bims-lorfki 2021-10-17 papers

Issue of 2021‒10‒17
six papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

Bioengineered. 2021 Oct 13.

The long non-coding RNA NNT-AS1 promotes clear cell renal cell carcinoma progression via regulation of the miR-137/ Y-box binding protein 1 axis.

Yadi Zhou, Zhenghao Zhang, Mingyi Wo, Wenfang Xu.

Long noncoding RNAs (LncRNAs) have been implicated in the progression of malignant tumors, including in clear cell renal cell carcinoma (ccRCC). However, the function and the specific mechanism of the lncRNA nicotinamide nucleotide transhydrogenase antisense RNA 1 (NNT-AS1) in ccRCC remains unknown. Thus, this study explored the role of NNT-AS1 in ccRCC. We evaluated NNT-AS1 expression in ccRCC specimens. Next, CCK-8 and Transwell assays were used to evaluate cell proliferation and metastatic abilities. The interaction between miR-137 and NNT-AS1 or Y-box binding protein 1 (YBX-1) was confirmed using a dual luciferase reporter assay. The results showed that NNT-AS1 was significantly upregulated in ccRCC specimens compared with normal tissues. Inhibition of NNT-AS1 restrained ccRCC proliferation and metastasis. Mechanistically, NNT-AS1 acted as a competitive endogenous RNA to sponge miR-137, which depressed ccRCC cells proliferation and metastasis. Moreover, with the use of bioinformatics analysis, the famous oncogene YBX-1 was selected as the potential target of miR-137. Luciferase assay also confirmed the interaction between miR-137 and YBX-1. Further functional studies demonstrated that that the inhibition effect of NNT-AS1 knockdown on ccRCC carcinogenesis could be partially reversed by overexpression of YBX-1, suggesting that NNT-AS1 promotes ccRCC progression through the miR-137/YBX-1 pathway. In summary, those findings indicate that NNT-AS1 promotes ccRCC progression via the miR-137/YBX-1 pathway, which may provide a promising therapeutic target for renal cell carcinoma.

Keywords: NNT-AS1; YBX-1; clear cell renal cell carcinoma; miR-137

DOI: https://doi.org/10.1080/21655979.2021.1992330

Front Med (Lausanne). 2021 ;8 719980

LncRNA SPANXA2-OT1 Participates in the Occurrence and Development of EMT in Calcium Oxalate Crystal-Induced Kidney Injury by Adsorbing miR-204 and Up-Regulating Smad5.

Haiyan Hu, Jie Zhang, Yinhui Li, Jiarong Ding, Wei Chen, Zhiyong Guo.

Objective: To explore the regulatory mechanism of long non-coding RNAs (lncRNAs) in the occurrence and development of epithelial-mesenchymal transition (EMT) in calcium oxalate crystal-induced kidney injury. Materials and Methods: Gene core technique was used to screen differentially expressed lncRNAs and mRNAs in HK-2 cells before and after calcium oxalate monohydrate (COM) stimulation; differentially expressed mRNAs were then analyzed using GO and pathway analysis. The role of target lncRNA in EMT in renal tubular epithelial cells induced by COM was further investigated by applying a series of in vitro experiments. Results: Four differentially expressed lncRNAs (ABCA9-AS1, SPANXA2-OT1, RP11-955H22.1, and RP11-748C4.1) were up-regulated after 48 h of COM stimulation compared to the control group, where up-regulated expression of lncRNA SPANXA2-OT1 was the most significant. Thus, lncRNA SPANXA2-OT1 was further examined. Interference lncRNA SPANXA2-OT1 reversed the down-regulation of E-cadherin and Pan-ck, and up-regulated Vimentin and α-SMA induced by COM stimulation. The application of miR204 inhibitor weakened the interference effect of interfering RNA on lncRNA SPANXA2-OT1 and promoted the occurrence of EMT. Moreover, the miR204 simulator alleviated the overexpression effect of lncRNA SPANXA2-OT1 on COM-stimulated renal tubular epithelial cells and inhibited the occurrence of EMT in renal tubular epithelial cells. Also, a dual-luciferase reporter assay showed that miR-204 could bind to lncRNA SPANXA2-OT1 and Smad5, while lncRNA SPANXA2-OT1 could inhibit cell proliferation and promote cell apoptosis. Conclusion: The lncRNA SPANXA2-OT1 is involved in the occurrence and development of EMT in renal tubular epithelial cells induced by crystalline kidney injury by adsorbing miR-204 and up-regulating Smad5.

Keywords: Smad5; crystalline kidney injury; epithelial-mesenchymal trans-differentiation; lncRNA SPANXA2-OT1; miR-204

DOI: https://doi.org/10.3389/fmed.2021.719980

Diabetol Metab Syndr. 2021 Oct 15. 13(1): 108

LncRNA KCNQ1OT1 promotes the development of diabetic nephropathy by regulating miR-93-5p/ROCK2 axis.

