RALA

Gene Summary

Gene:RALA; RAS like proto-oncogene A
Aliases: RAL
Location:7p14.1
Summary:The product of this gene belongs to the small GTPase superfamily, Ras family of proteins. GTP-binding proteins mediate the transmembrane signaling initiated by the occupancy of certain cell surface receptors. This gene encodes a low molecular mass ras-like GTP-binding protein that shares about 50% similarity with other ras proteins. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:ras-related protein Ral-A
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
Show (23)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 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.

  • Enzyme Inhibitors
  • Single Nucleotide Polymorphism
  • Xenograft Models
  • Neoplasm Invasiveness
  • Cell Proliferation
  • Vesicular Transport Proteins
  • ATP-Binding Cassette Transporters
  • Phosphorylation
  • Biomarkers, Tumor
  • RNA Interference
  • Gene Expression
  • Phosphatidylinositol 3-Kinases
  • src-Family Kinases
  • RALA
  • Enzyme Activation
  • Cell Movement
  • rho GTP-Binding Proteins
  • Cancer Gene Expression Regulation
  • Apoptosis
  • ras Proteins
  • Pancreatic Cancer
  • Signal Transduction
  • Transfection
  • Immunohistochemistry
  • siRNA
  • Lung Cancer
  • Mutation
  • Proto-Oncogene Proteins p21(ras)
  • Base Sequence
  • Staging
  • Colorectal Cancer
  • Neoplastic Cell Transformation
  • RAS Genes
  • Bladder Cancer
  • Chromosome 7
  • GTPase-Activating Proteins
  • Protein Transport
  • Neoplasm Metastasis
  • AKT1
  • Non-Small Cell Lung Cancer
  • Western Blotting
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: RALA (cancer-related)

Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, et al.
A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling.
Cell. 2016; 165(3):643-55 [PubMed] Free Access to Full Article Related Publications
Oncogenic activation of RAS genes via point mutations occurs in 20%-30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that ribosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.

Hobbs GA, Der CJ, Rossman KL
RAS isoforms and mutations in cancer at a glance.
J Cell Sci. 2016; 129(7):1287-92 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP-GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. Gain-of-function missense mutations in RAS genes are found in ∼25% of human cancers, prompting interest in identifying anti-RAS therapeutic strategies for cancer treatment. However, despite more than three decades of intense effort, no anti-RAS therapies have reached clinical application. Contributing to this failure has been an underestimation of the complexities of RAS. First, there is now appreciation that the four human RAS proteins are not functionally identical. Second, with >130 different missense mutations found in cancer, there is an emerging view that there are mutation-specific consequences on RAS structure, biochemistry and biology, and mutation-selective therapeutic strategies are needed. In this Cell Science at a Glance article and accompanying poster, we provide a snapshot of the differences between RAS isoforms and mutations, as well as the current status of anti-RAS drug-discovery efforts.

Ma W, Liu J, Xie J, et al.
Modulating the Growth and Imatinib Sensitivity of Chronic Myeloid Leukemia Stem/Progenitor Cells with Pullulan/MicroRNA Nanoparticles In Vitro.
J Biomed Nanotechnol. 2015; 11(11):1961-74 [PubMed] Related Publications
Chronic myeloid leukemia (CML) originates from normal hematopoietic stem cells acquiring Philadelphia chromosome (Ph) to generate BCR-ABL fusion gene whose protein product has deregulated tyrosine kinase activity. Specific inhibitors against BCR-ABL, such as Imatinib mesylate (IM), have greatly improved CML management; however, no single agent is a cure yet. Delivery of microRNA (miRNA) using non-viral vectors has been utilized to inhibit various cancer cells; however, the efficacy of this approach to target CML stem/progenitor cells has not been elucidated. In this study, we firstly validated that spermine-introduced pullulan (Ps) was a robust non-viral vector for delivery of miRNA to CML cells, including the CD34+ cells from clinical isolates. We then found that the miR-181a/RALA (V-ral simian leukemia viral oncogene homolog A) axis was aberrantly expressed in the CML CD34+ cells. The delivery of miR-181a specifically inhibited the growth of CML CD34+ cells, possibly via the inhibition of RALA. In contrast, miR-181a did not evidently affect the normal hematopoietic CD34+ cells. In addition, miR-181a increased IM sensitivity of the CD34+ CML cells. Taken together, we have therefore demonstrated that the delivery of miR-181a using Ps to CML stem/progenitor cells leads to their growth inhibition and enhancement of IM sensitivity, which will possibly be beneficial to CML treatment.

Wu J, Zhang H, Xu C, et al.
TIPE2 functions as a metastasis suppressor via negatively regulating β-catenin through activating GSK3β in gastric cancer.
Int J Oncol. 2016; 48(1):199-206 [PubMed] Related Publications
Tumor necrosis factor (TNF)-α-induced protein 8-like 2 (TNFAIP8L2, TIPE2) is a novel anti-inflammatory factor involved in maintaining immune homeostasis. Accumulating evidence has also shown that TIPE2 displays tumor-suppressive effects in several tumor types. Previous studies revealed that TIPE2 inhibits hepatocellular carcinoma metastasis by repressing Ral and Rac1 GTPases. However, its antimetastatic activity and underlying mechanism in other human cancers is largely unknown. We investigated TIPE2 in AGS, HGC-27 and SGC-7901 human gastric cancer cells compared with GES-1 normal human gastric mucous epithelial cells. We demonstrated that TIPE2 was expressed in GES-1 gastric mucous epithelial cells but lost in all three types of gastric cancer cells. We then performed a gain-of-function study by adenovirus-mediated TIPE2 overexpression (AdVTIPE2) and investigated the effects of TIPE2 on migration and invasion of AGS human gastric cancer cells. Wound healing and Transwell invasion assays showed that forced expression of TIPE2 markedly suppressed the gastric cancer cell migration and invasion in vitro. Mechanistically, TIPE2 remarkably reduced the total levels of pAKT, pGSK3β and β-catenin as well as the nuclear level of β-catenin in gastric cancer cells. The TIPE2-elicited antimetastatic effect in gastric cancer was closely associated with the inhibition of AKT signaling and enhancement of GSK3β activity followed by the degradation and decreased translocation to nucleus of β-catenin. These results provide the first compelling evidence that TIPE2 suppresses gastric cancer metastasis via downregulating β-catenin signaling through inhibiting AKT and activating GSK3β, indicating that TIPE2 is a promising therapeutic target for human gastric cancer metastasis.

