NOD2

Gene Summary

Gene:NOD2; nucleotide binding oligomerization domain containing 2
Aliases: CD, ACUG, BLAU, IBD1, YAOS, BLAUS, NLRC2, NOD2B, CARD15, CLR16.3, PSORAS1
Location:16q12.1
Summary:This gene is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharides (LPS) by recognizing the muramyl dipeptide (MDP) derived from them and activating the NFKB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:nucleotide-binding oligomerization domain-containing protein 2
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
Show (88)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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

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

Latest Publications: NOD2 (cancer-related)

Razmkhah F, Soleimani M, Mehrabani D, et al.
Leukemia microvesicles affect healthy hematopoietic stem cells.
Tumour Biol. 2017; 39(2):1010428317692234 [PubMed] Related Publications
Microvesicles are released by different cell types and shuttle mRNAs and microRNAs which have the possibility to transfer genetic information to a target cell and alter its function. Acute myeloid leukemia is a malignant disorder, and leukemic cells occupy all the bone marrow microenvironment. In this study, we investigate the effect of leukemia microvesicles on healthy umbilical cord blood hematopoietic stem cells to find evidence of cell information transferring. Leukemia microvesicles were isolated from acute myeloid leukemia patients and were co-incubated with healthy hematopoietic stem cells. After 7 days, cell count, hematopoietic stem cell-specific cluster of differentiation (CD) markers, colony-forming unit assay, and some microRNA gene expressions were assessed. Data showed a higher number of hematopoietic stem cells after being treated with leukemia microvesicles compared with control (treated with no microvesicles) and normal (treated with normal microvesicles) groups. Also, increased levels of microRNA-21 and microRNA-29a genes were observed in this group, while colony-forming ability was still maintained and high ranges of CD34(+), CD34(+)CD38(-), CD90(+), and CD117(+) phenotypes were observed as stemness signs. Our results suggest that leukemia microvesicles are able to induce some effects on healthy hematopoietic stem cells such as promoting cell survival and some microRNAs deregulation, while stemness is maintained.

Onishi H, Suyama K, Yamasaki A, et al.
CD24 Modulates Chemosensitivity of MCF-7 Breast Cancer Cells.
Anticancer Res. 2017; 37(2):561-565 [PubMed] Related Publications
The role of cluster of differentiation (CD) 24 in breast cancer remains unclear; previously, we showed that CD24 suppresses malignant phenotypes by inactivating Hedgehog signaling through signal transducer and activator of transcription (STAT) 1 inhibition. In this study, we examined how CD24 affects chemosensitivity in breast cancer cells. The CD44(+)CD24(+) breast cancer cell line MCF-7 was transfected with CD24 with/without STAT1 siRNA, and chemosensitivity to 5-fluorouracil (5-FU) and cis-diamminedichloroplatinum (CDDP) was measured. CD24 inhibition reduced chemosensitivity to 5-FU, while STAT1 inhibition did not affect chemosensitivity to 5-FU in CD24 siRNA-transfected cells. Conversely, CD24 inhibition did not affect chemosensitivity to CDDP, while STAT1 inhibition reduced chemosensitivity to CDDP in CD24 siRNA-transfected cells. STAT1 inhibition, but not CD24 inhibition, reduced expression of the ATP-binding cassette (ABC) transporter genes, ABCB1 and ABCG2. In conclusion, CD24 inhibition may modulate chemosensitivity according to drug type, but ABC transporter expression appears not to contribute to this mechanism. This study contributes to determining the role of CD24 in breast cancer.

Kim R, Park SI, Lee CY, et al.
Alternative new mesenchymal stem cell source exerts tumor tropism through ALCAM and N-cadherin via regulation of microRNA-192 and -218.
Mol Cell Biochem. 2017; 427(1-2):177-185 [PubMed] Free Access to Full Article Related Publications
Gliomas are the most common type of malignant primary brain tumors. Some treatments of gliomas exist, but they are rarely curative. Mesenchymal stem cells (MSCs) are emerging as potential modes of targeted cancer therapy owing to their capacity for homing toward tumor sites. It has been proposed that MSCs derived from various sources, such as bone marrow, adipose tissue and umbilical cord blood, can be used as cell-based therapy for brain tumors. Here, MSCs obtained from the synovial fluid of osteoarthritis or rheumatoid arthritis patients were investigated as therapeutic candidates. Specifically, we compared migratory and adhesive abilities, as well as expression levels of related genes and microRNA in bone marrow derived-MSCs (BMMSCs), adipose derived-MSCs (ADMSCs), and synovial fluid derived-MSCs (SFMSCs) after treatment with conditioned medium from gliomas. Migration and adhesion of SFMSCs increased through upregulation of the activated lymphocyte cell adhesion molecule (ALCAM) and N-cadherin by microRNA-192 and -218 downregulation, similar to BMMSCs and ADMSCs. Migratory capacities of all types of MSCs were evaluated in vivo, and SFMSCs migrated intensively toward gliomas. These results suggest that SFMSCs have potential for use in cell-based antitumor therapies.

