Role Of Ring Finger Protein Research Articles

Association of KRAS, NRAS, BRAF and PIK3CA gene mutations with clinicopathological features, prognosis and ring finger protein 215 expression in patients with colorectal cancer.

The relationships of KRAS, NRAS, BRAF and PIK3CA gene mutations with the clinicopathological features and prognosis of colorectal cancer (CRC) in patient are lacking. Furthermore, the role of ring finger protein 215 (RNF215) in CRC patients with KRAS, NRAS, BRAF and PIK3CA mutations remains unclear. In the present study, 182 surgical resection specimens from patients with primary CRC for retrospective analysis, were collected. KRAS/NRAS/BRAF/PIK3CA gene mutations were confirmed by an amplification-refractory mutation system. Immunohistochemistry (IHC) was conducted to confirm KRAS, NRAS, BRAF and PIK3CA protein expression. RNF215 expression in patients with CRC was evaluated using TIMER 2.0 database and IHC. The individual mutation rates of KRAS, NRAS, BRAF and PIK3CA were 40.7% (74/182), 4.4% (8/182), 4.4% (8/182) and 3.3% (6/182), respectively. The KRAS exon 2 mutation rate was the highest (61.5%, 64/104), and these mutations mainly occurred at codons 12 and 13. KRAS/NRAS/BRAF/PIK3CA wild-type CRC patients had significantly longer overall survival and disease-free survival than mutated KRAS/NRAS/BRAF/PIK3CA CRC patients (P<0.05). Overall, 45.4% (5/11) of patients with PIK3CA mutations had concomitant KRAS mutations. The KRAS/NRAS/BRAF/PIK3CA gene mutation rate in patients with lymph node metastasis (76.1%, 35/46) was significantly higher than that in patients without lymph node metastasis (50.8%, 69/136) (P=0.0027). There were no significant differences in IHC expression between patients with and without KRAS, NRAS, BRAF and PIK3CA mutations (P>0.05). The TIMER 2.0 analysis showed that RNF215 expression was significantly higher in the mutated BRAF group than in the wild-type BRAF group in CRC (P<0.05). In conclusion, KRAS is the most commonly mutated gene, and KRAS mutations may be a poor prognostic factor for patients with CRC. KRAS wild-type patient resistance may be related to PIK3CA gene mutations, although this needs further verification in larger cohorts. BRAF mutations may be associated with RNF215 expression in patients with CRC.

RNF152 Suppresses Fatty Acid Oxidation and Metastasis of Lung Adenocarcinoma by Inhibiting IRAK1-Mediated AKR1B10 Expression

Lung adenocarcinoma (LUAD) is a common subtype of primary lung cancer. Fatty acid oxidation plays a key role in LUAD development by providing energy for tumor cells. This study aimed to identify the role of ring finger protein 152 (RNF152) in LUAD. RNF152 was down-regulated in LUAD, and low RNF152 expression correlated with a poor prognosis in LUAD patients. RNF152 overexpression inhibited the proliferation and malignant phenotype of LUAD cells, whereas RNF152 knockdown exerted an opposite effect. Tumor cells overexpressing RNF152 showed less fatty acid oxidation compared with control cells, whereas RNF152 knockdown induced fatty acid uptake and oxidation. Further analysis revealed the binding reaction between RNF152 and interleukin-1 receptor-associated kinase 1 (IRAK1). RNF152 reduced the stability of IRAK1 in LUAD cells by promoting its ubiquitination. RNF152-overexpressed tumor cells exhibited a significantly lower level of Aldo-Keto reductase family 1 member 10 (AKR1B10), whereas up-regulation of IRAK1 restored the expression of AKR1B10 in RNF152-overexpressed cells. Furthermore, up-regulation of IRAK1 eliminated the antitumor effect of RNF152 in LUAD cells. Mouse xenograft models confirmed the inhibitory effect of RNF152 on the tumorigenesis and metastasis of LUAD. Taken together, RNF152 played a tumor suppressive role in LUAD by promoting IRAK1 ubiquitination and IRAK1-mediated down-regulation of AKR1B10, thereby reversing the malignant phenotype of LUAD.

