CD1A

Gene Summary

Gene:CD1A; CD1a molecule
Aliases: R4, T6, CD1, FCB6, HTA1
Location:1q23.1
Summary:This gene encodes a member of the CD1 family of transmembrane glycoproteins, which are structurally related to the major histocompatibility complex (MHC) proteins and form heterodimers with beta-2-microglobulin. The CD1 proteins mediate the presentation of primarily lipid and glycolipid antigens of self or microbial origin to T cells. The human genome contains five CD1 family genes organized in a cluster on chromosome 1. The CD1 family members are thought to differ in their cellular localization and specificity for particular lipid ligands. The protein encoded by this gene localizes to the plasma membrane and to recycling vesicles of the early endocytic system. Alternatively spliced transcript variants have been observed, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:T-cell surface glycoprotein CD1a
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

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

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 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.

Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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

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

Latest Publications: CD1A (cancer-related)

Maywald RL, Doerner SK, Pastorelli L, et al.
IL-33 activates tumor stroma to promote intestinal polyposis.
Proc Natl Acad Sci U S A. 2015; 112(19):E2487-96 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by nonepithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. Here, we identify interleukin 33 (IL-33) as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL-33 expression was induced in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1 (also referred to as IL1-R4 or ST2), localized predominantly to the stroma of adenoma and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL-33 in the Apc(Min/+) mouse model of intestinal tumorigenesis inhibited proliferation, induced apoptosis, and suppressed angiogenesis in adenomatous polyps, which reduced both tumor number and size. Similar to human adenomas, IL-33 expression localized to tumor epithelial cells and expression of IL1RL1 associated with two stromal cell types, subepithelial myofibroblasts and mast cells, in Apc(Min/+) polyps. In vitro, IL-33 stimulation of human subepithelial myofibroblasts induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduced mast cell accumulation in Apc(Min/+) polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Based on these findings, we propose that IL-33 derived from the tumor epithelium promotes polyposis through the coordinated activation of stromal cells and the formation of a protumorigenic microenvironment.

Imada Y, Yuki K, Migita K, et al.
A Japanese pedigree of familial cerebral cavernous malformations--a case report.
Hiroshima J Med Sci. 2014; 63(4):43-8 [PubMed] Related Publications
Familial cerebral cavernous malformations (FCCM) are autosomal-dominant vascular malformations. At present, 3 cerebral cavernous malformation genes (KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3) have been identified. Few genetic analyses of Japanese FCCM have been reported. A Japanese pedigree of 4 patients with FCCM has been reported that includes the genetic analysis of one of the patients. All 4 patients showed multiple lesions in the brain. Surgical removal was performed at our hospital due to enlargement or hemorrhage of the intracranial lesions in a 21-year-old female (Case 1) and a 30-year-old male (Case 2). The histological diagnoses were cavernous malformations. A 62-year-old female (Case 4), the mother of Cases 1, 2, and 3, suffered from intramedullary hemorrhage at T6-7 and surgical removal was performed at another hospital. Only one patient, a 32-year-old female (Case 3), did not show symptoms. The genetic analysis of Case 2 demonstrated heterozygous partial deletions of exons 12-15 of the KRIT1 gene.

Mauro L, Pellegrino M, Giordano F, et al.
Estrogen receptor-α drives adiponectin effects on cyclin D1 expression in breast cancer cells.
FASEB J. 2015; 29(5):2150-60 [PubMed] Related Publications
Obesity is a risk factor for breast cancer, largely due to altered expression of various adipocytokines. As it concerns adiponectin, there are not univocal results regarding its role in breast cancer occurrence and progression. Here, we demonstrate that in animals injected with human estrogen receptor (ER)-α-negative MDA-MB-231 cells pretreated with adiponectin (1 and 5 µg/ml), a significant reduction (60 and 40%, respectively) in tumor volume is observed, whereas an increased tumor growth (54 and 109%, respectively) is evidenced in the animals receiving human ER-α-positive MCF-7 cells. Moreover, cyclin D1 (CD1) mRNA and protein levels are decreased in MDA-MB-231 cells, whereas they are up-regulated in ER-α-positive cells by adiponectin. These findings fit with the opposite effects of adiponectin on CD1 promoter: 0.44- and 0.34-fold decrease in MDA-MB-231 cells and 0.63- and 0.95-fold increase in MCF-7 cells, treated with 1 and 5 µg/ml, respectively. Functional studies indicate that these effects are mediated by the specific protein 1 motif located in the CD1 promoter. In the absence of ER-α, the adiponectin-mediated down-regulation of CD1 involves the recruitment of corepressors. In the presence of ER-α, the adiponectin-induced expression of CD1 requires the involvement of an activator complex. In conclusion, we propose that a possible mechanism through which adiponectin differently affects breast cancer growth is the opposite modulation of CD1 levels accordingly to ER-α expression.

Zhan HQ, Chen H, Wang CF, Zhu XZ
A case of PSF-TFE3 gene fusion in Xp11.2 renal cell carcinoma with melanotic features.
Hum Pathol. 2015; 46(3):476-81 [PubMed] Related Publications
Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) with PSF-TFE3 gene fusion is a rare neoplasm. Only 22 cases of Xp11.2 RCCs with PSF-TFE3 have been reported to date. We describe an additional case of Xp11.2 RCC with PSF-TFE3 showing melanotic features. Microscopically, the histologic features mimic clear cell renal cell carcinoma. However, the dark-brown pigments were identified and could be demonstrated as melanins. Immunohistochemically, the tumor cells were widely positive for CD10, human melanoma black 45, and TFE3 but negative for cytokeratins, vimentin, Melan-A, microphthalmia-associated transcription factor, smooth muscle actin, and S-100 protein. Genetically, we demonstrated PSF-TFE3 fusion between exon 9 of PSF and exon 5 of TFE3. The patient was free of disease with 50 months of follow-up. The prognosis of this type of tumor requires more cases because of limited number of cases and follow-up period. Xp11.2 RCC with PSF-TFE3 inevitably requires differentiation from other kidney neoplasms. Immunohistochemical and molecular genetic analyses are essential for accurate diagnosis.

