Gene Summary

Gene:CD47; CD47 molecule
Aliases: IAP, OA3, MER6
Summary:This gene encodes a membrane protein, which is involved in the increase in intracellular calcium concentration that occurs upon cell adhesion to extracellular matrix. The encoded protein is also a receptor for the C-terminal cell binding domain of thrombospondin, and it may play a role in membrane transport and signal transduction. This gene has broad tissue distribution, and is reduced in expression on Rh erythrocytes. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:leukocyte surface antigen CD47
Source:NCBIAccessed: 01 September, 2019


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

Research Indicators

Publications Per Year (1994-2019)
Graph generated 02 September 2019 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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

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

Latest Publications: CD47 (cancer-related)

Cao Y, Zhu W, Chen W, et al.
Prognostic Value of BIRC5 in Lung Adenocarcinoma Lacking EGFR, KRAS, and ALK Mutations by Integrated Bioinformatics Analysis.
Dis Markers. 2019; 2019:5451290 [PubMed] Free Access to Full Article Related Publications
Objective: This study was aimed at investigating the prognostic significance of Baculoviral IAP repeat containing 5 (BIRC5) in lung adenocarcinoma (LAD) lacking EGFR, KRAS, and ALK mutations (triple-negative (TN) adenocarcinomas).
Methods: The gene expression profiles were obtained from Gene Expression Omnibus (GEO). The identification of the differentially expressed genes (DEGs) was performed by GeneSpring GX. Gene set enrichment analysis (GSEA) was used to execute gene ontology function and pathway enrichment analysis. The protein interaction network was constructed by Cytoscape. The hub genes were extracted by MCODE and cytoHubba plugin from the network. Then, using BIRC5 as a candidate, the prognostic value in LAD and TN adenocarcinomas was verified by the Kaplan-Meier plotter and The Cancer Genome Atlas (TCGA) database, respectively. Finally, the mechanism of BIRC5 was predicted by a coexpressed network and enrichment analysis.
Results: A total of 38 upregulated genes and 121 downregulated genes were identified. 9 hub genes were extracted. Among them, the mRNA expression of 5 genes, namely, BIRC5, MCM4, CDC20, KIAA0101, and TRIP13, were significantly upregulated among TN adenocarcinomas (all
Conclusion: Overexpressed in tumors, BIRC5 is associated with unfavorable overall survival in TN adenocarcinomas. BIRC5 is a potential predictor and therapeutic target in TN adenocarcinomas.

Imaoka M, Tanese K, Masugi Y, et al.
Macrophage migration inhibitory factor-CD74 interaction regulates the expression of programmed cell death ligand 1 in melanoma cells.
Cancer Sci. 2019; 110(7):2273-2283 [PubMed] Free Access to Full Article Related Publications
Expression of programmed cell death ligand 1 (PD-L1) on tumor cells contributes to cancer immune evasion by interacting with programmed cell death 1 on immune cells. γ-Interferon (IFN-γ) has been reported as a key extrinsic stimulator of PD-L1 expression, yet its mechanism of expression is poorly understood. This study analyzed the role of CD74 and its ligand macrophage migration inhibitory factor (MIF) on PD-L1 expression, by immunohistochemical analysis of melanoma tissue samples and in vitro analyses of melanoma cell lines treated with IFN-γ and inhibitors of the MIF-CD74 interaction. Immunohistochemical analyses of 97 melanoma tissue samples showed significant correlations between CD74 and the expression status of PD-L1 (P < .01). In vitro analysis of 2 melanoma cell lines, which are known to secrete MIF constitutively and express cell surface CD74 following IFN-γ stimulation, showed upregulation of PD-L1 levels by IFN-γ stimulation. This was suppressed by further treatment with the MIF-CD74 interaction inhibitor, 4-iodo-6-phenylpyrimidine. In the analysis of melanoma cell line WM1361A, which constitutively expresses PD-L1, CD74, and MIF in its non-treated state, treatment with 4-iodo-6-phenylpyrimidine and transfection of siRNAs targeting MIF and CD74 significantly suppressed the expression of PD-L1. Together, the results indicated that MIF-CD74 interaction directly regulated the expression of PD-L1 and helps tumor cells escape from antitumorigenic immune responses. In conclusion, the MIF-CD74 interaction could be a therapeutic target in the treatment of melanoma patients.

