bims-lorfki 2021-05-23 papers

Issue of 2021‒05‒23
four papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

J Cell Sci. 2020 Jan 01. pii: jcs.244020. [Epub ahead of print]

LncRNA MEG3 mediates renal cell cancer progression by regulating ST3Gal1 transcription and EGFR sialylation.

Aihong Gong, Xinyu Zhao, Yue Pan, Yu Qi, Shuangda Li, Yiran Huang, Yanru Guo, Xia Qi, Wei Zheng, Li Jia.

Long noncoding RNAs (lncRNAs) have emerged as important regulators of cancer progression. Abnormal sialylation leads to renal cell cancer (RCC) malignancy. However, the mechanism of lncRNA maternally expressed gene 3 (MEG3) mediates RCC progression by regulating ST3Gal1 transcription and EGFR sialylation is still unrevealed. Here, we found that the expression of MEG3 was higher in adjacent tissues than that in RCC tissues, as well as downregulated in RCC cell lines than that in normal renal cells. The proliferation, migration and invasion of RCC cell transfected with MEG3 were decreased, while the MEG3-knockdown cells showed the reversed results. The proliferative and metastatic ability in vivo were concordant to the behavior in vitro. ST3Gal1 was dysregulated and positively correlated to MEG3. By applying bioinformatics, c-Jun was identified as a transcription factor of ST3Gal1, while altered MEG3 regulated c-Jun expression. Furthermore, ST3Gal1 modulated EGFR sialylation to inhibit EGFR phosphorylation, which affected the PI3K/AKT pathway activation. Taken together, our study provided a novel mechanism to elucidate the role of MEG3/ST3Gal1/EGFR axis in RCC progression.

Keywords: EGFR; MEG3; Renal cell carcinoma; ST3Gal1

DOI: https://doi.org/10.1242/jcs.244020

Front Pharmacol. 2021 ;12 647650

lncRNA MALAT1 Promotes Renal Fibrosis in Diabetic Nephropathy by Targeting the miR-2355-3p/IL6ST Axis.

Haozi Huang, Guowei Zhang, Zhenying Ge.

Long noncoding RNA (lncRNAs) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been reported in diabetic nephropathy (DN) about its effect on podocyte function and cell heat shock induced by hyperglycemia. However, the biological mechanism of MALAT1 regulating DN fibrosis needs further study. In this study, SD rats were administrated with streptozotocin (STZ) to establish a diabetes model. In vitro, human renal tubular epithelial cells (HK-2 and 293T) were treated with high glucose (HG). Here, we found that MALAT1 was upregulated in renal tissues of diabetic rats and HG-treated cells, and HG treatment promoted cell proliferation and invasion. MALAT1 overexpression aggravated protein levels of collagen I (col I), collagen IV (col IV), fibronectin (FN), and laminin (LN) in HK-2 cells, while MALAT1 knockdown exerted the opposite effect. Moreover, the luciferase reporter gene and pull-down assays demonstrated that MALAT1 interacted with miR-2355-3p. The miR-2355-3p level was downregulated in diabetic rats and HG-treated cells, and MALAT1 overexpression inhibited the miR-2355-3p level. Bioinformatics prediction and luciferase reporter gene assay revealed that interleukin 6 signal transducer (IL6ST) was a target of miR-2355-3p. In addition, miR-2355-3p overexpression attenuated fibrosis-related gene levels in HG-treated cells by inhibiting IL6ST expression and inactivating the recombinant signal transducer and activator of the transcription 3 (STAT3) signaling pathway. Knockdown of miR-2355-3p reversed the inhibitory effect of MALAT1 knockdown on IL6ST, col I, col IV, FN, and LN protein levels in HG-induced cells. Overexpression of MALAT1 aggravated cell damage in HG-induced cells via the miR-2355-3p/IL6ST/STAT3 signaling pathway. Finally, enhanced renal fibrosis and kidney tissue damage were observed in diabetic rats. In conclusion, MALAT1 overexpression may enhance renal fibrosis in diabetic rats and cell damage in HG-induced HK-2 cells via the miR-2355-3p/IL6ST axis, which provides a new perspective of DN treatment.

Keywords: IL6ST; STAT3 pathway; diabetic nephropathy; lncRNA MALAT1; miR-2355-3p

DOI: https://doi.org/10.3389/fphar.2021.647650

Front Physiol. 2021 ;12 663216

Long Non-coding RNA MEG3 Promotes Renal Tubular Epithelial Cell Pyroptosis by Regulating the miR-18a-3p/GSDMD Pathway in Lipopolysaccharide-Induced Acute Kidney Injury.

