CD69

Gene Summary

Gene:CD69; CD69 molecule
Aliases: AIM, EA1, MLR-3, CLEC2C, GP32/28, BL-AC/P26
Location:12p13
Summary:This gene encodes a member of the calcium dependent lectin superfamily of type II transmembrane receptors. Expression of the encoded protein is induced upon activation of T lymphocytes, and may play a role in proliferation. Furthermore, the protein may act to transmit signals in natural killer cells and platelets. [provided by RefSeq, Aug 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:early activation antigen CD69
HPRD
Source:NCBIAccessed: 27 August, 2015

Ontology:

What does this gene/protein do?
Show (5)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 August 2015 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.

  • Natural Killer Cells
  • Cell Proliferation
  • Cancer Gene Expression Regulation
  • Viral Matrix Proteins
  • Receptors, Chemokine
  • Chronic Lymphocytic Leukemia
  • T-Lymphocytes
  • Breast Cancer
  • Monoclonal Antibodies
  • Signal Transduction
  • Immunophenotyping
  • Gene Expression Profiling
  • Lectins, C-Type
  • Chromosome 12
  • Gene Expression
  • CD8-Positive T-Lymphocytes
  • Immunotherapy
  • RTPCR
  • CD Antigens
  • Translocation
  • NF-kappa B
  • Antigens, CD274
  • Lymphocyte Activation
  • T-Lymphocyte Subsets
  • Adolescents
  • Oligonucleotide Array Sequence Analysis
  • Lymphocytes, Tumor-Infiltrating
  • Peritoneal Neoplasms
  • Vidarabine
  • ZAP-70 Protein-Tyrosine Kinase
  • Flow Cytometry
  • Cluster Analysis
  • Cultured Cells
  • Acute Lymphocytic Leukaemia
  • Tumor Markers
  • Up-Regulation
  • Antigens, Differentiation, T-Lymphocyte
  • Transfection
  • Messenger RNA
  • Leukocytes, Mononuclear
Tag cloud generated 27 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: CD69 (cancer-related)

Angelova S, Spassov B, Nikolova V, et al.
IS THE AMPLIFICATION OF c-MYC, MLL AND RUNX1 GENES IN AML AND MDS PATIENTS WITH TRISOMY 8, 11 AND 21 A FACTOR FOR A CLONAL EVOLUTION IN THEIR KARYOTYPE?
Tsitol Genet. 2015 May-Jun; 49(3):25-32 [PubMed] Related Publications
The aim of our study was 1) to define if the amplification of c-MYC, MLL and RUNX1 genes is related to the progressive changes of the karyotype in patients with AML and MDS with trisomy 8, 11 and 21 (+8, +11 and +21) in bone marrow and 2) can that amplification be accepted as part of the clonal evolution (CE). Karyotype analysis was performed in 179 patients with AML or MDS with the different chromosomal aberrations (CA) aged 16-81. The findings were distributed as follow: initiating balanced CA (n = 60), aneuploidia (n = 55), unbalanced CA (n = 64). Amplification of c-MYC, MLL and RUNX1 genes by means of fluorescence in situ hybridization (FISH) was found in 35% (7 out of 20) of AML and MDS patients with +8, +11 u +21 as single CA in their karyotype; in 63.6% of pts (7 out of 11)--with additional numerical or structural CA and in 75% (9 out of 12)--with complex karyotype. We assume that the amplification of the respective chromosomal regions in patients with +8, +11 and +21 is related to CE. Considering the amplification as a factor of CE, we established 3 patterns of karyotype development depending on the type of the initiating CA in it. Significant statistical differences were found between the three patterns regarding the karyotype distribution in the different stages of progression (p < 0.001).

Zhang X, He R, Ren F, et al.
Association of miR-146a rs2910164 polymorphism with squamous cell carcinoma risk: a meta-analysis.
J BUON. 2015 May-Jun; 20(3):829-41 [PubMed] Related Publications
PURPOSE: Recent evidence suggests that the rs2910164 variant of miR-146a is associated with the development of certain types of malignancies. Hence, the aim of this study was to investigate the association between this genetic variant and the susceptibility of squamous cell carcinoma (SCC).
METHODS: We performed a systematic search using PubMed, EMBASE, ISI Web of Science, Cochrane Central Register of Controlled Trials, ScienceDirect, Wiley Online Library and Chinese National Knowledge Infrastructure (CNKI) databases with the last search updated on November 15, 2014. Studies were pooled and summary odds ratios (ORs) were calculated. Potential sources of heterogeneity were sought out via subgroup analysis.
RESULTS: A total of 12 studies (5192 cases and 9945 controls) were found to be eligible for meta-analysis. Overall, no significant associations were found between miR-146a G/C polymorphism and SCC risk when all studies were pooled into the meta-analysis. In the subgroup analysis by cancer location, statistically significantly increased risks were found for cervical SCC/CSCC (CC vs CG+GG:OR = 0.521, 95% CI=0.412-0.657,p<0.001; CC+CG vs GG:OR=1.583, 95%CI=1.215-2.062,p=0.001); and for skin SCC (GC vs CC+GG:OR=2.533, 95% CI=1.989-3.224, p<0.001). In addition, the C allele and CC genotype of rs2910164 were found to be associated with an inverse risk of nasopharyngeal carcinoma (GG vs CC:OR=0.586, 95% CI=0.405-0.847, p=0.005; CC vs CG+GG:OR=1.496, 95% CI=1.189-1.881, p=0.001). Similarly, CC genotpe of rs2910164 was found to be inversely related to susceptibility of oral SCC (CC+CG vs. GG: OR=0.726, 95% CI=0.607-0.869, p<0.001).
CONCLUSIONS: The miR-146a rs2910164 polymorphism is associated with increased risk for cervical and skin SCC. In contrast, rs2910164 in miR-146a is related to decreased risk for nasopharyngeal and oral SCC.

