA transcription units. Non-coding RNAs are further divided into relatively abundant structural RNAs, such as small nuclear RNAs, and into a myriad of long non-coding RNAs (lncRNAs) of often low abundance and low stability. Although at least some lncRNA synthesis may reflect transcriptional 'noise', recent studies define unique functions for either specific lncRNAs or for the process of lncRNA synthesis. Notably, the transcription, processing and metabolism of lncRNAs are regulated differently from protein-coding genes. In this Review, we provide insight into the regulation of lncRNA transcription and processing gleaned from the application of recently devised nascent transcriptomics technology. We first compare and contrast different methodologies for studying nascent transcription. We then discuss the molecular mechanisms regulating lncRNA transcription, especially transcription initiation and termination, which emphasize fundamental differences in their expression as compared with protein-coding genes. When perturbed, lncRNA misregulation leads to genomic stress such as transcription-replication conflict and R-loop-mediated DNA damage. We discuss many unresolved but important questions about the synthesis and potential functions of lncRNAs.

DOI: https://doi.org/10.1038/s41580-021-00447-6