Ring finger protein 10 improves pirarubicin-induced cardiac inflammation by regulating the AP-1/Meox2 signaling pathway

ObjectivesPirarubicin (THP) is widely used in clinical antitumor therapy, but its cardiotoxicity seriously affects the therapeutic effect in patients. In the study, we investigated the role of ring finger protein 10 (RNF10) in cardiotoxicity induced by THP. Materials and methodsA cardiac toxicity model in Sprague-Dawley (SD) rats induced by THP was established. Changes in diet, weight, electrocardiogram (ECG), and echocardiography were observed. Serum levels of brain natriuretic peptide (BNP), creatine kinase MB (CK-MB), cardiac troponin T (cTnT), and lactate dehydrogenase (LDH) were measured. The expression of RNF10 in myocardium was observed by immunohistochemistry. The expressions of RNF10, activator protein-1 (AP-1), mesenchyme homeobox 2 (Meox2), total nuclear factor (NF)-κB p65 (T-P65), phosphorylated NF-κB p65 (PP65), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and mature IL-1β were detected by Western blot. A THP-induced H9c2 myocardial cell injury model was established. RNF10 was downregulated or overexpressed by RNF10 siRNA and a RNF10 lentiviral vector, respectively. Then, cell viability was measured. The expression of RNF10 in H9c2 cells was observed by immunofluorescence. All of the above signaling pathways were verified by Western blots. FindingsTHP caused a series of cardiotoxic manifestations in SD rats. Our studies suggested that THP caused cardiac inflammation by inhibiting the expression of RNF10, while overexpression of RNF10 antagonized the cardiotoxicity induced by THP. SignificanceOur study showed RNF10 improved THP-induced cardiac inflammation by regulating the AP-1/Meox2 signaling pathway. RNF10 may be a new target to treat THP-induced cardiotoxicity.

The E3 Ubiquitin Ligase Ring Finger Protein 5 Ameliorates NASH Through Ubiquitin-Mediated Degradation of 3-Hydroxy-3-Methylglutaryl CoA Reductase Degradation Protein 1.

NAFLD is the most prevalent chronic liver disease worldwide, but no effective pharmacological therapeutics are available for clinical use. NASH is the more severe stage of NAFLD. During this progress, dysregulation of endoplasmic reticulum (ER)-related pathways and proteins is one of the predominant hallmarks. We aimed to reveal the role of ring finger protein 5 (RNF5), an ER-localized E3 ubiquitin-protein ligase, in NASH and to explore its underlying mechanism. We first inspected the expression level of RNF5 and found that it was markedly decreased in livers with NASH in multiple species including humans. We then introduced adenoviruses for Rnf5 overexpression or knockdown into primary mouse hepatocytes and found that palmitic acid/oleic acid (PAOA)-induced lipid accumulation and inflammation in hepatocytes were markedly attenuated by Rnf5 overexpression but exacerbated by Rnf5 gene silencing. Hepatocyte-specific Rnf5 knockout significantly exacerbated hepatic steatosis, inflammatory response, and fibrosis in mice challenged with diet-induced NASH. Mechanistically, we identified 3-hydroxy-3-methylglutaryl CoA reductase degradation protein 1 (HRD1) as a binding partner of RNF5 by systematic interactomics analysis. RNF5 directly bound to HRD1 and promoted its lysine 48 (K48)-linked and K33-linked ubiquitination and subsequent proteasomal degradation. Furthermore, Hrd1 overexpression significantly exacerbated PAOA-induced lipid accumulation and inflammation, and short hairpin RNA-mediated Hrd1 knockdown exerted the opposite effects. Notably, Hrd1 knockdown significantly diminished PAOA-induced lipid deposition, and up-regulation of related genes resulted from Rnf5 ablation in hepatocytes. These data indicate that RNF5 inhibits NASH progression by targeting HRD1 in the ubiquitin-mediated proteasomal pathway. Targeting the RNF5-HRD1 axis may provide insights into the pathogenesis of NASH and pave the way for developing strategies for NASH prevention and treatment.