Song B, Yu J, Wu TS
CORRELATION BETWEEN C-erbB-2 WITH GASTRIC MUCOSAL ATYPICAL HYPERPLASIA AND GASTRIC CARCINOMA.
J Biol Regul Homeost Agents. 2015 Apr-Jun; 29(2):471-7 [PubMed] Related Publications
C-erbB-2 is a cancer gene originating from cells. The high-expression and amplification of C-erbB-2 and its protein products (P185) are found in a wide variety of tumors. The abnormal expression of C-erbB-2 has great influence on the occurrence and development of gastric carcinoma. This paper aimed to analyze the expression of C-erbB-2 in the tissues of gastric carcinoma, gastric mucosal atypical hyperplasia and gastritis, and discuss its role in the occurrence and development of gastric carcinoma. The morphological differences and connections among simple intestinal metaplasia (SIM), atypical intestinal metaplasia (AIM) and dysplasia in intestinal metaplasia through hematoxylin and eosin (HE) staining were studied. Three groups were set to detect the expression condition of C-erbB-2 by immunohistochemical method (IHC). The result showed that C-erbB-2 had no significant difference in AIM and gastric carcinoma, that is, AIM was closely related to gastric carcinoma. The positive expression was demonstrated of C-erbB-2 products (P185) in medium and gastric mucosa dysplasia tissues and was 29.41% and 66.67%, respectively, while it was 25%, 50% and 77.78% in high, medium and low differentiation of gastric carcinoma. It can be seen that there was a significant difference between them (P<0.05), and the expression degree was significantly enhanced (P<0.05); the expression degree in high differentiation gastric cancer tissue was significantly higher than the middle and low differentiation gastric cancer tissue. It was concluded that C-erbB-2 played an important role in the pathogenic mechanism of gastric carcinoma, and it might act on the later period of the gastric carcinoma, which provides objective reference index for the diagnosis and prognosis of gastric carcinoma and meanwhile provides instructional theoretical reference for the application of targeted drugs in the clinical treatment of gastric carcinoma.

Hosseini S, Hashemzadeh S, Estiar MA, et al.
Expression Analysis of Aurora-C and Survivin, Two Testis-Specific Genes, in Patients with Colorectal Cancer.
Clin Lab. 2015; 61(5-6):475-80 [PubMed] Related Publications
BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. The high frequency of positive families shows the importance of public awareness and screening strategies in those families. Cancer/testis (CT) antigens such as Aurora-C and Survivin are a group of antigens expressed in various tumor types of human cancers. Therefore, the aim of this study was to investigate the expression of Aurora-C and Survivin genes in malignant and normal tissues and their correlation to clinicopathological characteristics.
METHODS: Tumor samples were obtained from 33 patients and adjacent non-tumorous tissues from 7 patients were also used as control. Patients were diagnosed with various stages of colorectal cancer. The level of Aurora-C and Survivin genes were evaluated by using real-time quantitative Polymerase Chain Reaction.
RESULTS: The expression pattern of Survivin and Aurora-C revealed significant changes in tumor tissues when compared with normal tissues (p < 0.05). Also, these expressions were associated with the grade of disease and tumor size. There was no significant relationship between the expression of Survivin and Aurora-C genes (p > 0.05).
CONCLUSIONS: In conclusion, the overexpression of Aurora-C and Survivin genes may play an important role in the development of colorectal cancer and may play a potential role in cancer therapy.

Umair A, Tarakji B, Ibrahim A, et al.
Quantitative study of epigenetic signature in head and neck squamous cell carcinoma.
Turk J Med Sci. 2015; 45(2):372-86 [PubMed] Related Publications
BACKGROUND/AIM: The aberrant upregulation of Forkhead box protein M1 (FOXM1) plays a fundamental role in cancer initiation by perturbing stem cell differentiation. This study aims to investigate the role of FOXMI in epigenetic modification and gene expression of target genes in primary human oral keratinocytes, squamous cell carcinoma cell lines, and head and neck squamous cell carcinoma (HNSCC) tissue biopsies.
MATERIALS AND METHODS: A genome-wide promoter methylation microarray was used to compare HNSCC cell line (n = 8), primary human oral keratinocytes (NOK; n = 8) transduced with FOXM1 and EGFP, and HNSCC tissue biopsies (n = 3). Seventeen Foxm1B- induced differentially methylated genes were shortlisted. An absolute quantitative polymerase chain reaction was used to validate the differential promoter DNA methylation of each candidate gene induced by FOXML. These results were compared with the methylation status and altered gene expressions of candidate genes in a panel of genomic DNA and messenger RNA (mRNA) samples previously extracted from HNSCC tissue biopsies.
RESULTS: The results were consistent with our hypothesis, showing that aberrant. upregulation of FOXM1 expression in in vitro primary NOK induces a global hypomethylation pattern similar to the HNSCC cell line and has an inverse correlation with in vivo mRNA expression levels of HNSCC tissue biopsy.
CONCLUSION: Such epigenetic changes have tremendous clinical potential as biomarkers for early cancer detection and therapeutic interventions.

Weeber F, Koudijs MJ, Hoogstraat M, et al.
Effective Therapeutic Intervention and Comprehensive Genetic Analysis of mTOR Signaling in PEComa: A Case Report.
Anticancer Res. 2015; 35(6):3399-403 [PubMed] Related Publications
BACKGROUND/AIM: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms. The exact genetic alterations underlying the pathophysiology of PEComas are largely unknown, although it has been shown that activation of the Mammalian target of rapamycin (mTOR) signaling pathway plays a pivotal role. Herein we describe the successful treatment of a patient with metastatic PEComa with the mTOR inhibitor everolimus and a comprehensive analysis to identify mechanisms for response.
MATERIALS AND METHODS: Immunohistochemistry, array comparative genomic hybridization (aCGH) and genetic analyses were performed.
RESULTS: Immunohistochemistry confirmed constitutive activation of mTOR. aCGH revealed a hyperdiploid karyotype affecting large regions of the genome. Next-generation sequencing did not reveal any tumor-specific mutations in mTOR-related genes.
CONCLUSION: Our results show the complexity of determining causal genetic alterations that can predict responsiveness to mTOR inhibition, even for a tumor with a complete remission to this specific treatment.

Santala S, Talvensaari-Mattila A, Soini Y, Santala M
Cyclin E Expression Correlates with Cancer-specific Survival in Endometrial Endometrioid Adenocarcinoma.
Anticancer Res. 2015; 35(6):3393-7 [PubMed] Related Publications
AIM: The aim of the present study was to investigate the impact of cyclin E expression on cancer-specific survival, as well as on conventional clinocopathological and prognostic factors in endometrial endometrioid adenocarcinoma.
MATERIALS AND METHODS: The study consisted of 211 patients surgically treated for endometrial endometrioid adenocarcinoma at the Oulu University Hospital between 1992-2000. Tissue samples were immunohistochemically stained for cyclin E and clinicopathological data were retrospectively retrieved from the patients' records.
RESULTS: Cyclin E expression correlated with grade but not with the Fédération Internationale de Gynécologie Obstétrique (FIGO) stage or myometrial invasion. Univariate and multivariate survival analyses were performed between patients grouped according to a receiver operating characteristic (ROC) curve-derived cut-off value. A statistically significant difference in survival was demonstrated between patient groups in Kaplan-Meier analysis.
CONCLUSION: Contrary to previous literature, we found a correlation between cyclin E expression and prognosis. Further large-scale studies are required to confirm our findings.

