|
1
|
Wang XW, Tang YX, Li FX, Wang JL, Yao GP, Zeng DT, Tang YL, Chi BT, Su QY, Huang LQ, Qin DY, Chen G, Feng ZB, He RQ. Clinical significance of upregulated Rho GTPase activating protein 12 causing resistance to tyrosine kinase inhibitors in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:4244-4263. [DOI: 10.4251/wjgo.v16.i10.4244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/17/2024] [Accepted: 09/06/2024] [Indexed: 09/26/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major health challenge with high incidence and poor survival rates in China. Systemic therapies, particularly tyrosine kinase inhibitors (TKIs), are the first-line treatment for advanced HCC, but resistance is common. The Rho GTPase family member Rho GTPase activating protein 12 (ARHGAP12), which regulates cell adhesion and invasion, is a potential therapeutic target for overcoming TKI resistance in HCC. However, no studies on the expression of ARHGAP12 in HCC and its role in resistance to TKIs have been reported.
AIM To unveil the expression of ARHGAP12 in HCC, its role in TKI resistance and its potential associated pathways.
METHODS This study used single-cell RNA sequencing (scRNA-seq) to evaluate ARHGAP12 mRNA levels and explored its mechanisms through enrichment analysis. CellChat was used to investigate focal adhesion (FA) pathway regulation. We integrated bulk RNA data (RNA-seq and microarray), immunohistochemistry and proteomics to analyze ARHGAP12 mRNA and protein levels, correlating with clinical outcomes. We assessed ARHGAP12 expression in TKI-resistant HCC, integrated conventional HCC to explore its mechanism, identified intersecting FA pathway genes with scRNA-seq data and evaluated its response to TKI and immunotherapy.
RESULTS ARHGAP12 mRNA was found to be highly expressed in malignant hepatocytes and to regulate FA. In malignant hepatocytes in high-score FA groups, MDK-[integrin alpha 6 (ITGA6) + integrin β-1 (ITGB1)] showed specificity in ligand-receptor interactions. ARHGAP12 mRNA and protein were upregulated in bulk RNA, immunohistochemistry and proteomics, and higher expression was associated with a worse prognosis. ARHGAP12 was also found to be a TKI resistance gene that regulated the FA pathway. ITGB1 was identified as a crossover gene in the FA pathway in both scRNA-seq and bulk RNA. High expression of ARHGAP12 was associated with adverse reactions to sorafenib, cabozantinib and regorafenib, but not to immunotherapy.
CONCLUSION ARHGAP12 expression is elevated in HCC and TKI-resistant HCC, and its regulatory role in FA may underlie the TKI-resistant phenotype.
Collapse
Affiliation(s)
- Xiao-Wei Wang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yu-Xing Tang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Fu-Xi Li
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jia-Le Wang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Gao-Peng Yao
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Da-Tong Zeng
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Department of Pathology, Red Cross Hospital of Yulin City, Yulin 537000, Guangxi Zhuang Autonomous Region, China
| | - Yu-Lu Tang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Bang-Teng Chi
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Qin-Yan Su
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Lin-Qing Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Di-Yuan Qin
- Department of Computer Science and Technology, School of Computer and Electronic Information, Guangxi University, Nanning 530004, Guangxi Zhuang Autonomous Region, China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhen-Bo Feng
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Rong-Quan He
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| |
Collapse
|
|
2
|
Xue J, Zhou Z, Zhu Z, Sun Q, Zhu Y, Wu P. A high salt diet impairs the bladder epithelial barrier and activates the NLRP3 and NF‑κB signaling pathways to induce an overactive bladder in vivo. Exp Ther Med 2024; 28:362. [PMID: 39071900 PMCID: PMC11273259 DOI: 10.3892/etm.2024.12651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 05/22/2024] [Indexed: 07/30/2024] Open
Abstract
Overactive bladder (OAB) is a condition characterized by an urgency to urinate, which is associated with the urodynamic observation of detrusor overexcitation. Although the etiology of OAB is currently unclear, it has been suggested that in patients with OAB, disruption of bladder epithelial barrier integrity can disturb the normal contractile function of the detrusor. Additionally, dietary preferences have been suggested to influence the severity of OAB. Therefore, the aim of the present study was to investigate the effect of a high salt diet (HSD) on the development of OAB in a murine model. Mice were fed either a HSD or standard diet for 8 weeks, following which voiding characteristics and bladder barrier function were assessed. The present study demonstrated that a HSD in mice was associated with OAB-like symptoms such as increased urinary frequency and non-voiding bladder contractions. The HSD group demonstrated a thinner bladder mucus layer and decreased expression of bladder barrier markers, tight junction protein-1 and claudin-1, which may be potentially indicative of induced bladder damage. A HSD for 8 weeks in mice and a high salt treatment at the uroepithelium cellular (SV-HUC-1s) level resulted in increased uroepithelial oxidative stress and inflammatory cell infiltration, as indicated by increased expression levels of TNF-α and IL-1β, as well as activation of the nucleotide-binding domain leucine-rich-containing family pyrin domain-containing 3 (NLRP3) and NF-κB signaling pathways in vivo and in vitro. Therefore, the present study indicated that a HSD could be a potentially important risk factor for the development of OAB, as it may be associated with overactivation of contractile function of the bladder by impairing the integrity of the bladder epithelial barrier and activation of the NLRP3 and NF-κB signaling pathways. Remodeling of the bladder barrier and reduction of the inflammatory response may be potential targets for the treatment of OAB in the future.
Collapse
Affiliation(s)
- Jingwen Xue
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Zhipeng Zhou
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
- Department of Urology, Jinshan Branch of Fujian Provincial Hospital, Fuzhou, Fujian 350004, P.R. China
| | - Zhangrui Zhu
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Qi Sun
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yuexuan Zhu
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Peng Wu
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| |
Collapse
|
|
3
|
Hassan M, Shahzadi S, Yasir M, Chun W, Kloczkowski A. Therapeutic Implication of miRNAs as an Active Regulatory Player in the Management of Pain: A Review. Genes (Basel) 2024; 15:1003. [PMID: 39202362 PMCID: PMC11353898 DOI: 10.3390/genes15081003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 07/15/2024] [Accepted: 07/26/2024] [Indexed: 09/03/2024] Open
Abstract
Chronic pain is frequently associated with neuropathy, inflammation, or the malfunctioning of nerves. Chronic pain is associated with a significant burden of morbidity due to opioid use, associated with addiction and tolerance, and disability. MicroRNAs (miRs) are emerging therapeutic targets to treat chronic pain through the regulation of genes associated with inflammation, neuronal excitability, survival, or de-differentiation. In this review, we discuss the possible involvement of miRs in pain-related molecular pathways. miRs are known to regulate high-conviction pain genes, supporting their potential as therapeutic targets.
Collapse
Affiliation(s)
- Mubashir Hassan
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH 43205, USA; (S.S.); (A.K.)
| | - Saba Shahzadi
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH 43205, USA; (S.S.); (A.K.)
| | - Muhammad Yasir
- Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea; (M.Y.); (W.C.)
| | - Wanjoo Chun
- Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea; (M.Y.); (W.C.)
| | - Andrzej Kloczkowski
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH 43205, USA; (S.S.); (A.K.)
- Department of Pediatrics, The Ohio State University School of Medicine, Columbus, OH 43205, USA
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA
| |
Collapse
|
|
4
|
Talluri B, Addya S, Terashvili M, Medda BK, Banerjee A, Shaker R, Sengupta JN, Banerjee B. Adult zymosan re-exposure exacerbates the molecular alterations in the brainstem rostral ventromedial medulla of rats with early life zymosan-induced cystitis. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2024; 16:100160. [PMID: 39252992 PMCID: PMC11381896 DOI: 10.1016/j.ynpai.2024.100160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/23/2024] [Accepted: 07/23/2024] [Indexed: 09/11/2024]
Abstract
Recent evidence suggests that the descending modulatory pathways from the brainstem rostral ventromedial medulla (RVM) are important for bladder inflammatory pain. This study aimed to identify the long-term molecular changes in RVM neurons due to early life cystitis during neuronal development and the effect of reexposure later in adulthood. RVM tissues from two treatment protocols were used: (1) neonatal zymosan exposures with acute adult rechallenge (RC) and (2) only neonatal zymosan exposures (NRC). RNAseq analysis showed upregulation of several genes associated with synaptic plasticity (Grin1, Grip2, Notch1, Arc, and Scn2b) in the cystitis groups compared to controls in both protocols. The RC protocol exhibited a stronger treatment effect with significantly higher fold differences between the groups compared to the NRC protocol (p < 0.001, fold differences RC vs NRC). In microarrays, miR-34a-5p showed cystitis-induced downregulation in both protocols. Bioinformatics analysis identified multiple 3'UTRs complementary binding sites for miR-34a-5p on Grin2b, Notch1, Grip2, Scn2b, and Arc genes. The enhanced response in the RC protocol indicates a possible priming effect of early life cystitis on rechallenge in adulthood. These long-term molecular alterations may play a critical role in the development of chronic bladder pain conditions as seen in patients with Interstitial Cystitis/Bladder pain syndrome.