Sarhan D, D'Arcy P, Lundqvist A
Regulation of TRAIL-receptor expression by the ubiquitin-proteasome system.
Int J Mol Sci. 2014; 15(10):18557-73 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand- receptor (TRAIL-R) family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 or TRAIL-R2 initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of the death-inducing signaling complex (DISC), caspase activation and ultimately apoptosis. Conversely the decoy receptors TRAIL-R3 and TRAIL-R4, which lack the pro-apoptotic death domain, function to dampen the apoptotic response by competing for TRAIL ligand. The tissue restricted expression of the decoy receptors on normal but not cancer cells provides a therapeutic rational for the development of selective TRAIL-mediated anti-tumor therapies. Recent clinical trials using agonistic antibodies against the apoptosis-inducing TRAIL receptors or recombinant TRAIL have been promising; however the number of patients in complete remission remains stubbornly low. The mechanisms of TRAIL resistance are relatively unexplored but may in part be due to TRAIL-R down-regulation or shedding of TRAIL-R by tumor cells. Therefore a better understanding of the mechanisms underlying TRAIL resistance is required. The ubiquitin-proteasome system (UPS) has been shown to regulate TRAIL-R members suggesting that pharmacological inhibition of the UPS may be a novel strategy to augment TRAIL-based therapies and increase efficacies. We recently identified b-AP15 as an inhibitor of proteasome deubiquitinase (DUB) activity. Interestingly, exposure of tumor cell lines to b-AP15 resulted in increased TRAIL-R2 expression and enhanced sensitivity to TRAIL-mediated apoptosis and cell death in vitro and in vivo. In conclusion, targeting the UPS may represent a novel strategy to increase the cell surface expression of pro-apoptotic TRAIL-R on cancer cells and should be considered in clinical trials targeting TRAIL-receptors in cancer patients.

Cho JS, Park MH, Lee JS, Yoon JH
Reduced MUC4 expression is a late event in breast carcinogenesis and is correlated with increased infiltration of immune cells as well as promoter hypermethylation in invasive breast carcinoma.
Appl Immunohistochem Mol Morphol. 2015; 23(1):44-53 [PubMed] Related Publications
Altered expression of MUC4 is associated with tumor progression and immune surveillance, but the potential involvement of MUC4 in breast carcinogenesis has not been rigorously assessed. Immunohistochemical staining with anti-MUC4 antibody was performed in a total of 324 patients with 26 normal breasts, 25 usual ductal hyperplasia, 76 ductal carcinoma in situ, and 198 invasive breast carcinoma (IBC) using tissue microarray. Immunohistochemical staining for CD8, CD57, and CD1a and methylation-specific polymerase chain reaction were also performed in IBC. Reduced MUC4 expression in IBC was significantly higher than in usual ductal hyperplasia and ductal carcinoma in situ (P<0.001 and P<0.01, respectively). Reduced MUC4 expression in IBC was significantly correlated with promoter hypermethylation (P<0.05). No association between MUC4 expression and patient outcomes was identified. Intratumoral CD8 T cells and stromal CD57 natural killer cells were significantly increased in the reduced MUC4 expression group compared with those in the normal expression group (P<0.01 and P<0.05, respectively). Our results suggest that tumor progression in breast epithelium is accompanied by reduced MUC4 protein expression. Reduced MUC4 expression correlates with increased tumor-infiltrating CD8 T and NK cells as well as promoter hypermethylation in IBC.

Gossage L, Pires DE, Olivera-Nappa Á, et al.
An integrated computational approach can classify VHL missense mutations according to risk of clear cell renal carcinoma.
Hum Mol Genet. 2014; 23(22):5976-88 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
Mutations in the von Hippel-Lindau (VHL) gene are pathogenic in VHL disease, congenital polycythaemia and clear cell renal carcinoma (ccRCC). pVHL forms a ternary complex with elongin C and elongin B, critical for pVHL stability and function, which interacts with Cullin-2 and RING-box protein 1 to target hypoxia-inducible factor for polyubiquitination and proteasomal degradation. We describe a comprehensive database of missense VHL mutations linked to experimental and clinical data. We use predictions from in silico tools to link the functional effects of missense VHL mutations to phenotype. The risk of ccRCC in VHL disease is linked to the degree of destabilization resulting from missense mutations. An optimized binary classification system (symphony), which integrates predictions from five in silico methods, can predict the risk of ccRCC associated with VHL missense mutations with high sensitivity and specificity. We use symphony to generate predictions for risk of ccRCC for all possible VHL missense mutations and present these predictions, in association with clinical and experimental data, in a publically available, searchable web server.

Lepore M, de Lalla C, Gundimeda SR, et al.
A novel self-lipid antigen targets human T cells against CD1c(+) leukemias.
J Exp Med. 2014; 211(7):1363-77 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
T cells that recognize self-lipids presented by CD1c are frequent in the peripheral blood of healthy individuals and kill transformed hematopoietic cells, but little is known about their antigen specificity and potential antileukemia effects. We report that CD1c self-reactive T cells recognize a novel class of self-lipids, identified as methyl-lysophosphatidic acids (mLPAs), which are accumulated in leukemia cells. Primary acute myeloid and B cell acute leukemia blasts express CD1 molecules. mLPA-specific T cells efficiently kill CD1c(+) acute leukemia cells, poorly recognize nontransformed CD1c-expressing cells, and protect immunodeficient mice against CD1c(+) human leukemia cells. The identification of immunogenic self-lipid antigens accumulated in leukemia cells and the observed leukemia control by lipid-specific T cells in vivo provide a new conceptual framework for leukemia immune surveillance and possible immunotherapy.

Shevchuk Z, Filip A, Shevchuk V, Kashuba E
Number of Langerhans cells is decreased in premalignant keratosis and skin cancers.
Exp Oncol. 2014; 36(1):34-7 [PubMed] Related Publications
BACKGROUND: It was shown earlier that a number of CD207 positive Langerhans cells was lower in basal cell carcinomas than in the normal epidermis. Moreover, benign skin lesions presented a higher number of Langerhans cells when they were compared to malignant tumors.
AIM: To count Langerhans cells, assessing expression levels of CD1A and CD207 markers in actinic keratosis, basal and squamous cell carcinomas, compared with the normal skin. Comparison of Langerhans cells might give a valuable prognostic marker for skin cancer.
METHODS: Immunohistochemistry and methods of statistics were used.
RESULTS: Expression of CD1A and CD207 markers was assessed in tumor samples of actinic keratosis, cutaneous basal and squamous cell carcinomas, in comparison with the normal skin. In each cohort there were 40 patients (and 11 healthy individuals). We have shown that the number of Langerhans cells is considerably lower in cutaneous basal and squamous cell carcinomas, compared with their number in the normal skin (p < 0.0001).
CONCLUSIONS: CD1A expression correlated with CD207 expression only in the control group. There was no correlation in actinic keratosis, basal and squamous cell carcinoma. This may suggest an alteration of Langerhans cells phenotype in skin neoplastic diseases, making the number of Langerhans cells a valuable prognostic factor for skin tumors.

