Gene Summary

Gene:RASSF5; Ras association domain family member 5
Aliases: RAPL, Maxp1, NORE1, NORE1A, NORE1B, RASSF3
Summary:This gene is a member of the Ras association domain family. It functions as a tumor suppressor, and is inactivated in a variety of cancers. The encoded protein localizes to centrosomes and microtubules, and associates with the GTP-activated forms of Ras, Rap1, and several other Ras-like small GTPases. The protein regulates lymphocyte adhesion and suppresses cell growth in response to activated Rap1 or Ras. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:ras association domain-containing protein 5
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: RASSF5 (cancer-related)

Barnoud T, Schmidt ML, Donninger H, Clark GJ
The role of the NORE1A tumor suppressor in Oncogene-Induced Senescence.
Cancer Lett. 2017; 400:30-36 [PubMed] Free Access to Full Article Related Publications
The Ras genes are the most frequently mutated oncogenes in human cancer. However, Ras biology is quite complex. While Ras promotes tumorigenesis by regulating numerous growth promoting pathways, activated Ras can paradoxically also lead to cell cycle arrest, death, and Oncogene-Induced Senescence (OIS). OIS is thought to be a critical pathway that serves to protect cells against aberrant Ras signaling. Multiple reports have highlighted the importance of the p53 and Rb tumor suppressors in Ras mediated OIS. However, until recently, the molecular mechanisms connecting Ras to these proteins remained unknown. The RASSF family of tumor suppressors has recently been identified as direct effectors of Ras. One of these members, NORE1A (RASSF5), may be the missing link between Ras-induced senescence and the regulation of p53 and Rb. This occurs both quantitatively, by promoting protein stability, as well as qualitatively via promoting critical pro-senescent post-translational modifications. Here we review the mechanisms by which NORE1A can activate OIS as a barrier against Ras-mediated transformation, and how this could lead to improved therapeutic strategies against cancers having lost NORE1A expression.

Li S, Teng J, Li H, et al.
The Emerging Roles of RASSF5 in Human Malignancy.
Anticancer Agents Med Chem. 2018; 18(3):314-322 [PubMed] Related Publications
Ras association domain family member 5 (RASSF5, also named NORE1) is an identified member of the RASSF gene family which could bind selectively to activate Ras and function as an antineoplastic effector in multiple cellular regulations. While highly expressed in majority of normal tissues, RASSF5 is epigenetically inactivated by promoter hypermethylation in numerous cancer cell lines and primary cancers, suggesting it as a potential tumor suppressor. Nevertheless, the physiologic significance of RASSF5 in tumorigenesis remains unclear. We performed a systematic literature review and assessment from PUBMED and MEDLINE databases in this article. RASSF5 is involved in a series of cellular responses including apoptosis, senescence, cell cycle regulation, differentiation and cell proliferation and the inactivation of RASSF5 has been implicated to participate in the oncogenesis, progression and poor prognosis of human cancers. In this review, we mainly elucidate the acknowledged structure, progress in the verified functions and research advances of RASSF5 and the probably relevant signaling pathways. Based on these evidences, potentiality of RASSF5 as a new therapeutic target for human cancers may play a significant role in future oncotherapy.

Li TK, Yin K, Chen Z, et al.
MiR-214 regulates oral cancer KB cell apoptosis through targeting RASSF5.
Genet Mol Res. 2017; 16(1) [PubMed] Related Publications
Ras association domain family member 5 (RASSF5), a member of the Ras association domain family, induces cell apoptosis by phosphorylating FOXO3a, which triggers target gene BIM (pro-apoptotic factor) activation. MiR-214 is overexpressed in oral cancer tissue, indicating its possible involvement in oral cancer pathogenesis. Bioinformatics analysis has revealed a complimentary sequence between miR-214 and the 3'-UTR of RASSF5 mRNA. However, whether miR-124 regulates RASSF5 in oral cancer remains poorly understood. We aimed to investigate the role of miR-214 in RASSF5 expression regulation in oral cancer. Tumor and paracarcinoma tissues were obtained from 48 oral cancer patients to examine miR-214 and RASSF5 expression. The relationship between miR-214 and RASSF5 was investigated by dual luciferase reporter gene assay. Oral cancer KB cells were cultured in vitro and divided into inhibitor NC, miR-214 inhibitor, Scramble-pMD18, RASSF5-pMD18, and miR-214 inhibitor + RASSF5-pMD18 groups. Caspase 3 activity, cell apoptosis, and total protein expression were measured by spectrophotometry, flow cytometry, and western blot, respectively. MiR-214 expression was significantly increased, while that of RASSF5 decreased in oral cancer tumor tissues compared to paracarcinoma tissues. Luciferase assay showed that miR-214 suppressed RASSF5 expression by targeting its 3'-UTR. Down-regulation of miR-214 and/or enhancement of RASSF5 expression markedly increased FOXO3a phosphorylation, BIM expression, caspase 3 activity, and apoptosis. In conclusion, miR-214 expression was elevated and RASSF5 was down-regulated in oral cancer. Moreover, miR-214 regulated KB cell apoptosis through targeted inhibition of RASSF5 expression, FOXO3a phosphorylation, and BIM expression, suggesting its possible application as a novel therapeutic oral cancer target.