Lian S, Xie R, Ye Y, et al.
Simultaneous blocking of CD47 and PD-L1 increases innate and adaptive cancer immune responses and cytokine release.
EBioMedicine. 2019; 42:281-295 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Treatment multiple tumors by immune therapy can be achieved by mobilizing both innate and adaptive immunity. The programmed death ligand 1 (PD-L1; or CD274, B7-H1) is a critical "don't find me" signal to the adaptive immune system. Equally CD47 is a critical "don't eat me" signal to the innate immune system and a regulator of the adaptive immune response.
METHOD: Both of CD47 and PD-L1 are overexpressed on the surface of cancer cells to enable to escape immune-surveillance. We designed EpCAM (epithelial cell adhesion molecule)-targeted cationic liposome (LPP-P4-Ep) containing si-CD47 and si-PD-L1 could target high-EpCAM cancer cells and knockdown both CD47 and PD-L1 proteins.
FINDINGS: Efficient silencing of CD47 and PD-L1 versus single gene silencing in vivo by systemic administration of LPP-P4-Ep could significantly inhibited the growth of solid tumors in subcutaneous and reduced lung metastasis in lung metastasis model. Target delivery of the complexes LPP-P4-Ep increased anti-tumor T cell and NK cell response, and release various cytokines including IFN-γ and IL-6 in vivo and in vitro.
INTERPRETATION: This multi-nanoparticles showed significantly high-EpCAM tumor targeting and lower toxicity, and enhanced immune therapeutic efficacy. Our data indicated that dual-blockade tumor cell-specific innate and adaptive checkpoints represents an improved strategy for tumor immunotherapy. FUND: This research supported by the Ministry of Science and Technology of the People's Republic of China (grant number 2015CB931804); the National Natural Science Foundation of China (NSFC, grant numbers 81703555, U1505225 and 81773063), and the China Postdoctoral Science Foundation (grant number 2017 M620268).

Daubon T, Léon C, Clarke K, et al.
Deciphering the complex role of thrombospondin-1 in glioblastoma development.
Nat Commun. 2019; 10(1):1146 [PubMed] Free Access to Full Article Related Publications
We undertook a systematic study focused on the matricellular protein Thrombospondin-1 (THBS1) to uncover molecular mechanisms underlying the role of THBS1 in glioblastoma (GBM) development. THBS1 was found to be increased with glioma grades. Mechanistically, we show that the TGFβ canonical pathway transcriptionally regulates THBS1, through SMAD3 binding to the THBS1 gene promoter. THBS1 silencing inhibits tumour cell invasion and growth, alone and in combination with anti-angiogenic therapy. Specific inhibition of the THBS1/CD47 interaction using an antagonist peptide decreases cell invasion. This is confirmed by CD47 knock-down experiments. RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas demonstrates that THBS1 is one of the gene with the highest connectivity at the tumour borders. All in all, these data show that TGFβ1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion. Furthermore, tumour cell-bound CD47 is implicated in this process.

Vellanki SH, Cruz RGB, Richards CE, et al.
Antibiotic Tetrocarcin-A Down-regulates JAM-A, IAPs and Induces Apoptosis in Triple-negative Breast Cancer Models.
Anticancer Res. 2019; 39(3):1197-1204 [PubMed] Related Publications
BACKGROUND/AIM: Triple-negative breast cancers (TNBC) lack expression of three important receptors, and have limited treatment options. High expression of junctional adhesion molecule-A (JAM-A) has been linked with aggressive tumor phenotypes including TNBC. This study aimed to evaluate the bioactivity of a JAM-A-down-regulating compound, Tetrocarcin-A, in TNBC.
MATERIALS AND METHODS: TNBC cell viability, colony formation and xenograft growth were examined in Tetrocarcin-A-treated HCC38 human cells, 4T1 mouse cells or patient-derived primary cells. Protein expression of cell fate signaling effectors was examined by immunoblotting (versus transient JAM-A gene silencing). Apoptotic pathways were investigated in parallel.
RESULTS: Tetrocarcin-A reduced TNBC cell viability in vitro and in an in ovo/semi-in vivo xenograft model. Tetrocarcin-A-induced JAM-A down-regulation and reduced ERK phosphorylation, followed by c-FOS phosphorylation on its transcription-regulating residue, which down-regulated several inhibitor of apoptosis (IAP) proteins and induced caspase-dependent intrinsic pathway of apoptosis.
CONCLUSION: Tetrocarcin-A merits further investigation as a novel anti-tumor agent in TNBC.

Shibata N, Ohoka N, Hattori T, Naito M
Development of a Potent Protein Degrader against Oncogenic BCR-ABL Protein.
Chem Pharm Bull (Tokyo). 2019; 67(3):165-172 [PubMed] Related Publications
Chromosomal translocation occurs in some cancer cells, resulting in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to downregulate expression of the BCR-ABL protein. Recently, we have devised a protein knockdown system by hybrid molecules named Specific and Nongenetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers (SNIPER). This system is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins. In this review, we describe the development of SNIPER against BCR-ABL, and discuss the features and prospect for treatment of CML.

