Role Of miR-155 In Regulation Research Articles

MicroRNA-155 expression is associated with pulpitis progression by targeting SHIP1.

Pulpitis is a commonly seen oral inflammation condition in clinical practice, it can cause much pain for the patient and may induce infections in other systems. Much is still unknown for the pathogenic mechanism of pulpitis. In this work, we discovered that the expression of miR-155 was associated with dental pulpal inflammation both in vivo and in vitro. Our experiments of LPS stimulated odontoblast cell line MDPC-23 showed miR-155 could act as a positive regulator by increasing the production of pro-inflammatory cytokines IL-1β and IL-6 during inflammatory responses, whereas knockdown of miR-155 can reverse the effects. Bioinformatics analysis demonstrated that SHIP1 is a direct target of miR-155 in odontoblasts, this result was further verified at both mRNA and protein level. Inhibition of miR-155 resulted in the downregulation of inflammation factors, while co-transfection of si-SHIP1 and miR-155 inhibitor promoted the inflammatory responses. Treatment with miR-155 mimic or si-SHIP1 up-regulated the protein level of p-PI3K and p-AKT. By contrast, miR-155 inhibitor exerted the opposite effects. miR-155 mimics could upregulate the gene expression of IL-1β and IL-6. Co-transfection of LY294002 and miR-155 mimic attenuated the inflammatory responses. Consistent with in vitro results, miR-155-/- mice could alleviate inflammatory response, as well as decrease the activation of p-PI3K and p-AKT, whereas increase the activation of SHIP1. Our data revealed a novel role for miR-155 in regulation of dental pulpal inflammatory response by targeting SHIP1 through PI3K/AKT signaling pathway.

Induction of miR-155 after Brain Injury Promotes Type 1 Interferon and has a Neuroprotective Effect.

Traumatic brain injury (TBI) produces profound and lasting neuroinflammation that has both beneficial and detrimental effects. Recent evidence has implicated microRNAs (miRNAs) in the regulation of inflammation both in the periphery and the CNS. We examined the expression of inflammation associated miRNAs in the context of TBI using a mouse controlled cortical impact (CCI) model and found increased levels of miR-21, miR-223 and miR-155 in the hippocampus after CCI. The expression of miR-155 was elevated 9-fold after CCI, an increase confirmed by in situ hybridization (ISH). Interestingly, expression of miR-155 was largely found in neuronal nuclei as evidenced by co-localization with DAPI in MAP2 positive neurons. In miR-155 knock out (KO) mice expression of type I interferons IFNα and IFNβ, as well as IFN regulatory factor 1 and IFN-induced chemokine CXCL10 was decreased after TBI relative to wild type (WT) mice. Unexpectedly, miR-155 KO mice had increased levels of microglial marker Iba1 and increased neuronal degeneration as measured by fluoro-jade C (FJC) staining, suggesting a neuroprotective role for miR-155 in the context of TBI. This work demonstrates a role for miR-155 in regulation of the IFN response and neurodegeneration in the aftermath of TBI. While the presence of neuronal nuclear miRNAs has been described previously, their importance in disease states is relatively unknown. Here, we show evidence of dynamic regulation and pathological function of a nuclear miRNA in TBI.

MicroRNA-155 promotes atherosclerosis-signaling pathway through targeting gene/SOCS1 and IRAKM