Shen Y, Zhang XY, Chen X, et al.
Synthetic paclitaxel-octreotide conjugate reverses the resistance of paclitaxel in A2780/Taxol ovarian cancer cell line.
Oncol Rep. 2017; 37(1):219-226 [PubMed] Related Publications
The high mortality of ovarian cancer is partly due to the frequent resistance of ovarian cancer to current chemotherapy agents such as paclitaxel and platinum. Somatostatin analogue (SSTA) has been shown to inhibit the proliferation of some tumors through binding to somatostatin receptor (SSTR) and activation of Ras-, Rapl- and B-Raf-dependent extracellular signal-regulated kinase 2 (Erk2). It was reported that paclitaxel-octreotide conjugate (POC) exhibited enhanced tumor growth inhibition with reduced toxicity. In the present study, we prepared the POC and investigated its effects and mechanism for the reversal of drug resistance in paclitaxel-resistant ovarian cancer cell line. We demonstrated that treatment with POC led to more cell apoptosis than either paclitaxel or octreotide (OCT) alone. Moreover, the expression of multidrug resistance 1 (MDR1) and vascular endothelial growth factor (VEGF) mRNA, and protein decreased in a dose-dependent manner while the expression of SSTR remained stable following treatment with POC. Although the exact action, in vivo effects and pharmacologic kinetics of POC remain to be investigated, we have demonstrated the feasibility for the synthesis of POC, and more significantly, provided a potential approach to overcome the resistance of ovarian cancer against taxol. The findings also shed some new light on the mechanisms underlying the development of resistance to taxol by ovarian cancer cells.

Kanwal S, Jamil F, Ali A, Sehgal SA
Comparative Modeling, Molecular Docking, and Revealing of Potential Binding Pockets of RASSF2; a Candidate Cancer Gene.
Interdiscip Sci. 2017; 9(2):214-223 [PubMed] Related Publications
RASSF2, potential tumor suppressor gene, acts as a KRAS-specific effectors protein and may promote apoptosis and cell cycle arrest. It stabilizes STK3/MST2 by protecting it from proteasomal degradation. RASSF2 plays a significant role against the inhibition of cancer. MODELLER (9v15) and online servers (I-Tasser, SwissModel, 3D-JigSaw, ModWeb) were utilized to generate 3D structures of the RASSF2 based on homology modeling. A comparison between models predicted by MODELLER (9v15) and Web servers had been checked through utilized evaluation tools. The most potent model for RASSF2 was analyzed and selected for molecular docking studies. The binding pockets were revealed for binding studies through Site Hound. AutoDock Vina and AutoDock4 were utilized for molecular docking, and the attempt of this experiment was to identify the ligands for RASSF2. The selected compounds may act as regulators and regulate the normal activity of RASSF2. It was also analyzed and observed that the selected compounds showed least binding energy and high-affinity binding in predicted top binding domain. The determination of protein function is based on accurate identification of binding sites in protein structures. The binding site is known, and it may allow the ligand type and protein function to be determined by performing in silico and experimental procedures. The detection, comparison, and analysis of binding pockets are pivotal to drug discovery. It proposed that predicted structure is reliable for the structural insights and functional studies. The predicted binding pockets may lead to further analysis (drug discovery), used against cancer study.

Guo W, Dong Z, Guo Y, et al.
Decreased expression and frequent promoter hypermethylation of RASSF2 and RASSF6 correlate with malignant progression and poor prognosis of gastric cardia adenocarcinoma.
Mol Carcinog. 2016; 55(11):1655-1666 [PubMed] Related Publications
The RAS-association domain family (RASSF) consists of 10 members, and several members act as tumor suppressor genes and epigenetically inactivated in different tumor types. The present study investigated the role and methylation status of RASSF2, RASSF3, RASSF4, and RASSF6 in the pathogenesis and prognosis of GCA. Quantitative real-time RT-PCR, Western blot, and immunohistochemistry (IHC) methods were used respectively to detect the expression of RASSF2, RASSF3, RASSF4, and RASSF6 in 135 GCA cases and BS-MSP method was used to clarify the methylation status of these four genes. Decreased mRNA and protein expression of RASSF2, RASSF3, RASSF4, and RASSF6 were detected in GCA tumor tissues. Aberrant CpG island methylation of RASSF2, RASSF4, and RASSF6 were detected in GCA tumor tissues and were inversely correlated with the expression levels of these genes. Both of RASSF2 and RASSF6 expression and methylation were associated with TNM stage, depth of invasion, LN metastasis, distant metastasis or recurrence, and UGIC family history. GCA patients with simultaneous negative protein expression of RASSF2 and RASSF6 or with simultaneous methylation of both genes demonstrated poor patient survival. These results suggest that down-regulation of RASSF2, RASSF3, RASSF4, and RASSF6 is a tumor-specific phenomenon and the inactivation of RASSF2 and RASSF6 may be associated with tumor progression. Inactivation of RASSF2, RASSF4, and RASSF6 through CpG island methylation may play important roles in GCA carcinogenesis. A combination of RASSF2 and RASSF6 expression or hypermethylation may serve as useful prognostic biomarker for GCA. © 2015 Wiley Periodicals, Inc.

Delire B, Stärkel P
The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications.
Eur J Clin Invest. 2015; 45(6):609-23 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is still a major health problem, often diagnosed at an advanced stage. The multikinase inhibitor sorafenib is to date the sole approved systemic therapy. Several signalling pathways are implicated in tumour development and progression. Among these pathways, the Ras/MAPK pathway is activated in 50-100% of human HCCs and is correlated with a poor prognosis. The aim of this work was to review the main intracellular mechanisms leading to aberrant Ras pathway activation in HCC and the potential therapeutic implications.
MATERIALS AND METHODS: This review is based on the material found on PubMed up to December 2014. 'Ras signaling, Ras dysregulation, Ras inhibition, MAPK pathway, cancer, hepatocarcinoma and liver cancer' alone or in combination were the main terms used for online research.
RESULTS: Multiple mechanisms lead to the deregulation of the Ras pathway in liver cancer. Ras and Raf gene mutations are rare events in human hepatocarcinogenesis in contrast to experimental models in rodents. Downregulation of several Ras/MAPK pathway inhibitors such as GAPs, RASSF proteins, DUSP1, Sprouty and Spred proteins is largely implicated in the aberrant activation of this pathway in the context of wild-type Ras and Raf genes. Epigenetic or post-transcriptional mechanisms lead to the downregulation of these tumour suppressor genes.
CONCLUSION: Ras/MAPK pathway effectors may be considered as potential therapeutic targets in the field of HCC. In particular after the arrival of sorafenib, more Ras/MAPK inhibitors have emerged and are still in preclinical or clinical investigation for HCC therapy.