Gupta RK, Qureshi A, Choi JK
Histologic findings in skin biopsy in a JMML rash: a case report and review of literature.
Pediatr Dev Pathol. 2014 Mar-Apr; 17(2):130-3 [PubMed] Related Publications
Juvenile myelomonocytic leukemia (JMML), belonging to the category of myeloproliferative/myelodysplastic syndromes, is a rare pediatric hematologic malignancy with frequent skin manifestations commonly in the form of rashes. However, these rashes are not always biopsied and their immunophenotype studied in details. We report one such case in a 2-year-old boy who presented with a 1-month history of nonresolving fever, fatigue, and pallor along with a generalized maculopapular skin rash. The child also had mild hepatomegaly. A complete blood count with differential revealed a hemoglobin value of 8.6 g/L, leukocytosis (white blood cell count of 55.3 × 109/L), absolute monocytosis (27 × 109/L), immature granulocytes, and a platelet count of 126 × 109/L. The bone marrow aspirate showed a hypercellular marrow with trilineage hematopoiesis, 10% blasts (including promonocytes), increased monocytes (46%), and dysplastic changes in the erythroid and myeloid cell lines. These findings along with absence of a BCR-ABL1 fusion gene and a hemoglobin F level of 3.4% were consistent with the diagnosis of JMML, which was confirmed by subsequent positive granulocyte macrophage-colony stimulating factor hypersensitivity and NRAS mutation studies. A skin biopsy of the rash revealed a dermal infiltrate composed predominantly of atypical monocytic cells that were positive for CD68, myeloperoxidase, and lysozyme and negative for CD117, CD1a, and S100, consistent with JMML.

Zhu H, Huang M, Ren D, et al.
The synergistic effects of low dose fluorouracil and TRAIL on TRAIL-resistant human gastric adenocarcinoma AGS cells.
Biomed Res Int. 2013; 2013:293874 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
The TNF-related apoptosis-inducing ligand (TRAIL) is a TNF family member which has been under intense focus because of its remarkable ability to induce apoptosis in malignant human cells while leaving normal cells unscathed. However, many cancer cells remain resistant to TRAIL. In this study, we had investigated the synergistic effects of low dose fluorouracil (5-Fu) and TRAIL on TRAIL-resistant human gastric adenocarcinoma AGS cells and explored the potential mechanisms. Cell viability was analyzed by sulforhodamine B (SRB) assay and the synergistic effects were evaluated by Jin's formula and confirmed by both morphological changes under inverted microscope and flow cytometry. The expression of TRAIL-R1 (death receptor 4, DR4), TRAIL-R2 (DR5), TRAIL-R3 (decoy receptor, DcR1), TRAIL-R4 (DcR2), procaspase-3, procaspase-8, and procaspase-9 was detected by western blotting. Our results showed that there were significant synergistic effects of low dose 5-Fu and TRAIL on TRAIL-resistant AGS cells, and this effect was supposed to be mediated by decreasing DcR2 expression and increasing DR5 expression. The extrinsic and intrinsic apoptosis pathways were both activated. The data suggest that combined treatment of low dose 5-Fu and TRAIL can be an effective therapeutic approach for gastric adenocarcinoma.

Gulubova M, Manolova I, Ananiev J, et al.
Relationship of TGF-β1 and Smad7 expression with decreased dendritic cell infiltration in liver gastrointestinal cancer metastasis.
APMIS. 2013; 121(10):967-75 [PubMed] Related Publications
Immune responses and their modulation within the liver are critical to the outcome of liver malignancies. In late-stage tumors, secreted TGF-β promotes oncogenic functions and can confer tolerogenicity to some immune cells like DCs. The TGF-β signaling pathway is involved in the control of several biological processes, including immunosurveillance. The aim of the present study was to assess CD1a(+) and CD83(+) DCs and to evaluate the impact of TGF-β pathway on DCs maturation and distribution in the liver metastases from gastric and colorectal tumors. The percentage of CD83(+) DCs in the liver tissue, surrounding metastasis and in the metastasis-free liver was measured by flow cytometry, and TGF-β levels were assessed in the tissue supernatant from the peritumoral liver after mononuclear cell isolation and in the sera of the same patients. CD1a(+) and CD83(+) DCs were observed in the tumor stroma and border. Out of 73 patients, there was cytoplasmic reactivity: of TGF-β1 in 37 (50.7%); of Smad4 in 62 (84.9%); of Smad7 in 46 (63%), and of TGFβRII in 39 (53.4%) of the metastases. The TGF-β1 expression in tumor cell cytoplasm correlated with low CD1a(+) and low CD83(+) DCs infiltration. The tissue levels of TGF-β1, measured by ELISA in the supernatant were significantly increased in metastases than in normal liver. Using a two-color FACS analysis, we found that the percentage of HLA-DR(+) CD83(+) DCs in metastases was significantly decreased as compared with metastasis-free liver tissue. In conclusion, the positive and negative correlations between the mediators from the TGF-β pathway implied the existence of imbalance and suppression of this cytokine activity. The presence of increased TGF-β expression by immunohistochemistry in tumor cells was confirmed by detection of increased TGF-β tissue level in the supernatant from the tissue homogenate. The observation of low numbers of CD1a(+) and CD83(+) DCs in tumor stroma correlated with TGF-β overexpression in tumor cells, a fact that well documents the immunosuppressive role of TGF-β in metastasis development. The increased percentage of CD83(+) DCs in the peritumoral tissue supposes that there could be active recruitment or local differentiation of DCs in the metastasis border, but inside the tumor the immune cells recruitment and activity are suppressed by TGF-β and by other cytokines.