Song JX, Dian ZJ, Wen Y, et al.
Assessment of the Number and Phenotype of Macrophages in the Human BMB Samples of CML.
Biomed Res Int. 2016; 2016:8086398 [PubMed] Free Access to Full Article Related Publications
Macrophages have emerged as a key player in tumor biology. However, their number and phenotype in human bone marrow of biopsy (BMB) samples of chronic myeloid leukemia (CML) and their association with disease progression from an initial chronic phase (CP) to accelerated phase (AP) to advanced blast phase (BP) are still unclear. BMB samples from 127 CML patients and 30 patients with iron-deficiency anemia (IDA) as control group were analyzed by immunohistochemistry. The expression levels of CD68, CD163, and CD206 in BMB samples of CML patients were significantly higher than those in the patients of control group (P < 0.01), and we observed that their positive expression was gradually elevated during the transformation of CML-CP to AP to BP (P < 0.01). However, the expressions of CD68, CD163, and CD206 in released group were downregulated and contrasted to these in control group; there exists statistical significance (P < 0.01). The percentage ratio of CD163 and CD206 to CD68 was pronounced to be increasing from CML-CP to AP to BP (P < 0.01). Hence, the higher proportion of CD68(+), CD163(+) and CD206(+) macrophages in BMB samples can be considered a key factor for disease progression of CML patients. Targeting macrophages, especially the M2 phenotype may help in designing therapeutic strategies for CML.

Chekhonin IV, Gurina OI, Cherepanov SA, et al.
Pulsed Dendritic Cells for the Therapy of Experimental Glioma.
Bull Exp Biol Med. 2016; 161(6):792-796 [PubMed] Related Publications
We obtained the morphologically, cytofluorometrically, and functionally mature dendritic cells from rats that were pulsed with antigens of the C6 glioma tissue extract. The concentrations of angiogenesis antigens (VEGF, VEGFR-1, and VEGFR-2) and periglioma zone proteins (GFAP, connexin 43, and BSAT1) in the pulsing extract were measured by ELISA. Our results drove us to a conclusion that despite mature phenotype of pulsed dendritic cell, the antigenic composition of glioma tissue extracts should be modified.

Su Z, Ni P, Zhou C, Wang J
Myeloid-Derived Suppressor Cells in Cancers and Inflammatory Diseases: Angel or Demon?
Scand J Immunol. 2016; 84(5):255-261 [PubMed] Related Publications
Myeloid-derived suppressor cell (MDSC) is an important heterogeneous cell population that regulates innate and adaptive immune. The immunosuppressive potentiality is widely known. However, more and more data indicated that the heterogeneous cell population had immunostimulatory activities rather than immunosuppression in some microenvironments. Chronic inflammatory conditions contribute to accumulation of MDSCs. These pathologically activated cells played critical roles in cancer and inflammatory diseases. In this review, we mainly discuss the immunoregulation potentiality of MDSCs in cancer and inflammatory diseases.

Maestro MA, Molnár F, Mouriño A, Carlberg C
Vitamin D receptor 2016: novel ligands and structural insights.
Expert Opin Ther Pat. 2016; 26(11):1291-1306 [PubMed] Related Publications
INTRODUCTION: Vitamin D3 activates via its hormonal form 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), the transcription factor vitamin D receptor (VDR). VDR is expressed in most human tissues and has more than 1,000 target genes. Thus, 1α,25(OH)2D3 and its synthetic analogs have a broad physiological impact. The crystal structures of the VDR ligand-binding domain (LBD), and its various ligands, allows further the understanding of the receptor's molecular actions. Areas covered: We discuss the most important novel VDR ligands and the further insight derived from new structural information on VDR. Expert opinion: There is an increasing appreciation of the impact of vitamin D and its receptor VDR not only in bone biology, but also for metabolic diseases, immunological disorders, and cancer. Detailed structural analysis of the interaction of additional novel ligands with VDR highlight helices 6 and 7 of the LBD as being most critical for stabilizing the receptor for an efficient interaction with co-activator proteins, i.e. for efficient agonistic action. This permits the design of even more effective VDR agonists. In addition, chemists took more liberty in replacing major parts of the 1α,25(OH)2D3 molecule, such as the A- and CD-rings or the side chain, with significantly different structures, such as carboranes, and still obtained functional VDR agonists.

Liu G, Luan J, Li Q
CD4(+)Foxp3(-)IL-10(+) Tr1 Cells Promote Relapse of Diffuse Large B Cell Lymphoma by Enhancing the Survival of Malignant B Cells and Suppressing Antitumor T Cell Immunity.
DNA Cell Biol. 2016; 35(12):845-852 [PubMed] Related Publications
Diffuse large B cell lymphoma (DLBCL) is a common B cell malignancy. Complete remission can be achieved in most patients by conventional treatment with rituximab and chemotherapy. However, a subset of remission individuals will develop a relapsed disease for obscure reasons. CD4(+)Foxp3(-)IL-10(+) cell (Tr1) is a novel cell subtype with the capacity to suppress pro-inflammatory responses, but has not been extensively studied in most tumors. In this study, we investigated the potential role of Tr1 cells in DLBCL. We found that compared to that in healthy controls, the frequency of Tr1 cells was significantly increased in DLBCL patients, even during complete remission. Further study showed that these Tr1 cells were enriched in the CD25(low/-)Foxp3(-)CD49b(+)LAG-3(+) fraction and could be developed in vitro from naive CD45RA(+) CD4(+) T cells. To examine the effect of Tr1 upregulation, we cocultured the enriched in vitro-induced Tr1 cells (iTr1) with autologous primary DLBCL cells and CD3(+) T cells and found that iTr1 cells both enhanced the survival of CD20(+) DLBCL tumor cells and suppressed the antitumor response of CD3(+) T cells through the production of IL-10. Furthermore, the frequency of CD4(+)Foxp3(-)IL-10(+) Tr1 cells in DLBCL patients during complete remission is directly associated with the risk of relapse. Together, these results suggested that Tr1 cells contributed to tumor cell maintenance and may serve as a prognostic marker and therapeutic target.