Tanji N, Kikugawa T, Ochi T, et al.
Circulating Cytokine Levels in Patients with Prostate Cancer: Effects of Neoadjuvant Hormonal Therapy and External-beam Radiotherapy.
Anticancer Res. 2015; 35(6):3379-83 [PubMed] Related Publications
AIM: The aim of the study was to better characterize the temporal induction of inflammatory cytokines in the serum of patients with prostate cancer (PCa) treated with radiotherapy and to ascertain the influence of hormonal therapy upon those expressions.
PATIENTS AND METHODS: Between May 2007 and December 2009, 30 patients with localized PCa were treated with 3-dimensional conformal external-beam radiotherapy. Fifteen patients had received neoadjuvant hormonal therapy using a leuteinizing hormone-releasing hormone (LH-RH) analog for six months prior to radiotherapy. The cytokine levels were collectively measured using a multiplex assay system.
RESULTS: Seventeen cytokines were at detectable levels throughout the blood sampling times before and during radiotherapy. Hormonal therapy for six months significantly decreased the serum levels of fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor (VEGF). The levels of epidermal growth factor (EGF), granulocyte-colony stimulating factor (G-CSF), and interferon-gamma (IFNγ) significantly increased during radiotherapy. Most cytokine levels, except for eotaxin, G-CSF, growth-related oncogene (GRO), transforming growth factor-beta (TGFβ)-1 and TGFβ2, significantly increased during radiotherapy compared to the levels observed before radiotherapy.
CONCLUSION: The present study revealed the influence of hormonal, and of radiation therapy on the proinflammatory cytokine levels in the sera of patients with PCa. In addition, neoadjuvant hormonal therapy amplified the radiation-induced alteration of serum cytokines. Further studies to characterize the mechanism underlying a radiation- or hormone-induced inflammatory state are, therefore, necessary.

Lim do H, Kim WS, Kim SJ, et al.
Microarray Gene-expression Profiling Analysis Comparing PCNSL and Non-CNS Diffuse Large B-Cell Lymphoma.
Anticancer Res. 2015; 35(6):3333-40 [PubMed] Related Publications
AIM: The purpose of the present study was to compare microarray gene-expression profiling data between primary central nervous system (CNS) lymphoma and non-CNS lymphomas.
MATERIALS AND METHODS: We performed whole-genomic cDNA-mediated annealing, selection and ligation assay with 177 formalin-fixed paraffin-embedded tumor samples.
RESULTS: We identified 20 differentially expressed genes out of which 5 were predominantly expressed in CNS DLBCL compared to non-CNS DLBCL (C16orf59, SLC16A9, HPDL, SPP1, and MAG). SLC16A9 may be involved in aerobic glycolysis of malignant tumors. The alteration in gene expression of SPP1 in primary CNS lymphoma is involved in biological activity, such as CNS tropism, B-cell migration, proliferation, and aggressive clinical behavior. MAG may be an important adhesion molecule that contributes to perineural cancer invasion.
CONCLUSION: Genomic differences between CNS and non-CNS DLBCL exist and the most prominent genes are SPP1 and MAG. SPP1 may play a key role in CNS tropism of primary CNS lymphoma.

Litwin M, Dubis J, Arczyńska K, et al.
Correlation of HIWI and HILI Expression with Cancer Stem Cell Markers in Colorectal Cancer.
Anticancer Res. 2015; 35(6):3317-24 [PubMed] Related Publications
BACKGROUND/AIM: Cancer stem cells (CSCs) constitute a sub-population of tumor cells that possess stem cell properties, such as self-renewal and the ability of differentiation. The presence of CSCs is associated with metastatic potential, treatment resistance and poor patient prognosis. Recently, aberrant expression of P-element induced wimpy testis proteins-PIWI (HIWI and HILI) has been identified in various types of tumors. The aim of the study was to evaluate the clinical significance of the HIWI and HILI expression and its relationship with cancer stem cells markers in 72 patients with colorectal carcinoma (CRC).
MATERIALS AND METHODS: The expression level of HIWI and HILI and cancer stem cells markers in paired cancerous and non-cancerous tissues was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR) assay. Immunohistochemistry was performed to confirm the observed changes on mRNA level and detect tissue localization of PIWI proteins.
RESULTS: Significantly higher mRNA levels of HIWI and decreased HILI mRNA were measured in colorectal cancer tissues compared to corresponding non-cancerous samples. The changes in HIWI mRNA level in cancer tissues were correlated with OCT4 expression. Positive correlations between HILI level and SOX2 were also observed in cancerous tissues.
CONCLUSION: Our results indicate a reciprocal regulation between HIWI, HILI and some CSCs markers in colorectal cancer.

Lee CC, Ho HC, Su YC, et al.
MCP1-Induced Epithelial-Mesenchymal Transition in Head and Neck Cancer by AKT Activation.
Anticancer Res. 2015; 35(6):3299-306 [PubMed] Related Publications
AIM: To explore whether monocyte chemotactic protein-1 (MCP1) is associated with the epithelial-mesenchymal transition (EMT) and neck metastases in head and neck cancer (HNC).
MATERIALS AND METHODS: MCP1 and its related protein were evaluated using western blotting, and a migration assay for HNC cell lines. Thirty-five patients with HNC were recruited for the evaluation of MCP1 expression and pathologically-proven neck metastases from their tissue specimens.
RESULTS: MCP1 changed the phenotype of OML-1 cells to a spindle shape, with increased mobility. In OML3 cells, MCP1 knockdown with siRNA blocked EMT. Activation of protein kinase B (AKT) was positively associated with the EMT phenotype, and this transition was abrogated with a phosphoinositide 3 kinase (PI3K) inhibitor. By comparing clinical outcomes, the histological MCP1 score was associated with pathological neck metastases (p=0.027).
CONCLUSION: The overexpression of MCP1 in HNC cells may partially induce EMT through the AKT pathway. A high cellular expression of MCP1 was associated with pathological neck metastases.