Collapse
Affiliation(s)
- Bhavana Talluri
- Gastroenterology & Hepatology Division, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Sankar Addya
- Sydney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Maia Terashvili
- Gastroenterology & Hepatology Division, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Bidyut K Medda
- Gastroenterology & Hepatology Division, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Anjishnu Banerjee
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Reza Shaker
- Gastroenterology & Hepatology Division, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Jyoti N Sengupta
- Gastroenterology & Hepatology Division, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Banani Banerjee
- Gastroenterology & Hepatology Division, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| |
Collapse
|
|
5
|
Zhu B, Gao J, Zhang Y, Liao B, Zhu S, Li C, Liao J, Liu J, Jiang C, Zeng J. CircRNA/miRNA/mRNA axis participates in the progression of partial bladder outlet obstruction. BMC Urol 2022; 22:191. [PMID: 36434693 PMCID: PMC9700926 DOI: 10.1186/s12894-022-01132-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 10/25/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND More and more evidence showed that circRNA/miRNA/mRNA axis played a vital role in the pathogenesis of some diseases. However, the role of circRNA/miRNA/mRNA axis in partial bladder outlet obstruction (pBOO) remains unknown. Our study aimed to explore the complex regulatory mechanism of circRNA/miRNA/mRNA axis in pBOO. METHODS The pBOO rat model was established, and the bladder tissues were collected for mRNA sequencing. The differentially expressed mRNAs were analyzed by high-throughput sequencing, and the GO and KEGG analysis of the differentially expressed mRNAs were performed. Competing endogenous RNAs (ceRNAs) analysis identified the potential regulation function of circRNA/miRNA/mRNA axis in pBOO. qRT-PCR detected the expression of circRNA/miRNA/mRNA. miRanda software was performed to predict the relationship between circRNA and miRNA, miRNA and mRNA. RESULTS Compared with the sham group, a total of 571 mRNAs were differentially expressed in the pBOO group, of which 286 were up-regulated and 285 were down-regulated. GO analysis showed that the mRNAs were mainly involved in cellular process, single-organism process, and cell, etc. KEGG analysis showed that the enriched signaling pathways were metabolic pathways, cell adhesion molecules (CAMs), and HTLV-I infection, etc. Based on the previous transcriptome data and differentially expressed circRNAs, we drew the ceRNA network regulation diagram. qRT-PCR results confirmed that chr3:113195876|113197193/rno-miR-30c-1-3p/Gata4, chr1:126188351|126195625/rno-miR-153-5p/Diaph3, and chr9:81258380|81275269/rno-miR-135b-5p/Pigr axis may have ceRNA function. miRanda confirmed there have the binding sites of circRNA/miRNA/mRNA axis. CONCLUSIONS CircRNA/miRNA/mRNA axis was involved in the progression of pBOO. Our research on the circRNA/miRNA/mRNA axis revealed new pathogenesis and treatment strategies for pBOO.
Collapse
Affiliation(s)
- Baoyi Zhu
- grid.410737.60000 0000 8653 1072Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University (Qingyuan People’s Hospital), B24 Yinquan Road, Qingcheng, Qingyuan, 511500 Guangdong People’s Republic of China
| | - Jun Gao
- grid.410737.60000 0000 8653 1072Department of Basic Medical Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511518 Guangdong People’s Republic of China
| | - Yuying Zhang
- Department of Child Health Care, Shenzhen Longhua Maternity and Child Health Care Hospital, Shenzhen, 518000 Guangdong People’s Republic of China
| | - Baojian Liao
- grid.410737.60000 0000 8653 1072Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University (Qingyuan People’s Hospital), B24 Yinquan Road, Qingcheng, Qingyuan, 511500 Guangdong People’s Republic of China ,grid.9227.e0000000119573309Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510700 Guangdong People’s Republic of China
| | - Sihua Zhu
- grid.410737.60000 0000 8653 1072Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University (Qingyuan People’s Hospital), B24 Yinquan Road, Qingcheng, Qingyuan, 511500 Guangdong People’s Republic of China
| | - Chunling Li
- grid.410737.60000 0000 8653 1072Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University (Qingyuan People’s Hospital), B24 Yinquan Road, Qingcheng, Qingyuan, 511500 Guangdong People’s Republic of China
| | - Junhao Liao
- grid.410737.60000 0000 8653 1072Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University (Qingyuan People’s Hospital), B24 Yinquan Road, Qingcheng, Qingyuan, 511500 Guangdong People’s Republic of China
| | - Jianjia Liu
- grid.410737.60000 0000 8653 1072Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University (Qingyuan People’s Hospital), B24 Yinquan Road, Qingcheng, Qingyuan, 511500 Guangdong People’s Republic of China
| | - Chonghe Jiang
- grid.410737.60000 0000 8653 1072Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University (Qingyuan People’s Hospital), B24 Yinquan Road, Qingcheng, Qingyuan, 511500 Guangdong People’s Republic of China
| | - Jianwen Zeng
- grid.410737.60000 0000 8653 1072Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University (Qingyuan People’s Hospital), B24 Yinquan Road, Qingcheng, Qingyuan, 511500 Guangdong People’s Republic of China
| |
Collapse
|
|
6
|
Neuhaus J, Berndt-Paetz M, Gonsior A. Biomarkers in the Light of the Etiopathology of IC/BPS. Diagnostics (Basel) 2021; 11:diagnostics11122231. [PMID: 34943467 PMCID: PMC8700473 DOI: 10.3390/diagnostics11122231] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/23/2021] [Accepted: 11/26/2021] [Indexed: 12/25/2022] Open
Abstract
In this review, we focused on putatively interesting biomarkers of interstitial cystitis/bladder pain syndrome (IC/BPS) in relation to the etiopathology of this disease. Since its etiopathology is still under discussion, the development of novel biomarkers is critical for the correct classification of the patients in order to open personalized treatment options, on the one hand, and to separate true IC/BPS from the numerous confusable diseases with comparable symptom spectra on the other hand. There is growing evidence supporting the notion that the classical or Hunner-type IC (HIC) and the non-Hunner-type IC (NHIC) are different diseases with different etiopathologies and different pathophysiology at the full-blown state. While genetic alterations indicate close relationship to allergic and autoimmune diseases, at present, the genetic origin of IC/BPS could be identified. Disturbed angiogenesis and impairment of the microvessels could be linked to altered humoral signaling cascades leading to enhanced VEGF levels which in turn could enhance leucocyte and mast cell invasion. Recurrent or chronic urinary tract infection has been speculated to promote IC/BPS. New findings show that occult virus infections occurred in most IC/BPS patients and that the urinary microbiome was altered, supporting the hypothesis of infections as major players in IC/BPS. Environmental and nutritional factors may also influence IC/BPS, at least at a late state (e.g., cigarette smoking can enhance IC/BPS symptoms). The damage of the urothelial barrier could possibly be the result of many different causality chains and mark the final state of IC/BPS, the causes of this development having been introduced years ago. We conclude that the etiopathology of IC/BPS is complex, involving regulatory mechanisms at various levels. However, using novel molecular biologic techniques promise more sophisticated analysis of this pathophysiological network, resulting in a constantly improvement of our understanding of IC/BPS and related diseases.
Collapse
Affiliation(s)
- Jochen Neuhaus
- Department of Urology, Research Laboratory, University of Leipzig, 04103 Leipzig, Germany;
- Correspondence: ; Tel.: +49-341-9717-688
| | - Mandy Berndt-Paetz
- Department of Urology, Research Laboratory, University of Leipzig, 04103 Leipzig, Germany;
| | - Andreas Gonsior
- Department of Urology, University Hospital Leipzig AöR, 04103 Leipzig, Germany;
| |
Collapse
|
|
7
|
Hao F, Bi YN, Wang L, Wang Y, Ma J, Cui P, Li X, Sun S, Ning L, Huang Y, Jiao X, Chen D. miR-199a-5p suppresses epithelial- mesenchymal-transition in anaplastic thyroid carcinoma cells via targeting Snail signals. Cancer Biomark 2021; 29:317-326. [PMID: 32716347 DOI: 10.3233/cbm-201518] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of anaplastic thyroid carcinoma (ATC). miR-199a-5p was previously reported to act as a tumor suppressor or oncomiRNA in various types of cancer. However, its accurate expression, function, and mechanism in ATC remain unclear. Here, we find that miR-199a-5p is significantly downregulated in ATC tissues compared with adjacent non-cancerous tissues. Overexpression of miR-199a-5p significantly inhibits migration and invasion of ATC cells in vitro, and lung metastasis in vivo. Importantly, miR-199a-5p suppresses epithelial-mesenchymal transition (EMT) both in vitro and in vivo by targeting Snail. Taken together, this study reveals that miR-199a-5p is critical to the EMT progression in ATC cells. Targeting the pathway described here may be a novel approach for inhibiting metastasis of ATC.
Collapse
Affiliation(s)
- Fengyun Hao
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Ya-Nan Bi
- Operating Room, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Lei Wang
- Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yubing Wang
- Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Jilei Ma
- Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Ping Cui
- Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xuhua Li
- Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Shukai Sun
- Clinical Lab, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Liang Ning
- General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yichuan Huang
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xuelong Jiao
- General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Dong Chen
- General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| |
Collapse
|
|
8
|
von Siebenthal M, Besic M, Gheinani AH, Akshay A, Lizun-Platoni S, Kunz N, Burkhard FC, Monastyrskaya K. Urinary miRNA profiles discriminate between obstruction-induced bladder dysfunction and healthy controls. Sci Rep 2021; 11:10204. [PMID: 33986358 PMCID: PMC8119692 DOI: 10.1038/s41598-021-89535-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 04/28/2021] [Indexed: 02/07/2023] Open
Abstract
Urgency, frequency and incomplete emptying are the troublesome symptoms often shared between benign prostatic obstruction-induced (BLUTD) and neurogenic (NLUTD) lower urinary tract dysfunction. Previously, using bladder biopsies, we suggested a panel of miRNA biomarkers for different functional phenotypes of the bladder. Urine is a good source of circulating miRNAs, but sex- and age-matched controls are important for urinary metabolite comparison. In two groups of healthy subjects (average age 32 and 57 years old, respectively) the total protein and RNA content was very similar between age groups, but the number of secreted extracellular vesicles (uEVs) and expression of several miRNAs were higher in the young healthy male volunteers. Timing of urine collection was not important for these parameters. We also evaluated the suitability of urinary miRNAs for non-invasive diagnosis of bladder outlet obstruction (BOO). A three urinary miRNA signature (miR-10a-5p, miR-301b-3p and miR-363-3p) could discriminate between controls and patients with LUTD (BLUTD and NLUTD). This panel of representative miRNAs can be further explored to develop a non-invasive diagnostic test for BOO. The age-related discrepancy in the urinary miRNA content observed in this study points to the importance of selecting appropriate, age-matched controls.