Li J, Wang Y, Xue S, et al.
Effective combination treatment of lung cancer cells by single vehicular delivery of siRNA and different anticancer drugs.
Int J Nanomedicine. 2016; 11:4609-4624 [PubMed] Free Access to Full Article Related Publications
In recent years, lung cancer has become one of the fastest growing cancers in the world. Thus, the development of efficient combination therapy to treat lung cancer has attracted significant attention in the cancer therapy field. In this article, we developed a single vehicle drug delivery system, based on quantum dot (QD) nanoparticles, to deliver small interfering RNA (siRNA; target Bcl-2) and different anticancer drugs (carboplatin, paclitaxel, and doxorubicin) simultaneously for treating A549 lung cancer cells efficiently by combination therapy. The QD nanoparticles were conjugated with l-arginine (l-Arg) and different kinds of hydroxypropyl-cyclodextrins (HP-α-CDs, HP-β-CDs, and HP-γ-CDs) on the surface to form the delivery nanocarriers (QD nanocarriers). They were able to not only bind and transport the siRNA through electrostatic interactions with l-Arg residues but also accommodate various disparate anticancer drugs using different HP-CD modifications. Compared with free drug treatments, the use of QD nanocarriers to deliver Bcl-2 siRNA and different anticancer drugs simultaneously exerted a threefold to fourfold increase in cytotoxicity in A549 cells, which greatly improved the treatment efficacy through combined action. Furthermore, the QD nanocarriers could be used as a probe for real-time imaging of the drug delivery and release because of their strong fluorescence properties. These findings indicate that multifunctional QD nanocarriers hold great promise as a powerful tool for combination therapy for lung cancer.

Gil D, Ciołczyk-Wierzbicka D, Dulińska-Litewka J, Laidler P
Integrin-linked kinase regulates cadherin switch in bladder cancer.
Tumour Biol. 2016; 37(11):15185-15191 [PubMed] Free Access to Full Article Related Publications
Cadherin switch is specific of epithelial-mesenchymal transition (EMT) and is closely related to tumor cell invasion. However, the molecular mechanism that promotes the phenotypic changes remains unclear and elusive. We found that integrin-linked kinase (ILK) is a key factor involved in cadherin switch. The expression and activity of ILK are elevated in a variety of cancers but its mechanisms are not exactly understood. In this report, we studied the role and mechanism of ILK in EMT of human bladder cancer. We showed that silencing of ILK expression by small interfering RNA (siRNA) significantly abolished the nuclear translocation or the presence of markers associated with EMT like Snail, Twist, Zeb, and beta-catenin. ILK knockdown by siRNA suppressed N-cadherin expression and increased re-expression of E-cadherin in bladder cancer cells. We suggest that ILK is a major signaling factor involved in EMT. It is essential to understand the molecular mechanism of EMT in aim to possibly use it in search for new therapeutic targets.

Ma X, Zhang Y, Kang Y, et al.
A recombinant protein TmSm(T34A) can inhibit proliferation and proapoptosis to breast cancer stem cells(BCSCs) by down-regulating the expression of Cyclin D1.
Biomed Pharmacother. 2016; 84:373-381 [PubMed] Related Publications
Cancer stem cells (CSCs), a small fraction of cancer cells lines proved with stem cell characteristics, were regarded as "bad seeds" related to recurrence, metastasis and chemotherapy resistance of breast carcinoma in recent years. So inhibiting the growth or inducing the differentiation and apoptosis of CSCs were considered as one of the effective pathways to fight against breast cancer. Based on the recombinant protein TmSm(T34A) that was designed and prepared in our previous experiments for targeting survivin, an inhibitor of apoptosis protein(IAP), in this study, we explored the effects of TmSm(T34A) on BCSCs obtained by enriching in serum-free suspension, sorting and characterizing of MCF-7/ADM. The results showed that TmSm(T34A) could not only inhibit the proliferation and growth of BCSCs by decreasing CD44(+)CD24(-) proportion and down-regulating the expression of Cyclin D1 significantly, but also induce BCSCs apoptosis evidently. Furthermore, in BCSCs xenograft nude mice administrated TmSm(T34A), the tumor growth was slower than that of the control obviously. Thus it can be seen TmSm(T34A) would be a promising potential protein for treatment of breast cancer by effecting on BCSCs.

Zhang Z, Bu X, Chen H, et al.
Bmi-1 promotes the invasion and migration of colon cancer stem cells through the downregulation of E-cadherin.
Int J Mol Med. 2016; 38(4):1199-207 [PubMed] Free Access to Full Article Related Publications
Metastasis and recurrence are the challenges of cancer therapy. Recently, mounting evidence has suggested that cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) are critical factors in tumor metastasis and recurrence. The oncogene, Bmi-1, promotes the development of hematologic malignancies and many solid tumors. The aim of the present study was to elucidate the mechanisms through which Bmi-1 promotes the invasion and migration of colon CSCs (CCSCs) using the HCT116 colon cancer cell line. Sphere formation medium and magnetic‑activated cell sorting were used to enrich and screen the CCSCs. CD133 and CD44 were regarded as markers of CCSCs and they were found to be co-expressed in the HCT116 colon cancer cell line. Colony formation assay, cell proliferation assay and viability assay using the Cell Counting Kit-8, and transplantation assay using nude mice injected with CCSCs were used to examine the CCSCs. The CD133+CD44+ HCT116 cells exhibited greater cloning efficiency, an enhanced proliferative ability, increased cell viability and stronger tumorigenicity; these cells were used as the CCSCs for subsequent experiments. In addition, the invasive and migratory abilities of the CD133+CD44+ HCT116 cells were markedly decreased when Bmi-1 was silenced by small interfering RNA (siRNA). The results of RT-qPCR and western blot analysis suggested that Bmi-1 had a negative effect on E-cadherin expression. On the whole, our findings suggest that Bmi-1 promotes the invasion and migration of CCSCs through the downregulation of E-cadherin, possibly by inducing EMT. Our findings thus indicate that Bmi-1 may be a novel therapeutic target for the treatment of colon cancer.