Chendamarai E, Ganesan S, Alex AA, et al.
Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.
PLoS One. 2015; 10(3):e0121912 [PubMed] Free Access to Full Article Related Publications
There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens.

Guo W, Wang C, Guo Y, et al.
RASSF5A, a candidate tumor suppressor, is epigenetically inactivated in esophageal squamous cell carcinoma.
Clin Exp Metastasis. 2015; 32(1):83-98 [PubMed] Related Publications
As a result of alternative splicing and differential promoter usage, RASSF5 exists in at least three isoforms (RASSF5A-RASSF5C), which may play different roles in tumorigenesis. The present study was to detect the role of RASSF5A, B and C in esophageal squamous cell carcinoma (ESCC) and clarify the critical CpG sites of RASSF5A, in order to clarify more information on the role of RASSF5 with regard to the pathogenesis of ESCC. Frequent silencing of RASSF5A but not RASSF5B and RASSF5C were found in esophageal cancer cell lines and the silencing of RASSF5A may be reversed by 5-Aza-dC or TSA treatment. The aberrant CpG island 1 methylation of RASSF5A induces silencing of its expression in TE13 cell line. Decreased mRNA and protein expression of RASSF5A was observed in ESCC tumor tissues and was associated with RASSF5A CpG island 1 methylation status. Unlike RASSF5A, expression variation of RASSF5B and RASSF5C was not found in ESCC tissues. Aberrant promoter methylation of RASSF5C was also not found in ESCC. RASSF5A methylation and protein expression were independently associated with ESCC patients' survival. These data indicated that the inactivation of RASSF5A through CpG island 1 methylation may play an important role in ESCC carcinogenesis, RASSF5A may be a functional tumor suppressor and may serve as a prognostic biomarker for ESCC.

Han L, Dong Z, Wang C, et al.
Decreased expression and aberrant methylation of RASSF5A correlates with malignant progression of gastric cardia adenocarcinoma.
Mol Carcinog. 2015; 54(12):1722-33 [PubMed] Related Publications
Due to alternative splicing and differential promoter usage, RASSF5 exists in at least three isoforms, RASSF5A, RASSF5B, and RASSF5C. Expression and epigenetic inactivation of different transcripts of RASSF5 in gastric cardia adenocarcinoma (GCA) progression have not been evaluated. Quantitative real-time RT-PCR and immunohistochemistry (IHC) methods were used respectively to detect the role of RASSF5A, RASSF5B, and RASSF5C in 132 GCA cases and BS-MSP method was used to clarify the critical CpG sites of RASSF5A. Expression of RASSF5A and RASSF5C transcripts were easily detectable in all normal gastric cardia epithelial tissues; however, expression of RASSF5B was rare detected in normal gastric cardia epithelial tissues and tumor tissues. Both RASSF5A and RASSF5C expression were frequently downregulated in GCA tumor tissues and RASSF5A was more commonly down-regulated compared to RASSF5C. Abnormal reduction of RASSF5A was more commonly observed in advanced stage and poor differentiated tumors. The methylation frequency of CpG island 1 region of RASSF5A in GCA tumor tissues was significantly higher than that in corresponding normal tissues and was inversely correlated with RASSF5A expression. Aberrant promoter methylation of RASSF5C was not found in GCA. RASSF5A methylation and protein expression were independently associated with GCA patients' survival. These results indicate that down-regulation of RASSF5A and RASSF5C expression is a tumor-specific phenomenon and RASSF5A may be a more common target for inactivation in GCA. Inactivation of RASSF5A through CpG island 1 methylation may play an important role in GCA carcinogenesis and may serve as a prognostic biomarker for GCA.

Pinto R, De Summa S, Danza K, et al.
MicroRNA expression profiling in male and female familial breast cancer.
Br J Cancer. 2014; 111(12):2361-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gender-associated epigenetic alterations are poorly investigated in male and female familial breast cancer (fBC). MicroRNAs may contribute to the different biology in men and women particularly related to RASSF1A pathways.
METHODS: Microarray technology was used to evaluate miRNA profile in 24 male and 43 female fBC. Key results were validated using RT-qPCR in an external samples set. In vitro studies were carried out to verify microRNA-target gene interaction.
RESULTS: Pathway enrichment analysis with the 287 differentially expressed microRNAs revealed several signalling pathways differently regulated in male and female cases. Because we previously hypothesised a peculiar involvement of RASSF1A in male fBC pathogenesis, we focussed on the MAPK and the Hippo signalling pathways that are regulated by RASSF1A. Male miR-152 and miR-497 upregulation and RASSF1A and NORE1A interacting gene downregulation were observed, confirming a possible indirect interaction between miRNAs and the two genes.
CONCLUSIONS: For the first time, a different microRNA expression pattern in male and female fBC has been shown. Moreover, the importance of RASSF1A pathway in male fBC carcinogenesis has been confirmed, highlighting a possible role for miR-152 and miR-497 in controlling MAPK and Hippo signalling pathways, regulated by RASSF1A.