Hara R, Kikuchi H, Setoguchi T, et al.
Microarray analysis reveals distinct gene set profiles for gastric and intestinal gastrointestinal stromal tumors.
Anticancer Res. 2015; 35(6):3289-98 [PubMed] Related Publications
AIM: We sought to address the mechanisms by which intestinal gastrointestinal stromal tumors (GIST) have a markedly higher risk of recurrence than gastric GISTs.
MATERIALS AND METHODS: Gene expression levels were compared among six primary gastric, three intestinal and six metastatic liver GISTs using cDNA microarray. Protein levels of Slit homolog 2 (SLIT2) were analyzed by immunohistochemistry in 25 primary gastric and 10 intestinal GIST.
RESULTS: Intestinal GIST had gene expression profiles similar to clinically malignant and metastatic GIST. In gene set-enrichment analysis, the gene sets MITOTIC_CELL CYCLE and NEURON_DIFFERENTIATION were up-regulated and down-regulated, respectively, in intestinal GIST compared to gastric GIST. High-risk gastric GISTs and intestinal GIST, expressed similar levels of SLIT2 protein, which were lower than those of low-risk gastric GISTs.
CONCLUSION: The gene-expression profile of intestinal GISTs was similar to that of metastatic liver GISTs. Besides higher proliferative activity, down-regulation of SLIT2 might be involved in clinically malignant phenotypes of intestinal GIST.

Goda AE, Erikson RL, Ahn JS, Kim BY
Induction of G1 Arrest by SB265610 Involves Cyclin D3 Down-regulation and Suppression of CDK2 (Thr160) Phosphorylation.
Anticancer Res. 2015; 35(6):3235-43 [PubMed] Related Publications
BACKGROUND/AIM: The current study investigated the mechanisms underlying the antitumor activity of SB265610, a cysteine-amino acid-cysteine (CXC) chemokines receptor 2 (CXCR2) antagonist.
MATERIALS AND METHODS: Cell-cycle progression and regulatory molecules were assessed by flow cytometry, immunoblotting, real-time PCR and immunoprecipitation. Target validation was achieved via RNA interference.
RESULTS: G1 arrest induced by SB265610 occurred at concentrations lacking CXCR2 selectivity, persisted upon interleukin 8 (IL8) challenge, and did not affect IL8 downstream target expression. Profiling of G1 regulators revealed cyclin-dependent kinase 2 (CDK2) (Thr160) hypophosphorylation, cyclin D3 gene down-regulation, and p21 post-translational induction. However, only cyclin D3 and CDK2 contributed towards G1 arrest. Furthermore, SB265610 induced a sustained phosphorylation of the p38MAPK. Pharmacological interference with p38MAPK significantly abrogated SB265610-induced G1 arrest and normalized the expression of cyclin D3, with restoration of its exclusive binding to CDK6, but with weak recovery of CDK2 (Thr160) hypo-phosphorylation.
CONCLUSION: The present study described the mechanisms for the anti-proliferative activity of SB265610 which may be of value in IL8-rich tumor microenvironments.

Minafra L, Bravatà V, Russo G, et al.
Gene Expression Profiling of MCF10A Breast Epithelial Cells Exposed to IOERT.
Anticancer Res. 2015; 35(6):3223-34 [PubMed] Related Publications
BACKGROUND/AIM: Intraoperative electron radiation therapy (IOERT) is a therapeutic approach that delivers a single high dose of ionizing radiation (IR) directly to the tumor bed during cancer surgery. The main goal of IOERT is to counteract tumor growth by acting on residual cancer cells as well as to preserve healthy surrounding tissue from the side-effects of radiation therapy. The radiobiology of the healthy tissue response to IR is a topic of interest which may contribute to avoiding impairment of normal tissue and organ function and to reducing the risks of secondary cancer. The purpose of the study was to highlight cell and gene expression responses following IOERT treatment in the human non-tumorigenic MCF10A cell line in order to find new potential biomarkers of radiosensitivity/radioresistance.
MATERIAL AND METHODS: Gene-expression profiling of MCF10A cells treated with 9 and 23 Gy doses (IOERT boost and exclusive treatment, respectively), was performed by whole-genome cDNA microarrays. Real-time quantitative reverse transcription (qRT-PCR), immunofluorescence and immunoblot experiments were carried out to validate candidate IOERT biomarkers. Clonogenic tests and morphological evaluations to examine cellular effects induced by radiation were also conducted.
RESULTS: The study revealed a dose-dependent gene-expression profile and specific key genes that may be proposed as novel markers of radiosensitivity. Our results show consistent differences in non-tumorigenic cell tolerance and in the molecular response of MCF10A cells to different IOERTs. In particular, after 9 Gy of exposure, the selection of a radioresistant cell fraction was observed.
CONCLUSION: The possibility of clarifying the molecular strategies adopted by cells in choosing between death or survival after IR-induced damage opens-up new avenues for the selection of a proper personalized therapy schedule.

Kuramitsu Y, Tanaka I, Wang Y, et al.
Inflammation-Related Tumor Progression in Murine Fibrosarcoma Exhibited Over-expression of Sex-determining Region Y-box 2 (Sox2) Compared to Parental Regressor Cells.
Anticancer Res. 2015; 35(6):3217-21 [PubMed] Related Publications
BACKGROUND/AIM: Tumor progression is one of the most serious issues to overcome cancer disease. As a model of inflammation-induced tumor progression, we used the regressive murine fibrosarcoma cell clone QR-32 and the progressive malignant clone QRsP-11, that was derived from QR-32. Heat shock protein beta-1 (Hspb1) is a molecular chaperone. Hspb1 plays roles in not only cell protection but also chemo-resistance, tumorigenicity and protection from apoptosis. In a recent study, we showed that Hspb1 was up-regulated in QRsP-11 compared to QR-32.
MATERIALS AND METHODS: We compared the expression levels of Hspb1, Hsf1 and Sox2 in QR-32 and QRsP-11 cells by means of western blotting.
RESULTS: Hsf1, a transcription factor for Hspb1 was not increased in QRsP-11. Sex determining region Y-box 2 (Sox2) is a transcription factor, reported to interact with Hspb1. Sox2 was up-regulated in QRsP-11 compared to QR-32.
CONCLUSION: These results suggest that Sox2-Hspb1 signaling is a possible pathway responsible to tumor progression of QRsP-11.

