Smooth muscle SIRT1 reprograms endothelial cells to suppress angiogenesis after ischemia.
Dou Yong-Qing,Kong Peng,Li Chang-Lin,Sun Hong-Xing,Li Wei-Wei,Yu Yuan,Nie Lei,Zhao Li-Li,Miao Sui-Bing,Li Xiao-Kun,Dong Chen,Zhang Jin-Wen,Liu Yang,Huo Xiao-Xia,Chi Kui,Gao Xiang,Zhang Ning,Weng Lin,Yang Hongyuan,Zhang Fan,Han Mei
Vascular smooth muscle cells (VSMCs) undergo the phenotypic changes from contractile to synthetic state during vascular remodeling after ischemia. SIRT1 protects against stress-induced vascular remodeling via maintaining VSMC differentiated phenotype. However, the effect of smooth muscle SIRT1 on the functions of endothelial cells (ECs) has not been well clarified. Here, we explored the role of smooth muscle SIRT1 in endothelial angiogenesis after ischemia and the underlying mechanisms. We performed a femoral artery ligation model using VSMC specific human SIRT1 transgenic (-Tg) and knockout (KO) mice. Angiogenesis was assessed in by quantification of the total number of capillaries, wound healing and matrigel plug assays, and ECs by tube formation, proliferation and migration assays. The interaction of HIF1α with circRNA was examined by using RNA immunoprecipitation, RNA pull-down and hybridization assays. The blood flow recovery was significantly attenuated in -Tg mice, and markedly improved in -Tg mice treated with SIRT1 inhibitor EX527 and in -KO mice. The density of capillaries significantly decreased in the ischemic gastrocnemius of Tg mice compared with -KO and WT mice, with reduced expression of VEGFA, which resulted in decreased number of arterioles. We identified that the phenotypic switching of -Tg VSMCs was attenuated in response to hypoxia, with high levels of contractile proteins and reduced expression of the synthetic markers and NG2, compared with -KO and WT VSMCs. Mechanistically, -Tg VSMCs inhibited endothelial angiogenic activity induced by hypoxia via the exosome cZFP609. The cZFP609 was delivered into ECs, and detained HIF1α in the cytoplasm via its interaction with HIF1α, thereby inhibiting VEGFA expression and endothelial angiogenic functions. Meantime, the high cZFP609 expression was observed in the plasma of the patients with atherosclerotic or diabetic lower extremity peripheral artery disease, associated with reduced ankle-brachial index. Knockdown of cZFP609 improved blood flow recovery after hindlimb ischemia in Tg mice. : Our findings demonstrate that SIRT1 may impair the plasticity of VSMCs. cZFP609 mediates VSMCs to reprogram endothelial functions, and serves as a valuable indicator to assess the prognosis and clinical outcomes of ischemic diseases.
Circular RNAs in renal cell carcinoma: implications for tumorigenesis, diagnosis, and therapy.
Wang Ying,Zhang Yunjing,Wang Ping,Fu Xianghui,Lin Weiqiang
Renal cell carcinoma (RCC) is the most common malignant kidney tumor and has a high incidence rate. Circular RNAs (circRNAs) are noncoding RNAs with widespread distribution and diverse cellular functions. They are highly stable and have organ- and tissue-specific expression patterns. CircRNAs have essential functions as microRNA sponges, RNA-binding protein- and transcriptional regulators, and protein translation templates. Recent reports have shown that circRNAs are abnormally expressed in RCC and act as important regulators of RCC carcinogenesis and progression. Moreover, circRNAs have emerged as potential biomarkers for RCC diagnosis and prognosis and targets for developing new treatments. However, further studies are needed to better understand the functions of circRNAs in RCC. In this review, we summarize and discuss the recent research progress on RCC-associated circRNAs, with a focus on their potential for RCC diagnosis and targeted therapy.
Noncoding RNAs in acute kidney injury.
Brandenburger Timo,Salgado Somoza Antonio,Devaux Yvan,Lorenzen Johan M
Acute kidney injury (AKI) is an important health issue concerning ∼50% of patients treated in intensive care units. AKI mainly occurs after sepsis, acute ischemia, nephrotoxicity, or hypoxia and leads to severe damage of the kidney and to an increased risk of mortality. The diagnosis of AKI is currently based on creatinine urea levels and diuresis. Yet, novel markers may improve the accuracy of this diagnosis at an early stage of the disease, thereby allowing early prevention and therapy, ultimately leading to a reduction in the need for renal replacement therapy and decreased mortality. Non-protein-coding RNAs or noncoding RNAs are central players in development and disease. They are important regulatory molecules that allow a fine-tuning of gene expression and protein synthesis. This regulation is necessary to maintain homeostasis, and its dysregulation is often associated with disease development. Noncoding RNAs are present in the kidney and in body fluids and their expression is modulated during AKI. This review article assembles the current knowledge of the role of noncoding RNAs, including microRNAs, long noncoding RNAs and circular RNAs, in the pathogenesis of AKI. Their potential as biomarkers and therapeutic targets as well as the challenges to translate research findings to clinical application are discussed. Although microRNAs have entered clinical testing, preclinical and clinical trials are needed before long noncoding RNAs and circular RNAs may be considered as useful biomarkers or therapeutic targets of AKI.
Circ-AKT3 inhibits clear cell renal cell carcinoma metastasis via altering miR-296-3p/E-cadherin signals.