Collapse
Affiliation(s)
- Michelle von Siebenthal
- Urology Research Laboratory, Department for BioMedical Research DBMR, University of Bern, Bern, Switzerland
| | - Mustafa Besic
- Urology Research Laboratory, Department for BioMedical Research DBMR, University of Bern, Bern, Switzerland
| | - Ali Hashemi Gheinani
- Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School, Boston, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Akshay Akshay
- Urology Research Laboratory, Department for BioMedical Research DBMR, University of Bern, Bern, Switzerland
| | | | - Nadine Kunz
- Department of Urology, Inselspital University Hospital, 3010, Bern, Switzerland
| | - Fiona C Burkhard
- Urology Research Laboratory, Department for BioMedical Research DBMR, University of Bern, Bern, Switzerland.,Department of Urology, Inselspital University Hospital, 3010, Bern, Switzerland
| | - Katia Monastyrskaya
- Urology Research Laboratory, Department for BioMedical Research DBMR, University of Bern, Bern, Switzerland. .,Department of Urology, Inselspital University Hospital, 3010, Bern, Switzerland.
| |
Collapse
|
|
9
|
Cook JH, Melloni GEM, Gulhan DC, Park PJ, Haigis KM. The origins and genetic interactions of KRAS mutations are allele- and tissue-specific. Nat Commun 2021; 12:1808. [PMID: 33753749 PMCID: PMC7985210 DOI: 10.1038/s41467-021-22125-z] [Citation(s) in RCA: 112] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 03/01/2021] [Indexed: 02/07/2023] Open
Abstract
Mutational activation of KRAS promotes the initiation and progression of cancers, especially in the colorectum, pancreas, lung, and blood plasma, with varying prevalence of specific activating missense mutations. Although epidemiological studies connect specific alleles to clinical outcomes, the mechanisms underlying the distinct clinical characteristics of mutant KRAS alleles are unclear. Here, we analyze 13,492 samples from these four tumor types to examine allele- and tissue-specific genetic properties associated with oncogenic KRAS mutations. The prevalence of known mutagenic mechanisms partially explains the observed spectrum of KRAS activating mutations. However, there are substantial differences between the observed and predicted frequencies for many alleles, suggesting that biological selection underlies the tissue-specific frequencies of mutant alleles. Consistent with experimental studies that have identified distinct signaling properties associated with each mutant form of KRAS, our genetic analysis reveals that each KRAS allele is associated with a distinct tissue-specific comutation network. Moreover, we identify tissue-specific genetic dependencies associated with specific mutant KRAS alleles. Overall, this analysis demonstrates that the genetic interactions of oncogenic KRAS mutations are allele- and tissue-specific, underscoring the complexity that drives their clinical consequences.
Collapse
Affiliation(s)
- Joshua H Cook
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Giorgio E M Melloni
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Doga C Gulhan
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Peter J Park
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
| | - Kevin M Haigis
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
- Broad Institute, Cambridge, MA, USA.
- Harvard Digestive Disease Center, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
10
|
Zhao X, Zeng H, Lei L, Tong X, Yang L, Yang Y, Li S, Zhou Y, Luo L, Huang J, Xiao R, Chen J, Zeng Q. Tight junctions and their regulation by non-coding RNAs. Int J Biol Sci 2021; 17:712-727. [PMID: 33767583 PMCID: PMC7975691 DOI: 10.7150/ijbs.45885] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 10/06/2020] [Indexed: 02/06/2023] Open
Abstract
Tight junction (TJ) is a “zippering up” junction structure located at the uppermost portion of adjacent epithelial/endothelial cells in organs and tissues. TJs maintain the relative stability of intracellular substances and functions by closing or opening intercellular pathways, coordinating the entry and exit of molecules of different sizes and charges, and regulating the permeability of paracellular barrier. TJs also prevent microbial invasion, maintain epithelial/endothelial cell polarity, and regulate cell proliferation. TJs are widely present in the skin and mucosal epithelial barriers, intestinal epithelial barrier, glomerular filtration barrier, bladder epithelial barrier, blood-brain barrier, brain-blood tumor barrier, and blood-testis barrier. TJ dysfunction in different organs can lead to a variety of diseases. In addition to signal pathways, transcription factors, DNA methylation, histone modification, TJ proteins can also be regulated by a variety of non-coding RNAs, such as micro-RNAs, long-noncoding RNAs, and circular RNAs, directly or indirectly. This review summarizes the structure of TJs and introduces the functions and regulatory mechanisms of TJs in different organs and tissues. The roles and mechanisms of non-coding RNAs in the regulation of TJs are also highlighted in this review.
Collapse
Affiliation(s)
- Xiaojiao Zhao
- Department of Dermatology, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, P.R. China
| | - Hongliang Zeng
- Institute of Chinese Materia Medica, Hunan Academy of Chinese Medicine, Yuehua Road, Changsha, Hunan 410013, P.R. China
| | - Li Lei
- Department of Dermatology, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, P.R. China
| | - Xiaoliang Tong
- Department of Dermatology, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, P.R. China
| | - Lun Yang
- Department of Dermatology, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, P.R. China
| | - Yan Yang
- Department of Dermatology, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, P.R. China
| | - Si Li
- Department of Dermatology, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, P.R. China
| | - Ying Zhou
- Department of Dermatology, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, P.R. China
| | - Liping Luo
- Department of Dermatology, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, P.R. China
| | - Jinhua Huang
- Department of Dermatology, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, P.R. China
| | - Rong Xiao
- Department of Dermatology, Second Xiangya Hospital, Central South University, 139 Renminzhong Road, Changsha, Hunan 410013, P.R. China
| | - Jing Chen
- Department of Dermatology, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, P.R. China.,Institute of Chinese Materia Medica, Hunan Academy of Chinese Medicine, Yuehua Road, Changsha, Hunan 410013, P.R. China.,Department of Dermatology, Second Xiangya Hospital, Central South University, 139 Renminzhong Road, Changsha, Hunan 410013, P.R. China
| | - Qinghai Zeng
- Department of Dermatology, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, P.R. China.,Institute of Chinese Materia Medica, Hunan Academy of Chinese Medicine, Yuehua Road, Changsha, Hunan 410013, P.R. China.,Department of Dermatology, Second Xiangya Hospital, Central South University, 139 Renminzhong Road, Changsha, Hunan 410013, P.R. China
| |
Collapse
|
|
11
|
Lin Z, Hu H, Liu B, Chen Y, Tao Y, Zhou X, Li M. Biomaterial-assisted drug delivery for interstitial cystitis/bladder pain syndrome treatment. J Mater Chem B 2020; 9:23-34. [PMID: 33179709 DOI: 10.1039/d0tb02094j] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and painful bladder condition afflicting patients with increased urinary urgency and frequency as well as incontinence. Owing to the elusive pathogenesis of IC/BPS, obtaining effective therapeutic outcomes remains challenging. Current administrational routes such as intravesical-bladder injection improve the treatment efficacy and reduce systemic side effects. However, the bladder permeability barrier hinders drug penetration into the bladder wall to meet the desired therapeutic expectation. These issues can be addressed by encapsulating drugs into biomaterials. When appropriately exploited, they would increase the drug dwelling time in the bladder, enhance the penetration of mucosa and improve the therapeutic response of IC/BPS. In this review, we first elucidate the pathogenesis and animal models of IC/BPS. Then, we highlight recent representative biomaterial-assisted drug delivery systems for IC/BPS treatment. Finally, we discuss the challenges and outlook for further developing biomaterial-based delivery systems for IC/BPS management.
Collapse
Affiliation(s)
- Zhijun Lin
- Laboratory of Biomaterials and Translational Medicine, Department of Urology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China.
| | | | | | | | | | | | | |
Collapse
|
|
12
|
Serum LUCAT1 implicates the pathogenesis of muscle-invasive bladder cancer via targeting miR-199a-5p and miR-199b-5p. J Mol Histol 2020; 51:583-591. [PMID: 32844284 DOI: 10.1007/s10735-020-09907-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 08/20/2020] [Indexed: 12/24/2022]
Abstract
Muscle-invasive bladder cancer (MIBC) is a common malignancy of urinary system cancers, accounting for about 1/3 of all newly diagnosed bladder cancer cases. Due to its strong metastasis, the 5-year survival of MIBC is less than 50%, and in serious cases, the overall survival of metastatic bladder cancer patients is about 1.3 years. LncRNAs, a type of non-coding RNAs defined as the transcripts exceeding 200 nucleotides in length, are frequently aberrant in multiple cancers including cervical, ovarian, breast and bladder cancers. Recently, LUCAT1 (short for lung cancer-associated transcript 1), a lncRNA first reported to be involved in smoking-related lung cancer, has been observed to exhibit crucial roles in the epithelial-to-mesenchymal transition (EMT), migration and invasion processes of clear cell renal cell carcinoma (ccRCC) and colorectal cancer. However, whether it involves in the pathogenesis of MIBC remains underexplored. In the present study, LUCAT1 was up-regulated in the serum samples of MIBC patients and bladder cancer cell lines, as assessed using real-time PCR. Our in vitro data (including wound healing and trans-well assays) showed that LUCAT1 was required for the proliferation, EMT, migration and invasion processes of T24 cells. Moreover, LUCAT1 directly targeted miR-199a-5p and miR-199b-5p, as affirmed using the luciferase reporter assay, and manipulation of LUCAT1 significantly suppressed miR-199a-5p and miR-199b-5p. Collectively, our findings highlight an axis of LUCAT1/miR-199a/b-5p in MIBC pathogenesis. Therefore, LUCAT1 may possibly be a promising candidate for diagnostic biomarker and therapeutic target of MIBC.
Collapse
|
|
13
|
Cata JP, Gorur A, Yuan X, Berg NK, Sood AK, Eltzschig HK. Role of Micro-RNA for Pain After Surgery. Anesth Analg 2020; 130:1638-1652. [DOI: 10.1213/ane.0000000000004767] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
|
|
14
|
Hashemi Gheinani A, Bigger-Allen A, Wacker A, Adam RM. Systems analysis of benign bladder disorders: insights from omics analysis. Am J Physiol Renal Physiol 2020; 318:F901-F910. [PMID: 32116016 DOI: 10.1152/ajprenal.00496.2019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The signaling pathways and effectors that drive the response of the bladder to nonmalignant insults or injury are incompletely defined. Interrogation of biological systems has been revolutionized by the ability to generate high-content data sets that capture information on a variety of biomolecules in cells and tissues, from DNA to RNA to proteins. In oncology, such an approach has led to the identification of cancer subtypes, improved prognostic capability, and has provided a basis for precision treatment of patients. In contrast, systematic molecular characterization of benign bladder disorders has lagged behind, such that our ability to uncover novel therapeutic interventions or increase our mechanistic understanding of such conditions is limited. Here, we discuss existing literature on the application of omics approaches, including transcriptomics and proteomics, to urinary tract conditions characterized by pathological tissue remodeling. We discuss molecular pathways implicated in remodeling, challenges in the field, and aspirations for omics-based research in the future.