Safavi S, Hansson M, Karlsson K, et al.
Novel gene targets detected by genomic profiling in a consecutive series of 126 adults with acute lymphoblastic leukemia.
Haematologica. 2015; 100(1):55-61 [PubMed] Free Access to Full Article Related Publications
In contrast to acute lymphoblastic leukemia in children, adult cases of this disease are associated with a very poor prognosis. In order to ascertain whether the frequencies and patterns of submicroscopic changes, identifiable with single nucleotide polymorphism array analysis, differ between childhood and adult acute lymphoblastic leukemia, we performed single nucleotide polymorphism array analyses of 126 adult cases, the largest series to date, including 18 paired diagnostic and relapse samples. Apart from identifying characteristic microdeletions of the CDKN2A, EBF1, ETV6, IKZF1, PAX5 and RB1 genes, the present study uncovered novel, focal deletions of the BCAT1, BTLA, NR3C1, PIK3AP1 and SERP2 genes in 2-6% of the adult cases. IKZF1 deletions were associated with B-cell precursor acute lymphoblastic leukemia (P=0.036), BCR-ABL1-positive acute lymphoblastic leukemia (P<0.001), and higher white blood cell counts (P=0.005). In addition, recurrent deletions of RASSF3 and TOX were seen in relapse samples. Comparing paired diagnostic/relapse samples revealed identical changes at diagnosis and relapse in 27%, clonal evolution in 22%, and relapses evolving from ancestral clones in 50%, akin to what has previously been reported in pediatric acute lymphoblastic leukemia and indicating that the mechanisms of relapse may be similar in adult and childhood cases. These findings provide novel insights into the leukemogenesis of adult acute lymphoblastic leukemia, showing similarities to childhood disease in the pattern of deletions and the clonal relationship between diagnostic and relapse samples, but with the adult cases harboring additional aberrations that have not been described in pediatric acute lymphoblastic leukemia.

Schmidt ML, Donninger H, Clark GJ
Ras regulates SCF(β-TrCP) protein activity and specificity via its effector protein NORE1A.
J Biol Chem. 2014; 289(45):31102-10 [PubMed] Free Access to Full Article Related Publications
Ras is the most frequently activated oncogene found in human cancer, but its mechanisms of action remain only partially understood. Ras activates multiple signaling pathways to promote transformation. However, Ras can also exhibit a potent ability to induce growth arrest and death. NORE1A (RASSF5) is a direct Ras effector that acts as a tumor suppressor by promoting apoptosis and cell cycle arrest. Expression of NORE1A is frequently lost in human tumors, and its mechanism of action remains unclear. Here we show that NORE1A forms a direct, Ras-regulated complex with β-TrCP, the substrate recognition component of the SCF(β-TrCP) ubiquitin ligase complex. This interaction allows Ras to stimulate the ubiquitin ligase activity of SCF(β-TrCP) toward its target β-catenin, resulting in degradation of β-catenin by the 26 S proteasome. However, the action of Ras/NORE1A/β-TrCP is substrate-specific because IκB, another substrate of SCF(β-TrCP), is not sensitive to NORE1A-promoted degradation. We identify a completely new signaling mechanism for Ras that allows for the specific regulation of SCF(β-TrCP) targets. We show that the NORE1A levels in a cell may dictate the effects of Ras on the Wnt/β-catenin pathway. Moreover, because NORE1A expression is frequently impaired in tumors, we provide an explanation for the observation that β-TrCP can act as a tumor suppressor or an oncogene in different cell systems.

Burghel GJ, Lin WY, Whitehouse H, et al.
Identification of candidate driver genes in common focal chromosomal aberrations of microsatellite stable colorectal cancer.
PLoS One. 2013; 8(12):e83859 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Chromosomal instability (CIN) is a major driving force of microsatellite stable (MSS) sporadic CRC. CIN tumours are characterised by a large number of somatic chromosomal copy number aberrations (SCNA) that frequently affect oncogenes and tumour suppressor genes. The main aim of this work was to identify novel candidate CRC driver genes affected by recurrent and focal SCNA. High resolution genome-wide comparative genome hybridisation (CGH) arrays were used to compare tumour and normal DNA for 53 sporadic CRC cases. Context corrected common aberration (COCA) analysis and custom algorithms identified 64 deletions and 32 gains of focal minimal common regions (FMCR) at high frequency (>10%). Comparison of these FMCR with published genomic profiles from CRC revealed common overlap (42.2% of deletions and 34.4% of copy gains). Pathway analysis showed that apoptosis and p53 signalling pathways were commonly affected by deleted FMCR, and MAPK and potassium channel pathways by gains of FMCR. Candidate tumour suppressor genes in deleted FMCR included RASSF3, IFNAR1, IFNAR2 and NFKBIA and candidate oncogenes in gained FMCR included PRDM16, TNS1, RPA3 and KCNMA1. In conclusion, this study confirms some previously identified aberrations in MSS CRC and provides in silico evidence for some novel candidate driver genes.

Guo H, Liu H, Wei J, et al.
Functional single nucleotide polymorphisms of the RASSF3 gene and susceptibility to squamous cell carcinoma of the head and neck.
Eur J Cancer. 2014; 50(3):582-92 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: RASSF3 suppresses tumour formation through uncertain mechanisms, but it is an important gene of p53-dependent apoptosis. RASSF3 depletion impairs DNA repair after DNA damage, leading to polyploidy. The authors hypothesised that potential functional single-nucleotide polymorphisms (SNPs) of RASSF3 are associated with risk of squamous cell carcinoma of the head and neck (SCCHN).
METHODS: The authors used a functional SNP approach to evaluate the associations between common (minor allele frequency⩾0.05), putative functional variants in RASSF3 and risk of SCCHN. Four selected such functional SNPs (rs6581580 T>G, rs7313765 G>A, rs12311754 G>C and rs1147098 T>C) in RASSF3 were identified and genotyped in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population.
RESULTS: The authors found that two SNPs were significantly associated with SCCHN risk. Carriers of the variant rs6581580G and rs7313765A alleles were at a reduced SCCHN risk, compared with the corresponding common homozygotes [adjusted odds ratio (OR)=0.75 and 0.73 and 95% confidence interval (CI)=0.62-0.91 and 0.60-0.88, respectively, for dominant models; and Ptrend=0.012 and 0.041, respectively, for additive models], particularly for non-oropharyngeal tumours (adjusted OR=0.68 and 0.60 and 95% CI=0.53-0.86 and 0.47-0.77, respectively, for dominant models). In the genotype-phenotype correlation analysis of peripheral blood mononuclear cells from 102 cancer-free controls, the rs6581580 GG genotype was associated with significantly increased expression levels of RASSF3 mRNA (P=0.038), compared with the TT genotype. Additional functional experiments further showed that variant G allele of rs6581580 had a significantly stronger binding affinity to the nuclear protein extracts than the T allele.
CONCLUSION: Taken together, these findings indicate that the RASSF3 promoter rs6581580 T>G SNP is potentially functional, modulating susceptibility to SCCHN among non-Hispanic whites. Larger replication studies are needed to confirm our findings.