Vasseur R, Skrypek N, Duchêne B, et al.
The mucin MUC4 is a transcriptional and post-transcriptional target of K-ras oncogene in pancreatic cancer. Implication of MAPK/AP-1, NF-κB and RalB signaling pathways.
Biochim Biophys Acta. 2015; 1849(12):1375-84 [PubMed] Related Publications
The membrane-bound mucinMUC4 is a high molecularweight glycoprotein frequently deregulated in cancer. In pancreatic cancer, one of the most deadly cancers in occidental countries, MUC4 is neo-expressed in the preneoplastic stages and thereafter is involved in cancer cell properties leading to cancer progression and chemoresistance. K-ras oncogene is a small GTPase of the RAS superfamily, highly implicated in cancer. K-ras mutations are considered as an initiating event of pancreatic carcinogenesis and K-ras oncogenic activities are necessary components of cancer progression. However, K-ras remains clinically undruggable. Targeting early downstream K-ras signaling in cancer may thus appear as an interesting strategy and MUC4 regulation by K-ras in pancreatic carcinogenesis remains unknown. Using the Pdx1-Cre; LStopL-K-rasG12D mouse model of pancreatic carcinogenesis, we show that the in vivo early neo-expression of the mucin Muc4 in pancreatic intraepithelial neoplastic lesions (PanINs) induced by mutated K-ras is correlated with the activation of ERK, JNK and NF-κB signaling pathways. In vitro, transfection of constitutively activated K-rasG12V in pancreatic cancer cells led to the transcriptional upregulation of MUC4. This activation was found to be mediated at the transcriptional level by AP-1 and NF-κB transcription factors via MAPK, JNK and NF-κB pathways and at the posttranscriptional level by a mechanism involving the RalB GTPase. Altogether, these results identify MUC4 as a transcriptional and post-transcriptional target of K-ras in pancreatic cancer. This opens avenues in developing new approaches to target the early steps of this deadly cancer.

Dunne PD, Dasgupta S, Blayney JK, et al.
EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer.
Clin Cancer Res. 2016; 22(1):230-42 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.
EXPERIMENTAL DESIGN: EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.
RESULTS: Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.
CONCLUSIONS: These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target.

Wang CZ, Yuan P, Xu B, et al.
RLIP76 expression as a prognostic marker of breast cancer.
Eur Rev Med Pharmacol Sci. 2015; 19(11):2105-11 [PubMed] Related Publications
OBJECTIVE: RLIP (Ral-interacting protein)-76/RalBP11 (Ral-binding protein-1), a multifunctional protein and stress-inducible non-ABC transporter, have been proven to serve as a critical role in cancer development and progression; however, little is known about the pathological role of RLIP76 in breast cancer patients. The study aimed to determine the correlation between RLIP76 expression in breast cancer patient and clinical outcomes.
PATIENTS AND METHODS: Using RT-PCR and Western blot, messenger RNA (mRNA) and protein expression of RLIP76 were determined in breast cancer and adjacent normal mammary tissues. The relationship of RLIP76 expression with clinical characteristics of 245 breast cancer patients was analyzed by immunohistochemistry.
RESULTS: In the present study, our results indicated that RLIP76 mRNA and protein were highly expressed in the breast cancer tissues while compared with adjacent normal mammary tissues and the correlation with RLIP76 protein expression was significantly associated with age (the non-ABC transporter, stage and the expression were significantly associated-T2 vs. T3-T4, p < 0.01), lymph node metastasis (N0-N1 vs. N2-N3, p < 0.01), and PR (positive vs. negative, p < 0.01) in breast cancer patients; furthermore, we also found that RLIP76 protein overexpression was an unfavorable prognostic factor in the patients suffered from breast cancer.
CONCLUSIONS: RLIP76 overexpression serves as an unfavorable prognostic biomarker in breast cancer patients.

Monot M, Erny A, Gineys B, et al.
Early Steps of Jaagsiekte Sheep Retrovirus-Mediated Cell Transformation Involve the Interaction between Env and the RALBP1 Cellular Protein.
J Virol. 2015; 89(16):8462-73 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: Ovine pulmonary adenocarcinoma is a naturally occurring lung cancer in sheep induced by the Jaagsiekte sheep retrovirus (JSRV). Its envelope glycoprotein (Env) carries oncogenic properties, and its expression is sufficient to induce in vitro cell transformation and in vivo lung adenocarcinoma. The identification of cellular partners of the JSRV envelope remains crucial for deciphering mechanisms leading to cell transformation. We initially identified RALBP1 (RalA binding protein 1; also known as RLIP76 or RIP), a cellular protein implicated in the ras pathway, as a partner of JSRV Env by yeast two-hybrid screening and confirmed formation of RALBP1/Env complexes in mammalian cells. Expression of the RALBP1 protein was repressed in tumoral lungs and in tumor-derived alveolar type II cells. Through its inhibition using specific small interfering RNA (siRNA), we showed that RALBP1 was involved in envelope-induced cell transformation and in modulation of the mTOR (mammalian target of rapamycin)/p70S6K pathway by the retroviral envelope.
IMPORTANCE: JSRV-induced lung adenocarcinoma is of importance for the sheep industry. While the envelope has been reported as the oncogenic determinant of the virus, the cellular proteins directly interacting with Env are still not known. Our report on the formation of RALBP/Env complexes and the role of this interaction in cell transformation opens up a new hypothesis for the dysregulation observed upon virus infection in sheep.