Collapse
Affiliation(s)
- Ali Hashemi Gheinani
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts.,Department of Surgery, Harvard Medical School, Boston, Massachusetts
| | - Alexander Bigger-Allen
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts.,Biological and Biomedical Sciences PhD Program, Harvard Medical School, Boston, Massachusetts
| | - Amanda Wacker
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts.,Florida State University, Tallahassee, Florida
| | - Rosalyn M Adam
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts.,Department of Surgery, Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
|
15
|
Mouly L, Gilhodes J, Lemarié A, Cohen-Jonathan Moyal E, Toulas C, Favre G, Sordet O, Monferran S. The RND1 Small GTPase: Main Functions and Emerging Role in Oncogenesis. Int J Mol Sci 2019; 20:ijms20153612. [PMID: 31344837 PMCID: PMC6696182 DOI: 10.3390/ijms20153612] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 07/10/2019] [Accepted: 07/21/2019] [Indexed: 02/07/2023] Open
Abstract
The Rho GTPase family can be classified into classic and atypical members. Classic members cycle between an inactive Guanosine DiPhosphate -bound state and an active Guanosine TriPhosphate-bound state. Atypical Rho GTPases, such as RND1, are predominantly in an active GTP-bound conformation. The role of classic members in oncogenesis has been the subject of numerous studies, while that of atypical members has been less explored. Besides the roles of RND1 in healthy tissues, recent data suggest that RND1 is involved in oncogenesis and response to cancer therapeutics. Here, we present the current knowledge on RND1 expression, subcellular localization, and functions in healthy tissues. Then, we review data showing that RND1 expression is dysregulated in tumors, the molecular mechanisms involved in this deregulation, and the role of RND1 in oncogenesis. For several aggressive tumors, RND1 presents the features of a tumor suppressor gene. In these tumors, low expression of RND1 is associated with a bad prognosis for the patients. Finally, we highlight that RND1 expression is induced by anticancer agents and modulates their response. Of note, RND1 mRNA levels in tumors could be used as a predictive marker of both patient prognosis and response to anticancer agents.
Collapse
Affiliation(s)
- Laetitia Mouly
- Cancer Research Center of Toulouse, INSERM UMR1037, 31037 Toulouse, France
- Faculty of Pharmacy and Medecine, Université Toulouse III, 31062 Toulouse, France
| | - Julia Gilhodes
- Institut Claudius Regaud, IUCT-O, 31059 Toulouse, France
| | - Anthony Lemarié
- Cancer Research Center of Toulouse, INSERM UMR1037, 31037 Toulouse, France
- Faculty of Pharmacy and Medecine, Université Toulouse III, 31062 Toulouse, France
| | - Elizabeth Cohen-Jonathan Moyal
- Cancer Research Center of Toulouse, INSERM UMR1037, 31037 Toulouse, France
- Faculty of Pharmacy and Medecine, Université Toulouse III, 31062 Toulouse, France
- Institut Claudius Regaud, IUCT-O, 31059 Toulouse, France
| | - Christine Toulas
- Cancer Research Center of Toulouse, INSERM UMR1037, 31037 Toulouse, France
- Institut Claudius Regaud, IUCT-O, 31059 Toulouse, France
| | - Gilles Favre
- Cancer Research Center of Toulouse, INSERM UMR1037, 31037 Toulouse, France
- Faculty of Pharmacy and Medecine, Université Toulouse III, 31062 Toulouse, France
- Institut Claudius Regaud, IUCT-O, 31059 Toulouse, France
| | - Olivier Sordet
- Cancer Research Center of Toulouse, INSERM UMR1037, 31037 Toulouse, France
| | - Sylvie Monferran
- Cancer Research Center of Toulouse, INSERM UMR1037, 31037 Toulouse, France.
- Faculty of Pharmacy and Medecine, Université Toulouse III, 31062 Toulouse, France.
| |
Collapse
|
|
16
|
Diring J, Mouilleron S, McDonald NQ, Treisman R. RPEL-family rhoGAPs link Rac/Cdc42 GTP loading to G-actin availability. Nat Cell Biol 2019; 21:845-855. [PMID: 31209295 PMCID: PMC6960015 DOI: 10.1038/s41556-019-0337-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 04/29/2019] [Indexed: 12/29/2022]
Abstract
RPEL proteins, which contain the G-actin-binding RPEL motif, coordinate cytoskeletal processes with actin dynamics. We show that the ArhGAP12- and ArhGAP32-family GTPase-activating proteins (GAPs) are RPEL proteins. We determine the structure of the ArhGAP12/G-actin complex, and show that G-actin contacts the RPEL motif and GAP domain sequences. G-actin inhibits ArhGAP12 GAP activity, and this requires the G-actin contacts identified in the structure. In B16 melanoma cells, ArhGAP12 suppresses basal Rac and Cdc42 activity, F-actin assembly, invadopodia formation and experimental metastasis. In this setting, ArhGAP12 mutants defective for G-actin binding exhibit more effective downregulation of Rac GTP loading following HGF stimulation and enhanced inhibition of Rac-dependent processes, including invadopodia formation. Potentiation or disruption of the G-actin/ArhGAP12 interaction, by treatment with the actin-binding drugs latrunculin B or cytochalasin D, has corresponding effects on Rac GTP loading. The interaction of G-actin with RPEL-family rhoGAPs thus provides a negative feedback loop that couples Rac activity to actin dynamics.
Collapse
Affiliation(s)
- Jessica Diring
- Signalling and Transcription Group, The Francis Crick Institute, London, UK
| | - Stephane Mouilleron
- Structural Biology Science Technology Platform, The Francis Crick Institute, London, UK
| | - Neil Q McDonald
- Signalling and Structural Biology Group, The Francis Crick Institute, London, UK
- Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, London, UK
| | - Richard Treisman
- Signalling and Transcription Group, The Francis Crick Institute, London, UK.
| |
Collapse
|
|
17
|
Zhao Z, Liu D, Chen Y, Kong Q, Li D, Zhang Q, Liu C, Tian Y, Fan C, Meng L, Zhu H, Yu H. Ureter tissue engineering with vessel extracellular matrix and differentiated urine-derived stem cells. Acta Biomater 2019; 88:266-279. [PMID: 30716556 DOI: 10.1016/j.actbio.2019.01.072] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 01/14/2019] [Accepted: 01/31/2019] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To assess the possibility of ureter tissue engineering using vessel extracellular matrix (VECM) and differentiated urine-derived stem cells (USCs) in a rabbit model. METHODS VECM was prepared by a modified technique. USCs were isolated from human urine samples and cultured with an induction medium for the differentiation of the cells into urothelium and smooth muscle phenotypes. For contractile phenotype conversion, the induced smooth muscle cells were transfected with the miR-199a-5p plasmid. The differentiated cells were seeded onto VECM and cultured under dynamic conditions in vitro for 2 weeks. The graft was tubularized and wrapped by two layers of the omentum of a rabbit for vascularization. Then, the maturated graft was used for ureter reconstruction in vivo. RESULTS VECM has microporous structures that allow cell infiltration and exhibit adequate biocompatibility with seeding cells. USCs were isolated and identified by flow cytometry. After induction, the urothelium phenotype gene was confirmed at mRNA and protein levels. With the combined induction by TGF-β1 and miR-199a-5p, the differentiated cells can express the smooth muscle phenotype gene and convert to the contractile phenotype. After seeding cells onto VECM, the induced urothelium cells formed a single epithelial layer, and the induced smooth muscle cells formed a few cell layers during dynamic culture. After 3 weeks of omental maturation, tubular graft was vascularized. At 2 months post ureter reconstruction, histological evaluation showed a clearly layered structure of ureter with multilayered urothelium over the organized smooth muscle tissue. CONCLUSION By seeding differentiated USCs onto VECM, a tissue-engineered graft could form multilayered urothelium and organized smooth muscle tissue after ureteral reconstruction in vivo. STATEMENT OF SIGNIFICANCE Cell-based tissue engineering offers an alternative technique for urinary tract reconstruction. In this work, we describe a novel strategy for ureter tissue engineering. We modified the techniques of vessel extracellular matrix (VECM) preparation and used a dynamic culture system for seeding cells onto VECM. We found that VECM had the trait of containing VEGF and exhibited blood vessel formation potential. Urine-derived stem cells (USCs) could be differentiated into urothelial cells and functional contractile phenotype smooth muscle cells in vitro. By seeding differentiated USCs onto VECM, a tissue-engineered graft could form multilayered urothelium and organized smooth muscle tissue after ureteral reconstruction in vivo. This strategy might be applied in clinical research for the treatment of long-segment ureteral defect.
Collapse
Affiliation(s)
- Zhankui Zhao
- Department of Urology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272100, PR China.
| | - Deqian Liu
- Department of Urology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272100, PR China
| | - Ye Chen
- Department of Urology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272100, PR China
| | - Qingsheng Kong
- Department of Biochemistry, Jining Medical University, Jining, Shandong 272067, PR China; Collaborative Innovation Center, Jining Medical University, Jining, Shandong 272067, PR China
| | - Dandan Li
- Collaborative Innovation Center, Jining Medical University, Jining, Shandong 272067, PR China
| | - Qingxin Zhang
- Department of Radiology, Medical Imaging Center, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272100, PR China
| | - Chuanxin Liu
- Collaborative Innovation Center, Jining Medical University, Jining, Shandong 272067, PR China
| | - Yanjun Tian
- Collaborative Innovation Center, Jining Medical University, Jining, Shandong 272067, PR China
| | - Chengjuan Fan
- Department of Urology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272100, PR China
| | - Lin Meng
- Department of Urology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272100, PR China
| | - Haizhou Zhu
- Department of Urology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272100, PR China
| | - Honglian Yu
- Department of Biochemistry, Jining Medical University, Jining, Shandong 272067, PR China; Collaborative Innovation Center, Jining Medical University, Jining, Shandong 272067, PR China.
| |
Collapse
|
|
18
|
Do MicroRNAs Modulate Visceral Pain? BIOMED RESEARCH INTERNATIONAL 2018; 2018:5406973. [PMID: 30627562 PMCID: PMC6304628 DOI: 10.1155/2018/5406973] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 09/03/2018] [Accepted: 09/16/2018] [Indexed: 12/20/2022]
Abstract
Visceral pain, a common characteristic of multiple diseases relative to viscera, impacts millions of people worldwide. Although hundreds of studies have explored mechanisms underlying visceral pain, it is still poorly managed. Over the past decade, strong evidence emerged suggesting that microRNAs (miRNAs) play a significant role in visceral nociception through altering neurotransmitters, receptors and other genes at the posttranscriptional level. Under pathological conditions, one kind of miRNA may have several target mRNAs and several kinds of miRNAs may act on one target, suggesting complex interactions and mechanisms between miRNAs and target genes lead to pathological states. In this review we report on recent progress in examining miRNAs responsible for visceral sensitization and provide miRNA-based therapeutic targets for the management of visceral pain.