MiR-155 plays a role in the regulates various aspects of innate and adaptive immune response, physiological and pathological processes. Exogenous molecular control in vivo of miR-155 expression may inhibit malignant growth, viral infections, and attenuate the progression of cardiovascular diseases. Up-regulation of proinflammatory cytokines plays a central role in atherosclerosis. In this study, we investigated the role of miR-155 in regulating proinflammatory response in atherosclerosis. Hyperlipidemic C57BL/6 male mice model were fed with atherogenic-diet for 12-weeks. MiR-155 positively regulates proinflammatory cytokines and we found increased TNFα, IL-1b, IL-6 mRNA and NF-kB in hyperlipidemic mice. Furthermore, increased miR-155 levels are correlated with proinflammatory cytokine expression in hyperlipidemic mice. To understand the mechanism by which miR-155 regulates proinflammatory cytokines in atherosclerosis, we evaluated the miR-155 target genes SOCS1 and IRAKM. We found increased miR-155 and decreased expression of SOCS1 and IRAKM in hyperlipidemic mice. Interestingly inhibition of miR-155 by using a specific miR-155 silencing, inhibited proinflammatory cytokine in hyperlipidemic mice, suggesting a role of miR-155 in immune response regulation. Based on these observations, we conclude that miR-155 modulates proinflammatory response in hyperlipidemic mice via regulation of SOCS1 and IRAKM expression. Thus, modulation of miR-155 could be a strategy to regulate atherogenic diet-induced atherosclerosis where proinflammatory cytokine plays significant role in disease progression.

Overexpression of miR -155 Promotes Proliferation and Invasion of Human Laryngeal Squamous Cell Carcinoma via Targeting SOCS1 and STAT3

MicroRNA155 plays an important role in many solid malignancies. Expression and function of miR-155 in laryngeal carcinoma have not been fully understood. This study aims to investigate the expression and function of miR-155 in laryngeal squamous cell carcinoma (LSCC), the relationship between miR-155 and its downstream target suppressor of cytokine signaling 1 (SOCS1)-STAT3 pathway, and the related clinicopathological factors. Sixty-three samples of laryngeal squamous cell carcinoma and twenty-one samples of control mucosa obtained from total laryngectomy cases were analyzed using Western blot analysis and real-time PCR. Hep-2 cells were cultured and transfected with miR-155 mimic and ASO. Cell proliferation, migration and invasion assays were used to determine the role of miR-155 in regulation of LSCC growth, migration, and invasion, respectively. The expression levels of miR-155 in LSCC were significantly higher than those in the control mucosa tissues. Downregulation of SOCS1 expression and elevated expression of STAT3 were also observed in LSCC. The relevance of the three factors were statistically significant. Moreover, knockdown of miR-155 elevated SOCS1expression level, suppressed STAT3 expression, and inhibited hep-2 cells growth, migration and invasion. Whereas overexpression of miR-155 inhibited SOCS1expression, elevated STAT3 expression, and promoted hep-2 cells growth, migration and invasion. Furthermore, the miR-155 levels in T3 T4 stages, and poor/moderate cell differentiation were significantly higher than those in T2 stage and higher degree of cell differentiation. The STAT3 protein in poor/moderate cell differentiation was significantly higher than those in higher degree of cell differentiation. We firstly demonstrated the aberrant expression and function of miR-155 and itsdownstream targets in LSCC. The current findings suggest that miR-155 play promotingrole during the development of LSCC, and miR-155 may be a useful marker for the prognosis and assessment of therapeutic effects.

MicroRNA-155 regulates inflammation in alcoholic liver disease via targeting SOCS1 and SHIP1 (54.15)

Abstract Background Fatty liver and inflammation characterize alcoholic liver disease (ALD). Sensitization of liver macrophages (Kupffer cells; KCs) to gut-derived LPS and increased TNFα play a central role in ALD. MicroRNA-155 (miR) is a master regulator of inflammation. In this study we evaluated the role of miR-155 in regulating inflammation after chronic alcohol feeding. Methods C57Bl/6 female mice were fed with 5% alcohol (Liber-DeCarli diet) for 4 weeks and total liver and KCs were isolated. Results MiR-155 positively regulates TNFα and we found increased TNFα mRNA and protein in KCs of alcohol-fed mice. Furthermore increased miR-155 levels correlated with TNFα production in KCs of alcohol-fed mice. To dissect the mechanism by which miR-155 regulates TNFα in ALD, we evaluated the miR-155 target genes SOCS1, SHIP1 and IRAKM that are negative regulators of LPS signaling. We found increased miR-155 and decreased expression of SOCS1, SHIP1 and IRAKM in KCs of alcohol-fed mice. Importantly inhibition of miR-155 by using a specific miR-155 inhibitor, inhibited TNFα production in KCs of alcohol-fed mice, suggesting a role of miR-155 in TNFα regulation. C/EBPβ, another miR-155 target, regulates monocyte maturation and cytokine production. We found increased miR-155 and decreased DNA binding of C/EBPβ in livers of alcohol-fed mice. Conclusion Collectively our results indicate that alcohol induced-miR-155 contributes to inflammation via targeting multiple genes of LPS/TLR4 signaling.