Yang X, Huang WT, Wu HY, et al.
Novel drug candidate for the treatment of several soft‑tissue sarcoma histologic subtypes: A computational method using survival‑associated gene signatures for drug repurposing.
Oncol Rep. 2019; 41(4):2241-2253 [PubMed] Free Access to Full Article Related Publications
Systemic treatment options for soft tissue sarcomas (STSs) have remained unchanged despite the need for novel drug candidates to improve STS outcomes. Drug repurposing involves the application of clinical drugs to different diseases, reducing development time, and cost. It has also become a fast and effective way to identify drug candidates. The present study used a computational method to screen three drug‑gene interaction databases for novel drug candidates for the treatment of several common STS histologic subtypes through drug repurposing. STS survival‑associated genes were generated by conducting a univariate cox regression analysis using The Cancer Genome Atlas survival data. These genes were then applied to three databases (the Connectivity Map, the Drug Gene Interaction Database and the L1000 Fireworks Display) to identify drug candidates for STS treatment. Additionally, pathway analysis and molecular docking were conducted to evaluate the molecular mechanisms of the candidate drug. Bepridil was identified as a potential candidate for several STS histologic subtype treatments by overlapping the screening results from three drug‑gene interaction databases. The pathway analysis with the Kyoto Encyclopedia of Genes and Genomes predicted that Bepridil may target CRK, fibroblast growth factor receptor 4 (FGFR4), laminin subunit β1 (LAMB1), phosphoinositide‑3‑kinase regulatory subunit 2 (PIK3R2), WNT5A, cluster of differentiation 47 (CD47), elastase, neutrophil expressed (ELANE), 15‑hydroxyprostaglandin dehydrogenase (HPGD) and protein kinase cβ (PRKCB) to suppress STS development. Further molecular docking simulation suggested a relatively stable binding selectivity between Bepridil and eight proteins (CRK, FGFR4, LAMB1, PIK3R2, CD47, ELANE, HPGD, and PRKCB). In conclusion, a computational method was used to identify Bepridil as a potential candidate for the treatment of several common STS histologic subtypes. Experimental validation of these in silico results is necessary before clinical translation can occur.

Braný D, Dvorská D, Kúdela E, et al.
Potential of survivin for treatment of gynaecological tumour diseases.
Ceska Gynekol. Winter 2018; 83(3):226-231 [PubMed] Related Publications
OBJECTIVE: The main purpose of this article is to consolidate known facts about survivin, its contribution to inhibition of apoptosis, impact to tumorigenesis of gynaecological types of tumours. and possibilities of inhibition of survivin on molecular-genetic levels.
DESIGN: A review article.
SETTINGS: Division of Molecular Medicine, Biomedical Center in Martin, JLF UK Martin, Slovakia; Department of Gynaecology and Obstetrics JLF UK and UNM Martin, Slovakia; Division of Oncology, Biomedical Center, JLF UK Martin, Slovakia.
METHODS: An analysis of the literature using database search engines focused on aberations in fuction of survivin, primarily in case of gynaecological tumours and possibilities of its inhibition.
RESULTS AND CONCLUSIONS: Survivin is the smallest member of inhibitor of apoptosis (IAP) family. Despite of its size and affiliation to mentioned gene family, survivin can affect besides inhibition of apoptosis also proper process of mitosis, DNA reparation and angiogenesis. High levels of survivin expression are typical for fetal tissues during intrauterine developement. In healthy, adult tissues remain levels of survivin very low. Nonetheless, abundant expression of survivin is in many cases typical for various types of cancer, including gynaecologycal cancers Generally, it is possible to associate higher amounts of survivin with poor prognosis and resistance to chemo- or radiotherapy.

He Y, Bouwstra R, Wiersma VR, et al.
Cancer cell-expressed SLAMF7 is not required for CD47-mediated phagocytosis.
Nat Commun. 2019; 10(1):533 [PubMed] Free Access to Full Article Related Publications
CD47 is a prominent new target in cancer immunotherapy, with antagonistic antibodies currently being evaluated in clinical trials. For effective evaluation of this strategy it is crucial to identify which patients are suited for CD47-targeted therapy. In this respect, expression of the pro-phagocytic signal SLAMF7 on both macrophages and cancer cells was recently reported to be a requisite for CD47 antibody-mediated phagocytosis. Here, we demonstrate that in fact SLAMF7 expression on cancer cells is not required and does not impact on CD47 antibody therapy. Moreover, SLAMF7 also does not impact on phagocytosis induction by CD20 antibody rituximab nor associates with overall survival of Diffuse Large B-Cell Lymphoma patients. In contrast, expression of CD47 negatively impacts on overall and progression free survival. In conclusion, cancer cell expression of SLAMF7 is not required for phagocytosis and, in contrast to CD47 expression, should not be used as selection criterion for CD47-targeted therapy.