Collapse
|
|
19
|
MicroRNA-mediated downregulation of potassium-chloride-cotransporter and vesicular γ-aminobutyric acid transporter expression in spinal cord contributes to neonatal cystitis-induced visceral pain in rats. Pain 2018; 158:2461-2474. [PMID: 28885452 DOI: 10.1097/j.pain.0000000000001057] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Loss of GABAergic inhibition in pain pathways has been considered to be a key component in the development of chronic pain. In the present study, we intended to examine whether miR-92b-mediated posttranscriptional dysregulation of spinal potassium chloride cotransporter (KCC2) and vesicular γ-aminobutyric acid transporter (VGAT) plays a major role in the development and maintenance of long-term visceral hyperalgesia in neonatal zymosan-treated rats. Neonatal cystitis was induced by transurethral zymosan administration from postnatal (P) days 14 to 16 (protocol 1). Two other zymosan protocols were also used: adult rechallenge on P57 to 59 following neonatal P14 to 16 exposures (protocol 2), and adult zymosan exposures on P57 to 59 (protocol 3). Both neonatal and adult bladder inflammation protocols demonstrated an increase in spinal miR-92b-3p expression and subsequent decrease in KCC2 and VGAT expression in spinal dorsal horn neurons. In situ hybridization demonstrated a significant upregulation of miR-92b-3p in the spinal dorsal horn neurons of neonatal cystitis rats compared with saline-treated controls. In dual in situ hybridization and immunohistochemistry studies, we further demonstrated coexpression of miR-92b-3p with targets KCC2 and VGAT in spinal dorsal horn neurons, emphasizing a possible regulatory role both at pre- and post-synaptic levels. Intrathecal administration of lentiviral pLSyn-miR-92b-3p sponge (miR-92b-3p inhibitor) upregulated KCC2 and VGAT expression in spinal dorsal horn neurons. In behavioral studies, intrathecal administration of lentiviral miR-92b-3p sponge attenuated an increase in visceromotor responses and referred viscerosomatic hypersensitivity following the induction of cystitis. These findings indicate that miR-92b-3p-mediated posttranscriptional regulation of spinal GABAergic system plays an important role in sensory pathophysiology of zymosan-induced cystitis.
Collapse
|
|
20
|
Tumor Necrosis Factor-α Initiates miRNA-mRNA Signaling Cascades in Obstruction-Induced Bladder Dysfunction. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:1847-1864. [DOI: 10.1016/j.ajpath.2018.05.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 04/03/2018] [Accepted: 05/03/2018] [Indexed: 02/08/2023]
|
|
21
|
Improved isolation strategies to increase the yield and purity of human urinary exosomes for biomarker discovery. Sci Rep 2018; 8:3945. [PMID: 29500443 PMCID: PMC5834546 DOI: 10.1038/s41598-018-22142-x] [Citation(s) in RCA: 134] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 02/12/2018] [Indexed: 12/13/2022] Open
Abstract
Circulating miRNAs are detected in extracellular space and body fluids such as urine. Circulating RNAs can be packaged in secreted urinary extracellular vesicles (uEVs) and thus protected from degradation. Urinary exosome preparations might contain specific miRNAs, relevant as biomarkers in renal and bladder diseases. Major difficulties in application of uEVs into the clinical environment are the high variability and low reproducibility of uEV isolation methods. Here we used five different methods to isolate uEVs and compared the size distribution, morphology, yield, presence of exosomal protein markers and RNA content of uEVs. We present an optimized ultracentrifugation and size exclusion chromatography approach for highly reproducible isolation for 50-150 nm uEVs, corresponding to the exosomes, from 50 ml urine. We profiled the miRNA content of uEVs and total urine from the same samples with the NanoString platform and validated the data using qPCR. Our results indicate that 18 miRNAs, robustly detected in uEVs were always present in the total urine. However, 15 miRNAs could be detected only in the total urine preparations and might represent naked circulating miRNA species. This is a novel unbiased and reproducible strategy for uEVs isolation, content normalization and miRNA cargo analysis, suitable for biomarker discovery studies.
Collapse
|
|
22
|
Urinary Biomarkers for Bladder Outlet Obstruction. CURRENT BLADDER DYSFUNCTION REPORTS 2017. [DOI: 10.1007/s11884-017-0418-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
|
|
23
|
Song J, Hu Y, Li J, Zheng H, Wang J, Guo L, Ning R, Li H, Yang Z, Fan H, Liu L. Different microRNA profiles reveal the diverse outcomes induced by EV71 and CA16 infection in human umbilical vein endothelial cells using high-throughput sequencing. PLoS One 2017; 12:e0177657. [PMID: 28531227 PMCID: PMC5439704 DOI: 10.1371/journal.pone.0177657] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 05/01/2017] [Indexed: 12/21/2022] Open
Abstract
Enterovirus 71 (EV71) and Coxsackievirus A16 (CA16) remain the predominant pathogens in hand, foot, and mouth disease (HFMD), but the factors underlying the pathogenesis of EV71 and CA16 infections have not been elucidated. Recently, the functions of microRNAs (miRNAs) in pathogen-host interactions have been highlighted. In the present study, we performed comprehensive miRNA profiling in EV71- and CA16-infected human umbilical vein endothelial cells (HUVECs) at multiple time points using high-throughput sequencing. The results showed that 135 known miRNAs exhibited remarkable differences in expression. Of these, 30 differentially expressed miRNAs presented opposite trends in EV71- and CA16-infected samples. Subsequently, we mainly focused on the 30 key differentially expressed miRNAs through further screening to predict targets. Gene ontology (GO) and pathway analysis of the predicted targets showed the enrichment of 14 biological processes, 9 molecular functions, 8 cellular components, and 85 pathways. The regulatory networks of these miRNAs with predicted targets, GOs, pathways, and co-expression genes were determined, suggesting that miRNAs display intricate regulatory mechanisms during the infection phase. Consequently, we specifically analyzed the hierarchical GO categories of the predicted targets involved in biological adhesion. The results indicated that the distinct changes induced by EV71 and CA16 infection may be partly linked to the function of the blood-brain barrier. Taken together, this is the first report describing miRNA expression profiles in HUVECs with EV71 and CA16 infections using high-throughput sequencing. Our data provide useful insights that may help to elucidate the different host-pathogen interactions following EV71 and CA16 infection and offer novel therapeutic targets for these infections.
Collapse
Affiliation(s)
- Jie Song
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infections Disease, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China
| | - Yajie Hu
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infections Disease, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China
| | - Jiaqi Li
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infections Disease, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China
| | - Huiwen Zheng
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infections Disease, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China
| | - Jingjing Wang
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infections Disease, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China
| | - Lei Guo
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infections Disease, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China
| | - Ruotong Ning
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infections Disease, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China
| | - Hongzhe Li
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infections Disease, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China
| | - Zening Yang
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infections Disease, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China
| | - Haitao Fan
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infections Disease, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China
| | - Longding Liu
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infections Disease, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China
- * E-mail:
| |
Collapse
|
|
24
|
Gheinani AH, Kiss B, Moltzahn F, Keller I, Bruggmann R, Rehrauer H, Fournier CA, Burkhard FC, Monastyrskaya K. Characterization of miRNA-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunction. JCI Insight 2017; 2:e89560. [PMID: 28138557 DOI: 10.1172/jci.insight.89560] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Bladder outlet obstruction (BOO) induces significant organ remodeling, leading to lower urinary tract symptoms accompanied by urodynamic changes in bladder function. Here, we report mRNA and miRNA transcriptome sequencing of bladder samples from human patients with different urodynamically defined states of BOO. Patients' miRNA and mRNA expression profiles correlated with urodynamic findings. Validation of RNA sequencing results in an independent patient cohort identified combinations of 3 mRNAs (NRXN3, BMP7, UPK1A) and 3 miRNAs (miR-103a-3p, miR-10a-5p, miR-199a-3p) sufficient to discriminate between bladder functional states. All BOO patients shared cytokine and immune response pathways, TGF-β and NO signaling pathways, and hypertrophic PI3K/AKT signaling pathways. AP-1 and NFkB were dominant transcription factors, and TNF-α was the top upstream regulator. Integrated miRNA-mRNA expression analysis identified pathways and molecules targeted by differentially expressed miRNAs. Molecular changes in BOO suggest an increasing involvement of miRNAs in the control of bladder function from the overactive to underactive/acontractile states.
Collapse
Affiliation(s)
- Ali Hashemi Gheinani
- Urology Research Laboratory, Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Bernhard Kiss
- Department of Urology, University Hospital, Bern, Switzerland
| | - Felix Moltzahn
- Department of Urology, University Hospital, Bern, Switzerland
| | - Irene Keller
- Interfaculty Bioinformatics Unit, University of Bern, Bern, Switzerland
| | - Rémy Bruggmann
- Interfaculty Bioinformatics Unit, University of Bern, Bern, Switzerland
| | | | | | | | - Katia Monastyrskaya
- Urology Research Laboratory, Department of Clinical Research, University of Bern, Bern, Switzerland.,Department of Urology, University Hospital, Bern, Switzerland
| |
Collapse
|
|
25
|
Kashyap M, Pore S, Chancellor M, Yoshimura N, Tyagi P. Bladder overactivity involves overexpression of MicroRNA 132 and nerve growth factor. Life Sci 2016; 167:98-104. [PMID: 27789288 DOI: 10.1016/j.lfs.2016.10.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 10/21/2016] [Accepted: 10/23/2016] [Indexed: 11/15/2022]
Abstract
AIM Here, we assessed the expression of non-protein coding microRNAs (miRs), nerve growth factor and inflammatory molecules in the rat model of acetic acid induced bladder overactivity. MAIN METHODS Under isoflurane anesthesia, adult female Sprague-Dawley rats were instilled for 30min with either saline or NGF antisense oligonucleotide complexed with liposomes. 24h later, treated rats were exposed to either intravesical infusion of saline or saline containing 0.25% acetic acid at the rate of 0.04mL/min for 2h under urethane anesthesia (1g/kg; s.c). After CMG, bladder was harvested to study expression of NGF, cytokines and 8 specific miRNAs involved in bladder dysfunctions. The role of miR-132 in bladder overactivity was independently assessed through bladder wall transfection of plasmid encoding miR-132. KEY FINDINGS NGF overexpression in bladder overactivity was associated with ~2-fold upregulation and downregulation of miR-132 and miR-221, respectively. Pretreatment with NGF antisense restored the expression of miR-221 and miR-132 to control levels and also reduced the expression of NGF and cytokines (MCP-1 and sICAM-1). There was insignificant alteration in the expression of miR-199a-5p, and expression of, miR-210, miR-212, miR-155, miR-134 and miR-206 remained similar across the experimental groups. Bladder wall transfection of miR-132 plasmid in absence of acetic acid exposure was able to independently induce bladder overactivity, bladder hypertrophy and upregulate the expression of NGF and other cytokines. SIGNIFICANCE Overall, our work sheds light on the role of miR-132 in bladder overactivity, bladder hypertrophy, NGF signaling and expression of inflammatory mediators. Findings demonstrate that aberrant expression of NGF and miR-132 is involved in voiding dysfunctions.