Zhang SS, Huang ZW, Li LX, et al.
Identification of CD200+ colorectal cancer stem cells and their gene expression profile.
Oncol Rep. 2016; 36(4):2252-60 [PubMed] Related Publications
CD200 is a cell surface glycoprotein that has been implicated in a variety of human cancer cells. It has been proposed as a cancer stem cell (CSC) marker in colon cancer and is closely related to tumor immunosuppression. However, there is little functional data supporting its role as a true CSC marker, and the mechanism by which CD200 contributes to colorectal cancer has not been elucidated. In the present study, CD200+ and CD200- COLO 205 colorectal cancer cells were sorted out by flow cytometry, and colonosphere formation and Transwell migration assays were performed. Affymetrix Human U133 Plus2.0 arrays were used to screen the gene expression profiles of CD200+ and CD200- colorectal cancer cells. The results suggest that there are differentially expressed genes between the two subpopulations, including several important genes that function in cell proliferation, metastasis, apoptosis and the immune response. Pathway analysis revealed that the Wnt, MAPK and calcium signaling pathways were differentially expressed between CD200+ and CD200- cells. Moreover, several key genes upregulated in CD200+ cells were also highly overexpressed in CD44+CD133+ colorectal stem cells compared to the CD44-CD133- fraction of the same cell line. In the present study, we showed for the first time a correlation between CD200 expression and the Wnt signaling pathway in colon cancer cells.

Rubin B, Regazzo D, Redaelli M, et al.
Investigation of N-cadherin/β-catenin expression in adrenocortical tumors.
Tumour Biol. 2016; 37(10):13545-13555 [PubMed] Related Publications
β-catenin is a multifunctional protein; it is a key component of the Wnt signaling, and it plays a central role in cadherin-based adhesions. Cadherin loss promotes tumorigenesis by releasing membrane-bound β-catenin, hence stimulating Wnt signaling. Cadherins seem to be involved in tumor development, but these findings are limited in adrenocortical tumors (ACTs). The objective of this study was to evaluate alterations in key components of cadherin/catenin adhesion system and of Wnt pathway. This study included eight normal adrenal samples (NA) and 95 ACT: 24 adrenocortical carcinomas (ACCs) and 71 adrenocortical adenomas (ACAs). β-catenin mutations were evaluated by sequencing, and β-catenin and cadherin (E-cadherin and N-cadherin) expression was analyzed by quantitative reverse transcription PCR (qRT-PCR) and by immunohistochemistry (IHC). We identified 18 genetic alterations in β-catenin gene. qRT-PCR showed overexpression of β-catenin in 50 % of ACC (12/24) and in 48 % of ACA (21/44). IHC data were in accordance with qRT-PCR results: 47 % of ACC (7/15) and 33 % of ACA (11/33) showed increased cytoplasmic or nuclear β-catenin accumulation. N-cadherin downregulation has been found in 83 % of ACC (20/24) and in 59 % of ACA (26/44). Similar results were obtained by IHC: N-cadherin downregulation was observed in 100 % (15/15) of ACC and in 55 % (18/33) of ACA. β-catenin overexpression together with the aberrant expression of N-cadherin may play important role in ACT tumorigenesis. The study of differentially expressed genes (such as N-cadherin and β-catenin) may enhance our understanding of the biology of ACT and may contribute to the discovery of new diagnostic and prognostic tools.

Wachowiak R, Mayer S, Kaifi J, et al.
Prognostic Impact of Activated Leucocyte Cell Adhesion Molecule (ALCAM/CD166) in Infantile Neuroblastoma.
Anticancer Res. 2016; 36(8):3991-5 [PubMed] Related Publications
BACKGROUND/AIM: Activated leukocyte cell adhesion molecule (ALCAM/CD166) as a member of the 'immunoglobulin superfamily' is known to be involved in cancer cell proliferation and migration. The aim of this study was to investigate the expression of ALCAM in neuroblastoma tissues.
MATERIALS AND METHODS: ALCAM expression was analyzed in primary neuroblastoma specimens by immunohistochemistry on microarray sections. Histopathological and clinical data were correlated with ALCAM expression and survival analysis was performed.
RESULTS: Sixty-six children were included in the study. Strong expression of ALCAM was detected in 52 (79%) of the samples. Weak expression was significantly correlated with the International Neuroblastoma Staging System (INSS) stage (p=0.024) and positive n-MYC amplification (p=0.019). Recurrence-free survival (RFS) and overall survival (OS) were significantly shorter if ALCAM was expressed weakly (p=0.032 and p=0.001).
CONCLUSION: Weak ALCAM expression was significantly correlated with established markers for poor prognosis, as well as shorter RFS and OS. ALCAM might be considered as a prognostic marker for infantile neuroblastoma.