RNF43 is a Novel Tumor Suppressor and Prognostic Indicator in Clear Cell Renal Cell Carcinoma.

Identifying prognostic indicators of clear cell renal cell carcinoma (ccRCC) and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis. This study investigated the clinical significance and biological role of Ring finger protein 43 ( RNF43) in ccRCC. Two independent cohorts of patients with ccRCC were employed to determine the prognostic significance of RNF43 by immunohistochemistry and statistical analyses. In vitro and in vivo experiments, RNA-seq, and other techniques were used to determine the biological role of RNF43 in ccRCC and related molecular mechanisms. RNF43 expression was commonly decreased in ccRCC specimens, and low expression of RNF43 indicated a higher TNM stage, SSIGN score, and WHO/ISUP grade and short survival in patients with ccRCC. Additionally, RNF43 overexpression suppressed the proliferation, migration, and targeted drug resistance of ccRCC cells, while the knockdown of RNF43 enhanced these characteristics of ccRCC. RNF43 knockdown activated YAP signaling by decreasing YAP phosphorylation by p-LATS1/2 and increasing the transcription and nuclear distribution of YAP. By contrast, RNF43 overexpression showed the opposite effects. Decreasing YAP abolished the effect of RNF43 knockdown in promoting the malignant features of ccRCC. Additionally, restoring RNF43 expression suppressed the resistance of the targeted drug pazopanib in in vivo orthotopic ccRCC. Furthermore, combining the expression of RNF43 andYAP with TNM stage or the SSIGN score exhibited greater accuracy than any of these indicators alone in assessing the postoperative prognosis of ccRCC patients. In summary, our study identified a novel tumor suppressor, RNF43, which is also a prognostic indicator and potential target for ccRCC potential target for ccRCC.

RNF43 is a novel tumor-suppressor and prognostic indicator in clear cell renal cell carcinoma.

Identifying prognostic indicators of clear cell renal cell carcinoma (ccRCC) and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis. This study investigated the clinical significance and biological role of Ring finger protein 43 (RNF43) in ccRCC. Two independent cohorts of patients with ccRCC were employed to determine the prognostic significance of RNF43 by immunohistochemistry and statistical analyses. In vitro and in vivo experiments, RNA-seq, and other techniques were used to determine the biological role of RNF43 in ccRCC and related molecular mechanisms. RNF43 expression was commonly decreased in ccRCC specimens, and low expression of RNF43 indicated a higher TNM stage, SSIGN score, and WHO/ISUP grade and short survival in patients with ccRCC. Additionally, RNF43 overexpression suppressed the proliferation, migration, and targeted drug resistance of ccRCC cells, while the knockdown of RNF43 enhanced these characteristics of ccRCC. RNF43 knockdown activated YAP signaling by decreasing YAP phosphorylation by p-LATS1/2 and increasing the transcription and nuclear distribution of YAP. By contrast, RNF43 overexpression showed the opposite effects. Decreasing YAP abolished the effect of RNF43 knockdown in promoting the malignant features of ccRCC. Additionally, restoring RNF43 expression suppressed the resistance of the targeted drug pazopanib in in vivo orthotopic ccRCC. Furthermore, combining the expression of RNF43 and YAP with TNM stage or the SSIGN score exhibited greater accuracy than any of these indicators alone in assessing the postoperative prognosis of ccRCC patients. In summary, our study identified a novel tumor suppressor, RNF43, which is also a prognostic indicator and potential target for ccRCC.

Identification of the potential roles of ring finger protein 8 in TP53-mutant breast cancer.