Fukatsu A, Ishiguro F, Tanaka I, et al.
RASSF3 downregulation increases malignant phenotypes of non-small cell lung cancer.
Lung Cancer. 2014; 83(1):23-9 [PubMed] Related Publications
BACKGROUND: Ras-Association Family1A (RASSF1A) is a well-established tumor suppressor. Ten RASSF homologues comprise this family, and each member is considered a tumor suppressor. RASSF3 is one of the RASSF family members, but its function has not yet been clarified. Recently, we found that RASSF3 interacts with MDM2 and facilitates its ubiquitination, which induces apoptosis through p53 stabilization. However, the role of RASSF3 in human malignancies remains largely unknown.
PATIENTS AND METHODS: Ninety-five non-small cell lung cancer (NSCLC) patients from Nagoya University Hospital and 45 NSCLC patients from Aichi Cancer Center Hospital underwent pulmonary resection at each hospital, and lung cancer and corresponding non-cancerous lung tissues were collected. The expression levels of RASSF3 were analyzed using quantitative real-time reverse transcription PCR. We performed statistical analysis to investigate the correlation with RASSF3 expression and the clinicopathological characteristics. We also transfected RASSF3-siRNA into NSCLC cells, and performed motility assays to evaluate the influence on migration ability.
RESULTS: RASSF3 expression levels were downregulated in 125 of a total 140 NSCLCs. In a multivariate logistic regression analysis, the low RASSF3 expression group below the median value was independently correlated with progressive phenotypes (lymph node metastasis and pleural invasion), non-adenocarcinoma histology and wild-type epidermal growth factor receptor (EGFR) status. In motility assays, RASSF3-knockdown NSCLC cells increased the migration rate compared to the control cells.
CONCLUSIONS: We found that the expression levels of RASSF3 were frequently downregulated in NSCLCs. Downregulation of RASSF3 strongly correlated with the progressive phenotypes of NSCLCs and EGFR wild-type status. In vitro studies also suggested that RASSF3 downregulation increases migration ability of lung cancer cells. Together, our findings indicate RASSF3 is a candidate tumor suppressor gene of NSCLCs.

Zhou Y, Zhang X, Klibanski A
Genetic and epigenetic mutations of tumor suppressive genes in sporadic pituitary adenoma.
Mol Cell Endocrinol. 2014; 386(1-2):16-33 [PubMed] Free Access to Full Article Related Publications
Human pituitary adenomas are the most common intracranial neoplasms. Approximately 5% of them are familial adenomas. Patients with familial tumors carry germline mutations in predisposition genes, including AIP, MEN1 and PRKAR1A. These mutations are extremely rare in sporadic pituitary adenomas, which therefore are caused by different mechanisms. Multiple tumor suppressive genes linked to sporadic tumors have been identified. Their inactivation is caused by epigenetic mechanisms, mainly promoter hypermethylation, and can be placed into two groups based on their functional interaction with tumor suppressors RB or p53. The RB group includes CDKN2A, CDKN2B, CDKN2C, RB1, BMP4, CDH1, CDH13, GADD45B and GADD45G; AIP and MEN1 genes also belong to this group. The p53 group includes MEG3, MGMT, PLAGL1, RASSF1, RASSF3 and SOCS1. We propose that the tumor suppression function of these genes is mainly mediated by the RB and p53 pathways. We also discuss possible tumor suppression mechanisms for individual genes.

Peng H, Liu H, Zhao S, et al.
Silencing of RASSF3 by DNA hypermethylation is associated with tumorigenesis in somatotroph adenomas.
PLoS One. 2013; 8(3):e59024 [PubMed] Free Access to Full Article Related Publications
The pathogenic mechanisms underlying pituitary somatotroph adenoma formation, progression are poorly understood. To identify candidate tumor suppressor genes involved in pituitary somatotroph adenoma tumorigenesis, we used HG18 CpG plus Promoter Microarray in 27 human somatotroph adenomas and 4 normal human adenohypophyses. RASSF3 was found with frequent methylation of CpG island in its promoter region in somatotroph adenomas but rarely in adenohypophyses. This result was confirmed by pyrosequencing analysis. We also found that RASSF3 mRNA level correlated negatively to its gene promoter methylation level. RASSF3 hypermethylation and downregulation was also observed in rat GH3 and mouse GT1.1 somatotroph adenoma cell lines. 5-Aza-2' deoxycytidine and trichostatin-A treatment induced RASSF3 promoter demethylation, and restored its expression in GH3 and GT1.1 cell lines. RASSF3 overexpression in GH3 and GT1.1 cells inhibited proliferation, induced apoptosis accompanied by increased Bax, p53, and caspase-3 protein and decreased Bcl-2 protein expression. We also found that the antitumor effect of RASSF3 was p53 dependent, and p53 knockdown blocked RASSF3-induced apoptosis and growth inhibition. Taken together, our results suggest that hypermethylation-induced RASSF3 silencing plays an important role in the tumorigenesis of pituitary somatotroph adenomas.

Ng YK, Lau WS, Lui VW, et al.
Full-length Mst1 exhibits growth promoting function in human hepatocellular carcinoma cells.
FEBS Lett. 2013; 587(5):496-503 [PubMed] Related Publications
The putative tumor suppressor Mst1, when cleaved to its 36kDa cleaved form, amplifies apoptotic signals. We found that Mst1 was predominantly expressed in its full-length form in 76% (17/25 cases) of hepatocellular carcinoma (HCC) tumors. Mst1 cleavage was basically absent in HCC cells. Ectopic full-length Mst1 expression increased the growth of HCC cells by 55-80% within 3days after transfection. Expression of exogenous NORE1B, a tumor suppressor commonly lost in HCC tumors (~56% of our cohort), was sufficient to suppress the growth promotion of full-length Mst1. Hence, Mst1 exhibits a growth promoting activity in HCC cells upon NORE1B downregulation.