Zuurbier L, Gutierrez A, Mullighan CG, et al.
Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors.
Haematologica. 2014; 99(1):94-102 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
Three distinct immature T-cell acute lymphoblastic leukemia entities have been described including cases that express an early T-cell precursor immunophenotype or expression profile, immature MEF2C-dysregulated T-cell acute lymphoblastic leukemia cluster cases based on gene expression analysis (immature cluster) and cases that retain non-rearranged TRG@ loci. Early T-cell precursor acute lymphoblastic leukemia cases exclusively overlap with immature cluster samples based on the expression of early T-cell precursor acute lymphoblastic leukemia signature genes, indicating that both are featuring a single disease entity. Patients lacking TRG@ rearrangements represent only 40% of immature cluster cases, but no further evidence was found to suggest that cases with absence of bi-allelic TRG@ deletions reflect a distinct and even more immature disease entity. Immature cluster/early T-cell precursor acute lymphoblastic leukemia cases are strongly enriched for genes expressed in hematopoietic stem cells as well as genes expressed in normal early thymocyte progenitor or double negative-2A T-cell subsets. Identification of early T-cell precursor acute lymphoblastic leukemia cases solely by defined immunophenotypic criteria strongly underestimates the number of cases that have a corresponding gene signature. However, early T-cell precursor acute lymphoblastic leukemia samples correlate best with a CD1 negative, CD4 and CD8 double negative immunophenotype with expression of CD34 and/or myeloid markers CD13 or CD33. Unlike various other studies, immature cluster/early T-cell precursor acute lymphoblastic leukemia patients treated on the COALL-97 protocol did not have an overall inferior outcome, and demonstrated equal sensitivity levels to most conventional therapeutic drugs compared to other pediatric T-cell acute lymphoblastic leukemia patients.

Wilzén A, Krona C, Sveinbjörnsson B, et al.
ERBB3 is a marker of a ganglioneuroblastoma/ganglioneuroma-like expression profile in neuroblastic tumours.
Mol Cancer. 2013; 12(1):70 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
BACKGROUND: Neuroblastoma (NB) tumours are commonly divided into three cytogenetic subgroups. However, by unsupervised principal components analysis of gene expression profiles we recently identified four distinct subgroups, r1-r4. In the current study we characterized these different subgroups in more detail, with a specific focus on the fourth divergent tumour subgroup (r4).
METHODS: Expression microarray data from four international studies corresponding to 148 neuroblastic tumour cases were subject to division into four expression subgroups using a previously described 6-gene signature. Differentially expressed genes between groups were identified using Significance Analysis of Microarray (SAM). Next, gene expression network modelling was performed to map signalling pathways and cellular processes representing each subgroup. Findings were validated at the protein level by immunohistochemistry and immunoblot analyses.
RESULTS: We identified several significantly up-regulated genes in the r4 subgroup of which the tyrosine kinase receptor ERBB3 was most prominent (fold change: 132-240). By gene set enrichment analysis (GSEA) the constructed gene network of ERBB3 (n = 38 network partners) was significantly enriched in the r4 subgroup in all four independent data sets. ERBB3 was also positively correlated to the ErbB family members EGFR and ERBB2 in all data sets, and a concurrent overexpression was seen in the r4 subgroup. Further studies of histopathology categories using a fifth data set of 110 neuroblastic tumours, showed a striking similarity between the expression profile of r4 to ganglioneuroblastoma (GNB) and ganglioneuroma (GN) tumours. In contrast, the NB histopathological subtype was dominated by mitotic regulating genes, characterizing unfavourable NB subgroups in particular. The high ErbB3 expression in GN tumour types was verified at the protein level, and showed mainly expression in the mature ganglion cells.
CONCLUSIONS: Conclusively, this study demonstrates the importance of performing unsupervised clustering and subtype discovery of data sets prior to analyses to avoid a mixture of tumour subtypes, which may otherwise give distorted results and lead to incorrect conclusions. The current study identifies ERBB3 as a clear-cut marker of a GNB/GN-like expression profile, and we suggest a 7-gene expression signature (including ERBB3) as a complement to histopathology analysis of neuroblastic tumours. Further studies of ErbB3 and other ErbB family members and their role in neuroblastic differentiation and pathogenesis are warranted.

Varshney S, Bhadada SK, Saikia UN, et al.
Simultaneous expression analysis of vitamin D receptor, calcium-sensing receptor, cyclin D1, and PTH in symptomatic primary hyperparathyroidism in Asian Indians.
Eur J Endocrinol. 2013; 169(1):109-16 [PubMed] Related Publications
BACKGROUND: To explore underlying molecular mechanisms in the pathogenesis of symptomatic sporadic primary hyperparathyroidism (PHPT).
MATERIALS AND METHODS: Forty-one parathyroid adenomas from patients with symptomatic PHPT and ten normal parathyroid glands either from patients with PHPT (n=3) or from euthyroid patients without PHPT during thyroid surgery (n=7) were analyzed for vitamin D receptor (VDR), calcium-sensing receptor (CASR), cyclin D1 (CD1), and parathyroid hormone (PTH) expressions. The protein expressions were assessed semiquantitatively by immunohistochemistry, based on percentage of positive cells and staining intensity, and confirmed by quantitative real-time PCR.
RESULTS: Immunohistochemistry revealed significant reductions in VDR (both nuclear and cytoplasmic) and CASR expressions and significant increases in CD1 and PTH expressions in adenomatous compared with normal parathyroid tissue. Consistent with immunohistochemistry findings, both VDR and CASR mRNAs were reduced by 0.36- and 0.45-fold change (P<0.001) and CD1 and PTH mRNAs were increased by 9.4- and 17.4-fold change respectively (P<0.001) in adenomatous parathyroid tissue. PTH mRNA correlated with plasma PTH (r=0.864; P<0.001), but not with adenoma weight, while CD1 mRNA correlated with adenoma weight (r=0.715; P<0.001). There were no correlations between VDR and CASR mRNA levels and serum Ca, plasma intact PTH, or 25-hydroxyvitamin D levels. In addition, there was no relationship between the decreases in VDR and CASR mRNA expressions and the increases in PTH and CD1 mRNA expressions.
CONCLUSIONS: The expression of both VDR and CASR are reduced in symptomatic PHPT in Asian Indians. In addition, CD1 expression was greatly increased and correlated with adenoma weight, implying a potential role for CD1 in adenoma growth and differential clinical expression of PHPT.

Shon W, Peters MS, Reed KB, et al.
Atypical generalized eruptive histiocytosis clonally related to chronic myelomonocytic leukemia with loss of Y chromosome.
J Cutan Pathol. 2013; 40(8):725-9 [PubMed] Related Publications
Generalized eruptive histiocytosis, described in 1963 by Winklemann and Muller, is a reactive, self-healing form of non-Langerhans histiocytosis. Rare cases of atypical generalized eruptive histiocytosis have been reported in patients with hematopoietic malignancy, but the biological relationship between the two disorders is not known. We report an 84-year-old man with chronic myelomonocytic leukemia who presented with coalescing erythematous papules and plaques on the posterior neck, ear and lower lip, followed by development of blast crisis. Skin biopsy revealed a thick band-like dermal infiltrate of cells that exhibited morphologic features of macrophages or histiocytes and prominent elastolytic phagocytosis. These cells demonstrated a mature immunophenotype, expressing CD14 and CD68, with partial expression of CD13 but not CD1a, CD43, CD56, CD123, Langerin, or S-100 protein. Karyotype and fluorescence in situ hybridization analyses showed loss of the Y chromosome in bone marrow and skin specimens, providing evidence of a clonal relationship between the cutaneous eruption and the underlying chronic myelomonocytic leukemia. The presence of the same clone in skin and bone marrow specimens from our patient supports the possibility that atypical generalized eruptive histiocytosis is a marker for underlying hematopoietic malignancy. Discovery of additional cases may shed further light on the pathogenesis of this rare entity.