Xue Dingwei,Wang Huan,Chen Yuanlei,Shen Danyang,Lu Jieyang,Wang Mingchao,Zebibula Abudureheman,Xu Liwei,Wu Haiyang,Li Gonghui,Xia Liqun
BACKGROUND:Circular RNA (circRNA) is a type of circular endogenous RNA produced by special selective splicing and participates in progression of diverse diseases. However, the role of circRNA in clear cell renal cell carcinoma (ccRCC) is still rarely reported. METHODS:We detected lower circ-AKT3 expression in ccRCC using the circular RNA microarray. Then, qPCR array was applied to verify the expression of circ-AKT3 in between 60 ccRCC tissues and adjacent normal tissues, as well as ccRCC cell lines and human normal kidney cell (HK-2). We investigated the function of circ-AKT3 in ccRCC in vitro and in vivo and detected underlying mechanisms by Western blotting, bioinformatic analysis, RNA pull-down assay and luciferase reporter assay. RESULTS:Circ-AKT3 was verified significantly downregulated in ccRCC. Knockdown of circ-AKT3 promoted ccRCC migration and invasion, while overexpression of circ-AKT3 suppressed ccRCC metastasis. Further, circ-AKT3/miR-296-3p/E-cadherin axis was shown responsible for circ-AKT3 inhibiting ccRCC metastasis. CONCLUSION:Circ-AKT3 suppresses ccRCC metastasis by enforcing E-cadherin expression through competitively binding miR-296-3p. Circ-AKT3 may therefore serve as a novel therapeutic to better suppress ccRCC metastasis.
The Translational Landscape of the Human Heart.
van Heesch Sebastiaan,Witte Franziska,Schneider-Lunitz Valentin,Schulz Jana F,Adami Eleonora,Faber Allison B,Kirchner Marieluise,Maatz Henrike,Blachut Susanne,Sandmann Clara-Louisa,Kanda Masatoshi,Worth Catherine L,Schafer Sebastian,Calviello Lorenzo,Merriott Rhys,Patone Giannino,Hummel Oliver,Wyler Emanuel,Obermayer Benedikt,Mücke Michael B,Lindberg Eric L,Trnka Franziska,Memczak Sebastian,Schilling Marcel,Felkin Leanne E,Barton Paul J R,Quaife Nicholas M,Vanezis Konstantinos,Diecke Sebastian,Mukai Masaya,Mah Nancy,Oh Su-Jun,Kurtz Andreas,Schramm Christoph,Schwinge Dorothee,Sebode Marcial,Harakalova Magdalena,Asselbergs Folkert W,Vink Aryan,de Weger Roel A,Viswanathan Sivakumar,Widjaja Anissa A,Gärtner-Rommel Anna,Milting Hendrik,Dos Remedios Cris,Knosalla Christoph,Mertins Philipp,Landthaler Markus,Vingron Martin,Linke Wolfgang A,Seidman Jonathan G,Seidman Christine E,Rajewsky Nikolaus,Ohler Uwe,Cook Stuart A,Hubner Norbert
Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology.
The Landscape of Circular RNA in Cancer.
Vo Josh N,Cieslik Marcin,Zhang Yajia,Shukla Sudhanshu,Xiao Lanbo,Zhang Yuping,Wu Yi-Mi,Dhanasekaran Saravana M,Engelke Carl G,Cao Xuhong,Robinson Dan R,Nesvizhskii Alexey I,Chinnaiyan Arul M
Circular RNAs (circRNAs) are an intriguing class of RNA due to their covalently closed structure, high stability, and implicated roles in gene regulation. Here, we used an exome capture RNA sequencing protocol to detect and characterize circRNAs across >2,000 cancer samples. When compared against Ribo-Zero and RNase R, capture sequencing significantly enhanced the enrichment of circRNAs and preserved accurate circular-to-linear ratios. Using capture sequencing, we built the most comprehensive catalog of circRNA species to date: MiOncoCirc, the first database to be composed primarily of circRNAs directly detected in tumor tissues. Using MiOncoCirc, we identified candidate circRNAs to serve as biomarkers for prostate cancer and were able to detect circRNAs in urine. We further detected a novel class of circular transcripts, termed read-through circRNAs, that involved exons originating from different genes. MiOncoCirc will serve as a valuable resource for the development of circRNAs as diagnostic or therapeutic targets across cancer types.
N6-Methyladenosine Modification Controls Circular RNA Immunity.
Chen Y Grace,Chen Robert,Ahmad Sadeem,Verma Rohit,Kasturi Sudhir Pai,Amaya Laura,Broughton James P,Kim Jeewon,Cadena Cristhian,Pulendran Bali,Hur Sun,Chang Howard Y
Circular RNAs (circRNAs) are prevalent in eukaryotic cells and viral genomes. Mammalian cells possess innate immunity to detect foreign circRNAs, but the molecular basis of self versus foreign identity in circRNA immunity is unknown. Here, we show that N6-methyladenosine (mA) RNA modification on human circRNAs inhibits innate immunity. Foreign circRNAs are potent adjuvants to induce antigen-specific T cell activation, antibody production, and anti-tumor immunity in vivo, and mA modification abrogates immune gene activation and adjuvant activity. mA reader YTHDF2 sequesters mA-circRNA and is essential for suppression of innate immunity. Unmodified circRNA, but not mA-modified circRNA, directly activates RNA pattern recognition receptor RIG-I in the presence of lysine-63-linked polyubiquitin chain to cause filamentation of the adaptor protein MAVS and activation of the downstream transcription factor IRF3. CircRNA immunity has considerable parallel to prokaryotic DNA restriction modification system that transforms nucleic acid chemical modification into organismal innate immunity.