Junhui Deng, Wei Tan, Qinglin Luo, Lirong Lin, Luquan Zheng, Jurong Yang.

Background and Objective: Acute kidney injury (AKI) is a complication of sepsis. Pyroptosis of gasdermin D (GSDMD)-mediated tubular epithelial cells (TECs) play important roles in pathogenesis of sepsis-associated AKI. Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3), an imprinted gene involved in tumorigenesis, is implicated in pyroptosis occurring in multiple organs. Herein, we investigated the role and mechanisms of MEG3 in regulation of TEC pyroptosis in lipopolysaccharide (LPS)-induced AKI. Materials and Methods: Male C57BL/6 mice and primary human TECs were treated with LPS for 24 h to establish the animal and cell models, respectively, of sepsis-induced AKI. Renal function was assessed by evaluation of serum creatinine and urea levels. Renal tubule injury score was assessed by Periodic acid-Schiff staining. Renal pyroptosis was assessed by evaluating expression of caspase-1, GSDMD, and inflammatory factors IL-1β and IL-18. Cellular pyroptosis was assessed by analyzing the release rate of LDH, expression of IL-1β, IL-18, caspase-1, and GSDMD, and using EtBr and EthD2 staining. MEG3 expression in renal tissues and cells was detected using RT-qPCR. The molecular mechanisms of MEG3 in LPS-induced AKI were assessed through bioinformatics analysis, RNA-binding protein immunoprecipitation, dual luciferase reporter gene assays, and a rescue experiment. Results: Pyroptosis was detected in both LPS-induced animal and cell models, and the expression of MEG3 in these models was significantly up-regulated. MEG3-knockdown TECs treated with LPS showed a decreased number of pyroptotic cells, down-regulated secretion of LDH, IL-1β, and IL-18, and decreased expression of GSDMD, compared with those of controls; however, there was no difference in the expression of caspase-1 between MEG3 knockdown cells and controls. Bioinformatics analysis screened out miR-18a-3P, and further experiments demonstrated that MEG3 controls GSDMD expression by acting as a ceRNA for miR-18a-3P to promote TECs pyroptosis. Conclusion: Our study demonstrates that lncRNA MEG3 promoted renal tubular epithelial pyroptosis by regulating the miR-18a-3p/GSDMD pathway in LPS-induced AKI.

Keywords: GSDMD; MEG3; acute kidney injury; miR-18a-3p; pyroptosis; renal tubular epithelial cells; sepsis

DOI: https://doi.org/10.3389/fphys.2021.663216

Am J Transl Res. 2021 ;13(4): 2143-2162

Identification and biological characteristics of clear cell renal cell carcinoma associated urine-derived stem cells.

Shengjun Luo, Lan Shao, Ruizhi Geng, Qingyuan Liu, Wencheng Jiang, Mengjia Gong, Yuanyuan Zhang, Yunfeng He.

Urine-derived stem cells (USC) are isolated from voided urine and have demonstrated potential for use in tissue engineering and regenerative medicine therapies. Clear cell renal cell carcinoma (ccRCC) is a common urological malignancy that originates in the kidney. Since USC also originate in the kidney, the objective of this study was to investigate any biological differences between USC isolated from healthy patients and those isolated from ccRCC patients (rc-USC). We found that USC can be isolated from the voided urine of ccRCC patients (rc-USC) and have a morphology and function similar to those isolated from healthy donors. However, the rc-USC showed greater proliferation and invasion capacity than USC, and possessed some features of cancer cells; but the rc-UC were not able to form xenografts when implanted in vivo. We further performed RNA sequencing of rc-USC and USC and found several differentially expressed lncRNAs and mRNAs; however subsequent GO and KEGG enrichment analysis showed few pathway differences between these cells. Bioinformatic analyses and RT-PCR showed the expression of several known ccRCC-related genes in rc-USC expressed, as compared to USC derived from healthy donors. This study demonstrates that rc-USC displayed several cellular and genetic features of ccRCC cells, which suggests that this population of cells could provide a non-invasive approach for for the diagnosis, predication, disease modeling and therapeutic strategies targeting ccRCC.

Keywords: RNA sequencing; Urine-derived stem cells; clear cell renal cell cancer; mesenchymal stromal cells; tumor-associated stromal cells