Győrffy B, Stelniec-Klotz I, Sigler C, et al.
Effects of RAL signal transduction in KRAS- and BRAF-mutated cells and prognostic potential of the RAL signature in colorectal cancer.
Oncotarget. 2015; 6(15):13334-46 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Our understanding of oncogenic signaling pathways has strongly fostered current concepts for targeted therapies in metastatic colorectal cancer. The RALA pathway is novel candidate due to its independent role in controlling expression of genes downstream of RAS.We compared RALA GTPase activities in three colorectal cancer cell lines by GTPase pull-down assay and analyzed the transcriptional and phenotypic effects of transient RALA silencing. Knocking-down RALA expression strongly diminished the active GTP-bound form of the protein. Proliferation of KRAS mutated cell lines was significantly reduced, while BRAF mutated cells were mostly unaffected. By microarray analysis we identified common genes showing altered expression upon RALA silencing in all cell lines. None of these genes were affected when the RAF/MAPK or PI3K pathways were blocked.To investigate the potential clinical relevance of the RALA pathway and its associated transcriptome, we performed a meta-analysis interrogating progression-free survival of colorectal cancer patients of five independent data sets using Cox regression. In each dataset, the RALA-responsive signature correlated with worse outcome.In summary, we uncovered the impact of the RAL signal transduction on genetic program and growth control in KRAS- and BRAF-mutated colorectal cells and demonstrated prognostic potential of the pathway-responsive gene signature in cancer patients.

Aguilera Ó, González-Sancho JM, Zazo S, et al.
Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer.
Oncotarget. 2015; 6(8):5903-17 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Sporadic colorectal cancer (CRC) insurgence and progression depend on the activation of Wnt/β-catenin signaling. Dickkopf (DKK)-1 is an extracellular inhibitor of Wnt/β-catenin signaling that also has undefined β-catenin-independent actions. Here we report for the first time that a proportion of DKK-1 locates within the nucleus of healthy small intestine and colon mucosa, and of CRC cells at specific chromatin sites of active transcription. Moreover, we show that DKK-1 regulates several cancer-related genes including the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) and Ral-binding protein 1-associated Eps domain-containing 2 (REPS2), which are involved in detoxification of chemotherapeutic agents. Nuclear DKK-1 expression is lost along CRC progression; however, it remains high in a subset (15%) of CRC patients (n = 699) and associates with decreased progression-free survival (PFS) after chemotherapy administration and overall survival (OS) [adjusted HR, 1.65; 95% confidence interval (CI), 1.23-2.21; P = 0.002)]. Overexpression of ALDH1A1 and REPS2 associates with nuclear DKK-1 expression in tumors and correlates with decreased OS (P = 0.001 and 0.014) and PFS. In summary, our findings demonstrate a novel location of DKK-1 within the cell nucleus and support a role of nuclear DKK-1 as a predictive biomarker of chemoresistance in colorectal cancer.

Stremitzer S, Zhang W, Yang D, et al.
Genetic variations in angiopoietin and pericyte pathways and clinical outcome in patients with resected colorectal liver metastases.
Cancer. 2015; 121(11):1898-905 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Genes involved in the angiopoietin and pericyte pathways may become escape mechanisms under antivascular endothelial growth factor (anti-VEGF) therapy. The authors investigated whether variations within genes in these pathways are associated with clinical outcome in patients with colorectal liver metastases who undergo liver resection and receive perioperative, bevacizumab-based chemotherapy.
METHODS: Single nucleotide polymorphisms (SNPs) in 9 genes (angiopoietin-1 [ANGPT1]; ANGPT2; TEK tyrosine kinase, endothelial [TEK]; platelet-derived growth factor β [PDGFB]; β-type platelet-derived growth factor receptor [PDGFRB]; insulin-like growth factor 1 [IGF1]; transforming growth factor β1 [TGFB1]; RalA binding protein 1 [RALBP1]; and regulator of G-protein signaling 5 [RGS5]) were analyzed in samples of genomic DNA from 149 patients and were evaluated for associations with clinical outcome.
RESULTS: RALBP1 reference SNP 329007 (rs329007) A>G resulted in a significant difference in recurrence-free survival (A/A genotype, 14.0 months; A/G or G/G genotype, 9.2 months; hazard ratio [HR], 1.60; P = .024). PDGFB rs1800818 A>G was associated with 3-year overall survival rates (A/A genotype, 78%; A/G genotype, 69%; [HR 1.37]; G/G genotype, 53%; [HR 2.12]; P = .048). In multivariate analysis, RALBP1 rs329007 A>G remained significant (HR, 1.99; P = .002). PDGFB rs1800818 A>G and RALBP1 rs329007 A>G were correlated with radiologic response (A/A or A/G genotype, 86%; G/G genotype, 71% [P = .042]; A/A genotype, 78%; A/G or G/G genotype, 94% [P = .018], respectively). RALBP1 rs329007 A>G demonstrated significantly different rates of histologic response (A/A genotype: major histologic response, 35%; partial histologic response, 34%; no histologic response, 30%; A/G or G/G genotype: 46%, 13%, and 41%, respectively; P = .029). Recursive partitioning analysis revealed that ANGPT2 rs2442599 T>C and RALBP1 rs329007 A>G were the main SNPs that predicted histologic response and recurrence-free survival, whereas PDGFB rs1800818 A>G was the leading SNP that predicted overall survival. ANGPT2 rs2916702 C>T and rs2442631 G>A were significantly associated with the probability of achieving a cure.
CONCLUSIONS: The current data suggest that variations in genes involved in the angiopoietin and pericyte pathways may be predictive and/or prognostic biomarkers in patients with resected colorectal liver metastases who receive bevacizumab-based chemotherapy.