Lukosiute-Urboniene A, Jasukaitiene A, Silkuniene G, et al.
Human antigen R mediated post-transcriptional regulation of inhibitors of apoptosis proteins in pancreatic cancer.
World J Gastroenterol. 2019; 25(2):205-219 [PubMed] Free Access to Full Article Related Publications
AIM: To determine the association of human antigen R (HuR) and inhibitors of apoptosis proteins (IAP1, IAP2) and prognosis in pancreatic cancer.
METHODS: Protein and mRNA expression levels of IAP1, IAP2 and HuR in pancreatic ductal adenocarcinoma (PDAC) were compared with normal pancreatic tissue. The correlations among IAP1/IAP2 and HuR as well as their respective correlations with clinicopathological parameters were analyzed. The Kaplan-Meier method and log-rank tests were used for survival analysis. Immunoprecipitation assay was performed to demonstrate HuR binding to IAP1, IAP2 mRNA. PANC1 cells were transfected with either anti-HuR siRNA or control siRNA for 72 h and quantitative reverse transcription polymerase chain reaction (RT-PCR), western blot analysis was carried out.
RESULTS: RT-PCR analysis revealed that HuR, IAP1, IAP2 mRNA expression were accordingly 3.3-fold, 5.5-fold and 8.4 higher in the PDAC when compared to normal pancreas (
CONCLUSION: HuR mediated overexpression of IAP1 significantly correlates with poor outcomes and early progression of pancreatic cancer. Further studies are needed to assess the underlying mechanisms.

Zhang W, An F, Xia M, et al.
Increased HMGB1 expression correlates with higher expression of c-IAP2 and pERK in colorectal cancer.
Medicine (Baltimore). 2019; 98(3):e14069 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to investigate the relationship between high-mobility group box 1 (HMGB1) and colorectal cancer (CRC).In this prospective study, patients with CRC undergoing primary surgery and healthy subjects (control group) were enrolled from July 2013 to December 2014. The serum HMGB1 concentration and HMGB1 mRNA expression were determined using enzyme-linked immunosorbent assay reverse transcription-polymerase chain reaction, respectively. Immunohistochemical analysis was performed to determine HMGB1, pERK, and c-inhibitor of apoptosis protein 2 (c-IAP2) protein expression levels in the cancer tissues.A total 144 patients with CRC and 50 healthy subjects underwent serum HMGB1 testing. Resected specimens of 50 patients were used for HMGB1 mRNA and protein expression analyses. Mean serum HMGB1 level in the patients with CRC was higher than that of the control group (8.42 μg/L vs 1.79 μg/L, P < .05). Mean serum HMGB1 level in the patients with CRC with distant metastasis was significantly higher than that of the controls (13.32 μg/L vs 7.37 μg/L, P < .05). The HMGB1 mRNA and protein expression levels in the CRC tissues were significantly higher than those in the adjacent normal mucosa. HMGB1 protein expression positively correlated with the lymph node metastasis. There were positive correlations between HMGB1 and c-IAP2 (r = 0.457, P < .05), HMGB1 and pERK (r = 0.461, P < .05), as well as pERK and c-IAP2 (r = 0.399, P < .05).HMGB1 expression in CRC correlates with distant and lymph node metastasis. It may inhibit apoptosis by inducing activation of pERK and c-IAP2.

Zhang S, Yang Y, Weng W, et al.
Fusobacterium nucleatum promotes chemoresistance to 5-fluorouracil by upregulation of BIRC3 expression in colorectal cancer.
J Exp Clin Cancer Res. 2019; 38(1):14 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Emerging evidence suggests a potential relationship between gut microbiota and the host response to chemotherapeutic drugs including 5-fluorouracil (5-Fu). Fusobacterium nucleatum (Fn) has been linked to the initiation and progression of colorectal cancer (CRC). Unfortunately, little was known about the relationship between Fn infection and chemotherapeutic efficacy. Here, we investigate the potential relationship between Fn infection and chemotherapeutic efficacy of 5-Fu in CRC.
METHODS: Differentially expressed genes of CRC cell lines induced by Fn infection were analyzed based on a whole genome microarray analysis Then, we explored the relationship between upregulation of BIRC3 induced by Fn infection and chemoresistance to 5-Fu in vitro and in vivo. Furthermore, we dissected the mechanisms involved in Fn-induced BIRC3 expression. Finally, we investigated the clinical relevance of Fn infection, BIRC3 protein expression and chemoresistance to 5-Fu treatment in CRC patients.
RESULTS: BIRC3 was the most upregulated gene induced by Fn infection via the TLR4/NF-κB pathway in CRC cells; Fn infection reduced the chemosensitivity of CRC cells to 5-Fu through upregulation of BIRC3 in vitro and in vivo. High Fn abundance correlated with chemoresistance in advanced CRC patients who received standard 5-Fu-based adjuvant chemotherapy after radical surgery.
CONCLUSIONS: Our evidence suggests that Fn and BIRC3 may serve as promising therapeutic targets for reducing chemoresistance to 5-Fu treatment in advanced CRC.