Sethakorn N, Dulin NO
RGS expression in cancer: oncomining the cancer microarray data.
J Recept Signal Transduct Res. 2013; 33(3):166-71 [PubMed] Related Publications
Heterotrimeric G proteins mediate myriads of cell functions including control of cancer cell proliferation and migration. The family of the Regulators of G protein Signaling (RGS) proteins, in turn, controls the activity of G proteins through the acceleration of GTPase activity of the alpha subunits of G proteins. Increasing evidence suggest that the expression of certain RGS proteins is changed dramatically in various cancers, and in some instances, the control of cancer cell proliferation or migration by RGS proteins has been demonstrated. We assessed if common trends might exist in the expression of various RGS proteins in several types of cancer by examining microarray data using the Oncomine database. We focused on the largest R4 sub-family of RGS proteins, containing RGS1, RGS2, RGS3, RGS4, RGS5, RGS8, RGS13, RGS16 and RGS18. This analysis suggests that a number (up to 6) of RGS transcripts are exclusively downregulated in certain cancers, while being exclusively upregulated in other cancer types. Furthermore, significant changes in the expression of certain RGS proteins trended toward the same direction across various cancers. To illustrate, RGS1 is largely upregulated, whereas RGS2 is downregulated in the majority of solid tumors, whereas RGS5 transcripts are greatly increased in eight subtypes of lymphoma with no reports of downregulation in hematological malignancies. Together, these data suggest that (i) RGS proteins may have a combined and cell-specific role in a control of cancer cell function, and (ii) a given RGS protein may regulate the progression of various cancers through a common mechanism.

Hald SM, Bremnes RM, Al-Shibli K, et al.
CD4/CD8 co-expression shows independent prognostic impact in resected non-small cell lung cancer patients treated with adjuvant radiotherapy.
Lung Cancer. 2013; 80(2):209-15 [PubMed] Related Publications
BACKGROUND: Though traditionally regarded as immunosuppressive, radiotherapy may also stimulate immune cells and facilitate an anti-tumor immune response. We therefore aimed to explore the prognostic significance of immune cell markers in non-small cell lung cancer (NSCLC) patients treated with postoperative radiotherapy (PORT).
METHODS: In addition to demographic and clinicopathological information, tumor tissue samples were collected and tissue microarrays (TMAs) were constructed from 55 patients with stage I-IIIA NSCLC who received PORT. Tumor and stromal expression of CD1a+, CD3+, CD4+, CD8+, CD20+, CD56+, CD68+, CD117+ and CD138+ cells, as well as M-CSF and CSF-1R, was assessed by immunohistochemistry.
RESULTS: In univariate analysis, high co-expression of CD4+ and CD8+ T lymphocytes as well as high expression of CD1a+ dendritic cells in the tumor stroma correlated with improved disease-specific survival (DSS). In multivariate analysis patients with stromal ↓CD4/↓CD8 expression had a hazard ratio of 21.1 (CI95% 3.9-115.6, P<0.001) when compared to those with ↑CD4/↑CD8 expression.
CONCLUSIONS: Stromal ↓CD4/↓CD8 expression was an independent negative prognostic factor for survival in NSCLC patients receiving PORT, indicating a highly detrimental prognosis.

Kloten V, Becker B, Winner K, et al.
Promoter hypermethylation of the tumor-suppressor genes ITIH5, DKK3, and RASSF1A as novel biomarkers for blood-based breast cancer screening.
Breast Cancer Res. 2013; 15(1):R4 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
INTRODUCTION: For early detection of breast cancer, the development of robust blood-based biomarkers that accurately reflect the host tumor is mandatory. We investigated DNA methylation in circulating free DNA (cfDNA) from blood of breast cancer patients and matched controls to establish a biomarker panel potentially useful for early detection of breast cancer.
METHODS: We examined promoter methylation of seven putative tumor-suppressor genes (SFRP1, SFRP2, SFRP5, ITIH5, WIF1, DKK3, and RASSF1A) in cfDNA extracted from serum. Clinical performance was first determined in a test set (n = 261 sera). In an independent validation set (n = 343 sera), we validated the most promising genes for further use in early breast cancer detection. Sera from 59 benign breast disease and 58 colon cancer patients were included for additional specificity testing.
RESULTS: Based on the test set, we determined ITIH5 and DKK3 promoter methylation as candidate biomarkers with the best sensitivity and specificity. In both the test and validation set combined, ITIH5 and DKK3 methylation achieved 41% sensitivity with a specificity of 93% and 100% in healthy and benign disease controls, respectively. Combination of these genes with RASSF1A methylation increased the sensitivity to 67% with a specificity of 69% and 82% in healthy controls and benign disease controls, respectively.
CONCLUSIONS: Tumor-specific methylation of the three-gene panel (ITIH5, DKK3, and RASSF1A) might be a valuable biomarker for the early detection of breast cancer.

Kumar MM, Adurthi S, Ramachandran S, et al.
Toll-like receptors 7, 8, and 9 expression and function in primary human cervical cancer Langerhans cells: evidence of anergy.
Int J Gynecol Cancer. 2013; 23(1):184-92 [PubMed] Related Publications
OBJECTIVE: Human papillomavirus oncoproteins E6 and E7 down modulate Toll-like receptor (TLR) 9 expression in infected keratinocytes. We explored the status of expression and function of TLR7, TLR8, and TLR9 in primary human Langerhans cells (LCs) isolated from cervical tumors.
METHODOLOGY: Single-cell suspensions were made from fresh tissues of squamous cell carcinoma (International Federation of Gynecology and Obstetrics stage IB2); myeloid dendritic cells were purified using CD1c magnetic activated cell separation kits. Langerhans cells were further flow sorted into CD1a*CD207* cells. Acute monocytic leukemia cell line THP-1-derived LCs (moLCs) formed the controls. mRNA from flow-sorted LCs was reverse transcribed to cDNA and TLR7, TLR8, and TLR9 amplified. Monocyte-derived Langerhans cells and cervical tumor LCs were stimulated with TLR7, TLR8, and TLR9 ligands. Culture supernatants were assayed for interleukin (IL) 1β, IL-6, IL-10, IL-12p70, interferon (IFN) α, interferon γ, and tumor necrosis factor (TNF) α by Luminex multiplex bead array. Human papillomavirus was genotyped.
RESULTS: We have for the first time demonstrated that the acute monocytic leukemia cell line THP-1 can be differentiated into LCs in vitro. Although these moLCs expressed all the 3 TLRs, tumor LCs expressed TLR7 and TLR8, but uniformly lacked TLR9. Also, moLCs secreted IL-6, IL-1β, and tumor necrosis factor α to TLR8 ligand and interferon α in response to TLR9 ligand; in contrast, tumor LCs did not express any cytokine to any of the 3 TLR ligands. Human papillomavirus type 16 was one of the common human papillomavirus types in all cases.
CONCLUSIONS: Cervical tumor LCs lacked TLR9 expression and were functionally anergic to all the 3: TLR7, TLR8, and TLR9 ligands, which may play a crucial role in immune tolerance. The exact location of block(s) in TLR7 and TLR8 signaling needs to be investigated, which would have important immunotherapeutic implications.