Breast cancer is one of the malignant tumors with the highest mortality rate. With the development of precise treatment technology for cancer, numerous molecular targets have been identified and applied in the treatment of diseases. The present study investigated the potential role of ring finger protein 8 (RNF8) in TP53-mutant breast cancer and explored its possible mechanisms of action through a combination of bioinformatics techniques and cell biology. The results revealed that significantly different genes were expressed in RNF8-knockout mice sequencing data compared with in the control group in the presence of TP53 mutations. Downregulated genes were significantly enriched in several pathways of cell proliferation and apoptosis regulation, development and transcription regulation, while upregulated genes were mainly enriched in immune response-associated signaling pathways. Therefore, the consensus genes of the major signaling pathways were further analyzed, revealing that among patients with TP53 wild-type breast cancer, the prognosis of patients with low expression levels of fibroblast growth factor receptor 1, LIM homeobox 2 and EPH receptor B2 was improved compared with that of patients with high expression levels, while among patients with TP53-mutant breast cancer, there was no significant difference in survival status. In addition, among patients with TP53-mutant breast cancer, the prognosis of patients with high BR serine/threonine kinase 1 expression was significantly improved compared with that in patients with low expression. Finally, cell biology experiments demonstrated that in TP53-mutant breast cancer cells (HCC1937), inhibition of RNF8 significantly inhibited the proliferation of TP53-mutant HCC1937 cells and promoted their apoptosis. The present findings may enrich the understanding of the role of RNF8 and indicated that RNF8 may be used as a potential molecular target in TP53-mutant breast cancer, which may lead to the development of clinical treatment strategies.

Ring Finger Protein 11 (RNF11) Modulates Dopamine Release in Drosophila

Recent work indicates a role for RING finger protein 11 (RNF11) in Parkinson disease (PD) pathology, which involves the loss of dopaminergic neurons. However, the role of RNF11 in regulating dopamine neurotransmission has not been studied. In this work, we tested the effect of RNF11 RNAi knockdown or overexpression on stimulated dopamine release in the larval Drosophila central nervous system. Dopamine release was stimulated using optogenetics and monitored in real-time using fast-scan cyclic voltammetry at an electrode implanted in an isolated ventral nerve cord. RNF11 knockdown doubled dopamine release, but there was no decrease in dopamine from RNF11 overexpression. RNF11 knockdown did not significantly increase stimulated serotonin or octopamine release, indicating the effect is dopamine specific. Dopamine clearance was also changed, as RNF11 RNAi flies had a higher Vmax and RNF11 overexpressing flies had a lower Vmax than control flies. RNF11 RNAi flies had increased mRNA levels of dopamine transporter (DAT) in RNF11, confirming changes in DAT. In RNF11 RNAi flies, release was maintained better for stimulations repeated at short intervals, indicating increases in the recycled releasable pool of dopamine. Nisoxetine, a DAT inhibitor, and flupenthixol, a D2 antagonist, did not affect RNF11 RNAi or overexpressing flies differently than control. Thus, RNF11 knockdown causes early changes in dopamine neurotransmission, and this is the first work to demonstrate that RNF11 affects both dopamine release and uptake. RNF11 expression decreases in human dopaminergic neurons during PD, and that decrease may be protective by increasing dopamine neurotransmission in the surviving dopaminergic neurons.

Ring finger protein 180 is associated with biological behavior and prognosis in patients with non-small cell lung cancer.

There are few studies on the role of ring finger protein (RNF)180 in non-small cell lung cancer (NSCLC). The present study investigated the expression of RNF180 in NSCLC and its associations with the clinical factors and prognosis of NSCLC. The mRNA and protein expression levels of RNF180 were detected via reverse transcription-quantitative PCR and western blotting. Methylation-specific PCR (MSP) analysis was utilized to detect the methylation of RNF180. RNF180 expression levels were analyzed via immunohistochemistry. The protein and mRNA expression levels of RNF180 were lower in NSCLC cell lines compared with in the non-tumor cell line. Immunohistochemistry revealed that 64 patients that were negative for RNF180, while MSP detection analysis demonstrated that 60 patients exhibited RNF180 promoter methylation. The methylation status of RNF180 was significantly associated with RNF180 expression level. Among all factors evaluated, logistic regression analysis indicated that only T stage was significantly associated with RNF180 expression. Cox multivariate analysis demonstrated that RNF180 expression was an independent predictor of overall survival in patients with NSCLC. Methylation in the promoter of RNF180 was shown to reduce its expression levels. In summary, low RNF180 expression levels were associated with poor biological behaviors, thus RNF180 expression level may be used as a clinical marker to predict the prognosis of patients with NSCLC.