Yi S, Niu D, Bai F, et al.
Soluble Expression of a Human MnSOD and Hirudin Fusion Protein in Escherichia coli, and Its Effects on Metastasis and Invasion of 95-D Cells.
J Microbiol Biotechnol. 2016; 26(11):1881-1890 [PubMed] Related Publications
Manganese superoxide dismutase (MnSOD) is a vital enzyme that protects cells from free radicals through eliminating superoxide radicals (O²⁻). Hirudin, a kind of small active peptide molecule, is one of the strongest anticoagulants that can effectively cure thrombus diseases. In this study, we fused Hirudin to the C terminus of human MnSOD with the GGGGS linker to generate a novel dual-feature fusion protein, denoted as hMnSOD-Hirudin. The hMnSOD-Hirudin gene fragment was cloned into the pET15b (SmaI, CIAP) vector, forming a recombinant pET15b-hMnSOD-Hirudin plasmid, and then was transferred into Escherichia coli strain Rosetta-gami for expression. SDS-PAGE was used to detect the fusion protein, which was expected to be about 30 kDa upon IPTG induction. Furthermore, the hMnSOD-Hirudin protein was heavily detected as a soluble form in the supernatant. The purification rate observed after Ni NTA affinity chromatography was above 95%. The hMnSOD-Hirudin protein yield reached 67.25 mg per liter of bacterial culture. The identity of the purified protein was confirmed by western blotting. The hMnSOD-Hirudin protein activity assay evinced that the antioxidation activity of the hMnSOD-Hirudin protein obtained was 2,444.0 ± 96.0 U/mg, and the anticoagulant activity of the hMnSOD-Hirudin protein was 599.0 ± 35.0 ATU/mg. In addition, in vitro bioactivity assay showed that the hMnSODHirudin protein had no or little cytotoxicity in H9c2, HK-2, and H9 (human CD₄⁺, T cell) cell lines. Transwell migration assay and invasion assay showed that the hMnSOD-Hirudin protein could suppress human lung cancer 95-D cell metastasis and invasion in vitro.

Iorio F, Knijnenburg TA, Vis DJ, et al.
A Landscape of Pharmacogenomic Interactions in Cancer.
Cell. 2016; 166(3):740-54 [PubMed] Free Access to Full Article Related Publications
Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature of cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here, we report how cancer-driven alterations identified in 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, and gene expression) can be mapped onto 1,001 molecularly annotated human cancer cell lines and correlated with sensitivity to 265 drugs. We find that cell lines faithfully recapitulate oncogenic alterations identified in tumors, find that many of these associate with drug sensitivity/resistance, and highlight the importance of tissue lineage in mediating drug response. Logic-based modeling uncovers combinations of alterations that sensitize to drugs, while machine learning demonstrates the relative importance of different data types in predicting drug response. Our analysis and datasets are rich resources to link genotypes with cellular phenotypes and to identify therapeutic options for selected cancer sub-populations.

Zhou X, Liu XZ, Fan GT, et al.
Expression of Matrix Metalloproteinase-9 and CD34 in Giant Cell Tumor of Bone.
Orthop Surg. 2016; 8(2):220-5 [PubMed] Related Publications
OBJECTIVE: Giant cell tumor of bone (GCTB) invades extensively and metastasizes, however, the pathological grade and imaging findings are not accurate predictors of its prognosis. Thus, the aim of this study was to explore the relationships between expression of cluster of differentiation (CD)34 and matrix metalloproteinase-9 (MMP-9) and the biological behavior of GCTB with the hope of identifying predictors of prognosis.
METHODS: Sixty-eight patients with GCTBs attending our institution from September 2008 to August 2013 were enrolled in this prospective study and grouped according to tumor location. Relevant patient characteristics were assessed. Additionally, the expression of CD34 and MMP-9 in these patients was assayed by an immunohistochemistry staining procedure and the relationships between CD34/MMP-9 and microvessel density (MVD) analyzed by Spearman correlation analysis.
RESULTS: It was found that CD34 factor localizes in the cytoplasm of the endothelial cells of small blood vessels in the tumor stroma and is strongly expressed in GCTBs. In addition, radiological grading showed that there was significantly more CD34 antibody-labeled MVD in invasive than in non-invasive tumors (P < 0.05) and significantly more CD34 antibody-labeled MVD in patients who developed recurrences than in those who did not (P < 0.05). Expression of MMP-9 was localized in the cytoplasm of tumor cells and the rate of MMP-9 positivity in GCTBs was significantly higher in active and invasive tumors than in non-invasive tumors (P < 0.01). Moreover, there were significantly more MVDs in MMP-9-positive than in MMP-9 negative tumors (P < 0.01). CD34 and MMP-9 are positively correlated with MVD values in GCTBs and closely correlated with their grade of malignancy.
CONCLUSION: Expression of CD34 and MMP-9 accurately predicts clinical behavior detection and prognosis of GCTBs.

Sun B, Wan Z, Shen J, et al.
DNA hypomethylation of CD133 promoter is associated with recurrent glioma.
Oncol Rep. 2016; 36(2):1062-8 [PubMed] Related Publications
Gliomas are the most common type of brain tumor in the central nervous system of adults, and are highly aggressive, resistant to treatment, and prone to recurrence. Brain tumor stem cells (BTSCs) are implicated in tumor initiation and recurrence. Cluster of differentiation (CD)133 is currently the most widely used BTSC marker; however, its role in glioma development and progression is largely unknown. In this study, we evaluated CD133 expression in pairs of primary and recurrent human glioma specimens from 24 patients. We found that recurrent gliomas have aberrantly upregulated CD133 levels. To clarify the mechanism underlying this observation, we assessed CD133 promoter (P)2 methylation status by bisulfite sequencing and found that P2 hypomethylation was associated with the increase in CD133 expression and glioma recurrence. These results suggest that CD133 overexpression in BTSCs due to P2 hypomethylation underlies glioma recurrence, which may provide insight into the mechanism of glioma recurrence and provide a basis for novel therapies for glioma treatment.