Bradly DP, Gattuso P, Pool M, et al.
CDKN2A (p16) promoter hypermethylation influences the outcome in young lung cancer patients.
Diagn Mol Pathol. 2012; 21(4):207-13 [PubMed] Related Publications
PURPOSE: Non-small cell lung cancer (NSCLC) occurs most frequently in individuals older than 60 years of age. Currently, no biological indicators associated with NSCLC in younger patients (30 to 60 y) have been identified. To explore epigenetic influences, promoter methylation of selected tumor suppressor genes was analyzed in early-stage NSCLC patients ranging in age from 30 to 87 years at diagnosis.
EXPERIMENTAL DESIGN: The analysis was performed on formalin-fixed tumor tissue from 193 surgically treated NSCLC patients (127, older than 60 y; 66, 60 y and younger). Methylation was quantified in p16, MGMT, DAPK, RASSF1, CDH1, LET7-3-a, NORE1(RASSF5), and PTEN promoters by pyrosequencing. p16 protein expression was assessed by immunohistochemistry (IHC). Outcome, defined by time to recurrence and overall survival, was evaluated by Kaplan-Meier analysis.
RESULTS: Promoter methylation levels were generally higher in patients older than 60 years of age than in patients 60 years or younger at diagnosis. Of the genes tested, methylation levels of the p16 promoter showed age-related differences. Although p16 promoter methylation was significantly lower using cut-points of 50 years or younger and 40 years or younger (P=0.001 to 0.012, respectively), p16 protein expression increased with age. Patients 60 years or younger with p16 promoter hypermethylation had a significantly shortened time to recurrence (P=0.002) and a shortened survival time (P=0.011). No effect of p16 hypermethylation was seen in patients older than 60 years.
CONCLUSIONS: p16 promoter hypermethylation was associated with a worse outcome in patients with age at diagnosis of 60 years or younger, but was not associated with the outcome in the older than 60-year age group. Overall, these data support methylation-dependent and methylation-independent age-related regulation of p16 expression with differential effects on the outcome after surgical resection for early-stage NSCLC.

Kiss NB, Kogner P, Johnsen JI, et al.
Quantitative global and gene-specific promoter methylation in relation to biological properties of neuroblastomas.
BMC Med Genet. 2012; 13:83 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In this study we aimed to quantify tumor suppressor gene (TSG) promoter methylation densities levels in primary neuroblastoma tumors and cell lines. A subset of these TSGs is associated with a CpG island methylator phenotype (CIMP) in other tumor types.
METHODS: The study panel consisted of 38 primary tumors, 7 established cell lines and 4 healthy references. Promoter methylation was determined by bisulphate Pyrosequencing for 14 TSGs; and LINE-1 repeat element methylation was used as an indicator of global methylation levels.
RESULTS: Overall mean TSG Z-scores were significantly increased in cases with adverse outcome, but were unrelated to global LINE-1 methylation. CIMP with hypermethylation of three or more gene promoters was observed in 6/38 tumors and 7/7 cell lines. Hypermethylation of one or more TSG (comprising TSGs BLU, CASP8, DCR2, CDH1, RASSF1A and RASSF2) was evident in 30/38 tumors. By contrast only very low levels of promoter methylation were recorded for APC, DAPK1, NORE1A, P14, P16, TP73, PTEN and RARB. Similar involvements of methylation instability were revealed between cell line models and neuroblastoma tumors. Separate analysis of two proposed CASP8 regulatory regions revealed frequent and significant involvement of CpG sites between exon 4 and 5, but modest involvement of the exon 1 region.
CONCLUSIONS/SIGNIFICANCE: The results highlight the involvement of TSG methylation instability in neuroblastoma tumors and cell lines using quantitative methods, support the use of DNA methylation analyses as a prognostic tool for this tumor type, and underscore the relevance of developing demethylating therapies for its treatment.

Fernandes MS, Carneiro F, Oliveira C, Seruca R
Colorectal cancer and RASSF family--a special emphasis on RASSF1A.
Int J Cancer. 2013; 132(2):251-8 [PubMed] Related Publications
The RAS-association domain family, commonly referred to as RASSF, is a family of 10 members (RASSF1-10) implicated in a variety of key biological processes, including cell cycle regulation, apoptosis and microtubule stability. Furthermore, RASSFs have been implicated in tumorigenesis and several family members are now thought to be tumor suppressors. As opposed to the KRAS oncogene, for which mutational activation is frequent in colorectal cancer (CRC), RASSFs are found to be silenced mainly by aberrant promoter methylation. In particular, RASSF1A, RASSF2 and RASSF5 methylation has been associated with CRC development, though the mechanisms of action remain poorly understood. This review focus on the current knowledge of RASSF inactivation in CRC, particularly RASSF1A, and on the implications RASSFs may have as potential biomarkers and for the development of new targeted therapies for CRC.