Harman AN, Bye CR, Nasr N, et al.
Identification of lineage relationships and novel markers of blood and skin human dendritic cells.
J Immunol. 2013; 190(1):66-79 [PubMed] Related Publications
The lineage relationships and fate of human dendritic cells (DCs) have significance for a number of diseases including HIV where both blood and tissue DCs may be infected. We used gene expression profiling of human monocyte and DC subpopulations sorted directly from blood and skin to define the lineage relationships. We also compared these with monocyte-derived DCs (MDDCs) and MUTZ3 Langerhans cells (LCs) to investigate their relevance as model skin DCs. Hierarchical clustering analysis showed that myeloid DCs clustered according to anatomical origin rather than putative lineage. Plasmacytoid DCs formed the most discrete cluster, but ex vivo myeloid cells formed separate clusters of cells both in blood and in skin. Separate and specific DC populations could be determined within skin, and the proportion of CD14(+) dermal DCs (DDCs) was reduced and CD1a(+) DDCs increased during culture, suggesting conversion to CD1a(+)-expressing cells in situ. This is consistent with origin of the CD1a(+) DDCs from a local precursor rather than directly from circulating blood DCs or monocyte precursors. Consistent with their use as model skin DCs, the in vitro-derived MDDC and MUTZ3 LC populations grouped within the skin DC cluster. MDDCs clustered most closely to CD14(+) DDCs; furthermore, common unique patterns of C-type lectin receptor expression were identified between these two cell types. MUTZ3 LCs, however, did not cluster closely with ex vivo-derived LCs. We identified differential expression of novel genes in monocyte and DC subsets including genes related to DC surface receptors (including C-type lectin receptors, TLRs, and galectins).

Razumienko EJ, Scollard DA, Reilly RM
Small-animal SPECT/CT of HER2 and HER3 expression in tumor xenografts in athymic mice using trastuzumab Fab-heregulin bispecific radioimmunoconjugates.
J Nucl Med. 2012; 53(12):1943-50 [PubMed] Related Publications
UNLABELLED: Heterodimerization of human epidermal growth factor receptor 2 (HER2) with HER3 initiates aberrant downstream growth-signaling pathways in tumors. Our objective was to construct bispecific radioimmunoconjugates (bsRICs) that recognize HER2 and HER3 and evaluate their ability to image tumors in athymic mice that express one or both receptors using small-animal SPECT/CT.
METHODS: bsRICs were constructed by reacting the maleimide-derivatized trastuzumab Fab fragments that bind HER2 with a thiolated form of the HER3-binding peptide of heregulin-β1 (HRG) with or without a 12- or 24 mer polyethylene glycol (PEG) spacer. bsRICs were derivatized with diethylenetriaminepentaacetic acid for labeling with (111)In. The ability of (111)In-bsRICs to bind HER2 or HER3 was determined in competition assays with unlabeled Fab or HRG on cells expressing one or both receptors. Tumor and normal-tissue uptake were examined in CD1 athymic mice bearing subcutaneous tumor xenografts that expressed HER2, HER3, or both receptors, with or without the preadministration of unlabeled Fab or HRG to determine the specificity of uptake.
RESULTS: Conjugation of Fab to HRG was confirmed by sodium dodecyl sulphate polyacrylamide gel electrophoresis-Western blot and size-exclusion high-performance liquid chromatography. Improved HER2 and HER3 binding and greater displacement of binding by competitors was found for (111)In-bsRICs that incorporated a PEG spacer, with the PEG(24) spacer being optimal. The highest uptake of (111)In-bsRICs (7.8% ± 2.1% injected dose per gram [%ID/g]) in BT-474 human breast cancer xenografts (HER2-positive/HER3-positive) occurred at 48 h after injection. The preadministration of trastuzumab Fab decreased uptake in SK-OV-3 (HER2-positive/HER3-negative) human ovarian cancer xenografts from 7.0 ± 1.2 to 2.6 ± 1.5 %ID/g (P < 0.001). The preadministration of an excess of HRG decreased uptake in MDA-MB-468 (HER2-negative/HER3-positive) human breast cancer xenografts from 4.4 ± 0.9 to 2.6 ± 0.5 %ID/g (P < 0.05). All tumors were imaged by small-animal SPECT/CT.
CONCLUSION: (111)In-bsRICs composed of trastuzumab Fab and HRG exhibited specific binding in vitro to tumor cells displaying HER2 or HER3 and were taken up specifically in vivo in tumors expressing one or both receptors, permitting tumor visualization by small-animal SPECT/CT. These agents could be useful for imaging heterodimerized HER2 and HER3 receptors because their bivalent properties may result in preferential binding to the heterodimerized forms. The approach may also be extended to constructing bsRICs for visualizing other peptide growth factor receptors.