Zhou B, Bu G, Zhou Y, et al.
Knockdown of CDC2 expression inhibits proliferation, enhances apoptosis, and increases chemosensitivity to temozolomide in glioblastoma cells.
Med Oncol. 2015; 32(1):378 [PubMed] Related Publications
Cell division cycle 2 (CDC2) is always overexpressed in malignant tumor cells and is correlated with chemosensitivity, but it is unclear whether CDC2 overexpression contributes to the chemoresistance potential of glioma cells. The aim of study was to determine the relationship of CDC2 expression with the prognosis and chemoresistance of glioblastoma. In this study, the glioblastoma U87 and U251 cell lines were steadily transfected with a lentivirus vector expressing a short hairpin RNA-targeting CDC2. Expression of CDC2 was evaluated in glioblastoma and cell lines by immunohistochemistry and Western blot analysis. The relationship between CDC2 expression and clinicopathological characteristics was analyzed. Using RNA interference, the effects of CDC2 on chemosensitivity to temozolomide (TMZ) were investigated in U87 and U251 cell lines in vitro. Combined CDC2 knockdown and TMZ treatment inhibited cell proliferation and induced apoptosis in vitro more effectively than either treatment alone. qRT-PCR and Western blot analysis showed that cells underexpressing CDC2 revealed lower expression of the anti-apoptotic protein B cell lymphoma-2 and increased expression of the apoptosis effector caspase-3 compared to U87 and U251 cells transfected with a control vector. Furthermore, expression levels of CDC2 in U87 and U251 cells were related to the IC50 of the antitumor drug TMZ. Knockdown of CDC2 expression was associated with decreased expression of Ral-binding protein 1, a classical chemotherapy drugs transporter. These results indicate that the ability to suppress the malignant phenotype by down-regulating CDC2 expression may provide a new gene therapy approach for overcoming CDC2-associated chemoresistance in patients with malignant glioma.

Tal Y, Yaakobi S, Horovitz-Fried M, et al.
An NCR1-based chimeric receptor endows T-cells with multiple anti-tumor specificities.
Oncotarget. 2014; 5(21):10949-58 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The Ral (Ras-like) GTP-binding proteins (RalA and RalB), as effectors of the proto-oncogene Natural killer (NK) cells are an important component of the anti-tumor response. Tumor recognition by NK cells was found to be partly triggered by molecules termed natural cytotoxic receptors (NCRs). Adoptive transfer of genetically-engineered tumor-reactive T-lymphocytes can mediate remarkable tumor regressions mostly in melanoma and leukemia patients. Yet, the application of such treatments to other cancers is needed and dependent on the isolation of receptors that could facilitate efficient recognition of these malignancies. Herein, we aimed at combining NK tumor recognition capability with the genetic modification of T-cells to provide the latter with a means to recognize several tumors in a non-MHC restricted way. Consequently, we generated and evaluated several chimeric receptors based on the extracellular domain of NCR1 (NKp46) fused to multiple signaling moieties and assess their antitumor activity when retrovirally expressed in T-cells. Following co-culture with different tumors, primary human T-lymphocytes expressing a chimeric NCR1 molecule recognized target cells derived from lung, cervical carcinoma, leukemia and pancreatic cancer. In addition, this receptor mediated an upregulation of surface activation markers and significant antitumor cytotoxicity both in vitro and in vivo. These results have meaningful implications for the immunotherapeutic treatment of cancer using gene-modified T-cells.

Zhang Y, Song X, Gong W, et al.
RLIP76 blockade by siRNA inhibits proliferation, enhances apoptosis, and suppresses invasion in HT29 colon cancer cells.
Cell Biochem Biophys. 2015; 71(2):579-85 [PubMed] Related Publications
RLIP76, a multidomain protein which is a downstream effector of the small GTP ases RalA and RalB, is known to play a role in biological activities in a variety of malignant cancer cells. However, little study has been done on the role of RLIP76 in CRC. In this study, a RLIP76-targeted siRNA-containing vector was used to investigate the effect of RLIP76 knockdown on cellular functions in human CRC cell line HT29. Quantitative RT-PCR and Western blot analysis revealed that the expression levels of RLIP76 mRNA and protein in HT29 cells were significantly suppressed after transfection. Our results indicated that RLIP76 downregulation in HT29 CRC cells suppressed cell growth, enhanced cell apoptosis, induced cell cycle arrest, and inhibited cell invasion by decreasing MMP2 expression. Although the mechanisms through which RLIP76 regulates the cellular functions needs further investigation, our results indicate that RLIP76 may represent as a potential target of gene therapy for CRC treatment.