Djos A, Martinsson T, Kogner P, Carén H
The RASSF gene family members RASSF5, RASSF6 and RASSF7 show frequent DNA methylation in neuroblastoma.
Mol Cancer. 2012; 11:40 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hypermethylation of promotor CpG islands is a common mechanism that inactivates tumor suppressor genes in cancer. Genes belonging to the RASSF gene family have frequently been reported as epigenetically silenced by promotor methylation in human cancers. Two members of this gene family, RASSF1A and RASSF5A have been reported as methylated in neuroblastoma. Data from our previously performed genome-wide DNA methylation array analysis indicated that other members of the RASSF gene family are targeted by DNA methylation in neuroblastoma.
RESULTS: In the current study, we found that several of the RASSF family genes (RASSF2, RASSF4, RASSF5, RASSF6, RASSF7, and RASSF10) to various degrees were methylated in neuroblastoma cell lines and primary tumors. In addition, several of the RASSF family genes showed low or absent mRNA expression in neuroblastoma cell lines. RASSF5 and RASSF6 were to various degrees methylated in a large portion of neuroblastoma tumors and RASSF7 was heavily methylated in most tumors. Further, CpG methylation sites in the CpG islands of some RASSF family members could be used to significantly discriminate between biological subgroups of neuroblastoma tumors. For example, RASSF5 methylation highly correlated to MYCN amplification and INRG stage M. Furthermore, high methylation of RASSF6 was correlated to unfavorable outcome, 1p deletion and MYCN amplification in our tumor material.
IN CONCLUSION: This study shows that several genes belonging to the RASSF gene family are methylated in neuroblastoma. The genes RASSF5, RASSF6 and RASSF7 stand out as the most promising candidate genes for further investigations in neuroblastoma.

Lee D, Park SJ, Sung KS, et al.
Mdm2 associates with Ras effector NORE1 to induce the degradation of oncoprotein HIPK1.
EMBO Rep. 2012; 13(2):163-9 [PubMed] Free Access to Full Article Related Publications
The Ras effector NORE1 is frequently silenced in primary adenocarcinomas, although the significance of this silencing for tumorigenesis is unclear. Here we show that NORE1 induces polyubiquitination and proteasomal degradation of oncoprotein HIPK1 by facilitating its interaction with the Mdm2 E3 ubiquitin ligase. Endogenous HIPK1 is stabilized in Nore1-deficient mouse embryonic fibroblasts, and depletion of HIPK1 in NORE1-silenced lung adenocarcinoma cells inhibits anchorage-independent cell growth and tumour formation in nude mice. These findings indicate that the control of HIPK1 stability by Mdm2-NORE1 has a major effect on cell behaviour, and epigenetic inactivation of NORE1 enables adenocarcinoma formation in vivo through HIPK1 stabilization.

Zhang Y, Wang R, Song H, et al.
Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer.
Cancer Lett. 2011; 303(1):21-8 [PubMed] Related Publications
Aberrant DNA methylation is a common phenomenon in human cancer. The aims of this study were to investigate the methylation profiles of non-small cell lung cancer (NSCLC) in the Chinese population. Twenty tumor suppressor genes (TSGs) were determined of the methylation status using methylation-specific PCR in 78 paired NSCLC specimens and adjacent normal tissues, as well as in 110 Stage I/II NSCLC and 50 cancer-free plasmas. The results showed that, nine genes (APC, CDH13, KLK10, DLEC1, RASSF1A, EFEMP1, SFRP1, RARβ and p16(INK4A)) demonstrated a significantly higher frequency of methylation in NSCLC compared with the normal tissues (P≤0.001), while the others (RUNX3, hMLH1, DAPK, BRCA1, p14(ARF), MGMT, NORE1A, FHIT, CMTM3, LSAMP and OPCML) showed relatively low sensitivity or specificity. Furthermore, methylation of multiple genes was more frequentin cancerous tissue, CpG island methylator phenotype positive (CIMP+) cases were detected in 65.38% of (51/78) NSCLC while only in 1.28% (1/78) of adjacent normal tissues (P<0.001), and CIMP+ was associated with advanced stage (P=0.017), lymphatic metastasis (P=0.001) and adverse 2-year progression-free survival (P=0.027). The nine genes validated in tissues also showed a significantly higher frequency of tumor-specific hypermethylation in NSCLC plasma, as compared with the cancer-free plasmas, and a 5-gene set (APC, RASSF1A, CDH13, KLK10 and DLEC1) achieved a sensitivity of 83.64% and a specificity of 74.0% for cancer diagnosis. Thus, the results indicated that methylated alteration of multiple genes plays an important role in NSCLC pathogenesis and a panel of candidate epigenetic biomarkers for NSCLC detection in the Chinese population was identified.

Overmeyer JH, Maltese WA
Death pathways triggered by activated Ras in cancer cells.
Front Biosci (Landmark Ed). 2011; 16:1693-713 [PubMed] Free Access to Full Article Related Publications
Ras GTPases are best known for their ability to serve as molecular switches regulating cell growth, differentiation and survival. Gene mutations that result in expression of constitutively active forms of Ras have been linked to oncogenesis in animal models and humans. However, over the past two decades, evidence has gradually accumulated to support a paradoxical role for Ras proteins in the initiation of cell death pathways. In this review we survey the literature pointing to the ability of activated Ras to promote cell death under conditions where cancer cells encounter apoptotic stimuli or Ras is ectopically expressed. In some of these cases Ras acts through known effectors and well defined apoptotic death pathways. However, in other cases it appears that Ras operates by triggering novel non-apoptotic death mechanisms that are just beginning to be characterized. Understanding these mechanisms and the factors that go into changing the nature of Ras signaling from pro-survival to pro-death could set the stage for development of novel therapeutic approaches aimed at manipulating pro-death Ras signaling pathways in cancer.

Underhill-Day N, Hill V, Latif F
N-terminal RASSF family: RASSF7-RASSF10.
Epigenetics. 2011; 6(3):284-92 [PubMed] Free Access to Full Article Related Publications
Epigenetic inactivation of tumor suppressor genes is a hallmark of cancer development. RASSF1A (Ras Association Domain Family 1 isoform A) tumor suppressor gene is one of the most frequently epigenetically inactivated genes in a wide range of adult and children's cancers and could be a useful molecular marker for cancer diagnosis and prognosis. RASSF1A has been shown to play a role in several biological pathways, including cell cycle control, apoptosis and microtubule dynamics. RASSF2, RASSF4, RASSF5 and RASSF6 are also epigenetically inactivated in cancer but have not been analysed in as wide a range of malignancies as RASSF1A. Recently four new members of the RASSF family were identified these are termed N-Terminal RASSF genes (RASSF7-RASSF10). Molecular and biological analysis of these newer members has just begun. This review highlights what we currently know in respects to structural, functional and molecular properties of the N-Terminal RASSFs.