Xu Z, Padmore R, Faught C, et al.
Langerhans cell sarcoma with an aberrant cytoplasmic CD3 expression.
Diagn Pathol. 2012; 7:128 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
UNLABELLED: Langerhans cell sarcoma is a rare and aggressive high grade hematopoietic neoplasm with a dismal prognosis. It has a unique morphological and immunotypic profile with a CD1a/ langerin/S100 + phenotype. T cell lineage markers except for CD4 in Langerhans cell sarcoma have not been documented previously. We report a case of 86 year-old male of Caucasian descent who presented with an enlarging right neck mass over 2 months with an underlying unknown cause of anemia. Computed tomography scan of the neck, chest and abdomen revealed generalized lymphadenopathy and mild splenomegaly suspicious for lymphoma. Diagnostic core biopsy performed on right neck mass revealed a possible T cell lymphoma with expression of T cell lineage specific marker CD3 but conclusive diagnosis could not be made due to insufficient core biopsy sample. Further excisional biopsy performed on a left inguinal node showed a hematopoietic neoplasm with features of Langerhans cell sarcoma with a focal cytoplasmic CD3 expression in 30-40% of the tumor cells. PCR for T cell receptor (TCR) gene rearrangement failed to demonstrate a clonal gene rearrangement in the tumor cells arguing against a T cell lineage transdifferentiation, suggesting an aberrant CD3 expression. To the best of our knowledge, this case represents the first report of Langerhans cell sarcoma with an aberrant cytoplasmic CD3 expression.
VIRTUAL SLIDES: http://www.diagnosticpathology.diagnomx.eu/vs/2065486371761991.

Pruitt FL, He Y, Franco OE, et al.
Cathepsin D acts as an essential mediator to promote malignancy of benign prostatic epithelium.
Prostate. 2013; 73(5):476-88 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
BACKGROUND: Stromal-epithelial interactions are important in both development and prostate cancer. Stromal changes have been shown to be powerful prognostic indicators of prostate cancer progression and of patient death helping to define lethal versus indolent phenotypes. The specific molecular underpinnings of these interactions are incompletely understood. We investigated whether stromal cathepsin D (CathD) overexpression affects prostate tumorigenesis through a paracrine mechanism.
METHODS: Normal prostate fibroblasts (NPF) were retrovirally transduced to overexpress cyclin D1 (CD1) and were designated NPF(CD1) . Cathepsin D expression was knocked down using shRNA in cancer associated fibroblasts (CAF) and NPF(CD1) . We analyzed these stromal cell lines using immunohistochemistry, Western blot, and tissue recombination.
RESULTS: An examination of human prostate tissue revealed significantly increased stromal staining of CathD in malignant prostate tissue. Overexpression of CD1 in normal prostate fibroblasts (NPF(CD1) ) produced a phenotype similar to, but more moderate than, CAF in a tissue recombination model. Knockdown studies revealed that CathD is required for NPF(CD1) motility and invasive growth in vitro. BPH-1 cell proliferation was found to be induced when cultured with NPF(CD1) conditioned medium, this effect was inhibited when CathD was knocked down in NPF(CD1) cells. Overexpression of CathD in prostate stromal cells induced malignancy in adjacent epithelium, and this transformation was inhibited when stromal CathD expression was knocked down in CAF.
CONCLUSIONS: The study presented here demonstrates increased CathD expression is seen in human CAF. The upregulation of CD1 results in concomitant increases in CathD expression. Elevated CathD expression in the stroma contributes to tumor promotion.

Angénieux C, Waharte F, Gidon A, et al.
Lysosomal-associated transmembrane protein 5 (LAPTM5) is a molecular partner of CD1e.
PLoS One. 2012; 7(8):e42634 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
The CD1e protein participates in the presentation of lipid antigens in dendritic cells. Its transmembrane precursor is transported to lysosomes where it is cleaved into an active soluble form. In the presence of bafilomycin, which inhibits vacuolar ATPase and consequently the acidification of endosomal compartments, CD1e associates with a 27 kD protein. In this work, we identified this molecular partner as LAPTM5. The latter protein and CD1e colocalize in trans-Golgi and late endosomal compartments. The quantity of LAPTM5/CD1e complexes increases when the cells are treated with bafilomycin, probably due to the protection of LAPTM5 from lysosomal proteases. Moreover, we could demonstrate that LAPTM5/CD1e association occurs under physiological conditions. Although LAPTM5 was previously shown to act as a platform recruiting ubiquitin ligases and facilitating the transport of receptors to lysosomes, we found no evidence that LATPM5 controls either CD1e ubiquitination or the generation of soluble lysosomal CD1e proteins. Notwithstanding these last observations, the interaction of LAPTM5 with CD1e and their colocalization in antigen processing compartments both suggest that LAPTM5 might influence the role of CD1e in the presentation of lipid antigens.

Szabo A, Osman RM, Bacskai I, et al.
Temporally designed treatment of melanoma cells by ATRA and polyI: C results in enhanced chemokine and IFNβ secretion controlled differently by TLR3 and MDA5.
Melanoma Res. 2012; 22(5):351-61 [PubMed] Related Publications
In the last three decades, the incidence of melanoma has increased worldwide and no effective treatment modalities have been developed yet. All-trans retinoic acid (ATRA) and polyinosinic:polycytidylic acid (polyI:C) are strong inducers of toll-like receptor 3 (TLR3) and MDA5 expression, and polyI:C-induced TLR3 and MDA5 signaling specifically causes cell death in melanoma cells in vitro. We addressed the question of whether ATRA pretreatment could enhance the efficacy of polyI:C and, if so, would ATRA have any additional effects on this process. We found that the combined treatment of human melanoma cells with ATRA and polyI:C strongly increased the expression of TLR3 and MDA5 in both WM35 and WM983A cells associated with significantly higher mRNA and secreted levels of interferon β (IFNβ), CXCL1, CXCL8/IL-8, CXCL9, and CXCL10 than cells treated with either ATRA or polyI:C. Silencing of MDA5 by siRNA moderately affected IFNβ secretion, whereas TLR3 knockdown interfered with both CXCL chemokine and IFNβ production. Furthermore, the supernatants of ATRA+polyI:C-activated cultures increased the migration of both human monocyte-derived macrophages and CD1a dendritic cells significantly as compared with the supernatants of cells treated with either ATRA or polyI:C, and this effect occurred in a TLR3-dependent manner. In conclusion, consecutive treatment with ATRA and polyI:C results in strong, TLR3/MDA5-mediated chemokine and IFN responses in cultured human melanoma cells, which triggers a functional migratory response in professional antigen-presenting cells. This novel mode of concomitant activation may represent a more efficient treatment option for future melanoma therapy.