Yang K, Xu J, Liu Q, et al.
Expression and significance of CD47, PD1 and PDL1 in T-cell acute lymphoblastic lymphoma/leukemia.
Pathol Res Pract. 2019; 215(2):265-271 [PubMed] Related Publications
Although dose intensification strategies achieve a favorable prognosis for pediatric patients of T-lmphoblastic lymphoma/leukemia (T-LBL/ALL), numerous side effects have been followed. Molecular targeted therapies will be needed to optimize the current treatment strategy for T-LBL/ALL. The aim of this study was to analyse expression and significance of CD47, PD1 and PDL1 in. T-LBL/ALL. We performed immunohistochemistry staining and real time fluorescence quantitative PCR (qRT-PCR) on FFPE tissues. Immunohistochemistry results showed that the high expression rate of CD47 protein was 46.4% (26/56) and the positive expression rate of PDL1 protein was 37.5% (21/56). PD1 expression was observed in tumor infiltrating lymphocytes in approximately 20% of T-LBL/ALL patients, but not expressed on tumor cells of T-LBL/ALL. And the results of qRT-PCR showed that the relative expression levels of CD47, PDL1 and PD1 mRNA in 56 cases of T LBL/ALL were significantly higher than those in control group (6.915 vs 4.050, 12.255 vs 2.575, 37.990 vs 3.615), and the differences were all statistically significant (p all <0.05). Univariate analysis showed that age, CD47 protein, CD47 mRNA,PDL1 protein and PDL1 mRNA expression were closely correlated with prognosis (P all <0.05). We found that the overall one-year survival rates of patients with a high expression (≥M) of CD47 and PDL1 mRNA were higher than in patients with low expression (25 years old. Multivariate Cox regression analysis showed that the high expression of CD47 and PDL1 protein were independent prognostic factors (both p < 0.05). In a word, PD1/PDL1 and CD47 may be involved in the disease progression and prognosis of T-LBL/ALL, and detection and targeting of CD47 and PD1/PDL1 may provide a rational basis to for treatment of T-LBL/ALL.

Zhang Z, Song N, Peng Y, et al.
Evironmental pollutant perfluorodecanoic acid upregulates cIAP2 to suppress gastric cell senescence.
Oncol Rep. 2019; 41(2):981-988 [PubMed] Related Publications
The role of perfluorodecanoic acid (PFDA) in gastric carcinogenesis and its mechanism remains unknown. Our previous research revealed that PFDA regulated the growth of human gastric cells. However, its core molecules and basic mechanisms are still not clear. In the present study, cDNA microarrays were used to determine mRNA changes in AGS cells after treatment with PFDA. DAVID analysis of the genes with >2‑fold increased expression in microarray data revealed five genes which were involved in cancer pathways. The most upregulated gene was cIAP2, whose upregulation in AGS was confirmed by western blot analysis and quantitative PCR (qPCR) analyses. In order to investigate the role of cIAP2 in cell proliferation, cIAP2 siRNA was employed to regulate cIAP2 expression following PFDA treatment. The results revealed that the growth rate of cIAP2‑knockdown cells was reduced by about 50% compared to the control. Given that our previous flow cytometric assays revealed no significant change (3.7 vs. 6.4%) in the percentage of apoptotic cells when PFDA was added to the medium and cIAP2 expression was upregulated, we next applied flow cytometry to assess whether cIAP2 would lead to cell cycle variations. The research data revealed that the proportion of cells in the G1, S and G2 phases was not significantly altered with the decrease of cIAP2 expression. Finally, the role of cIAP2 in AGS cell senescence was investigated, and the results indicated that cell senescence was significantly increased in the cIAP2 siRNA group in comparison to the control siRNA group. Since p53 has been identified as a tumor suppressor and its molecular alterations are common in different human tumors, we investigated the relationship of p53 with cIAP2. The experimental results demonstrated that cIAP2 regulated the expression of p53 and thus was likely to be a potential mechanism for PFDA‑induced growth promotion. Overall, the results revealed that PFDA may suppress cellular senescence induced by p53 through the regulation of cIAP2 protein expression.