Tecleab A, Zhang X, Sebti SM
Ral GTPase down-regulation stabilizes and reactivates p53 to inhibit malignant transformation.
J Biol Chem. 2014; 289(45):31296-309 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Ral GTPases are critical effectors of Ras, yet the molecular mechanism by which they induce malignant transformation is not well understood. In this study, we found the expression of K-Ras, RalB, and sometimes RalA, but not AKT1/2 and c-Raf, to be required for maintaining low levels of p53 in human cancer cells that harbor mutant K-Ras and wild-type p53. Down-regulation of K-Ras, RalB, and sometimes RalA increases p53 protein levels and results in a p53-dependent up-regulation of the expression of p21(WAF). K-Ras, RalA, and RalB depletion increases p53 stability as demonstrated by ataxia telangiectasia-mutated kinase activation, increased Ser-15 phosphorylation, and a significant (up to 6-fold) increase in p53 half-life. Furthermore, depletion of K-Ras and RalB inhibits anchorage-independent growth and invasion and interferes with cell cycle progression in a p53-dependent manner. Depletion of RalA inhibits invasion in a p53-dependent manner. Thus, expression of K-Ras and RalB and possibly RalA proteins is critical for maintaining low levels of p53, and down-regulation of these GTPases reactivates p53 by significantly enhancing its stability, and this contributes to suppression of malignant transformation.

Tang SC, Chen YC
Novel therapeutic targets for pancreatic cancer.
World J Gastroenterol. 2014; 20(31):10825-44 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16(INK4A) and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.

Volz NB, Stintzing S, Zhang W, et al.
Genes involved in pericyte-driven tumor maturation predict treatment benefit of first-line FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer.
Pharmacogenomics J. 2015; 15(1):69-76 [PubMed] Related Publications
Pericytes are crucial for angiogenesis. The impact of pericyte function to bevacizumab efficacy in mCRC treatment has not been comprehensively examined. This retrospective study investigated germline polymorphisms in genes related to early pericyte maturation to predict bevacizumab efficacy in 424 patients of two clinical trials treated first line with FOLFIRI+bevacizumab. Eight single-nucleotide polymorphisms (SNPs) were tested for potential biomarker value: RGS5 (regulator of G-protein signaling 5; rs1056515, rs2661280), PDGFR-β (platelet-derived growth factor receptor-β; rs2229562, rs2302273), CSPG4 (chondroitin sulfate proteoglycan NG2; rs8023621, rs1127648) and RALBP1 (RalA binding protein 1; rs10989, rs329007). For progression-free survival (PFS), PDGFR-β (rs2302273) was able to define significantly different patient cohorts in uni- and multivariate testing. RALPB1 (rs329007) showed predictive value for tumor response. The C allele in RGS5 (rs2661280) predicted longer overall survival and CSPG4 rs1127648 was associated with differences in PFS, but for both value was lost when multivariate analysis was applied. A comprehensive statistical analysis revealed that the biomarker value of the SNPs was dependent on primary tumor location. This is the first study to identify pericyte germline polymorphisms associated with clinical outcome in mCRC patients treated first line with FOLFIRI+bevacizumab. The differences seen with regard to primary tumor location may lead to further research to understand the clinical outcome differences seen in right- and left-sided colon cancer.

Vu HL, Aplin AE
Targeting TBK1 inhibits migration and resistance to MEK inhibitors in mutant NRAS melanoma.
Mol Cancer Res. 2014; 12(10):1509-19 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: Melanoma is a devastating form of skin cancer with limited therapeutic options. Fifteen to 20% of patients with melanoma have an activating mutation in the GTPase, NRAS. The major downstream effectors of RAS are RAFs (ARAF, BRAF, and CRAF), phosphoinositide 3-kinase (PI3K), and the Ral guanine exchange factors (RalGEF). TANK-binding kinase 1 (TBK1) is an atypical IκB kinase family member that acts downstream of RalGEFs. Whereas many studies have analyzed RAF and PI3K signaling in mutant NRAS melanoma, the role of RalGEF/Ral is understudied and TBK1 has not been examined. To address this, TBK1 was modulated with knockdown approaches and targeted therapies to determine the role of TBK1 in motility, apoptosis, and signaling. In melanoma, NRAS overexpression increased TBK1 phosphorylation. TBK1 depletion inhibited migration and invasion, whereas its constitutive overexpression led to an increase in invasion. In three-dimensional systems that mimic the dermal microenvironment, TBK1 depletion or inhibition cooperated with MEK inhibitors to promote apoptosis, particularly in the context of MEK-insensitive mutant NRAS. This effect was absent in melanoma cells that are wild-type for NRAS. These results suggest the utility of TBK1 inhibitors as part of a treatment regimen for patients with mutant NRAS melanoma, for whom there are no current effective therapies.
IMPLICATIONS: TBK1 promotes the malignant properties of NRAS-mutant melanoma and its targeting, in combination with MEK, promotes apoptosis, thus providing a potential novel targeted therapeutic option.