Furmanczyk PS, Lisle AE, Caldwell RB, et al.
Langerhans cell sarcoma in a patient with hairy cell leukemia: common clonal origin indicated by identical immunoglobulin gene rearrangements.
J Cutan Pathol. 2012; 39(6):644-50 [PubMed] Related Publications
Histiocytic/dendritic cell sarcomas are rare tumors, a few of which have been reported in association with B-cell lymphoma/leukemia. Isolated reports have documented identical immunoglobulin gene rearrangements suggesting a common clonal origin for both the sarcoma and the B-cell neoplasm from individual patients. We report a case of a 75-year-old male with hairy cell leukemia who subsequently developed Langerhans cell sarcoma 1 year after his primary diagnosis of leukemia. The bone marrow biopsy containing hairy cell leukemia and skin biopsies of Langerhans cell sarcoma were evaluated by routine histology, immunohistochemistry, flow cytometric immunophenotyping and PCR-based gene rearrangement studies of the immunoglobulin heavy chain and kappa genes. The hairy cell leukemia showed characteristic morphologic, immunohistochemical and flow cytometric features. The Langerhans cell sarcoma showed pleomorphic cytology, a high mitotic rate and characteristic immunohistochemical staining for Langerin, S100 and CD1a. There was no evidence of B-cell differentiation or a background B-cell infiltrate based on the absence of immunoreactivity with antibodies to multiple B-cell markers. Identical immunoglobulin gene rearrangements were identified in both the hairy cell leukemia and Langerhans cell sarcoma specimens. Despite the phenotypic dissimilarity of the two neoplasms, identical immunoglobulin gene rearrangements indicate a common origin.

Goodwin CB, Yang Z, Yin F, et al.
Genetic disruption of the PI3K regulatory subunits, p85α, p55α, and p50α, normalizes mutant PTPN11-induced hypersensitivity to GM-CSF.
Haematologica. 2012; 97(7):1042-7 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
Juvenile myelomonocytic leukemia is a lethal disease of children characterized by hypersensitivity of hematopoietic progenitors to granulocyte macrophage-colony stimulating factor. Mutations in PTPN11, the gene encoding the protein tyrosine phosphatase Shp2, are common in juvenile myelomonocytic leukemia and induce hyperactivation of the phosphoinositide-3-kinase pathway. We found that genetic disruption of Pik3r1, the gene encoding the Class IA phosphoinositide-3-kinase regulatory subunits p85α, p55α and p50α, significantly reduced hyperproliferation and hyperphosphorylation of Akt in gain-of-function Shp2 E76K-expressing cells. Elevated protein levels of the phosphoinositide-3-kinase catalytic subunit, p110δ, in the Shp2 E76K-expressing Pik3r1-/- cells suggest that p110δ may be a crucial mediator of mutant Shp2-induced phosphoinositide-3-kinase hyperactivation. Consistently, treatment with the p110δ-specific inhibitor, IC87114, or the clinical grade pan-phosphoinositide-3-kinase inhibitor, GDC-0941, reduced granulocyte macrophage-colony stimulating factor hypersensitivity. Treatment with the farnesyltransferase inhibitor, tipifarnib, showed that Shp2 E76K induces hyperactivation of phosphoinositide-3-kinase by both Ras-dependent and Ras-independent mechanisms. Collectively, these findings implicate Class IA phosphoinositide-3-kinase as a relevant molecular target in juvenile myelomonocytic leukemia.

Kumar A, Xu J, Sung B, et al.
Evidence that GTP-binding domain but not catalytic domain of transglutaminase 2 is essential for epithelial-to-mesenchymal transition in mammary epithelial cells.
Breast Cancer Res. 2012; 14(1):R4 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
INTRODUCTION: The expression of proinflammatory protein tissue transglutaminase 2 (TG2) is frequently upregulated in multiple cancer cell types. However, the exact role of TG2 in cancer cells is not well-understood. We recently initiated studies to determine the significance of TG2 in cancer cells and observed that sustained expression of TG2 resulted in epithelial-to-mesenchymal transition (EMT) and promoted cancer stem cell (CSC) traits in mammary epithelial cells. These results suggested that TG2 could serve as a promising therapeutic target for overcoming chemoresistance and inhibiting metastatic spread of cancer cells.
METHODS: Using various mutant constructs, we analyzed the activity of TG2 that is essential for promoting the EMT-CSC phenotype.
RESULTS: Our results suggest that catalytically inactive TG2 (TG2-C277S) is as effective as wild-type TG2 (TG2-WT) in inducing the EMT-CSC in mammary epithelial cells. In contrast, overexpression of a GTP-binding-deficient mutant (TG2-R580A) was completely incompetent in this regard. Moreover, TG2-dependent activation of the proinflammatory transcription factor NF-κB is deemed essential for promoting the EMT-CSC phenotype in mammary epithelial cells.
CONCLUSIONS: Our results suggest that the transamidation activity of TG2 is not essential for promoting its oncogenic functions and provide a strong rationale for developing small-molecule inhibitors to block GTP-binding pockets of TG2. Such inhibitors may have great potential for inhibiting the TG2-regulated pathways, reversing drug resistance and inhibiting the metastasis of cancer cells.

Uchibori K, Kasamatsu A, Sunaga M, et al.
Establishment and characterization of two 5-fluorouracil-resistant hepatocellular carcinoma cell lines.
Int J Oncol. 2012; 40(4):1005-10 [PubMed] Article available free on PMC after 12/11/2015 Related Publications
5-Fluorouracil (5-FU) chemotherapy is the first choice treatment for advanced hepatocellular carcinoma (HCC), and resistance is the major obstacle to successful treatment. Recent studies have reported that epithelial-to-mesenchymal transition (EMT) is associated with chemoresistance in cancers. We speculated that EMT and 5-FU metabolism are related to the mechanism of 5-FU resistance. First, two 5-FU-resistant cell lines, HLF-R4 and HLF-R10, were established from the HLF undifferentiated human HCC cell line. Whereas cell growth was similar in the HLF and HLF-R cell lines, HLF-Rs are about 4- and 10-fold more resistant compared with the HLF cells; thus, we named these cell lines HLF-R4 and HLF-R10, respectively. The terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay also showed a dramatically decreased number of apoptotic cells in the HLF-Rs after treatment with 5-FU. We next assessed the characteristics of the HLF, HLF-R4 and HLF-R10 cells. Consistent with our hypothesis, the HLF-Rs had typical morphologic phenotypes of EMT, loss of cell-cell adhesion, spindle-shaped morphology and increased formation of pseudopodia. Real-time quantitative reverse transcriptase polymerase chain reaction data showed downregulated E-cadherin and upregulated Twist-1 and also indicated that EMT changes occurred in the HLF-Rs. We also found decreased ribonucleotide reductase and increased multidrug resistance protein 5 genes in the HLF-R cells. Our results suggested that the metabolism of EMT and 5-FU has important roles in 5-FU chemoresistance in the HLF-R cells, and that the HLF-R cells would be useful in vitro models for understanding the 5-FU-resistant mechanisms in HCC.

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