Li D, Liu J, Wang X, et al.
Biological Potential and Mechanism of Prodigiosin from
Int J Mol Sci. 2018; 19(11) [PubMed] Free Access to Full Article Related Publications
Tripyrrole molecules have received renewed attention due to reports of numerous biological activities, including antifungal, antibacterial, antiprotozoal, antimalarial, immunosuppressive, and anticancer activities. In a screen of bacterial strains with known toxicities to termites, a red pigment-producing strain, HDZK-BYSB107, was isolated from

Yang Y, Sun P, Xu W, Xia W
High BIRC7 Expression Might Be an Independent Prognostic Indicator of Poor Recurrence-Free Survival in Patients With Prostate Cancer.
Technol Cancer Res Treat. 2018; 17:1533033818809694 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: BIRC7, which encodes Baculoviral inhibitor of apoptosis (IAP) repeat-containing protein 7, is an oncogene in multiple types of cancer. In this study, we examined the association between BIRC7 expression and the clinicopathological characteristics of prostate cancer, the independent prognostic value of BIRC7 in terms of recurrence-free survival, and the molecular mechanisms of its dysregulation.
METHODS: Data mining was performed using data from The Cancer Genome Atlas. The patients were divided into high and low BIRC7 expression groups according to the Youden index determined by receiver operating characteristic curves for recurrence. Subgroup analysis was performed according to T stages and Gleason score.
RESULTS: BIRC7 was significantly upregulated in prostate cancer tissues (N = 497) than in normal prostate tissues (N = 52). High BIRC7 expression group had lower ratios of overall response rate and medium-grade (Gleason score 6-7) tumors and higher proportions of nodal invasion and recurrence after surgery. Although Kaplan-Meier curves showed that high BIRC7 expression was generally associated with poor recurrence-free survival, the following subgroup analysis only confirmed the association in T3/T4 and medium-grade tumors. Multivariate analysis showed that BIRC7 expression was not an independent indicator of recurrence-free survival in T2 or high-grade tumors, but was independently associated with poor recurrence-free survival in T3/T4 tumors (hazard ratio: 4.249, 95% confidence interval: 1.563-11.546, P = .005) and in medium-grade tumors (hazard ratio: 6.041, 95% confidence interval: 1.763-20.703, P = .004). DNA amplification was associated with significantly upregulated BIRC7 expression. There was also a weak negative correlation between BIRC7 expression and its DNA methylation (Pearson r = -0.23).
CONCLUSION: Based on these findings, we infer that BIRC7 upregulation might serve as a valuable biomarker of increased recurrence risk in advanced T stages and medium-grade prostate cancer. Its expression is at least regulated by both copy number alteration and DNA methylation.

Yan B, Chen Q, Shimada K, et al.
Histone deacetylase inhibitor targets CD123/CD47-positive cells and reverse chemoresistance phenotype in acute myeloid leukemia.
Leukemia. 2019; 33(4):931-944 [PubMed] Related Publications
Chemoresistance may be due to the survival of leukemia stem cells (LSCs) that are quiescent and not responsive to chemotherapy or lie on the intrinsic or acquired resistance of the specific pool of AML cells. Here, we found, among well-established LSC markers, only CD123 and CD47 are correlated with AML cell chemosensitivities across cell lines and patient samples. Further study reveals that percentages of CD123

Hehlgans S, Booms P, Güllülü Ö, et al.
Radiation Sensitization of Basal Cell and Head and Neck Squamous Cell Carcinoma by the Hedgehog Pathway Inhibitor Vismodegib.
Int J Mol Sci. 2018; 19(9) [PubMed] Free Access to Full Article Related Publications
Vismodegib, an inhibitor of the Hedgehog signaling pathway, is an approved drug for monotherapy in locally advanced or metastatic basal cell carcinoma (BCC). Data on combined modality treatment by vismodegib and radiation therapy, however, are rare. In the present study, we examined the radiation sensitizing effects of vismodegib by analyzing viability, cell cycle distribution, cell death, DNA damage repair and clonogenic survival in three-dimensional cultures of a BCC and a head and neck squamous cell carcinoma (HNSCC) cell line. We found that vismodegib decreases expression of the Hedgehog target genes glioma-associated oncogene homologue (GLI1) and the inhibitor of apoptosis protein (IAP) Survivin in a cell line- and irradiation-dependent manner, most pronounced in squamous cell carcinoma (SCC) cells. Furthermore, vismodegib significantly reduced proliferation in both cell lines, while additional irradiation only slightly further impacted on viability. Analyses of cell cycle distribution and cell death induction indicated a G1 arrest in BCC and a G2 arrest in HNSCC cells and an increased fraction of cells in SubG1 phase following combined treatment. Moreover, a significant rise in the number of phosphorylated histone-2AX/p53-binding protein 1 (γH2AX/53BP1) foci in vismodegib- and radiation-treated cells was associated with a significant radiosensitization of both cell lines. In summary, these findings indicate that inhibition of the Hedgehog signaling pathway may increase cellular radiation response in BCC and HNSCC cells.