Koo S, Martin G, Toussaint LG
MicroRNA-145 Promotes the Phenotype of Human Glioblastoma Cells Selected for Invasion.
Anticancer Res. 2015; 35(6):3209-15 [PubMed] Related Publications
BACKGROUND/AIM: Novel treatment strategies aiming to eliminate or attenuate the invasive phenotype of glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, could offer a profound therapeutic benefit to patients. We previously demonstrated one method to create invasive sub-populations of GBM cells (IM3 cells) and a positive regulatory role for the miR-143/-145 locus in enhancing the invasion of GBM cells. Herein, we investigated the correlation between miR-145 and srGAP1 (SLIT-ROBO Rho GTPase-activating protein1) that is purported to be a target of miR-145 and involved in migration and invasion.
MATERIALS AND METHODS: IM3 cells were created by a serial selection by using Boyden chambers®. Antisense-miR-145 was transfected into IM3 cells by using lipofectamine 2000. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blot were employed to analyze the expression of srGAP1.
RESULTS: The invasiveness of U87-IM3 and U251-IM3 is attenuated by transfection of antisense miR-145. In addition, srGAP1 was down-regulated in U87-IM3 and U251-IM3 cells compared to parental cells.
CONCLUSION: The elevated miR-145 present in invasive glioblastoma cells (IM3 cells) targets and down-regulated srGAP1, thereby allowing downstream G-proteins to remain in their active state and promote the observed invasive phenotype.

Yin G, Tang D, Dai J, et al.
Combination Efficacy of Astragalus membranaceus and Curcuma wenyujin at Different Stages of Tumor Progression in an Imageable Orthotopic Nude Mouse Model of Metastatic Human Ovarian Cancer Expressing Red Fluorescent Protein.
Anticancer Res. 2015; 35(6):3193-207 [PubMed] Related Publications
BACKGROUND/AIM: The present study determined the efficacy of extracts of Astragalus membranaceus (AM) and Curcuma wenyujin (CW), a traditional Chinese medicine herbal mixture, at different tumor stages of an orthotopic nude mouse model of human ovarian cancer expressing red fluorescent protein.
MATERIALS AND METHODS: The tumor-bearing mice were treated with cisplatinum (CDDP), AM, CW, or a combination of AM and CW in each of three tumor stages, using the same regimen. Group 1 received saline as negative control. Group 2 received CDDP i.p. as positive control with a dose of 2 mg/kg, every three days. Group 3 received AM daily via oral gavage, at a dose of 9120 mg/kg. Group 4 received CW daily via oral gavage, at a dose of 4560 mg/kg. Groups 5, 6 and 7 received combinations of AM and CW daily via oral gavage at low (AM, 2280 mg/kg; CW, 1140 mg/kg), medium (AM, 4560 mg/kg; CW 2280 mg/kg), and high (AM, 9120 mg/kg; CW, 4560 mg/kg) doses. The expression of angiogenesis- and apoptosis-related genes in the tumors were analyzed by immunohistochemistry for matrix metalloproteinase 2 (MMP-2), vascular endothelial growth factor (VEGF) fibroblast growth factor 2 (FGF-2), B-cell lymphoma 2 (Bcl-2) and cyclooxygenase 2 (Cox-2), and by polymerase chain reaction for MMP-2, FGF-2 and Bcl-2.
RESULTS: CDDP, AM, and its combination with CW-induced significant growth inhibition of Stage I tumors. Strong efficacy of the combination of AM and CW at high dose was observed. Monotherapy with CDDP, AM, CW, and the combination treatments did not significantly inhibit Stage II and III tumors. The expression of MMP-2, VEGF, FGF-2, and Cox-2 was significantly reduced in Stage I tumors treated with AM, CW, and their combination, suggesting a possible role of these angiogenesis- and apoptosis-related genes in the observed efficacy of the agents tested.
CONCLUSION: This study is the first report on the efficacy of anticancer agents at different stages of ovarian cancer in an orthotopic mouse model. As the tumor progressed, it became treatment-resistant, similar to the clinical situation, further demonstrating the utility of the model and the need for agents acrtive in advanced-stage ovarian cancer.

Hug KA, Anthony L, Eldeiry D, et al.
Expression and Tissue Distribution of MicroRNA-21 in Malignant and Benign Breast Tissues>.
Anticancer Res. 2015; 35(6):3175-83 [PubMed] Related Publications
BACKGROUND/AIM: miR-21 is a common OncomiR in human cancer. The present study analyzed the distribution and expression of miR-21 in breast tumor tissues so as to examine the role of miR-21 in the carcinogenesis of breast cancer.
MATERIALS AND METHODS: Sixteen malignant and 10 benign breast tissue specimens were analyzed using a miRNA chromogenic in situ hybridization (CISH) assay. The locations of miR-21 CISH-positive cells in breast tissues were observed and its expression level was semi-quantified by ISH scoring.
RESULTS: Positive in situ staining of miR-21 was detected in the cytoplasm of malignant epithelial cells in most of the high-grade infiltrating ductal carcinoma specimens. miR-21-positive spindle-like cells were found to surround tumor cell islands. High miR-21 ISH scores were correlated with positive lymph node status. miR-21 expression was low in most types of benign breast tissues.
CONCLUSION: miR-21 is a potential biomarker for breast cancer prognosis.

Michalska MM, Samulak D, Bieńkiewicz J, et al.
Association between -41657C/T single nucleotide polymorphism of DNA repair gene XRCC2 and endometrial cancer risk in Polish women.
Pol J Pathol. 2015; 66(1):67-71 [PubMed] Related Publications
AIM OF THE STUDY: The XRCC2 gene plays a crucial role in double-strand DNA break repair by homologous recombination. Current literature provides clear evidence that XRCC2 polymorphisms may be associated with the development of certain types of cancer; however, still little is known about their association with endometrial cancer (EC).
MATERIAL AND METHODS: The single nucleotide polymorphism (SNP) -41657C/T (rs718282) of the XRCC2 gene was investigated by PCR-RFLP in 304 patients with EC and in 200 age- and sex-matched non-cancer controls.
RESULTS: The analysis revealed a relationship between XRCC2 -41657C/T polymorphism and the incidence of EC. Endometrial cancer patients showed overrepresentation of the T allele of the SNP. The T/T homozygous variant increased the cancer risk. There were no significant differences between the distribution of XRCC2 -41657C/T genotypes in the subgroups according to histological grade.
CONCLUSIONS: This is the first study that links the SNP -41657C/T (rs718282) of the XRCC2 gene with EC in Polish women. The results support the hypothesis that this polymorphism may be positively correlated with the incidence of EC.