Lee CK, Lee JH, Lee MG, et al.
Epigenetic inactivation of the NORE1 gene correlates with malignant progression of colorectal tumors.
BMC Cancer. 2010; 10:577 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: NORE1 (RASSF5) is a newly described member of the RASSF family with Ras effector function. NORE1 expression is frequently inactivated by aberrant promoter hypermethylation in many human cancers, suggesting that NORE1 might be a putative tumor suppressor. However, expression and mutation status of NORE1 and its implication in colorectal tumorigenesis has not been evaluated.
METHODS: Expression, mutation, and methylation status of NORE1A and NORE1B in 10 cancer cell lines and 80 primary tumors were characterized by quantitative PCR, SSCP, and bisulfite DNA sequencing analyses. Effect of NORE1A and NORE1B expression on tumor cell growth was evaluated using cell number counting, flow cytometry, and colony formation assays.
RESULTS: Expression of NORE1A and NORE1B transcript was easily detectable in all normal colonic epithelial tissues, but substantially decreased in 7 (70%) and 4 (40%) of 10 cancer cell lines and 31 (38.8%) and 25 (31.3%) of 80 primary carcinoma tissues, respectively. Moreover, 46 (57.6%) and 38 (47.5%) of 80 matched tissue sets exhibited tumor-specific reduction of NORE1A and NORE1B, respectively. Abnormal reduction of NORE1 was more commonly observed in advanced stage and high grade tumors compared to early and low grade tumors. While somatic mutations of the gene were not identified, its expression was re-activated in all low expressor cells after treatment with the demethylating agent 5-aza-dC. Bisulfite DNA sequencing analysis of 31 CpG sites within the promoter region demonstrated that abnormal reduction of NORE1A is tightly associated with promoter CpG sites hypermethylation. Moreover, transient expression and siRNA-mediated knockdown assays revealed that both NORE1A and NORE1B decrease cellular growth and colony forming ability of tumor cells and enhance tumor cell response to apoptotic stress.
CONCLUSION: Our data indicate that epigenetic inactivation of NORE1 due to aberrant promoter hypermethylation is a frequent event in colorectal tumorigenesis and might be implicated in the malignant progression of colorectal tumors.

Schagdarsurengin U, Richter AM, Hornung J, et al.
Frequent epigenetic inactivation of RASSF2 in thyroid cancer and functional consequences.
Mol Cancer. 2010; 9:264 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The Ras association domain family (RASSF) encodes for distinct tumor suppressors and several members are frequently silenced in human cancer. In our study, we analyzed the role of RASSF2, RASSF3, RASSF4, RASSF5A, RASSF5C and RASSF6 and the effectors MST1, MST2 and WW45 in thyroid carcinogenesis.
RESULTS: Frequent methylation of the RASSF2 and RASSF5A CpG island promoters in thyroid tumors was observed. RASSF2 was methylated in 88% of thyroid cancer cell lines and in 63% of primary thyroid carcinomas. RASSF2 methylation was significantly increased in primary thyroid carcinoma compared to normal thyroid, goiter and follicular adenoma (0%, 17% and 0%, respectively; p < 0.05). Patients which were older than 60 years were significantly hypermethylated for RASSF2 in their primary thyroid tumors compared to those younger than 40 years (90% vs. 38%; p < 0.05). RASSF2 promoter hypermethylation correlated with its reduced expression and treatment with a DNA methylation inhibitor reactivated RASSF2 transcription. Over-expression of RASSF2 reduced colony formation of thyroid cancer cells. Functionally our data show that RASSF2 interacts with the proapoptotic kinases MST1 and MST2 and induces apoptosis in thyroid cancer cell lines. Deletion of the MST interaction domain of RASSF2 reduced apoptosis significantly (p < 0.05).
CONCLUSION: These results suggest that RASSF2 encodes a novel epigenetically inactivated candidate tumor suppressor gene in thyroid carcinogenesis.

Shinmura K, Tao H, Nagura K, et al.
Suppression of hydroxyurea-induced centrosome amplification by NORE1A and down-regulation of NORE1A mRNA expression in non-small cell lung carcinoma.
Lung Cancer. 2011; 71(1):19-27 [PubMed] Related Publications
The candidate tumor suppressor NORE1A is a nucleocytoplasmic shuttling protein, and although a fraction of the NORE1A in cells is localized to their centrosomes, the role of centrosomal NORE1A has not been elucidated. In this study we investigated the role of NORE1A in the numerical integrity of centrosomes and chromosome stability in lung cancer cells. Exposure of p53-deficient H1299 lung cancer cell line to hydroxyurea (HU) resulted in abnormal centrosome amplification (to 3 or more centrosomes per cell) as determined by immunofluorescence analysis with anti-γ-tubulin antibody, and forced expression of wild-type NORE1A partially suppressed the centrosome amplification. The nuclear export signal (NES) mutant (L377A/L384A) of NORE1A did not localize to centrosomes and did not suppress the centrosome amplification induced by HU. Fluorescence in situ hybridization analyses with probes specific for chromosomes 2 and 16 showed that wild-type NORE1A, but not NES-mutant NORE1A, suppressed chromosome instability in HU-exposed H1299 cells that was likely to have resulted from centrosome amplification. We next examined the status of NORE1A mRNA expression in non-small cell lung carcinoma (NSCLC) and detected down-regulation of NORE1A mRNA expression in 25 (49%) of 51 primary NSCLCs by quantitative real-time-polymerase chain reaction analysis. These results suggest that NORE1A has activity that suppresses the centrosome amplification induced by HU and that NORE1A mRNA down-regulation is one of the common gene abnormalities in NSCLCs, both of which imply a key preventive role of NORE1A against the carcinogenesis of NSCLC.

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