Ring finger protein 121 is a potent regulator of adeno-associated viral genome transcription.

Adeno-associated viruses (AAV) are Dependoparvoviruses that have shown promise as recombinant vectors for gene therapy. While infectious pathways of AAV are well studied, gaps remain in our understanding of host factors affecting vector genome expression. Here, we map the role of ring finger protein 121 (RNF121), an E3 ubiquitin ligase, as a key regulator of AAV genome transcription. CRISPR-mediated knockout of RNF121 (RNF121 KO) in different cells markedly decreased AAV transduction regardless of capsid serotype or vector dose. Recombinant AAV transduction is partially rescued by overexpressing RNF121, but not by co-infection with helper Adenovirus. Major steps in the AAV infectious pathway including cell surface binding, cellular uptake, nuclear entry, capsid uncoating and second strand synthesis are unaffected. While gene expression from transfected plasmids or AAV genomes is unaffected, mRNA synthesis from AAV capsid-associated genomes is markedly decreased in RNF121 KO cells. These observations were attributed to transcriptional arrest as corroborated by RNAPol-ChIP and mRNA half-life measurements. Although AAV capsid proteins do not appear to be direct substrates of RNF121, the catalytic domain of the E3 ligase appears essential. Inhibition of ubiquitin-proteasome pathways revealed that blocking Valosin Containing Protein (VCP/p97), which targets substrates to the proteasome, can selectively and completely restore AAV-mediated transgene expression in RNF121 KO cells. Expanding on this finding, transcriptomic and proteomic analysis revealed that the catalytic subunit of DNA PK (DNAPK-Cs), a known activator of VCP, is upregulated in RNF121 KO cells and that the DNA damage machinery is enriched at sites of stalled AAV genome transcription. We postulate that a network of RNF121, VCP and DNA damage response elements function together to regulate transcriptional silencing and/or activation of AAV vector genomes.

Activation of the mammalian target of rapamycin signaling pathway underlies a novel inhibitory role of ring finger protein 182 in ventricular remodeling after myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) is a major cause of cardiovascular disease, leading to mortality and disability associated with coronary occlusion worldwide. A correlation of mammalian target of rapamycin (mTOR)/nuclear factor-kappa B (NF-κB) signaling pathway has been observed with brain damage resulting from myocardial ischemia. Therefore, by establishing MIRI rat model, this study aimed to explore whether ring finger protein 182 (RNF182) regulates the mTOR signaling pathway affecting MIRI. Initially, MIRI rat model was successfully established, followed by either treatment of shRNF182 or phosphoesterase (PITE) (inhibitor of the mTOR signaling pathway). Then, the serum levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), and left ventricular end-diastolic pressure (LVEDP) were determined, followed by detection of myocardial infarct sizes and myocardial cell apoptosis. Moreover, the levels of related genes/proteins were determined to further determine the mechanisms of RNF182 in MIRI. First, RNF182 was upregulated in MIRI. Another key observation of this study was that rats with shRNF182 presented with downregulated SOD, GSH-Px, and MDA in serum, accompanied by decreased levels of LVEF, LVFS, LVSP, and LVEDP. In addition, both reduced myocardial infarct sizes and apoptosis of myocardial cells were observed after silencing RNF182. Furthermore, silencing of the RNF182 was observed to downregulate Bcl 2-associated X and cysteine proteinase 3 but upregulate mTOR, ribosome protein subunit 6 kinase 1, eukaryotic elongation factor 2, and B-cell lymphoma-2. Importantly, the effects of RNF182 silencing were reversed after PITE treatment. In conclusion, our study demonstrates that RNF182 silencing can prevent ventricular remodeling in rats after MIRI by activating the mTOR signaling pathway.