Collapse
Affiliation(s)
- Mahendra Kashyap
- Department of Urology, University of Pittsburgh, Pittsburgh, United States
| | - Subrata Pore
- Department of Urology, University of Pittsburgh, Pittsburgh, United States
| | - Michael Chancellor
- Department of Urology, University of Pittsburgh, Pittsburgh, United States
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh, Pittsburgh, United States
| | - Pradeep Tyagi
- Department of Urology, University of Pittsburgh, Pittsburgh, United States.
| |
Collapse
|
|
26
|
Abstract
UNLABELLED DNA 5-hydroxylmethylcytosine (5hmC) catalyzed by ten-eleven translocation methylcytosine dioxygenase (TET) occurs abundantly in neurons of mammals. However, the in vivo causal link between TET dysregulation and nociceptive modulation has not been established. Here, we found that spinal TET1 and TET3 were significantly increased in the model of formalin-induced acute inflammatory pain, which was accompanied with the augment of genome-wide 5hmC content in spinal cord. Knockdown of spinal TET1 or TET3 alleviated the formalin-induced nociceptive behavior and overexpression of spinal TET1 or TET3 in naive mice produced pain-like behavior as evidenced by decreased thermal pain threshold. Furthermore, we found that TET1 or TET3 regulated the nociceptive behavior by targeting microRNA-365-3p (miR-365-3p). Formalin increased 5hmC in the miR-365-3p promoter, which was inhibited by knockdown of TET1 or TET3 and mimicked by overexpression of TET1 or TET3 in naive mice. Nociceptive behavior induced by formalin or overexpression of spinal TET1 or TET3 could be prevented by downregulation of miR-365-3p, and mimicked by overexpression of spinal miR-365-3p. Finally, we demonstrated that a potassium channel, voltage-gated eag-related subfamily H member 2 (Kcnh2), validated as a target of miR-365-3p, played a critical role in nociceptive modulation by spinal TET or miR-365-3p. Together, we concluded that TET-mediated hydroxymethylation of miR-365-3p regulates nociceptive behavior via Kcnh2. SIGNIFICANCE STATEMENT Mounting evidence indicates that epigenetic modifications in the nociceptive pathway contribute to pain processes and analgesia response. Here, we found that the increase of 5hmC content mediated by TET1 or TET3 in miR-365-3p promoter in the spinal cord is involved in nociceptive modulation through targeting a potassium channel, Kcnh2. Our study reveals a new epigenetic mechanism underlying nociceptive information processing, which may be a novel target for development of antinociceptive drugs.
Collapse
|
|
27
|
Abstract
Biomarkers are measurable characteristics reflective of the physiological or diseased state and a crucial feature in rendering personalized medicine more precise. Dysregulated expression of circulating microRNAs (miRNAs) in bodily fluids is being explored as noninvasive clinical biomarker for a variety of disorders including chronic pain. High-precision qPCR-based signal amplification of these miRNAs enables the detection of small changes making them ideal biomarker candidates. Presence of circulating miRNAs in exosomes, small vesicles that mediate intercellular communication, opens up novel avenues for target intervention and biomarker discovery. miRNA signatures specific to different pain conditions, and their reversal on treatment in patients and animal models can be beneficial in patient stratification, prognosis, and in bridging preclinical and clinical results. Identification of multiple miRNAs as opposed to reliance on one specific molecule as a biomarker could improve treatment efficacies in an extremely heterogeneous pain patient population. Additionally, owing to the stability of miRNAs, retrospective studies could be performed using banked samples from completed clinical trials. Irrespective of the phase and outcome, these studies can provide insights on molecular underpinnings influencing treatment outcome, or specific therapeutic intervention. Identification of miRNAs altered in chronic pain states will have a significant impact on the identification of right leads, targets, doses, and patients. Effective implementation of miRNA-based biomarkers would provide treatment guidance for clinicians, better clinical trial designs for pharmaceutical companies, all leading to individualized care and better treatment outcome for chronic pain patients.
Collapse
Affiliation(s)
- Sujay Ramanathan
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Seena K Ajit
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
| |
Collapse
|
|
28
|
Argade S, Chermansky C, Tyagi P. Biomarkers for interstitial cystitis/painful bladder syndrome. ACTA ACUST UNITED AC 2015; 12:87-90. [PMID: 26696241 DOI: 10.2217/whe.15.93] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Shilpa Argade
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | | | - Pradeep Tyagi
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
| |
Collapse
|
|
29
|
Yu X, Li Z, Chan MTV, Wu WKK. microRNA deregulation in keloids: an opportunity for clinical intervention? Cell Prolif 2015; 48:626-30. [PMID: 26486103 DOI: 10.1111/cpr.12225] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 08/08/2015] [Indexed: 12/12/2022] Open
Abstract
Keloids are defined as benign dermal scars invading adjacent healthy tissue, characterized by aberrant fibroblast dynamics and overproduction of extracellular matrix. However, the aetiology and molecular mechanism of keloid production remain poorly understood. Recent discoveries have shed new light on the involvement of a class of non-coding RNAs known as microRNAs (miRNA), in keloid formation. A number of miRNAs have differential expression in keloid tissues and keloid-derived fibroblasts. These miRNAs have been characterized as novel regulators of cellular processes pertinent to wound healing, including extracellular matrix deposition and fibroblast proliferation. Delineating the functional significance of miRNA deregulation may help us better understand pathogenesis of keloids, and promote development of miRNA-directed therapeutics against this condition.
Collapse
Affiliation(s)
- Xin Yu
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100042, China
| | - Zheng Li
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Matthew T V Chan
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, 999077, China
| | - William K K Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, 999077, China.,State Key Laboratory of Digestive Disease, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, 999077, China
| |
Collapse
|
|
30
|
Koeck I, Burkhard FC, Monastyrskaya K. Activation of common signaling pathways during remodeling of the heart and the bladder. Biochem Pharmacol 2015; 102:7-19. [PMID: 26390804 DOI: 10.1016/j.bcp.2015.09.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 09/14/2015] [Indexed: 12/12/2022]
Abstract
The heart and the urinary bladder are hollow muscular organs, which can be afflicted by pressure overload injury due to pathological conditions such as hypertension and bladder outlet obstruction. This increased outflow resistance induces hypertrophy, marked by dramatic changes in the organs' phenotype and function. The end result in both the heart and the bladder can be acute organ failure due to advanced fibrosis and the subsequent loss of contractility. There is emerging evidence that microRNAs (miRNAs) play an important role in the pathogenesis of heart failure and bladder dysfunction. MiRNAs are endogenous non-coding single-stranded RNAs, which regulate gene expression and control adaptive and maladaptive organ remodeling processes. This Review summarizes the current knowledge of molecular alterations in the heart and the bladder and highlights common signaling pathways and regulatory events. The miRNA expression analysis and experimental target validation done in the heart provide a valuable source of information for investigators working on the bladder and other organs undergoing the process of fibrotic remodeling. Aberrantly expressed miRNA are amendable to pharmacological manipulation, offering an opportunity for development of new therapies for cardiac and bladder hypertrophy and failure.
Collapse
Affiliation(s)
- Ivonne Koeck
- Urology Research Laboratory, Department Clinical Research, University of Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland
| | | | - Katia Monastyrskaya
- Urology Research Laboratory, Department Clinical Research, University of Bern, Switzerland; Department of Urology, University Hospital, Bern, Switzerland.
| |
Collapse
|
|
31
|
Computational functional genomics based analysis of pain-relevant micro-RNAs. Hum Genet 2015; 134:1221-38. [DOI: 10.1007/s00439-015-1600-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 09/01/2015] [Indexed: 02/07/2023]
|
|
32
|
Song JL, Nigam P, Tektas SS, Selva E. microRNA regulation of Wnt signaling pathways in development and disease. Cell Signal 2015; 27:1380-91. [PMID: 25843779 PMCID: PMC4437805 DOI: 10.1016/j.cellsig.2015.03.018] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 03/24/2015] [Accepted: 03/24/2015] [Indexed: 12/19/2022]
Abstract
Wnt signaling pathways and microRNAs (miRNAs) are critical regulators of development. Aberrant Wnt signaling pathways and miRNA levels lead to developmental defects and diverse human pathologies including but not limited to cancer. Wnt signaling pathways regulate a plethora of cellular processes during embryonic development and maintain homeostasis of adult tissues. A majority of Wnt signaling components are regulated by miRNAs which are small noncoding RNAs that are expressed in both animals and plants. In animal cells, miRNAs fine tune gene expression by pairing primarily to the 3'untranslated region of protein coding mRNAs to repress target mRNA translation and/or induce target degradation. miRNA-mediated regulation of signaling transduction pathways is important in modulating dose-sensitive response of cells to signaling molecules. This review discusses components of the Wnt signaling pathways that are regulated by miRNAs in the context of development and diseases. A fundamental understanding of miRNA functions in Wnt signaling transduction pathways may yield new insight into crosstalks of regulatory mechanisms essential for development and disease pathophysiology leading to novel therapeutics.