Mutlu P, Mutlu M, Yalcin S, et al.
Detection of XRCC1 gene polymorphisms in Turkish head and neck squamous cell carcinoma patients: a comparative analysis with different populations.
J BUON. 2015 Mar-Apr; 20(2):540-7 [PubMed] Related Publications
PURPOSE: X-ray repair cross-complementing (XRCC1) is one of the most important genes for the maintenance of genomic integrity and protection of cells from DNA damage. Although tobacco and alcohol consumption are the major risk factors for the development of head and neck squamous cell carcinoma (HNSCC), sequence variation in XRCC1 gene may alter HNSCC susceptibility. Reports on the relationship between HNSCC and polymorphisms in XRCC1 gene have been inconsistent so far. The aim of this study was to investigate the association of XRCC1 Arg194Trp and Arg399Gln single nucleotide polymorphisms (SNP), smoking and alcohol consumption with the risk of HNSCC in Turkish population and also to compare to these results with the ones from both Turkish and different populations in the literature. The frequencies of Arg194Trp and Arg399Gln SNPs were studied in 55 HNSCC and 69 healthy individuals.
METHODS: Genomic DNA was isolated from peripheral blood and SNP was genotyped by PCR-RFLP method.
RESULTS: The genotype and allele frequencies of both polymorphisms were not statistically different between the HNSCC and control groups. On the other hand, smoking and chronic alcohol consumption were associated with risk of HNSCC, but there was no association between Arg194Trp, Arg399Gln polymorphisms, smoking and alcohol consumption in HNSCC cases.
CONCLUSION: These results indicate that both Arg194Trp and Arg399Gln polymorphisms were not associated with the development of HNSCC in Turkish population. In addition, the allele frequencies of polymorphisms were in line with other Turkish population results that were studied previously. However, compared to different populations, there were marked differences in allele frequencies.

Chung YR, Kim H, Park SY, et al.
Distinctive role of SIRT1 expression on tumor invasion and metastasis in breast cancer by molecular subtype.
Hum Pathol. 2015; 46(7):1027-35 [PubMed] Related Publications
The aim of this study was to evaluate silent mating type information regulation 2 homolog 1 (SIRT1) expression levels by subtype and evaluate its predictive power of axillary lymph node metastasis (LNM) and its association with clinical outcome. A total of 427 patients diagnosed with invasive ductal carcinoma were chosen, immunohistochemical staining for SIRT1 expression was performed on tissue microarrays, and in vitro experiments with each intrinsic subtype of human breast cancer cell line were carried out. Increased expression of SIRT1 in hormone receptor-positive breast cancer and HER2 breast cancer subtype significantly correlated with lower risks of LNM. On the contrary, in triple-negative breast cancer, increased SIRT1 expression was more frequently observed in LNM-positive subgroup than LNM-negative subgroup. Combination of statistically significant, independent parameters including SIRT1 revealed predictive performance for LNM with area under the curve of 0.602, 0.587, and 0.726 for hormone receptor-positive breast cancer, HER2 breast cancer, and triple-negative breast cancer subtype, respectively. Inhibition of SIRT1 expression with small interfering RNA suppressed tumor invasion in MDA-MB-231, specifically. This is the first study to examine SIRT1 expression in breast cancer by subtype, and we have observed the potentially different role of SIRT1 gene having tumor-suppressive or tumor-promoting influence depending on the subtype; thus, different associations between SIRT1 expression and prognosis by subtype should be considered in its target therapy.

Panou V, Vyberg M, Weinreich UM, et al.
The established and future biomarkers of malignant pleural mesothelioma.
Cancer Treat Rev. 2015; 41(6):486-95 [PubMed] Related Publications
Malignant pleural mesothelioma (MPM) is an asbestos-related cancer with a median survival of 12months. The MPM incidence is 1-6/100,000 and is increasing as a result of historic asbestos exposure in industrialized countries and continued use of asbestos in developing countries. Lack of accurate biomarkers makes diagnosis, prognostication and treatment prediction of MPM challenging. The aim of this review is to identify the front line of MPM biomarkers with current or potential clinical impact. Literature search using the PubMed and PLoS One databases, the related-articles function of PubMed and the reference lists of associated publications until April 26th 2015 revealed a plethora of candidate biomarkers. The current gold standard of MPM diagnosis is a combination of two positive and two negative immunohistochemical markers in the epithelioid and biphasic type, but sarcomatous type do not have specific markers, making diagnosis more difficult. Mesothelin in serum and pleural fluid may serve as adjuvant diagnostic with high specificity but low sensitivity. Circulating proteomic and microRNA signatures, fibulin-3, tumor cell gene-ratio test, transcriptomic, lncRNA, glycopeptides, pleural fluid FISH assay, hyaluronate/N-ERC mesothelin and deformability cytometry may be important future markers. Putative predictive markers for pemetrexed-platinum are tumor TS and TYMS, for vinorelbine the ERCC1, beta-tubuline class III and BRCA1. Mutations of the BAP1 gene are potential markers of MPM susceptibility. In conclusion, the current status of MPM biomarkers is not satisfactory but encouraging as more sensitive and specific non-invasive markers are emerging. However, prospective validation is needed before clinical application.

Ramos-Solano M, Meza-Canales ID, Torres-Reyes LA, et al.
Expression of WNT genes in cervical cancer-derived cells: Implication of WNT7A in cell proliferation and migration.
Exp Cell Res. 2015; 335(1):39-50 [PubMed] Related Publications
According to the multifactorial model of cervical cancer (CC) causation, it is now recognized that other modifications, in addition to Human papillomavirus (HPV) infection, are necessary for the development of this neoplasia. Among these, it has been proposed that a dysregulation of the WNT pathway might favor malignant progression of HPV-immortalized keratinocytes. The aim of this study was to identify components of the WNT pathway differentially expressed in CC vs. non-tumorigenic, but immortalized human keratinocytes. Interestingly, WNT7A expression was found strongly downregulated in cell lines and biopsies derived from CC. Restoration of WNT7A in CC-derived cell lines using a lentiviral gene delivery system or after adding a recombinant human protein decreases cell proliferation. Likewise, WNT7A silencing in non-tumorigenic cells markedly accelerates proliferation. Decreased WNT7A expression was due to hypermethylation at particular CpG sites. To our knowledge, this is the first study reporting reduced WNT7A levels in CC-derived cells and that ectopic WNT7A restoration negatively affects cell proliferation and migration.