Kim EY, Kim A, Kim SK, et al.
KRAS oncogene substitutions in Korean NSCLC patients: clinical implication and relationship with pAKT and RalGTPases expression.
Lung Cancer. 2014; 85(2):299-305 [PubMed] Related Publications
OBJECTIVES: Since different conformation of each KRAS mutant leads to inherent downstream signaling, its distribution, influence on the clinical outcome, and effect on the signaling mediators were investigated in the Korean NSCLC patients whose tumor have KRAS mutation.
MATERIALS AND METHODS: Mutation at KRAS codons 12 and 13 was evaluated in 1420 Korean NSCLC by direct sequencing and expression of RalA, RalB, and pAKT-Ser473 was evaluated by immunohistochemistry in 30 cases whose KRAS mutant tumor tissues were available.
RESULTS: Eighty-two (5.8%) out of 1420 patients harbored a KRAS mutation either in codon 12 or 13. Gly12Asp was the most frequent (34.1%), followed by Gly12Cys (22.0%) and Gly12Val (13.4%). Transversion at codons 12 and 13, which includes Gly12Cys, Gly12Val, Gly12Ala, Gly13Cys, and Gly12Phe was detected in 45 cases (54.9%) and transition, including Gly12Asp, Gly12Ser, and Gly13Asp was detected in 37 cases (45.1%). Male and smoking history were associated with transversion (p=0.001 and 0.006, respectively; χ(2)-test), and multivariate analysis showed that gender was an independent influencing factor (p=0.026; Cochran-Mantel-Haenszel test). Multivariate analysis on survival revealed that KRAS mutation subtype did not influence overall survival of the patients with KRAS mutations after adjustment for age, gender, performance status, and stage. There were no differences in the nuclear and cytoplasmic expression of pAKT-Ser473 between transversion and transition mutants. Expression of Ral-GTPases, RalA and RalB, did not differ between transversion and transition mutants, however, strong expression of RalB in the tissue of patients with KRAS mutants was associated with advanced stages (P-value=0.020, χ(2)-test).
CONCLUSIONS: In this study population, not only the frequency of KRAS mutation but also the distribution of its subtypes differed from those of Western studies, with unique influencing factors. Clinical outcome and expression of pAKT-Ser473, RalA, and RalB did not differ among subtypes.

Dai L, Li J, Ortega R, et al.
Preferential autoimmune response in prostate cancer to cyclin B1 in a panel of tumor-associated antigens.
J Immunol Res. 2014; 2014:827827 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Previous studies have demonstrated that sera from patients with prostate cancer (PCa) contain autoantibodies that react with tumor-associated antigens (TAAs). Autoantibodies to cyclin B1 and fourteen other TAAs were detected by enzyme-linked immunosorbent assay (ELISA) and Western blotting in 464 sera from patients with PCa, benign prostatic hyperplasia (BPH), and other controls. Autoantibodies to cyclin B1 were detected in 31.0% of sera from randomly selected patients with PCa versus 4.8% in sera with BPH. In the further analysis, 31.4% of sera from PCa patients at the early stage contained anti-cyclin B1 autoantibody, and even 29.4% of patients who had normal prostate-specific antigen (PSA) levels in their serum samples were observed anti-cyclin B1 positive. The cumulative positive rate of autoantibodies against seven selected TAAs (cyclin B1, survivin, p53, DFS70/LEDGFp75, RalA, MDM2, and NPM1) in PCa reached 80.5%, significantly higher than that in normal control sera. In summary, autoantibody to cyclin B1 might be a potential biomarker for the immunodiagnosis of early stage PCa, especially useful in patients with normal PSA level. This study further supports the hypothesis that a customized TAA array can be used for enhancing anti-TAA autoantibody detection, and it may constitute a promising and powerful tool for immunodiagnosis of PCa.

Ezzeldin M, Borrego-Diaz E, Taha M, et al.
RalA signaling pathway as a therapeutic target in hepatocellular carcinoma (HCC).
Mol Oncol. 2014; 8(5):1043-53 [PubMed] Related Publications
Ral (Ras like) leads an important proto-oncogenic signaling pathway down-stream of Ras. In this work, RalA was found to be significantly overactivated in hepatocellular carcinoma (HCC) cells and tissues as compared to non-malignant samples. Other elements of RalA pathway such as RalBP1 and RalGDS were also expressed at higher levels in malignant samples. Inhibition of RalA by gene-specific silencing caused a robust decrease in the viability and invasiveness of HCC cells. Additionally, the use of geranyl-geranyl transferase inhibitor (GGTI, an inhibitor of Ral activation) and Aurora kinase inhibitor II resulted in a significant decrease in the proliferation of HCC cells. Furthermore, RalA activation was found to be at a higher level of activation in HCC stem cells that express CD133. Transgenic mouse model for HCC (FXR-Knockout) also revealed an elevated level of RalA-GTP in the liver tumors as compared to background animals. Finally, subcutaneous mouse model for HCC confirmed effectiveness of inhibition of aurora kinase/RalA pathway in reducing the tumorigenesis of HCC cells in vivo. In conclusion, RalA overactivation is an important determinant of malignant phenotype in differentiated and stem cells of HCC and can be considered as a target for therapeutic intervention.

Li Y, Sun Y, Fan L, et al.
Paris saponin VII inhibits growth of colorectal cancer cells through Ras signaling pathway.
Biochem Pharmacol. 2014; 88(2):150-7 [PubMed] Related Publications
Dysregulation of the Ras signaling pathway plays a key role in the progression of colorectal cancer. When bound to GTP, Ras is activated and stimulates several downstream effectors' pathways, including the Raf/MEK/ERK kinase cascade, the PI3-kinase/AKT/mTor pathway, and the Ral GTPase pathway. Saponins extracted from Liliaceae family herbs have strong antitumor activities with low toxicity. In this study, Paris saponin VII (PSVII), isolated from Trillium tschonoskii Maxim., was evaluated on human colorectal cancer cells (HT-29 and SW-620), a mouse model of colitis associated colorectal cancer (CACC) and a murine model of xenograft tumor. It was found that PSVII inhibited colorectal cancer cell growth in a concentration-dependent manner. The IC50 values of PSVII for growth inhibition of HT-29 and SW-620 cells were 1.02 ± 0.05 μM and 4.90 ± 0.23 μM. It could induce cell apoptosis, together with cell cycle arrest in G1 phase, and trigger apoptosis in a caspase-3-dependent manner. PSVII-induced growth inhibitory effect was associated with disturbance of MAPK pathway by down-regulating MEK1/2, ERK1/2 phosphorylation, and suppression of AKT pathway by reducing AKT and GSK-3β phosphorylation. In the CACC mouse model, PSVII protected mice from intestinal toxicities and carcinogenesis induced by 1,2-dimethylhydrazine (DMH) and dextran sodium sulfate (DSS). In the model of xenograft tumor, PSVII remarkably decreased the xenograft tumor size and triggered the apoptosis of tumor cells. Both in vitro and in vivo study showed that PSVII inhibited Ras activity. Taken together, PSVII might be a potential therapeutic reagent for colorectal cancer through targeting Ras signaling pathway.