Collapse
Affiliation(s)
- Jia L Song
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
| | - Priya Nigam
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Senel S Tektas
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Erica Selva
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| |
Collapse
|
|
33
|
Su P, Zhao F, Cao Z, Zhang J, Aschner M, Luo W. Mir-203-mediated tricellulin mediates lead-induced in vitro loss of blood-cerebrospinal fluid barrier (BCB) function. Toxicol In Vitro 2015; 29:1185-94. [PMID: 25975750 DOI: 10.1016/j.tiv.2015.05.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2015] [Revised: 04/20/2015] [Accepted: 05/05/2015] [Indexed: 10/23/2022]
Abstract
The blood-cerebrospinal fluid barrier (BCB) plays a critical role in the maintenance of optimal brain function. Tricellulin (TRIC), a protein localized at the tricellular contact sites of epithelial cells is involved in the formation of tight junctions in various epithelial barriers. However, little is known about its expression in the choroidal epithelial cells. It is well established that lead (Pb) exposure increases the leakage of the BCB. The purpose of this study is to investigate the expression and localization of TRIC in choroidal epithelial cells in vitro and whether altered TRIC expression mediates Pb-induced loss of barrier function. We found that TRIC protein and mRNA were expressed in choroidal epithelial cells in vitro and TRIC was localized at the tricellular contacts, colocalizing with occludin. Downregulation of TRIC by siRNA increased the BCB permeability corroborated by altered transendothelial electrical resistance (TEER) and FITC-dextran flux. Treatment with 10μM Pb reduced TRIC protein expression, but overexpression of TRIC alleviated the Pb-induced increase in BCB permeability. Bioinformatics analysis showed that mir-203 was a potential microRNA (miRNA) binding motif on TRIC 3'UTR, and that Pb exposure increased the expression of mir-203. Treatment with a mir-203 inhibitor increased TRIC protein expression and attenuated the Pb-induced BCB leakage. Our results establish that TRIC plays an important role in regulating BCB function.
Collapse
Affiliation(s)
- Peng Su
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Fang Zhao
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Zipeng Cao
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Jianbin Zhang
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Wenjing Luo
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
| |
Collapse
|
|
34
|
Zhang J, Banerjee B. Role of MicroRNA in Visceral Pain. J Neurogastroenterol Motil 2015; 21:159-71. [PMID: 25843071 PMCID: PMC4398244 DOI: 10.5056/jnm15027] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 03/19/2015] [Accepted: 03/27/2015] [Indexed: 12/30/2022] Open
Abstract
The long-lasting nociceptive transmission under various visceral pain conditions involves transcriptional and/or translational alteration in neurotransmitter and receptor expression as well as modification of neuronal function, morphology and synaptic connections. Although it is largely unknown how such changes in posttranscriptional expression induce visceral pain, recent evidence strongly suggests an important role for microRNAs (miRNAs, small non-coding RNAs) in the cellular plasticity underlying chronic visceral pain. MicroRNAs are small noncoding RNA endogenously produced in our body and act as a major regulator of gene expression by either through cleavage or translational repression of the target gene. This regulation is essential for the normal physiological function but when disturbed can result in pathological conditions. Usually one miRNA has multiple targets and target mRNAs are regulated in a combinatorial fashion by multiple miRNAs. In recent years, many studies have been performed to delineate the posttranscriptional regulatory role of miRNAs in different tissues under various nociceptive stimuli. In this review, we intend to discuss the recent development in miRNA research with special emphases on miRNAs and their targets responsible for long term sensitization in chronic pain conditions. In addition, we review miRNAs expression and function data for different animal pain models and also the recent progress in research on miRNA-based therapeutic targets for the treatment of chronic pain.
Collapse
Affiliation(s)
- Jian Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin Milwaukee, WI , USA
| | - Banani Banerjee
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin Milwaukee, WI , USA
| |
Collapse
|
|
35
|
Hashemi Gheinani A, Burkhard FC, Rehrauer H, Aquino Fournier C, Monastyrskaya K. MicroRNA MiR-199a-5p regulates smooth muscle cell proliferation and morphology by targeting WNT2 signaling pathway. J Biol Chem 2015; 290:7067-86. [PMID: 25596533 DOI: 10.1074/jbc.m114.618694] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
MicroRNA miR-199a-5p impairs tight junction formation, leading to increased urothelial permeability in bladder pain syndrome. Now, using transcriptome analysis in urothelial TEU-2 cells, we implicate it in the regulation of cell cycle, cytoskeleton remodeling, TGF, and WNT signaling pathways. MiR-199a-5p is highly expressed in the smooth muscle layer of the bladder, and we altered its levels in bladder smooth muscle cells (SMCs) to validate the pathway analysis. Inhibition of miR-199a-5p with antimiR increased SMC proliferation, reduced cell size, and up-regulated miR-199a-5p targets, including WNT2. Overexpression of WNT2 protein or treating SMCs with recombinant WNT2 closely mimicked the miR-199a-5p inhibition, whereas down-regulation of WNT2 in antimiR-expressing SMCs with shRNA restored cell phenotype and proliferation rates. Overexpression of miR-199a-5p in the bladder SMCs significantly increased cell size and up-regulated SM22, SM α-actin, and SM myosin heavy chain mRNA and protein levels. These changes as well as increased expression of ACTG2, TGFB1I1, and CDKN1A were mediated by up-regulation of the smooth muscle-specific transcriptional activator myocardin at mRNA and protein levels. Myocardin-related transcription factor A downstream targets Id3 and MYL9 were also induced. Up-regulation of myocardin was accompanied by down-regulation of WNT-dependent inhibitory Krüppel-like transcription factor 4 in miR-199a-5p-overexpressing cells. In contrast, Krüppel-like transcription factor 4 was induced in antimiR-expressing cells following the activation of WNT2 signaling, leading to repression of myocardin-dependent genes. MiR-199a-5p plays a critical role in the WNT2-mediated regulation of proliferative and differentiation processes in the smooth muscle and may behave as a key modulator of smooth muscle hypertrophy, which is relevant for organ remodeling.
Collapse
Affiliation(s)
- Ali Hashemi Gheinani
- From the Urology Research Laboratory, Department Clinical Research, University of Bern, 3010 Bern, Switzerland
| | - Fiona C Burkhard
- Department of Urology, University Hospital, 3010 Bern, Switzerland, and
| | | | | | - Katia Monastyrskaya
- From the Urology Research Laboratory, Department Clinical Research, University of Bern, 3010 Bern, Switzerland,
| |
Collapse
|
|
36
|
Sun L, Zhu J, Wu M, Sun H, Zhou C, Fu L, Xu C, Mei C. Inhibition of MiR-199a-5p reduced cell proliferation in autosomal dominant polycystic kidney disease through targeting CDKN1C. Med Sci Monit 2015; 21:195-200. [PMID: 25588980 PMCID: PMC4304454 DOI: 10.12659/msm.892141] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND With a prevalence of about 1:500 to 1:1,000, autosomal dominant polycystic kidney disease (ADPKD) often causes renal failure, with many serious complications. However, there is no Food and Drug Administration (FDA) approved therapy available. MATERIAL/METHODS MiR-199a-5p level in ADPKD patient samples, rat model, and cell lines were determined with Realtime PCR assay. After miR-199a-5p inhibitor was transfected, we detected the cell proliferation and apoptosis using an MTT assay and an Annexin V-FITC staining kit, respectively. Finally, TargetScan version 5.1 was used to predict the miRNA target and the target gene of miR-199a-5p was proved by a Luciferase assay. RESULTS We identified a dramatically up-regulated microRNA, miR-199a-5p, in ADPKD tissues and cell lines. Our data show that inhibition of miR-199a-5p suppressed cyst cells proliferation and induced cell apoptosis. We found that miR-199a-5p might exert this effect through targeting CDKN1C/p57. CONCLUSIONS Up-regulation of miR-199a-5p in ADPKD tissues might promote cell proliferation through suppressing CDKN1C, suggesting miR-199a-5p as a novel target for ADPKD treatment.
Collapse
Affiliation(s)
- Lijun Sun
- Division of Nephrology, Nephrology Institute of CPLA, Changzheng Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Jiaqi Zhu
- Division of Nephrology, Nephrology Institute of CPLA, Changzheng Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Ming Wu
- Division of Nephrology, Nephrology Institute of CPLA, Changzheng Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Haipeng Sun
- Division of Nephrology, Nephrology Institute of CPLA, Changzheng Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Chenchen Zhou
- Division of Nephrology, Nephrology Institute of CPLA, Changzheng Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Lili Fu
- Division of Nephrology, Nephrology Institute of CPLA, Changzheng Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Chenggang Xu
- Division of Nephrology, Nephrology Institute of CPLA, Changzheng Hospital, Second Military Medical University, Shanghai, China (mainland)
| | - Changlin Mei
- Division of Nephrology, Nephrology Institute of CPLA, Changzheng Hospital, Second Military Medical University, Shanghai, China (mainland)
| |
Collapse
|
|
37
|
Abstract
Pain is an important protective system that alerts organisms to actual or possible tissue damage. However, a variety of pathologies can lead to chronic pain that is no longer beneficial. Lesions or diseases of the somatosensory nervous system cause intractable neuropathic pain that occasionally lasts even after the original pathology subsides. Chronic inflammatory diseases like arthritis are also associated with severe pain. Because conventional analgesics such as non-steroidal anti-inflammatory drugs and opioids have limited efficacy and/or severe adverse events associated with long-term use, chronic pain remains a major problem in clinical practice. Recently, causal roles of microRNAs in chronic pain and their therapeutic potential have been emerging. microRNA expressions are altered not only at the primary origin of pain, but also along the somatosensory pathways. Notably, microRNA expressions are differentially affected depending on the causes of chronic pain. This chapter summarizes current insights into the roles of microRNAs in pain based on the underlying pathologies.
Collapse
Affiliation(s)
- Atsushi Sakai
- Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan.
| | - Hidenori Suzuki
- Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan.
| |
Collapse
|
|
38
|
Contrast enhanced magnetic resonance imaging as a diagnostic tool to assess bladder permeability and associated colon cross talk: preclinical studies in a rat model. J Urol 2014; 193:1394-400. [PMID: 25463988 DOI: 10.1016/j.juro.2014.10.120] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2014] [Indexed: 12/13/2022]
Abstract
PURPOSE Interstitial cystitis/painful bladder syndrome is a devastating disease associated with multiple symptoms. It is usually diagnosed based on pain, urgency and frequency in the absence of other known causes. To our knowledge there is no diagnostic test to date. MATERIALS AND METHODS In a model of rats intravesically exposed to protamine sulfate we performed in vivo diagnostic contrast enhanced magnetic resonance imaging with intravesical administration of Gd-diethylenetriamine pentaacetic acid contrast medium via a catheter to visualize increased bladder urothelium permeability. Gd-diethylenetriamine pentaacetic acid was administered intravenously to visualize secondary tissue effects in the colon. RESULTS Bladder urothelium and colon mucosa were assessed 24 hours after bladder protamine sulfate exposure. Enhanced contrast magnetic resonance imaging established bladder urothelium leakage of Gd-diethylenetriamine pentaacetic acid according to the change in magnetic resonance imaging signal intensity in rats exposed to protamine sulfate vs controls (mean ± SD 399.7% ± 68.7% vs 39.2% ± 12.2%, p < 0.0001) as well as colon related uptake of contrast agent (mean 65.2% ± 17.1% vs 20.8% ± 9.8%, p < 0.01) after bladder protamine sulfate exposure. The kinetics of Gd-diethylenetriamine pentaacetic acid uptake and excretion were also assessed during 20 minutes of bladder and 30 minutes of colon exposure with increased signal intensity at 7 and 12 minutes, respectively. CONCLUSIONS These preliminary studies indicate that contrast enhanced magnetic resonance imaging can be used to monitor primary bladder urothelium loss of permeability and secondary enhanced contrast medium in the colon mucosa. It can be considered a potential clinical diagnostic method for interstitial cystitis/painful bladder syndrome that involves loss of the permeability barrier. It can also be used to assess visceral organ cross talk.