Gleeson FC, Kipp BR, Voss JS, et al.
Endoscopic ultrasound fine-needle aspiration cytology mutation profiling using targeted next-generation sequencing: personalized care for rectal cancer.
Am J Clin Pathol. 2015; 143(6):879-88 [PubMed] Related Publications
OBJECTIVES: In an era of precision medicine, our aim was to determine the frequency and theranostic potential of mutations identified in malignant lymph nodes (LNs) sampled by endoscopic ultrasound fine-needle aspiration (EUS FNA) of patients with rectal cancer by targeted next-generation sequencing (NGS).
METHODS: The NGS Ion AmpliSeq Cancer Hotspot Panel v2 (Life Technologies, Carlsbad, CA) and MiSeq (Illumina, San Diego, CA) sequencers were used to sequence and assess for 2,800 or more possible mutations in 50 established cancer-associated genes.
RESULTS: Among 102 patients, 89% had 194 pathogenic alterations identified in 19 genes. The identification of KRAS, NRAS, or BRAF mutations suggests that 42% are likely nonresponders to anti-epidermal growth factor receptor therapy. Among KRAS, NRAS, or BRAF wild-type patients, alterations in eight genes linked to alternative therapies were identified in 44%.
CONCLUSIONS: Our data demonstrate the successful ability to apply a single multiplex test to allow multigene mutation detection from malignant LN cytology specimen DNA collected by EUS FNA.

Ito T, Hamasaki M, Matsumoto S, et al.
p16/CDKN2A FISH in Differentiation of Diffuse Malignant Peritoneal Mesothelioma From Mesothelial Hyperplasia and Epithelial Ovarian Cancer.
Am J Clin Pathol. 2015; 143(6):830-8 [PubMed] Related Publications
OBJECTIVES: It can be difficult to differentiate diffuse malignant peritoneal mesothelioma (DMPM) from reactive mesothelial hyperplasia (RMH) or peritoneal dissemination of gynecologic malignancies, such as epithelial ovarian cancer (EOC), which cause a large amount of ascites. Detection of the homozygous deletion of p16/CDKN2A (p16) by fluorescence in situ hybridization (FISH) is an effective adjunct in the diagnosis of malignant pleural mesothelioma. The aim of this study was to investigate the ability of the p16 FISH assay to differentiate DMPM from RMH and EOC.
METHODS: p16 FISH was performed in 28 DMPMs (successful in 19), 30 RMHs, and 40 EOC cases. The cutoff values of p16 FISH were more than 10% for homozygous deletion and more than 40% for heterozygous deletion.
RESULTS: According to the above criteria, nine (47.4%) of 19 successful DMPM cases were homozygous deletion positive, and three (15.8%) of 19 were heterozygous deletion positive, whereas all RMH cases were negative for the p16 deletion. In all four major histologic subtypes of EOC, neither p16 homozygous nor heterozygous deletions were detected. To differentiate DMPM from RMH or EOC, the sensitivity of the p16 homozygous deletion was 32% (9/28), and the specificity was 100%.
CONCLUSIONS: Our study suggests that p16 FISH analysis is useful in differentiating DMPM from RMH and EOC when homozygous deletion is detected.

Chernock RD, Hagemann IS
Molecular pathology of hereditary and sporadic medullary thyroid carcinomas.
Am J Clin Pathol. 2015; 143(6):768-77 [PubMed] Related Publications
OBJECTIVES: Medullary thyroid carcinoma (MTC) is a relatively uncommon type of thyroid malignancy, with unique histologic features and molecular pathology. It is important to recognize, because its management, which is in part driven by the genetic basis of this disease, is different from follicular-derived thyroid tumors. The aim of this article is to briefly review the histopathologic features of MTC and then explore its molecular pathology, including the role of molecular diagnostic testing and the use of targeted therapy for advanced disease.
METHODS: A review of published literature was performed.
RESULTS: A subset of MTC cases is hereditary and due to germline mutations in the RET tyrosine kinase receptor gene. Somatic mutations in either RET or RAS are also present in most sporadic tumors.
CONCLUSIONS: Molecular genetic testing is routinely performed to identify hereditary cases. In addition, understanding the molecular basis of both hereditary and sporadic MTC has led to the development of targeted therapy with tyrosine kinase inhibitors. Although additional data are needed, tumor mutation status may affect response to targeted therapy. Therefore, it is possible that genetic testing of tumor tissue to predict treatment response, as is currently done for other cancer types, may come into practice in the future.

Socolov D, Anghelache I, Ilea C, et al.
Benign breast disease and the risk of breast cancer in the next 15 years.
Rev Med Chir Soc Med Nat Iasi. 2015 Jan-Mar; 119(1):135-40 [PubMed] Related Publications
AIM: Fibrocystic mastosis (FCM) is defined by the totality of dystrophic changes of the mammary tissue, the grouping in the form of fibrosis of epithelial, cystic, metaplastic and hyperplastic alterations. A very good estimation of the cancer risk is related specifically to the microscopic aspect. Other factors, the family history as well as the presence of an inherited gene determining the increase in the risk of breast cancer are also considered. But, if a woman known with fibrocystic mastosis has not undergone any biopsy, then it is impossible to calculate the specific individual risk of developing cancer.
MATERIAL AND METHODS: The data collected as a study material and considered refer to: the total num- ber of cases investigated and diagnosed with fibrocystic mastosis, the annual distribution of this disease cases, the distribution of the cases according to age groups, admission reasons, clinical examination, personal pathologic history clinically significant for the basic disease (the main diagnosis), the family medical history significant for the basic disease, the anatomopathological diagnosis.
RESULTS: Between 2004 and 2006, at "Cuza Vodă" Obstetrics and Gynecology Hospital of Iaşi, a maximum number of cases is noticed in 2006, when there were 147 cases, and the lowest number of cases was in 2005. There was high frequency of the anatomopathological examinations that highlighted the presence of fibrocystic lesions (both proliferative and non-proliferative), and the second most often diagnosis is fibroadenoma. Though fibrocystic mastosis is not clearly defined, it is still admitted that in order to support this diagnosis it is first compulsory to exclude malignant tumours.
CONCLUSIONS: Only in 5% of the women with fibrocystic mastosis cellular changes can be revealed in the form of atypical hyperplasia, which are a risk factor for cancer. The lesion that delimits cancer from non-cancer is ductal carcinoma in situ. An incidence of over 20% is present in the countries that use mammographic screening programmes, mammographic surveillance programmes and programmes for the guided localization of nonpalpable lesions of the mammary gland.

