bims-lorfki 2021-09-12 papers

Issue of 2021‒09‒12
four papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

Ren Fail. 2021 Dec;43(1): 1288-1297

LncRNA MALAT1-deficiency restrains lipopolysaccharide (LPS)-induced pyroptotic cell death and inflammation in HK-2 cells by releasing microRNA-135b-5p.

Jie Huang, Chen Xu.

Long non-coding RNAs (LncRNAs) participate in the regulation of chronic kidney disease (CKD), and acute kidney injury (AKI) is identified as an important risk factor for CKD. This study investigated the involvement of a novel LncRNA MALAT1 in regulating lipopolysaccharide (LPS)-induced cell pyroptosis and inflammation in the human renal tubular epithelial HK-2 cells. Here, the HK-2 cells were subjected to LPS (2 μg/mL) treatment to establish cellular AKI models in vitro, and we validated that LPS triggered NLRP3-mediated pyroptotic cell death, promoted cell apoptosis and inflammation-associated cytokines secretion to induce HK-2 cell injury. Then, a novel LncRNA MALAT1/miRNA (miRNA)-135b-5p axis was verified to rescue cell viability in LPS treated HK-2 cells by targeting NLRP3. Mechanistically, miRNA-135b-5p bound to LncRNA MALAT1, and LncRNA MALAT1 positively regulated NLRP3 through acting as RNA sponger for miRNA-135b-5p. Further gain- and loss-of-function experiments evidenced that both LncRNA MALAT1 ablation and miRNA-135b-5p overexpression reversed LPS-induced cell pyroptosis, apoptosis, and inflammation in the HK-2 cells, and the protective effects of LncRNA MALAT1 knock-down on LPS-treated HK-2 cells were abrogated by silencing miRNA-135b-5p. In general, our study firstly investigated the role of the LncRNA MALAT1/ miRNA-135b-5p/NLRP3 signaling cascade in regulating LPS-induced inflammatory death in HK-2 cells.

Keywords: Chronic kidney disease; LncRNA MALAT1; NLRP3-mediated cell pyroptosis; cell apoptosis; microRNA-135b-5p

DOI: https://doi.org/10.1080/0886022X.2021.1974037

Aging (Albany NY). 2021 Sep 08. 13(undefined):

LncRNA SNHG17 promotes tumor progression and predicts poor survival in human renal cell carcinoma via sponging miR-328-3p.

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

Accumulating data shows that dysregulation of long non-coding RNAs (lncRNAs) are involved in human tumors' occurrence and progression. Small nucleolar RNA host genes (SNHGs) are recently revealed to play a carcinogenic role in various human neoplasms. However, the functions and underlying mechanisms of lncRNA SNHG17 in renal cell carcinoma (RCC) are still elusive. We analyzed the relationship between SNHG17 expression levels and clinicopathologic characteristics and prognosis in patients with RCC according to TCGA RNA-sequencing data and our cohort data. Loss-of-function and gain-of-function experiments were conducted to examine the biological behaviors of SNHG17 on RCC cell proliferation, migration, invasion, apoptosis, and tumor growth in vivo. The interaction between SNHG17, miR-328-3p, and Histone'sH2Avariant (H2AX) was verified by bioinformatics, dual-luciferase reporter gene, and RNA immunoprecipitation (RIP). Highly expressed SNHG17 was evident in RCC tissue samples and cell lines, and SNHG17 overexpression was related to advanced TNM stage and reduced relapse-free and overall survival of patients with RCC. Knockdown of SNHG17 prohibited malignant phenotypes, whereas ectopic SNHG17 expression showed the opposite effects. More importantly, SNHG17 could upregulate the expression of H2AX by acting as a miR-328-3p sponge. In vivo experiments confirmed that SNHG17 promoted the growth of RCC tumors. SNHG17/miR-328-3p/H2AXaxis might be involved in RCC progression, which provided a potential therapeutic target for RCC.

Keywords: H2AX; SNHG17; miR-328-3p; renal cell carcinoma

DOI: https://doi.org/10.18632/aging.203440

Am J Physiol Renal Physiol. 2021 09 06.

LncRNA GAS5 protects against TGF-β-induced renal fibrosis via the Smad3/miRNA-142-5p axis.

Yingying Zhang, Rui-Zhi Tan, Ying Yu, Yangyang Niu, Chen Yu.

Increasing evidence shows that long noncoding RNAs (lncRNAs) play an important role in kidney disease. In this study, we investigated the role of lncRNA growth arrest-specific 5 (GAS5) in the pathogenesis of renal fibrosis. We found that GAS5 was markedly decreased in the fibrotic kidney of a unilateral ureteral obstructive (UUO) nephropathy mouse model by using real-time PCR. In addition, GAS5 was expressed in mouse tubular epithelial cells (mTECs) and interstitial fibroblasts in normal renal tissue and was especially highly expressed in the cytoplasm. In vitro experiments showed that GAS5 was downregulated by TGF-b1 in a dose- and time-dependent manner. Overexpression of GAS5 blocked TGF-b1-induced collagen I and fibronectin expression and vice versa. Mechanistic studies revealed that Smad3 but not Smad2 drove the regulation of GAS5. More importantly, GAS5 interacted with miR-142-5p and was involved in the renoprotective effect by participating in the competing endogenous RNA (ceRNA) network. Finally, we also found that knockdown of GAS5 promoted TGF-β1-induced mTEC apoptosis via the Smad3 pathway. Taken together, our results have uncovered a lncRNA/miRNA ceRNA network-based mechanism that modulates extracellular matrix formation and cell apoptosis via the Smad3 pathway.

Keywords: extracellular matrix; long noncoding RNA; ompeting endogenous RNA; renal fibrosis

DOI: https://doi.org/10.1152/ajprenal.00085.2021

Bioengineered. 2021 Dec;12(1): 6275-6285

A novel long non-coding RNA-based prognostic signature for renal cell carcinoma patients with stage IV and histological grade G4.

Ning Li, Haiying Zhang, Keyao Hu, Jianfeng Chu.

This study aimed to establish a lncRNA-based signature for predicting the prognosis of patients with high stage and grade renal cell carcinoma (RCC). According to the Surveillance, Epidemiology, and End Results (SEER) database, sex, age, grade, stage, surgery, chemotherapy, radiation, tumor size, and marital status were the independent prognostic factors for RCC and also had significant correlations with the overall survival through Cox univariate and multivariate analyses. Noticeably, among these influencing factors, the histological classification of undifferentiated group and pathological stage IV had the greatest prognostic risks for RCC patients. Furthermore, based on the samples at stage IV and histological grade G4 from The Cancer Genome Atlas (TCGA) portal, 9 key lncRNAs, including KIAA2012, CCNT2-AS1, ITPKB-AS1, TBX2-AS1, NUTM2A-AS1, LINC02522, LINC02384, LINC01559, and LINC00865 were identified and a prognostic signature was constructed by Lasso analysis and Cox regression model. The Kaplan-Meier analysis suggested that patients at stage IV and histological grade of G4 in high risk score group had a worse overall survival than that in low risk score group. The following receiver operating characteristic curve (ROC) curves also showed that this signature possesses a better predictive power performance. Pathway enrichment analysis discovered that 9 lncRNAs held potential roles in cell division, cell cycle, DNA damage and cytokines levels in RCC. This work indicates that the established 9-lncRNA signature has a good capacity in predicting the prognosis of RCC patients with stage IV and histological grade of G4, and may be helpful for guiding the treatment strategies for RCC patients.

Keywords: RCC; lncRNA signature; prognosis; survival

DOI: https://doi.org/10.1080/21655979.2021.1971022