Guin S, Ru Y, Wynes MW, et al.
Contributions of KRAS and RAL in non-small-cell lung cancer growth and progression.
J Thorac Oncol. 2013; 8(12):1492-501 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
INTRODUCTION: KRAS mutations are poor prognostic markers for patients with non-small-cell lung cancer (NSCLC). RALA and RALB GTPases lie downstream of RAS and are implicated in RAS-mediated tumorigenesis. However, their biological or prognostic role in the context of KRAS mutation in NSCLC is unclear.
METHODS: Using expression analysis of human tumors and a panel of cell lines coupled with functional in vivo and in vitro experiments, we evaluated the prognostic and functional importance of RAL in NSCLC and their relationship to KRAS expression and mutation.
RESULTS: Immunohistochemical (N = 189) and transcriptomic (N = 337) analyses of NSCLC patients revealed high RALA and RALB expression was associated with poor survival. In a panel of 14 human NSCLC cell lines, RALA and RALB had higher expression in KRAS mutant cell lines whereas RALA but not RALB activity was higher in KRAS mutant cell lines. Depletion of RAL paralogs identified cell lines that are dependent on RAL expression for proliferation and anchorage independent growth. Overall, growth of NSCLC cell lines that carry a glycine to cystine KRAS mutation were more sensitive to RAL depletion than those with wild-type KRAS. The use of gene expression and outcome data from 337 human tumors in RAL-KRAS interaction analysis revealed that KRAS and RAL paralog expression jointly impact patient prognosis.
CONCLUSION: RAL GTPase expression carries important additional prognostic information to KRAS status in NSCLC patients. Simultaneously targeting RAL may provide a novel therapeutic approach in NSCLC patients harboring glycine to cystine KRAS mutations.

Kashatus DF
Ral GTPases in tumorigenesis: emerging from the shadows.
Exp Cell Res. 2013; 319(15):2337-42 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Oncogenic Ras proteins rely on a series of key effector pathways to drive the physiological changes that lead to tumorigenic growth. Of these effector pathways, the RalGEF pathway, which activates the two Ras-related GTPases RalA and RalB, remains the most poorly understood. This review will focus on key developments in our understanding of Ral biology, and will speculate on how aberrant activation of the multiple diverse Ral effector proteins might collectively contribute to oncogenic transformation and other aspects of tumor progression.

Huang C, Wang WM, Gong JP, Yang K
Oncogenesis and the clinical significance of K-ras in pancreatic adenocarcinoma.
Asian Pac J Cancer Prev. 2013; 14(5):2699-701 [PubMed] Related Publications
The RAS family genes encode small GTP-binding cytoplasmic proteins. Activated KRAS engages multiple effector pathways, notably the RAF-mitogen-activated protein kinase, phosphoinositide-3-kinase (PI3K) and RalGDS pathways. In the clinical field, K-ras oncogene activation is frequently found in human cancers and thus may serve as a potential diagnostic marker for cancer cells in circulation. This mini-review aims to summarise information on Ras-induced oncogenesis and the clinical significance of K-ras.

Sun D, Jones NR, Manni A, Lazarus P
Characterization of raloxifene glucuronidation: potential role of UGT1A8 genotype on raloxifene metabolism in vivo.
Cancer Prev Res (Phila). 2013; 6(7):719-30 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Raloxifene is a second-generation selective estrogen receptor modulator used for the prevention and treatment of osteoporosis and the prevention of breast cancer in postmenopausal women. Raloxifene is extensively metabolized by glucuronidation to form raloxifene-6-glucuronide (ral-6-Gluc) and raloxifene-4'-glucuronide (ral-4'-Gluc). The goal of the present study was to determine whether functional polymorphisms in active UGTs could play a role in altered raloxifene glucuronidation in vivo. Using homogenates from HEK293 UGT-overexpressing cell lines, raloxifene was shown to be glucuronidated primarily by the hepatic UGTs 1A1 and 1A9 and the extra-hepatic UGTs 1A8 and 1A10; no detectable raloxifene glucuronidation activity was found for UGT2B enzymes. Functional UGT1A1 transcriptional promoter genotypes were significantly (Ptrend = 0.005) associated with ral-6-Gluc formation in human liver microsomes, and, consistent with the decreased raloxifene glucuronidation activities observed in vitro with cell lines overexpressing UGT1A8 variants, the UGT1A8*2 variant was significantly (P = 0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-4'-Gluc exhibited 1:100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised about 99% of the circulating raloxifene dose in raloxifene-treated subjects, with ral-4'-Gluc comprising ~70% of raloxifene glucuronides. Plasma ral-6-Gluc (Ptrend = 0.0025), ral-4'-Gluc (Ptrend = 0.001), and total raloxifene glucuronides (Ptrend = 0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] versus intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] versus fast metabolizers [UGT1A8 (*2/*2). These data suggest that raloxifene metabolism may be dependent on UGT1A8 genotype and that UGT1A8 genotype may play an important role in overall response to raloxifene.