Li Zhao, Huaqian Chen, Lin Wu, Zhengdong Li, Ren Zhang, Yan Zeng, Tao Yang, Hualing Ruan.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been reported to play vital roles in diabetic nephropathy (DN). The aim of this study was to explore the function of mechanism of lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) in DN.METHODS: DN cell models were established using high glucose (HG) treatment in human glomerular mesangial cells (HGMC) and human renal glomerular endothelial cells (HRGEC). The expression levels of KCNQ1OT1, microRNA-93-5p (miR-93-5p), and Rho associated coiled-coil containing protein kinase 2 (ROCK2) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK-8) assay and flow cytometry were used to detect cell proliferation and apoptosis, respectively. ROCK2 and apoptosis/fibrosis-related protein levels were examined by western blot. The predicted interaction between miR-93-5p and KCNQ1OT1 or ROCK2 was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay.
RESULTS: KCNQ1OT1 was upregulated in DN patients and DN cell models. KCNQ1OT1 knockdown inhibited cell proliferation and fibrosis and induced apoptosis in DN cell models. MiR-93-5p was a direct target of KCNQ1OT1, and miR-93-5p inhibition restored the KCNQ1OT1 knockdown-mediated effects on cell proliferation, fibrosis and apoptosis in DN cell models. In addition, ROCK2 was identified as a target of miR-93-5p, and miR-93-5p overexpression suppressed cell proliferation and fibrosis and accelerated apoptosis by targeting ROCK2 in DN cell models. Moreover, KCNQ1OT1 regulated ROCK2 expression by binding to miR-93-5p.
CONCLUSION: KCNQ1OT1 knockdown inhibited cell proliferation and fibrosis and induced apoptosis in DN by regulating miR-93-5p/ROCK2 axis, providing potential value for the treatment of DN.

Keywords: Diabetic nephropathy; KCNQ1OT1; ROCK2; miR-93-5p

DOI: https://doi.org/10.1186/s13098-021-00726-4

Cancer Lett. 2021 Oct 07. pii: S0304-3835(21)00513-9. [Epub ahead of print]523 121-134

Circular RNA circSNX6 promotes sunitinib resistance in renal cell carcinoma through the miR-1184/GPCPD1/ lysophosphatidic acid axis.

Kang-Bo Huang, Yi-Hui Pan, Guan-Nan Shu, Hao-Hua Yao, Xi Liu, Mi Zhou, Jin-Huan Wei, Zhen-Hua Chen, Jun Lu, Zi-Hao Feng, Wei Chen, Hui Han, Zhou-San Zheng, Jun-Hang Luo, Jia-Xing Zhang.

Sunitinib resistance is a major challenge in systemic therapy for renal cell carcinoma (RCC). The role of circular RNAs (circRNAs) in regulating sunitinib resistance of RCC is largely unknown. We established sunitinib-resistant RCC cell lines in vivo. Through RNA-sequencing, we identified circSNX6, whose expression is upregulated in sunitinib-resistant cells compared with their parental cells. High circSNX6 expression was correlated with sunitinib resistance and worse oncologic outcomes in a cohort of 81 RCC patients. In vitro and in vivo experiments confirmed that circSNX6 could promote sunitinib resistance in RCC. circSNX6 acts as a molecular "sponge" to relieve the suppressive effect of microRNA (miR)-1184 on its target gene, glycerophosphocholine phosphodiesterase 1 (GPCPD1), which increases intracellular lysophosphatidic acid (LPA) levels and, ultimately, promotes sunitinib resistance in RCC cells. Our findings demonstrated that the circSNX6/miR-1184/GPCPD1 axis had a critical role in regulation of intracellular LPA levels and sunitinib resistance in RCC; they also provide a novel prognostic indicator and promising therapeutic targets.

Keywords: GPCPD1; Renal cell carcinoma; Sunitinib resistance; circSNX6; miR-1184

DOI: https://doi.org/10.1016/j.canlet.2021.10.003

Acta Biochim Pol. 2021 Oct 14.

LncRNA Hoxb3os protects podocytes from high glucose-induced cell injury through autophagy dependent on the Akt-mTOR signaling pathway.

Juan Jin, Jianguang Gong, Li Zhao, Yiwen Li, Qiang He.

BACKGROUND: Diabetic nephropathy (DN) is in the first place of the causes that lead to end-stage renal disease in the world. Thus, it is urgent to develop a novel diagnostic or therapeutic strategy that could stop the progression of diabetic nephropathy.METHODS: RNA-sequencing was conducted in high glucose (HG)-treated MPC5 cells (podocytes). Cell morphology was examined under a light microscope. Upon high-glucose challenge, the effects of lncRNA Hoxb3os overexpression on MPC5 cells apoptosis, viability, autophagy and Akt-mTOR signaling were evaluated using flow cytometry, Cell Counting Kit-8, qRT-PCR, and Western blotting. TUNEL staining and ELISA were performed to confirm the establishment of DN model in db/db mice.
RESULTS: High-glucose exposure dramatically altered lncRNA expression profile in MPC5 cells (fold change>2), including 305 upregulated lncRNAs and 451 downregulated lncRNAs. LncRNA Hoxb3os expression was significantly reduced in the HG-induced podocyte damage model, as well as in the renal tissues from db/db mice with spontaneous DN. Overexpression of Hoxb3os significantly reduced the apoptosis rate and increased the viability of MPC5 cells under HG conditions. Further study revealed that exogenous Hoxb3os increased autophagy level in HG-exposed MPC5 cells via abrogating Akt-mTOR signaling pathway and that the process was possibly implicated in the upregulation of SIRT1.
CONCLUSION: LncRNA Hoxb3os protected podocytes from HG-induced damage by regulating Akt-mTOR pathway and cell autophagy. Thus, lncRNA Hoxb3os appears as a potential biomarker in the diagnosis and treatment of DN in the future.

DOI: https://doi.org/10.18388/abp.2020_5483