Collapse
|
|
39
|
Bali KK, Kuner R. Noncoding RNAs: key molecules in understanding and treating pain. Trends Mol Med 2014; 20:437-48. [PMID: 24986063 PMCID: PMC4123187 DOI: 10.1016/j.molmed.2014.05.006] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 05/22/2014] [Accepted: 05/28/2014] [Indexed: 12/14/2022]
Abstract
A comprehensive understanding of diverse ncRNAs in modulating pain is lacking. Among ncRNAs, miRNAs have been relatively well studied in pain regulation. lncRNAs also hold large potential for pain regulation. ncRNAs offer potential therapeutic options for treating chronic pain. Although noncoding RNAs (ncRNAs) were initially considered to be transcriptional byproducts, recent technological advances have led to a steady increase in our understanding of their importance in gene regulation and disease pathogenesis. In keeping with these developments, pain research is also experiencing rapid growth in the investigation of links between ncRNAs and pathological pain. Although the initial focus was on analyzing expression and dysregulation of candidate miRNAs, elucidation of other ncRNAs and ncRNA-mediated functional mechanisms in pain modulation has just commenced. Here we review the major ncRNA literature available to date with respect to pain modulation and discuss tools and opportunities available for testing the impact of other types of ncRNA on pain.
Collapse
Affiliation(s)
- Kiran Kumar Bali
- Institute for Pharmacology, Im Neuenheimer Feld 366, Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit with European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
| | - Rohini Kuner
- Institute for Pharmacology, Im Neuenheimer Feld 366, Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit with European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
| |
Collapse
|
|
40
|
Yang H, Rao JN, Wang JY. Posttranscriptional Regulation of Intestinal Epithelial Tight Junction Barrier by RNA-binding Proteins and microRNAs. Tissue Barriers 2014; 2:e28320. [PMID: 24843843 PMCID: PMC4022605 DOI: 10.4161/tisb.28320] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 02/16/2014] [Accepted: 02/21/2014] [Indexed: 12/19/2022] Open
Abstract
Intestinal epithelial tight junctions (TJs) are a specialized structure that determines the cell polarity and prevents the diffusion of toxins, allergens, and pathogens from the lumen into the tissue. TJs are highly dynamic and its constituent protein complexes undergo continuously remodeling and turnover under tight regulation by numerous extracellular and intracellular factors. RNA-binding proteins (RBPs) and microRNAs (miRNAs) regulate gene expression at the posttranscriptional level and are involved in many aspects of cellular physiology. An increasing body of evidence indicates that RBPs including HuR and CUG-binding protein 1 and miRNAs such as miR-192 modulate the stability and translation of mRNAs encoding TJ proteins and play an important role in the control of intestinal epithelial TJ barrier function. In this mini-review article, we highlight the changes in TJ expression and intestinal epithelial TJ barrier function after activation or inactivation of RBPs and miRNAs and further analyze in some detail the mechanisms through which the stability and translation of TJ mRNAs are regulated by RBPs and miRNAs.
Collapse
Affiliation(s)
- Hong Yang
- Cell Biology Group; Department of Surgery; University of Maryland School of Medicine; Baltimore, MD USA ; Baltimore Veterans Affairs Medical Center; Baltimore, MD USA
| | - Jaladanki N Rao
- Cell Biology Group; Department of Surgery; University of Maryland School of Medicine; Baltimore, MD USA ; Baltimore Veterans Affairs Medical Center; Baltimore, MD USA
| | - Jian-Ying Wang
- Cell Biology Group; Department of Surgery; University of Maryland School of Medicine; Baltimore, MD USA ; Department of Pathology; University of Maryland School of Medicine; Baltimore, MD USA ; Baltimore Veterans Affairs Medical Center; Baltimore, MD USA
| |
Collapse
|
|
41
|
Nadorp B, Soreq H. Predicted overlapping microRNA regulators of acetylcholine packaging and degradation in neuroinflammation-related disorders. Front Mol Neurosci 2014; 7:9. [PMID: 24574962 PMCID: PMC3918661 DOI: 10.3389/fnmol.2014.00009] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 01/21/2014] [Indexed: 01/13/2023] Open
Abstract
MicroRNAs (miRNAs) can notably control many targets each and regulate entire cellular pathways, but whether miRNAs can regulate complete neurotransmission processes is largely unknown. Here, we report that miRNAs with complementary sequence motifs to the key genes involved in acetylcholine (ACh) synthesis and/or packaging show massive overlap with those regulating ACh degradation. To address this topic, we first searched for miRNAs that could target the 3′-untranslated regions of the choline acetyltransferase (ChAT) gene that controls ACh synthesis; the vesicular ACh transporter (VAChT), encoded from an intron in the ChAT gene and the ACh hydrolyzing genes acetyl- and/or butyrylcholinesterase (AChE, BChE). Intriguingly, we found that many of the miRNAs targeting these genes are primate-specific, and that changes in their levels associate with inflammation, anxiety, brain damage, cardiac, neurodegenerative, or pain-related syndromes. To validate the in vivo relevance of this dual interaction, we selected the evolutionarily conserved miR-186, which targets both the stress-inducible soluble “readthrough” variant AChE-R and the major peripheral cholinesterase BChE. We exposed mice to predator scent stress and searched for potential associations between consequent changes in their miR-186, AChE-R, and BChE levels. Both intestinal miR-186 as well as BChE and AChE-R activities were conspicuously elevated 1 week post-exposure, highlighting the previously unknown involvement of miR-186 and BChE in psychological stress responses. Overlapping miRNA regulation emerges from our findings as a recently evolved surveillance mechanism over cholinergic neurotransmission in health and disease; and the corresponding miRNA details and disease relevance may serve as a useful resource for studying the molecular mechanisms underlying this surveillance.
Collapse
Affiliation(s)
- Bettina Nadorp
- Department of Biological Chemistry and the Center for Bioengineering, The Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem Jerusalem, Israel
| | - Hermona Soreq
- Department of Biological Chemistry and the Center for Bioengineering, The Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem Jerusalem, Israel
| |
Collapse
|
|
42
|
Kynast KL, Russe OQ, Geisslinger G, Niederberger E. Novel findings in pain processing pathways: implications for miRNAs as future therapeutic targets. Expert Rev Neurother 2014; 13:515-25. [DOI: 10.1586/ern.13.34] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
|
|
43
|
Tan PH, Pao YY, Cheng JK, Hung KC, Liu CC. MicroRNA-based therapy in pain medicine: Current progress and future prospects. ACTA ACUST UNITED AC 2013; 51:171-6. [PMID: 24529673 DOI: 10.1016/j.aat.2013.11.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 11/14/2013] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are small noncoding RNA molecules of 18-25 nucleotides in length that regulate gene expression involved in fundamental cell processes. The induction and chronification of pain is associated with many expressional changes in pain-related proteins. miRNA has the potential to regulate gene and protein expression associated with the induction and chronification of pain. Thus, miRNAs might have promise in therapy and as a diagnostic and prognostic biomarker in pain medicine. The application of miRNA has been an emerging field in pain research in recent years. Many studies focusing on the regulation of miRNAs under different tissue and nociceptive stimuli have been performed in recent years. In this review, we intend to introduce the most recent research in the field of miRNA related with pain medicine such as the expression and function of miRNA in different animal pain model, the challenge of application and delivery of miRNA in vivo, the potential toxic effects of miRNA and future problems in clinical application that need to be resolved. This review focuses on the results of miRNA in animal studies and the prospect for future success.
Collapse
Affiliation(s)
- Ping-Heng Tan
- Department of Anesthesiology, E-Da Hospital, Kaohsiung, Taiwan; School of Medicine, I-Shou University, Kaohsiung, Taiwan.
| | - Yun-Ying Pao
- Department of Anesthesiology, E-Da Hospital, Kaohsiung, Taiwan
| | - Jen-Kun Cheng
- Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan
| | - Kuo-Chuan Hung
- Department of Anesthesiology, E-Da Hospital, Kaohsiung, Taiwan
| | - Chien-Cheng Liu
- Department of Anesthesiology, E-Da Hospital, Kaohsiung, Taiwan
| |
Collapse
|
|
44
|
Gheinani AH, Burkhard FC, Monastyrskaya K. Deciphering microRNA code in pain and inflammation: lessons from bladder pain syndrome. Cell Mol Life Sci 2013; 70:3773-89. [PMID: 23463234 PMCID: PMC11113193 DOI: 10.1007/s00018-013-1275-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Revised: 01/22/2013] [Accepted: 01/28/2013] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs), a novel class of molecules regulating gene expression, have been hailed as modulators of many biological processes and disease states. Recent studies demonstrated an important role of miRNAs in the processes of inflammation and cancer, however, there are little data implicating miRNAs in peripheral pain. Bladder pain syndrome/interstitial cystitis (BPS/IC) is a clinical syndrome of pelvic pain and urinary urgency/frequency in the absence of a specific cause. BPS is a chronic inflammatory condition that might share some of the pathogenetic mechanisms with its common co-morbidities inflammatory bowel disease (IBD), asthma and autoimmune diseases. Using miRNA profiling in BPS and the information about validated miRNA targets, we delineated the signaling pathways activated in this and other inflammatory pain disorders. This review projects the miRNA profiling and functional data originating from the research in bladder cancer and immune-mediated diseases on the BPS-specific miRNAs with the aim to gain new insight into the pathogenesis of this enigmatic disorder, and highlighting the common regulatory mechanisms of pain and inflammation.
Collapse
Affiliation(s)
- Ali Hashemi Gheinani
- Department of Clinical Research, Urology Research Laboratory, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland
| | | | - Katia Monastyrskaya
- Department of Clinical Research, Urology Research Laboratory, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland
| |
Collapse
|