Abstract 3986: MicroRNA-155 regulates angiogenesis by targeting Von Hippel-Lindau (VHL) tumor suppressor

Abstract Expression of microRNA-155 (miR-155) is frequently up-regulated in various types of human malignancy, including different forms of B cell lymphoma and carcinoma of breast, lung, colon, head/neck, and kidney; however, its role in cancer angiogenesis remains undefined. In this study, we demonstrate the critical role of miR-155 in regulation of angiogenesis through down-regulation of VHL; in addition we show elevated miR-155 levels in breast cancer correlates to high grade and late stage tumor as well as metastasis and poor overall survival. Stable ectopic expression of miR-155 in human umbilical vein endothelial cells induces tube formation in the absence of VEGF; whereas knockdown of miR-155 inhibits tube formation in the presence of VEGF. Further, we identified VHL as a direct target of miR-155. Stable overexpression of miR-155 results in repression of VHL protein; and knockdown of miR-155 rescues VHL expression. Introduction of VHL cDNA lacking 3’ untranslated region abrogates miR-155 induced tube formation. In addition, evaluation of miR-155 expression in primary breast cancers and normal mammary tissues show miR-155 high in 67 of 154 (43.5%) patients with breast cancer as compared to normal breast tissues. Elevated miR-155 is associated with high grade (49/76, 64.5%) versus low grade (18/78, 23.1%) and late stage (37/70, 52.9%) versus early stage (30/84, 35.7%) as well as invasive (53/85, 62.4%) versus non-invasive (14/69, 20.3%) breast carcinoma. Interestingly, miR-155 is also frequently overexpressed in lymph node-positive tumor (i.e., ≥ 10; 20/32, 62.5%) than node-negative (i.e., < 10; 47/122, 38.2%). Furthermore, patients whose tumors express high levels of miR-155 have shorter overall survival than those of tumors with low levels of miR-155. Our findings indicate that miR-155 plays an important role in tumor angiogenesis by targeting VHL and could be a prognostic marker and a critical therapeutic target in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3986. doi:10.1158/1538-7445.AM2011-3986

MicroRNA-155 Regulates Cell Survival, Growth, and Chemosensitivity by Targeting FOXO3a in Breast Cancer

Breast cancer is the second leading cause of cancer death in women. Despite improvement in treatment over the past few decades, there is an urgent need for development of targeted therapies. miR-155 (microRNA-155) is frequently up-regulated in breast cancer. In this study, we demonstrate the critical role of miR-155 in regulation of cell survival and chemosensitivity through down-regulation of FOXO3a in breast cancer. Ectopic expression of miR-155 induces cell survival and chemoresistance to multiple agents, whereas knockdown of miR-155 renders cells to apoptosis and enhances chemosensitivity. Further, we identified FOXO3a as a direct target of miR-155. Sustained overexpression of miR-155 resulted in repression of FOXO3a protein without changing mRNA levels, and knockdown of miR-155 increases FOXO3a. Introduction of FOXO3a cDNA lacking the 3'-untranslated region abrogates miR-155-induced cell survival and chemoresistance. Finally, inverse correlation between miR-155 and FOXO3a levels were observed in a panel of breast cancer cell lines and tumors. In conclusion, our study reveals a molecular link between miR-155 and FOXO3a and presents evidence that miR-155 is a critical therapeutic target in breast cancer.