Nguyen T, Mège RM
N-Cadherin and Fibroblast Growth Factor Receptors crosstalk in the control of developmental and cancer cell migrations.
Eur J Cell Biol. 2016; 95(11):415-426 [PubMed] Related Publications
Cell migrations are diverse. They constitutemajor morphogenetic driving forces during embryogenesis, but they contribute also to the loss of tissue homeostasis and cancer growth. Capabilities of cells to migrate as single cells or as collectives are controlled by internal and external signalling, leading to the reorganisation of their cytoskeleton as well as by the rebalancing of cell-matrix and cell-cell adhesions. Among the genes altered in numerous cancers, cadherins and growth factor receptors are of particular interest for cell migration regulation. In particular, cadherins such as N-cadherin and a class of growth factor receptors, namely FGFRs cooperate to regulate embryonic and cancer cell behaviours. In this review, we discuss on reciprocal crosstalk between N-cadherin and FGFRs during cell migration. Finally, we aim at clarifying the synergy between N-cadherin and FGFR signalling that ensure cellular reorganization during cell movements, mainly during cancer cell migration and metastasis but also during developmental processes.

He Y, Rivard CJ, Rozeboom L, et al.
Lymphocyte-activation gene-3, an important immune checkpoint in cancer.
Cancer Sci. 2016; 107(9):1193-7 [PubMed] Free Access to Full Article Related Publications
Immunotherapy has recently become widely used in lung cancer. Many oncologists are focused on cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death ligand-1 (PD-L1) and programmed cell death-1 (PD-1). Immunotherapy targeting the PD-1/PD-L1 checkpoints has shown promising efficacy in non-small cell lung cancer (NSCLC), but questions remain to be answered. Among them is whether the simultaneous inhibition of other checkpoints could improve outcomes. Lymphocyte-activation gene-3 (LAG-3) is another vital checkpoint that may have a synergistic interaction with PD-1/PD-L1. Here we review the LAG-3 function in cancer, clinical trials with agents targeting LAG-3 and the correlation of LAG-3 with other checkpoints.

Liu W, Rodgers GP
Olfactomedin 4 expression and functions in innate immunity, inflammation, and cancer.
Cancer Metastasis Rev. 2016; 35(2):201-12 [PubMed] Related Publications
Olfactomedin 4 (OLFM4) is an olfactomedin domain-containing glycoprotein. Multiple signaling pathways and factors, including NF-κB, Wnt, Notch, PU.1, retinoic acids, estrogen receptor, and miR-486, regulate its expression. OLFM4 interacts with several other proteins, such as gene associated with retinoic-interferon-induced mortality 19 (GRIM-19), cadherins, lectins, nucleotide oligomerization domain-1 (NOD1) and nucleotide oligomerization domain-2 (NOD2), and cathepsins C and D, known to regulate important cellular functions. Recent investigations using Olfm4-deficient mouse models have provided important clues about its in vivo biological functions. Olfm4 inhibited Helicobacter pylori-induced NF-κB pathway activity and inflammation and facilitated H. pylori colonization in the mouse stomach. Olfm4-deficient mice exhibited enhanced immunity against Escherichia coli and Staphylococcus aureus infection. Olfm4 deletion in a chronic granulomatous disease mouse model rescued them from S. aureus infection. Olfm4 deletion in mice treated with azoxymethane/dextran sodium sulfate led to robust intestinal inflammation and intestinal crypt hyperplasia. Olfm4 deletion in Apc (Min/+) mice promoted intestinal polyp formation as well as adenocarcinoma development in the distal colon. Further, Olfm4-deficient mice spontaneously developed prostatic epithelial lesions as they age. OLFM4 expression is correlated with cancer differentiation, stage, metastasis, and prognosis in a variety of cancers, suggesting its potential clinical value as an early-stage cancer marker or a therapeutic target. Collectively, these data suggest that OLFM4 plays important roles in innate immunity against bacterial infection, gastrointestinal inflammation, and cancer. In this review, we have summarized OLFM4's initial characterization, expression, regulation, protein interactions, and biological functions.

Han ML, Wang F, Gu YT, et al.
MicroR-760 suppresses cancer stem cell subpopulation and breast cancer cell proliferation and metastasis: By down-regulating NANOG.
Biomed Pharmacother. 2016; 80:304-10 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: Emerging evidences suggest that cancer stem cells are responsible for tumor aggressive, metastasis and therapeutic resistance. To data, the mechanism underlying breast cancer stem cell (BCSC) population within tumor metastasis remains to be fully elucidated. The current study was to investigate the potential role of microRNA-760 (miR-760) and its associated target gene in population and metastasis of BCSC.
METHODS: Characteristic BCSCs surface markers (CD44(+)/CD24(-/low)) were determined by flow cytometry in breast cancer MCF-7 and BT-549 cells. Quantitative RT-PCR was used to evaluate miR-760 and NANOG mRNA expression. Expression of NANOG protein was determined using western blot. Cell proliferation was determined by MTT assay. The model of breast cancer cell xenograft was used to evaluate the effect of miR-760 on tumor growth.
RESULTS: BT-549 cell has substantially more CD44(+)/CD24(-/low) subpopulation than MCF-7 cell. Moreover, BT-549 cell expressed lower level of miR-760 and higher level of NANOG than MCF-7cell. By result from cellular miR-760 modulation, we found that miR-760 overexpression suppressed CD44(+)/CD24(-/low) population as well as inhibited cell proliferation and migration of BT-549. On the contrary, knockdown of miR-760 promoted CD44(+)/CD24(-/low) population and migration of MCF-7 cells. By luciferase reporter assay, miR-760 was proved to be functional associated with NANOG via regulating its expression. This functional interaction was showed to be involved in controlling proliferation and migration of MCF-7 and BT-549 cell.
CONCLUSION: These data suggest that the target of miR-760/NANOG axis may represent a new therapeutic approach to suppress breast cancer stem cell subpopulation thereby prevent cancer metastasis.