Tazat K, Harsat M, Goldshmid-Shagal A, et al.
Dual effects of Ral-activated pathways on p27 localization and TGF-β signaling.
Mol Biol Cell. 2013; 24(11):1812-24 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Constitutive activation or overactivation of Ras signaling pathways contributes to epithelial tumorigenesis in several ways, one of which is cytoplasmic mislocalization of the cyclin-dependent kinase inhibitor p27(Kip1) (p27). We previously showed that such an effect can be mediated by activation of the Ral-GEF pathway by oncogenic N-Ras. However, the mechanism(s) leading to p27 cytoplasmic accumulation downstream of activated Ral remained unknown. Here, we report a dual regulation of p27 cellular localization by Ral downstream pathways, based on opposing effects via the Ral effectors RalBP1 and phospholipase D1 (PLD1). Because RalA and RalB are equally effective in mislocalizing both murine and human p27, we focus on RalA and murine p27, which lacks the Thr-157 phosphorylation site of human p27. In experiments based on specific RalA and p27 mutants, complemented with short hairpin RNA-mediated knockdown of Ral downstream signaling components, we show that activation of RalBP1 induces cytoplasmic accumulation of p27 and that this event requires p27 Ser-10 phosphorylation by protein kinase B/Akt. Of note, activation of PLD1 counteracts this effect in a Ser-10-independent manner. The physiological relevance of the modulation of p27 localization by Ral is demonstrated by the ability of Ral-mediated activation of the RalBP1 pathway to abrogate transforming growth factor-β-mediated growth arrest in epithelial cells.

Yang D, Zhu Z, Wang W, et al.
Expression profiles analysis of pancreatic cancer.
Eur Rev Med Pharmacol Sci. 2013; 17(3):311-7 [PubMed] Related Publications
BACKGROUND: [Corrected] Pancreatic cancer is the fourth most common cause of cancer-related deaths across the globe and has a poor prognosis.
AIM: To investigate the characteristics of genomic expression profiles of pancreatic cancer and screen differentially expressed genes.
MATERIALS AND METHODS: Using GSE16515 dataset downloaded from GEO (Gene Expression Omnibus) database, we first screened the differentially expressed genes (DEGs) in pancreatic cancer by packages in R language. The key functions of DEGs were investigated by GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis. The potential functionally important SNP (Single Nucleotide Polymorphism) was selected from the dbSNP database.
RESULTS: A total of 1270 DEGs were identified. Most of them were predicted to be involved in pancreatic cancer development by sequence variant. Six genes (CDC42, STAT1, RALA, BCL2L1, TGFA, and EGF) were enriched in the known pancreatic cancer pathway. All these six genes had SNP, usually mutation at A/G and C/T point.
CONCLUSIONS: Our results provide some underlying biomarkers for early diagnosis of pancreatic cancer.

Sehrawat A, Yadav S, Awasthi YC, et al.
P300 regulates the human RLIP76 promoter activity and gene expression.
Biochem Pharmacol. 2013; 85(8):1203-11 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
A 76-kDa Ral-interacting protein (RLIP76) has been implicated in the pathogenesis of cancer and diabetes. It is often over expressed in human malignant cell lines and human tumor samples and has been associated with metastasis and chemoresistance. RLIP76 homozygous knockout mice exhibit increased insulin sensitivity, hypoglycemia, and hypolipidemia, and resist cancer development. Little is known about the mechanism by which the expression of RLIP76 is regulated. In the present study, we functionally characterized the RLIP76 promoter using deletion mapping and mutational analysis to investigate the regulation of RLIP76 transcription. We have identified the promoter regions important for RLIP76 transcription, including a strong cis-activating element in the proximal promoter containing overlapping consensus cMYB and cETS binding sites. Transcription factor cMYB and the coactivator p300 associated with RLIP76 gene promoter as shown by CHIP assay. Knockdown of p300 in HEK293 cells reduced the activity of the promoter fragment containing wild type cMYB/cETS binding site in comparison to that with deleted or mutated cMYB/cETS binding site. Knockdown of p300 also decreased the RLIP76 expression as indicated by immunoblotting, immunocytochemistry and flow cytometry analysis. Thus, we report for the first time that p300 associates with the RLIP76 promoter via an overlapping cMYB and cETS binding site and regulates RLIP76 promoter activity and its expression.

Monica V, Familiari U, Chiusa L, et al.
Messenger RNA and protein expression of thymidylate synthase and DNA repair genes in thymic tumors.
Lung Cancer. 2013; 79(3):228-35 [PubMed] Related Publications
BACKGROUND: Thymic epithelial tumors include several entities with different biologic behavior. Chemotherapy is indicated in advanced disease, but limited data exist on gene expression correlation with the response to chemotherapeutic agents.
PATIENTS AND METHODS: A series of 69 thymic neoplasms (7 A-, 6 AB-, 6 B1-, 10 B2-, 14 B3-thymomas, 22 carcinomas and 4 combined tumors) was collected to assess gene expression of thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), ribonucleotide reductase subunit 1 (RRM1), topoisomerase 2α (TOP2A) and mTOR.
RESULTS: A strong linear correlation between TS gene and protein expression was observed (P<0.0001, R=0.40). TS expression was significantly lower in pure A-thymomas and thymic carcinomas (P<0.0001) and progressively decreasing from B1-type to thymic carcinomas (B1>B2>B3>C; P<0.0001). RRM1 and TOP2A mRNA expression levels were significantly correlated with TS levels (both P=0.03) with a similar trend of expression among histotypes. RRM1 and TOP2A high levels were significantly correlated with high TS (P=0.03) and low tumor stages (I-II) (P<0.0001 and P<0.01, respectively). No relevant changes of ERCC1 and mTOR were detected.
CONCLUSIONS: Low TS and, to a minor extent, RRM1 and TOP2A expression were detected in aggressive thymic tumors. These findings should be prospectively considered in selecting the most appropriate chemotherapy.

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