Regulation of androgen receptor signaling by ubiquitination during folliculogenesis and its possible dysregulation in polycystic ovarian syndrome

Although chronic hyperandrogenism suppresses antral follicular development, a phenomenon often observed in polycystic ovarian syndrome (PCOS), whether and how deregulation of androgen receptor (AR) signaling is involved, is not well understood. In the present study, we examined the role of ring finger protein 6 (RNF6) in AR ubiquitination and the possible dysregulation in the expression and actions of growth differentiation factor 9 (GDF9) and kit-ligand (Kitlg) in a chronic androgenized PCOS rat model. 5α-dihydrotestosterone (DHT) treatment in vivo inhibited antral follicle growth, a response mediated through increased RNF6 content, suppressed K63- but increased K48-linked AR ubiquitination as well as the mRNA expression and content of soluble KIT-L (sKitlg) and content of GDF9. These androgenic responses were attenuated by gonadotropin treatment in vivo. Growth of antral follicles from DHT-treated rats in vitro was significantly slower when compared to those of control but was significantly enhanced by exogenous GDF9, suggesting the DHT-induced antral follicular growth arrest is in part the results of GDF9 suppression. Our findings indicate how hyperandrogenism modulates RNF6 content and subsequently AR ubiquitination, resulting in antral follicle growth arrest in a chronically androgenized PCOS rat model.

Abstract 4825: Functional role of Ring Finger Protein 43 in intestinal stem cell during colorectal tumorigenesis

Abstract Background: Colorectal cancer is one of the most general causes of cancer related death. Ring Finger Protein 43(RNF43) is an E3 ubiquitin ligase that suppresses the Wint signaling pathway and is known as a tumor suppressor gene. Previous studies reported RNF43 mutation leads to inactivation of RNF43 in pancreatic, ovarian, colorectal cancer and so on. Subsequently, Wnt signaling activation is associtated with tumor progression in these types of cancers. However, functional role of RNF43 for tumor formation is not clear in colorectal cancer. Aim: To investigate the functional role of RNF43 in colorectal cancer by using RNF43 knockout mice. Method: We prepared RNF43 knockout mice by using CRISPR/Cas9 system. To induce colorectal tumor in mice, we used Azoxymethane-Dextran sulfate sodium (AOM-DSS) model. First, we injected AOM 10mg/kg into the peritoneal cavity. After 7days from injection, drunk 2% DSS water to mice for 7days. We sacrificed the mice and evaluated the tumor incidence and tumor size after 8, 10, 12, and 16 weeks from injection. Next, we prepared the small intestine organoid from RNF43 wild and knockout mice. Then we compared the organoid size and formation rate. In vitro analysis, we prepared colon cancer cell lines (COLO205, SW620, HCT116) and evaluated the effect on cell proliferation in suppression of RNF43 and normal condition. Result: There was no significant difference in the tumor incidence and tumor size at 8, 10, and 12weeks after AOM injection. However, at 16 weeks, the tumor size of RNF43 knockout mice was significantly bigger than that of RNF43 wild type mice. (p&amp;lt;0.001) Further examination of the intestinal organoid revealed that the organoids derived from RNF43 knockout mice tended to get bigger than those from wild type mice. In vitro analysis, cell proliferation of RNF43 mutant cell line (HCT116) was significantly increased compared with RNF43 wild type cell lines (COLO205, SW620). RNF43 silencing significantly increased cell proliferation in RNF43 wild type cell lines (p&amp;lt;0.001), whereas did not affected in RNF43 mutant cell line. Conclusion: Our results suggest that RNF43 expression suppresses epithelial cell growth in the intestine, and the dysregulation of Wint signaling via RNF43 disruption promote intestinal stem cell expansion and colorectal tumorigenesis. Citation Format: Tsugio Eto, Takatsugu Ishimoto, Eri Oda, Daisuke Kuroda, Kota Arima, Mayuko Ohuchi, Kenichi Nakamura, Hiroshi Sawayama, Koichi Kinoshita, Masaaki Iwatsuki, Yoshifumi Baba, Yasuo Sakamoto, Naoya Yoshida, Hideo Baba. Functional role of Ring Finger Protein 43 in intestinal stem cell during colorectal tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4825. doi:10.1158/1538-7445.AM2017-4825

Role of Ring Finger Protein 213 in Moyamoya Disease.