Micheli E, Altieri A, Cianni L, et al.
Perylene and coronene derivatives binding to G-rich promoter oncogene sequences efficiently reduce their expression in cancer cells.
Biochimie. 2016; 125:223-31 [PubMed] Related Publications
A novel approach to cancer therapeutics is emerging in the field of G-quadruplex (G4) ligands, small molecules designed to stabilize four-stranded structures that can form at telomeres as well as in other genomic sequences, including oncogene promoter sequences, 5'-UTR regions and introns. In this study, we investigated the binding activity of perylene and coronene derivatives PPL3C, CORON and EMICORON to G4 structures formed within the promoter regions of two important cancer-related genes, c-MYC and BCL-2, and their biochemical effects on gene and protein expression. In order to fully characterize the ability of the selected ligands to bind and stabilize the G4 structures originated by the c-MYC and BCL-2 promoter sequences, we performed electrospray ionization mass spectrometry (ESI-MS), Fluorescence Resonance Energy Transfer (FRET) measurements, Circular Dichroism (CD) spectra and polymerase stop assay. Altogether our results showed that the ligands had a high capacity in binding and stabilizing the G4 structures within the c-MYC and BCL-2 promoter sequences in vitro. Notably, when we evaluated by quantitative real-time PCR and western blotting analysis, the effects of treatment with the different G4 ligands on c-MYC and BCL2 expression in a human melanoma cell line, EMICORON appeared the most effective compound in reducing the mRNA and protein levels of both genes. These results encourage to consider EMICORON as a promising example of multimodal class of an antineoplastic drug, affecting different tumor crucial pathways simultaneously: telomere maintenance (as previously described), cell proliferation and apoptosis via down-regulation of both c-MYC and BCL-2 (this paper).

Kim YA, Lee HJ, Heo SH, et al.
MxA expression is associated with tumor-infiltrating lymphocytes and is a prognostic factor in triple-negative breast cancer.
Breast Cancer Res Treat. 2016; 156(3):597-606 [PubMed] Related Publications
Interferons (IFNs) play an important role in tumor-immune system interactions. As one of the main mediators of IFNs, myxovirus resistance A (MxA) is upregulated in various cancers. However, the exact role of MxA in breast cancer is not fully understood. As part of the immune response to tumors, tumor-infiltrating lymphocytes (TILs) have prognostic significance in breast cancer. The aim of our present study was to examine the relationship between MxA and immune system components, including the amount of TILs and human leukocyte antigen (HLA) expression, in breast cancer. TILs, MxA expression, HLA intensity, and clinicopathological factors were retrospectively analyzed in 688 patients with primary breast cancer between 1993 and 1998 and in 705 patients with triple-negative breast cancer (TNBC) between 2004 and 2011. MxA expression was higher in TNBC tumors than in other subtypes. High MxA levels were associated with a higher histologic grade, abundant TILs, and stronger HLA-ABC expression in both the TNBC subtype within the consecutive breast cancer cohort and the validation TNBC cohort. MxA expression showed a significant positive correlation with TILs, the number of CD8(+) cells, and the number of CD69(+) cells in the validation TNBC cohort. High MxA levels and abundant TILs were found to be independent prognostic factors for disease-free survival in patients with TNBC. These results indicate that MxA expression is closely related to TILs in TNBC and, along with TILs, provides prognostic information after chemotherapy in patients with TNBC.

Ma T, Zhao Y, Wei K, et al.
MicroRNA-124 Functions as a Tumor Suppressor by Regulating CDH2 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer.
Cell Physiol Biochem. 2016; 38(4):1563-74 [PubMed] Related Publications
BACKGROUND/AIMS: Abnormal expression of microRNA-124 (miR-124) was found in non-small cell lung cancer (NSCLC). However, the association between miR-124 and CDH2 has not been reported yet. This study aims to reveal the inhibiting effects of miR-124 on the expression of CDH2 in NSCLC.
METHODS: Quantitative real-time polymerase chain reaction was used to evaluate the expression of miR-124 and CDH2 in NSCLC tissues. Cell viability, apoptosis and invasion assays were carried out in NSCLC cell lines after transfection. The regulation mechanism was confirmed by luciferase report assay and western blot (WB).
RESULTS: Significantly decreased expression of miR-124 was found in NSCLC specimens and cell lines. Overexpression of miR-124 apparently suppressed the proliferation and invasion of NSCLC cell lines in vitro. Luciferase report assay and WB revealed that CDH2 was a target gene of miR-124. Furthermore, results of WB showed that epithelial-mesenchymal transition (EMT) could be inhibited by up-regulation of miR-124.
CONCLUSIONS: Taken together, our findings present the first evidence that miR-124 could suppress the expression of CDH2 and regulate EMT, which might lead to a potential therapeutic strategy focusing on miR-124 and CDH2 for human lung cancer.

