bims-lorfki 2020-09-27 papers

Issue of 2020‒09‒27
four papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

Front Oncol. 2020 ;10 1430

Long Non-Coding RNA Profile Study Identifies an Immune-Related lncRNA Prognostic Signature for Kidney Renal Clear Cell Carcinoma.

Zhuolun Sun, Changying Jing, Chutian Xiao, Tengcheng Li.

Kidney renal clear cell carcinoma (KIRC) is the predominant pathological subtype of renal cell carcinoma (RCC) in adults. Long non-coding RNAs (lncRNAs) are an important class of gene expression regulators and serve fundamental roles in immune regulation. The intent of this study is to develop a novel immune-related lncRNA signature to accurately predict the prognosis for KIRC patients. Here, we performed genome-wide comparative analysis of lncRNA expression profiles in 537 KIRC patients from The Cancer Genome Atlas (TCGA) database. Cox regression model-identified immune-related lncRNAs were extracted for constructing a novel five immune-related lncRNA signature (AC008105.3, LINC02084, AC243960.1, AC093278.2, and AC108449.2) with the ability to predict the prognosis of KIRC patients. Univariate and multivariate Cox regression analyses demonstrated that the signature could act as an independent prognostic predictor for overall survival (OS). With the further investigation on different clinicopathological parameters, we found that the signature could divide KIRC samples into high-risk groups with shorter OS and low-risk groups with longer OS in different subgroups. Principal component analysis suggested that the five immune-related lncRNA signature drew a clear distinction between high- and low-risk groups based on the immune-related lncRNAs. The different immune status between the two groups was observed in gene set enrichment analysis and the ESTIMATE algorithm. Except for AC093278.2, the expressions of the other four lncRNAs expression were significantly upregulated in tumor tissues. In summary, the identified immune-lncRNA signature had important clinical implications in prognosis prediction and could be exploited as underlying immune therapeutic targets for KIRC patients.

Keywords: immune; kidney renal clear cell carcinoma; long non-coding RNA; overall survival; prognostic signature

DOI: https://doi.org/10.3389/fonc.2020.01430

Ren Fail. 2020 Nov;42(1): 994-1003

Novel lncRNA XLOC_032768 protects against renal tubular epithelial cells apoptosis in renal ischemia-reperfusion injury by regulating FNDC3B/TGF-β1.

Xiangjun Zhou, Yongwei Li, Cheng Wu, Weimin Yu, Fan Cheng.

Renal ischemia-reperfusion injury is a leading cause of acute kidney injury, but its underlying mechanism remains poorly understood and effective therapies are still lacking. Here, we identified lncRNA XLOC_032768 as a novel target in renal ischemia-reperfusion injury by analyzing differentially expressed genes of the transcriptome data. PCR results show that XLOC_032768 was markedly downregulated in the kidney during renal ischemia-reperfusion in mice and in cultured kidney cells during hypoxia. Upon induction in vitro, XLOC_032768 overexpression repressed the expression of fibronectin type III domain containing 3B (FNDC3B) and tubular epithelial cells apoptosis. Administration of XLOC_032768 preserved FNDC3B expression and attenuated renal tubular epithelial cells apoptosis, resulting in protection against kidney injury in mice. Knockdown of FNDC3B markedly reduced the expression of TGF-β1 and apoptosis of renal tubular cells. Thus, XLOC_032768/FNDC3B/TGF-β1signaling pathway in ischemia-reperfusion injury may be targeted for therapy.

Keywords: Acute renal injury; cell death; hypoxia; ischemia-reperfusion; lncRNA

DOI: https://doi.org/10.1080/0886022X.2020.1818579

Eur Rev Med Pharmacol Sci. 2020 Sep;pii: 22814. [Epub ahead of print]24(17): 8756-8766

LncRNA FGD5-AS1/miR-5590-3p axis facilitates the proliferation and metastasis of renal cell carcinoma through ERK/AKT signalling.

Y Yang, M-H Dong, H-M Hu, Q-H Min, L Xiao.