Objective:The aim of this study was to help people comprehensively understand the research advances related to ring finger protein 213 (RNF213) in moyamoya disease (MMD) and to understand the disease at the molecular level to provide a new perspective of the diagnosis of the disease.Data Sources:This review was based on data in articles published between 2005 and 2015 that were retrieved from the PubMed database. The search terms included RNF213, MMD, intracranial major artery stenosis/occlusion (ICASO), genotype, phenotype, mutant and variants, and the combinations of these terms.Study Selection:Articles related to MMD and RNF213 were selected for review, and we also reviewed publications related to ICASO.Results:RNF213 is not only associated with MMD but also associated with intracranial major artery stenosis. In addition, RNF213 variants exhibit apparent ethnic diversity; specifically, the c.14576G>A variant is mainly detected in Korean, Chinese, and Japanese populations, particularly the latter population. The genotypes of RNF213 correlate with the phenotypes of MMD; for example, the homozygous c.14576G>A variant is associated with early-onset, severe symptoms, and an unfavorable prognosis. Furthermore, the RNF213 c.14576G>A variant should be considered during the diagnosis of MMD because no patients with quasi-MMD have been reported to carry the RNF213 c.14576G>A variant whereas 66 of 78 patients with definite MMD have been found to carry this variant.Conclusions:The growing literature demonstrates that MMD is primarily caused by the synergy of genetic and environmental factors, and unknown genetic modifiers might play roles in the etiology of MMD. Further research should be conducted to clarify the pathogenic mechanism of MMD.

Clinical and experimental role of ring finger protein 180 on lymph node metastasis and survival in gastric cancer.

The hypermethylation of ring finger protein (RNF) 180 DNA promoter is significantly associated with lymph node metastasis of gastric cancer. The present study explored the potential mechanism of RNF180-regulated lymph node metastasis of gastric cancer. Associations between clinicopathological and survival data and RNF180 expression in gastric cancer tissues were analysed. The effects of RNF180 re-expression on gastric cancer cells were determined by means of proliferation, invasion, growth and lymphangiogenesis assays. A genome microarray was used to find potential target genes associated with lymphatic metastasis of gastric cancer cells regulated by RNF180. RNF180 was silenced or downregulated in 99 (73·9 per cent) of 134 gastric cancer tissues compared with 41·8 per cent of paired non-tumour tissues from patients. As an independent prognostic indicator of gastric cancer, RNF180 expression in gastric cancer tissues was negatively related to the number of metastatic lymph nodes. RNF180 was also downregulated in all seven gastric cancer cell lines examined. The re-expression of RNF180 in gastric cancer cells inhibited colony formation, proliferation, migration and invasion in vitro; re-expression of RNF180 also suppressed tumour growth and lymphangiogenesis in mice. Furthermore, re-expression of RNF180 downregulated the expression of hepatocyte growth factor, matrix metalloproteinase (MMP) 2, MMP-14, vascular endothelial growth factor C/D and chemokine receptor 7 in gastric cancer cells; it also downregulated the expression of podoplanin in tumour tissue of nude mice. RNF180 appears to act as a suppressor gene that inhibits lymph node metastasis in gastric cancer. Biological mechanisms that lead to lymph node metastasis in gastric cancer have not been clarified. Ring finger protein (RNF) 180 has been shown to participate in the processes of lymph node metastasis in several human malignancies. In this study, silencing or downregulation of RNF180 expression was significantly associated with lymph node metastasis of gastric cancer. In vitro, RNF180 expression suppressed the common biological characteristics of gastric cancer cells (HGC-27), including proliferation, invasion, lymphangio genesis and chemotaxis. RNF180 expression also inhibited tumour growth and tumour lymphangiogenesis in vivo. These results show that RNF180 is capable of inhibiting lymph node metastasis of gastric cancer by suppressing the intracellular activation of malignant molecular signals. Therefore, RNF180 could be considered as a promising biomarker for evaluation of the tumour aggressiveness and may be a target for future therapeutic intervention.

Experimental immunology Potential role of RING finger protein 166 (RNF166), a member of an ubiquitin ligase subfamily, involved in regulation of T cell activation

Experimental immunology Potential role of RING finger protein 166 (RNF166), a member of an ubiquitin ligase subfamily, involved in regulation of T cell activation