Deml KF, Schildhaus HU, Compérat E, et al.
Clear cell papillary renal cell carcinoma and renal angiomyoadenomatous tumor: two variants of a morphologic, immunohistochemical, and genetic distinct entity of renal cell carcinoma.
Am J Surg Pathol. 2015; 39(7):889-901 [PubMed] Article available free on PMC after 01/07/2016 Related Publications
Clear cell papillary renal cell carcinoma (ccpRCC) and renal angiomyoadenomatous tumor (RAT) share morphologic similarities with clear cell (ccRCC) and papillary RCC (pRCC). It is a matter of controversy whether their morphologic, immunophenotypic, and molecular features allow the definition of a separate renal carcinoma entity. The aim of our project was to investigate specific renal immunohistochemical biomarkers involved in the hypoxia-inducible factor pathway and mutations in the VHL gene to clarify the relationship between ccpRCC and RAT. We investigated 28 ccpRCC and 9 RAT samples by immunohistochemistry using 25 markers. VHL gene mutations and allele losses were investigated by Sanger sequencing and fluorescence in situ hybridization. Clinical follow-up data were obtained for a subset of the patients. No tumor recurrence or tumor-related death was observed in any of the patients. Immunohistochemistry and molecular analyses led to the reclassification of 3 tumors as ccRCC and TFE3 translocation carcinomas. The immunohistochemical profile of ccpRCC and RAT samples was very similar but not identical, differing from both ccRCC and pRCC. Especially, the parafibromin and hKIM-1 expression exhibited differences in ccpRCC/RAT compared with ccRCC and pRCC. Genetic analysis revealed VHL mutations in 2/27 (7%) and 1/7 (14%) ccpRCC and RAT samples, respectively. Fluorescence in situ hybridization analysis disclosed a 3p loss in 2/20 (10%) ccpRCC samples. ccpRCC and RAT have a specific morphologic and immunohistochemical profile, but they share similarities with the more aggressive renal tumors. On the basis of our results, we regard ccpRCC/RAT as a distinct entity of RCCs.

Bourdoumis A, Chrisofos M, Stasinou T, et al.
The Role of PCA 3 as a Prognostic Factor in Patients with Castration-resistant Prostate Cancer (CRPC) Treated with Docetaxel.
Anticancer Res. 2015; 35(5):3075-9 [PubMed] Related Publications
AIM: To investigate potential fluctuations in prostate cancer antigen 3 (PCA 3) scores in castration-resistant prostate cancer (CRPC) patients treated with docetaxel and investigate the assay as a potential prognostic factor.
PATIENTS AND METHODS: This was a prospective observational cohort study. Inclusion criteria included patients on hormonal treatment who were recently diagnosed with CRPC. Exclusion criteria included patients previously having radical treatment (surgery or radiotherapy) and patients who have completed the first cycle of chemotherapy. All urine samples were collected and analyzed using the Progensa® assay. Samples were collected before starting chemotherapy and at 12 months. A prospective database was created including routine blood tests, prostate staging and prostate-specific antigen (PSA) levels throughout the study period. The effects of chemotherapy were also recorded.
RESULTS: Between January 2010 and February 2013, 12 patients were included in the study out of an initial cohort of 23 patients with CRPC. Mean follow-up was 14.8 months. Mean age at CRPC diagnosis was 73.8 years (±3.6 SD). Mean Gleason score was 8, with PSA 84.23 ng/ml (±158 SD). Mean duration of androgen deprivation treatment (ADT) was 45.16 months (±34.9 SD). Mean time to castrate-resistant state was 46.58 months (±35.3 SD). All twelve (n=12, 100%) patients had non-assessable PCA 3 scores at baseline and at 12 months follow-up. As a direct consequence, statistical analysis was not performed as the anticipated change in PCA 3 scores was not identified and correlation between measurable differences was not possible. All patients tolerated chemotherapy and completed the scheduled cycles with no serious adverse effects.
CONCLUSION: To our knowledge, this is the first prospective study to demonstrate lack of expression of PCA3 in CRPC, with the result apparently not influenced by chemotherapy. There appears to be a strong association between hormonal treatment and lack of PCA 3 expression. It is still unknown whether disease progression per se affects PCA 3 scores. The gradual reduction and eventual complete non-expression of PCA 3 with ongoing treatment and disease progression provide an insight towards molecular pathways that may be connected to castration-resistant state.

Nabeki B, Ishigami S, Uchikado Y, et al.
Interleukin-32 expression and Treg infiltration in esophageal squamous cell carcinoma.
Anticancer Res. 2015; 35(5):2941-7 [PubMed] Related Publications
BACKGROUND/AIM: Interleukin-32 (IL32) has been newly-identified as a proinflammatory cytokine. In the present study, we aimed to clarify the clinical role of IL32-positive cells in esophageal squamous cell cancer (ESCC) and regulatory T-cell (Treg) infiltration in the stroma. A total of 179 patients with ESCC who underwent surgical resection from 1990 to 2004 were eligible for this study. The expression of IL32 and the degree of stromal infiltration by Tregs were examined simultaneously. The association between each factor and the clinicopathological features was analyzed. Sixty and 74 out of 179 patients with ESCC were regarded as having IL32-positive tumors and many Tregs (high-Treg group), respectively. The IL32-positive and high-Treg groups had significantly deeper tumor invasion than did the IL32-negative and low-Treg groups (p<0.05, for both groups). The multivariate analysis indicated that a combination of IL32 expression and presence of Tregs was one of the poor independent factors (p<0.05). IL32 expression and Treg infiltration in ESCC play an important synergistic role in tumor growth and invasion. The combination of IL32 positivity and degree of infiltration of Treg is a useful prognostic marker in ESCC.

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