Liu F, Sun Y, Liu B, et al.
Insulin-like growth factor-1 induces epithelial-mesenchymal transition in hepatocellular carcinoma by activating survivin.
Oncol Rep. 2018; 40(2):952-958 [PubMed] Related Publications
Insulin-like growth factor-1 (IGF-1), a small polypeptide hormone similar to insulin in protein structures, has been identified as an activator of epithelial-mesenchymal transition (EMT) pathways in several types of cancers. As a member of the inhibitor of apoptosis protein (IAP) family, survivin is implicated in the EMT of some cancers. However, the role of survivin on IGF-1-mediated EMT of hepatocellular carcinoma (HCC) has not been clarified. In the present study, we demonstrated that survivin was involved in the EMT process induced by IGF-1 in HCC cell line SMMC7721. With administration of different concentrations of IGF-1, survivin mRNA and protein expression were significantly increased and stimulated EMT in the tested cell line, while the increased invasive and migratory abilities of HCC cells and activation of the EMT process induced by IGF-1 were reversed after silencing of survivin expression by transfecting small interfering RNA. This was further confirmed by the observation of morphological changes, the decrease of invasive and migratory abilities and the downregulation of EMT markers, N-cadherin, vimentin and Snail, and the upregulation of E-cadherin. In conclusion, survivin may play a vital role in the IGF-1 signaling pathway by mediating EMT in HCC through the upregulation of the expression of EMT markers, and the knockdown of survivin expression may suppress the metastasis of HCC, which may provide new insights for the molecular therapy of HCC patients in clinical treatment.

Lee SR, Jin H, Kim WT, et al.
Tristetraprolin activation by resveratrol inhibits the proliferation and metastasis of colorectal cancer cells.
Int J Oncol. 2018; 53(3):1269-1278 [PubMed] Related Publications
Resveratrol (RSV) is a polyphenolic compound that naturally occurs in grapes, peanuts and berries. Considerable research has been conducted to determine the benefits of RSV against various human cancer types. Tristetraprolin (TTP) is an AU-rich element-binding protein that regulates mRNA stability and has decreased expression in human cancer. The present study investigated the biological effect of RSV on TTP gene regulation in colon cancer cells. RSV inhibited the proliferation and invasion/metastasis of HCT116 and SNU81 colon cancer cells. Furthermore, RSV induced a dose-dependent increase in TTP expression in HCT116 and SNU81 cells. The microarray experiment revealed that RSV significantly increased TTP expression by downregulating E2F transcription factor 1 (E2F1), a downstream target gene of TTP and regulated genes associated with inflammation, cell proliferation, cell death, angiogenesis and metastasis. Although TTP silencing inhibited TTP mRNA expression, the expression was subsequently restored by RSV. Small interfering RNA-induced TTP inhibition attenuated the effects of RSV on cell growth. In addition, RSV induced the mRNA-decaying activity of TTP and inhibited the relative luciferase activity of baculoviral IAP repeat containing 3 (cIAP2), large tumor suppressor kinase 2 (LATS2), E2F1, and lin‑28 homolog A (Lin28) in HCT116 and SNU81 cells. Therefore, RSV enhanced the inhibitory activity of TTP in HCT116 and SNU81 cells by negatively regulating cIAP2, E2F1, LATS2, and Lin28 expression. In conclusion, RSV suppressed the proliferation and invasion/metastasis of colon cancer cells by activating TTP.