OBJECTIVE: Amongst noncoding RNAs, competing endogenous RNAs (ceRNAs) are popular and interesting regulatory mechanisms involved in oncogenesis and tumour progression. LncRNA FGD5-AS1, also known as miR-5590-3p, is involved in the regulatory role of ceRNA in many cancers. However, the roles of lncRNA FGD5-AS1 or miR-5590-3p in renal cell carcinoma (RCC) remain unclear. We investigated how FGD5-AS1 and miR-5590-3p regulated clear cell proliferation and metastasis in RCC.PATIENTS AND METHODS: Real Time-quantitative PCR (RT-qPCR) was used to detect the expression of FGD5-AS1 in tumour issues and renal cancer cell lines. MTT, scratch test and transwell assay were performed to confirm the effect of FGD5-AS1 on the proliferation, migration or invasion of the above cell lines. RNA pull-down and Luciferase assays were used to detect the target site between FGD5-AS1 and miR-5590-3p. In addition, we examined the proteins related to ERK/AKT signalling related via Western blot analysis. Finally, we used the RT-qPCR method to detect the mRNA levels of E-cadherin and vimentin.
RESULTS: LncRNA FGD5-AS1 was highly expressed in renal cancer tissues, especially in patients with metastasis. This effect facilitated the proliferation, migration, epithelial-mesenchymal transition and invasion of renal cancer cells. Silencing the expression of FGD5-AS1 with FGD5-AS1 siRNA significantly inhibited the malignancy of tumour cells. RNA pull-down and Luciferase assays demonstrated that FGD5-AS1 targeted miR-5590-3p to interact with miR-5590-3p negatively. Furthermore, miR-5590-3p inhibitors could eliminate the FGD5-AS1 siRNA-induced upregulation of E-cadherin and downregulation of vimentin.
CONCLUSIONS: Mechanistically, lncRNA FGD5-AS1 can competitively interact with miR-5590-3p and regulate the downstream signalling of ErkAKT to enhance the malignancy of tumours. This lncRNA could become a potential target molecule for treating and diagnosing RCC.

DOI: https://doi.org/10.26355/eurrev_202009_22814

Biochem Biophys Res Commun. 2020 Sep 21. pii: S0006-291X(20)31775-7. [Epub ahead of print]

Ablation of lncRNA MIAT mitigates high glucose-stimulated inflammation and apoptosis of podocyte via miR-130a-3p/TLR4 signaling axis.

Min Zhang, Sumei Zhao, Chen Xu, Yang Shen, Jing Huang, Shen Shen, Yanchun Li, Xiangmei Chen.

Podocyte injury has been considered as a major contributor to the progression of diabetic nephropathy (DN). Long non-coding RNAs (lncRNAs) are being found to be involved in DN pathogenesis. The current research was designed to elucidate the potential role and latent molecular mechanism of long non-coding RNA MIAT in HG-induced podocyte injury. Our data demonstrated that MIAT expression was substantially elevated but miR-130a-3p was diminished in HG-challenged podocytes. Additionally, lack of MIAT mitigated HG-evoked inflammatory reaction in podocytes as evidenced by the diminished the release of inflammatory mediators TNF-α, IL-6 and IL-1β. Moreover, depletion of MIAT evidently amplified cell viability and alleviated HG-triggered apoptosis, reflected as the downregulation of Bax expression concomitant with the enhancement of Bcl-2 expression in HG-exposed podocytes. Mechanistically, MIAT effectively modulated TLR4 expression through acting as a competing endogenous sponge of miR-130a-3p, and TLR4 was confirmed as a specific target gene of miR-130a-3p. More importantly, the miR-130a-3p/TLR4 crosstalk contributed to the protective effect of MIAT knockdown on HG-provoked podocyte damage. Collectively, these findings highlighted that blocking MIAT/miR-130a-3p/TLR4 network play vital regulatory roles in mitigating HG-induced inflammation damage and apoptosis, thereby protecting podocyte from HG-stimulated injury, implying that MIAT might be a promising therapeutic strategy for developing effective treatments against DN progression.

Keywords: Apoptosis; Diabetic nephropathy (DN); Inflammation; LncRNA MIAT; miR-130a-3p/TLR4 signaling

DOI: https://doi.org/10.1016/j.bbrc.2020.09.034