Miyazaki R, Anayama T, Hirohashi K, et al.
In Vitro Drug Sensitivity Tests to Predict Molecular Target Drug Responses in Surgically Resected Lung Cancer.
PLoS One. 2016; 11(4):e0152665 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase (ALK) inhibitors have dramatically changed the strategy of medical treatment of lung cancer. Patients should be screened for the presence of the EGFR mutation or echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene prior to chemotherapy to predict their clinical response. The succinate dehydrogenase inhibition (SDI) test and collagen gel droplet embedded culture drug sensitivity test (CD-DST) are established in vitro drug sensitivity tests, which may predict the sensitivity of patients to cytotoxic anticancer drugs. We applied in vitro drug sensitivity tests for cyclopedic prediction of clinical responses to different molecular targeting drugs.
METHODS: The growth inhibitory effects of erlotinib and crizotinib were confirmed for lung cancer cell lines using SDI and CD-DST. The sensitivity of 35 cases of surgically resected lung cancer to erlotinib was examined using SDI or CD-DST, and compared with EGFR mutation status.
RESULTS: HCC827 (Exon19: E746-A750 del) and H3122 (EML4-ALK) cells were inhibited by lower concentrations of erlotinib and crizotinib, respectively than A549, H460, and H1975 (L858R+T790M) cells were. The viability of the surgically resected lung cancer was 60.0 ± 9.8 and 86.8 ± 13.9% in EGFR-mutants vs. wild types in the SDI (p = 0.0003). The cell viability was 33.5 ± 21.2 and 79.0 ± 18.6% in EGFR mutants vs. wild-type cases (p = 0.026) in CD-DST.
CONCLUSIONS: In vitro drug sensitivity evaluated by either SDI or CD-DST correlated with EGFR gene status. Therefore, SDI and CD-DST may be useful predictors of potential clinical responses to the molecular anticancer drugs, cyclopedically.

Guillory T, Li S, Bergsagel DJ, et al.
Hematogones With Lambda Light Chain Restriction in a 4-Year-Old Boy With Burkitt Lymphoma: A Potential Diagnostic Pitfall.
Lab Med. 2016; 47(2):163-70 [PubMed] Free Access to Full Article Related Publications
Hematogones are immature normal B cell precursors with a characteristic immunophenotype profile on flow cytometry that typically do not express surface immunoglobulin light chains. In this report, we describe a case in which the hematogones exhibit light chain restriction. Our patient was a 4-year-old boy with a complicated medical history involving treatment for a presumed bilateral Wilms tumor of the kidney that on later resection was diagnosed as Burkitt lymphoma. Flow cytometry analysis of his bone marrow revealed a small distinct population of cells expressing dim cluster of differentiation (CD)10, CD19, CD22, CD38, dim CD58, human leukocyte antigen-D related (HLA-DR), and dim CD45, which are characteristic of hematogones. These cells, however, demonstrated dim surface immunoglobulin lambda light-chain restriction. Molecular study results for immunoglobulin heavy and kappa light-chain gene rearrangements were negative. We present this case to raise awareness of the potential pitfalls of working up bone marrow for involvement by B cell lymphoproliferative disorder.

Su M, Huang CX, Dai AP
Immune Checkpoint Inhibitors: Therapeutic Tools for Breast Cancer.
Asian Pac J Cancer Prev. 2016; 17(3):905-10 [PubMed] Related Publications
Breast cancer is one of the major threats to female health, and its incidence is rapidly increasing in many countries. Currently, breast cancer is treated with surgery, followed by chemotherapy or radiation therapy, or both. However, a substantial proportion of breast cancer patients might have a risk for local relapse that leads to recurrence of their disease and/or metastatic breast cancer. Therefore searching for new and potential strategies for breast cancer treatment remains necessary. Immunotherapy is an attractive and promising approach that can exploit the ability of the immune system to identify and destroy tumors and thus prevent recurrence and metastatic lesions. The most promising and attractive approach of immunotherapeutic research in cancer is the blockade of immune checkpoints. In this review, we discuss the potential of certain inhibitors of immune checkpoints, such as antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1) and lymphocyte activation gene-3 (LAG-3), in breast cancer therapeutics. Immune checkpoint inhibitors may represent future standards of care for breast cancer as monotherapy or combined with standard therapies.

Li L, Tian Y, Shi C, et al.
Over-Expression of CD200 Predicts Poor Prognosis in Cutaneous Squamous Cell Carcinoma.
Med Sci Monit. 2016; 22:1079-84 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: CD200 is reported to be involved in tumor progression and can serve as a prognostic marker in several cancers. The purpose of this study was to evaluate the prognostic significance of CD200 in cutaneous squamous cell carcinoma (CSCC).
MATERIAL/METHODS: The relative mRNA and protein expression of CD200 in the tumor tissues and corresponding normal tissues of 102 CSCC patients were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis, respectively. The chi-square test was used to analyze the association between CD200 expression and clinical features of CSCC patients. In addition, the overall survival of the patients according to the expression level of CD200 was estimated by Kaplan-Meier analysis and the prognostic significance of the gene was analyzed by Cox regression analysis.
RESULTS: Increased expression of CD200 was detected in the tumor tissues compared with the corresponding normal tissues both at mRNA and protein level. And CD200 expression level was associated with tumor differentiation grade (P=0.041) and clinical stage (P=0.004). Patients with high expression level of CD200 had a shorter overall survival than those with low expression (31.3 months vs. 41.9 months) and there was a significant difference between them (log-rank test, P<0.001). Cox regression analysis indicated that CD200 could be an independent marker for the prognosis of CSCC.
CONCLUSIONS: CD200 is up-regulated and may be a novel biomarker for the prognosis in CSCC, and it may be a potential therapeutic target for CSCC.

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