Rada M, Nallanthighal S, Cha J, et al.
Inhibitor of apoptosis proteins (IAPs) mediate collagen type XI alpha 1-driven cisplatin resistance in ovarian cancer.
Oncogene. 2018; 37(35):4809-4820 [PubMed] Related Publications
Although, cisplatin resistance is a major challenge in the treatment of ovarian cancer, the precise mechanisms underlying cisplatin resistance are not fully understood. Collagen type XI alpha 1 (COL11A1), a gene encoding a minor fibrillar collagen of the extracellular matrix, is identified as one of the most upregulated genes in cisplatin-resistant ovarian cancer and recurrent ovarian cancer. However, the exact functions of COL11A1 in cisplatin resistance are unknown. Here we demonstrate that COL11A1 binds to integrin α1β1 and discoidin domain receptor 2 (DDR2) and activates downstream signaling pathways to inhibit cisplatin-induced apoptosis in ovarian cancer cells. Mechanistically, we show that COL11A1 activates Src-PI3K/Akt-NF-kB signaling to induce the expression of three inhibitor apoptosis proteins (IAPs), including XIAP, BIRC2, and BIRC3. Genetic and pharmacological inhibition of XIAP, BIRC2, and BIRC3 is sufficient to restore cisplatin-induced apoptosis in ovarian cancer cells in the presence of COL11A1 in ovarian cancer cells and xenograft mouse models, respectively. We also show that the components of COL11A1- integrin α1β1/DDR2- Src-PI3K/Akt-NF-kB-IAP signaling pathway serve as poor prognosis markers in ovarian cancer patients. Taken together, our results suggest novel mechanisms by which COL11A1 confers cisplatin resistance in ovarian cancer. Our study also uncovers IAPs as promising therapeutic targets to reduce cisplatin resistance in ovarian cancer, particularly in recurrent ovarian cancer expressing high levels of COL11A1.

Liu YD, Ji CB, Li SB, et al.
Toll-like receptor 2 stimulation promotes colorectal cancer cell growth via PI3K/Akt and NF-κB signaling pathways.
Int Immunopharmacol. 2018; 59:375-383 [PubMed] Related Publications
Toll-like receptor (TLR) 2 is a key regulator of innate immune responses and has been shown to play an important role in inflammation-associated cancers. In this study, we aimed to evaluate the role of TLR2 in colorectal cancer (CRC). We demonstrated that TLR2 mRNA and protein expression was significantly upregulated in tumors from CRC patients and indicated poor prognosis. Using the TLR2 agonist Pam3Cys (P3C) to activate TLR2 signaling in human CRC cell lines, we showed that TLR2 drives cellular proliferation, which was dependent upon PI3K/Akt and NF-κB signaling pathways and was associated with the upregulation of anti-apoptotic genes BCL2A1, WISP1 and BIRC3. Likewise, pharmacological blockade of PI3K/Akt and NF-κB pathways mitigated the CRC pro-survival effects of TLR2 stimulation. Furthermore, genetic ablation of TLR2 using CRISPR/Cas9 suppressed CRC cell proliferation, invasion and migration. Taken together, these findings demonstrate that TLR2 plays an important role in colorectal tumorigenesis and may represent a promising therapeutic target in CRC.

Pan W, Luo Q, Yan X, et al.
A novel SMAC mimetic APG-1387 exhibits dual antitumor effect on HBV-positive hepatocellular carcinoma with high expression of cIAP2 by inducing apoptosis and enhancing innate anti-tumor immunity.
Biochem Pharmacol. 2018; 154:127-135 [PubMed] Related Publications
Check point inhibitor anti-PD1 antibody produced some efficacy in Hepatocellular Carcinoma (HCC) patients previously treated with sorafenib. Unfortunately, HCC patients with hepatitis B virus (HBV) infection did not respond as well as uninfected patients. Previously, Second mitochondria-derived activator of caspases (SMAC) mimetics-the antagonist for inhibitor of apoptosis proteins (IAPs) can rapidly reduce serum hepatitis B virus DNA in animal model. APG-1387 is a novel SMAC-mimetic, small molecule inhibitor targeting inhibitor of apoptosis proteins (IAPs). In our study, firstly, we found that HCC patients with copy number alteration of cIAP1, cIAP2, and XIAP had a dismal prognosis. Then, we discovered that APG-1387 alone could induce apoptosis of PLC/PRF/5 which was HBV positive both in-vitro and in-vivo. Furthermore, we found that APG-1387 significantly up-regulated the expression of calreticulin and HLA-DR in PLC/PRF/5 via activating non-classic NF-κB pathway. Also, compared to vehicle group, APG-1387 increased NK cell counts by 5 folds in PLC/PRF/5 xenograft model. In-vitro, APG-1387 positively regulated T cells by reducing Treg differentiation and down-regulating PD1 expression in CD4 T cell. Moreover, APG-1387 had no impact on memory T cells. Consequently, our results suggest that APG1387 could be a good candidate to combine with anti-PD1 antibody treatment to overcome low responds of check point inhibitors in HBV positive HCC.

Tong B, Wang M
CD47 is a novel potent immunotherapy target in human malignancies: current studies and future promises.
Future Oncol. 2018; 14(21):2179-2188 [PubMed] Related Publications
Recently, many immunosuppressive checkpoints such as PD-L1, CTLA-4 and CD47, were identified in succession and serve as potential immunotherapy targets in human cancers. Among them, CD47, a 'marker-of-self' protein that is overexpressed broadly across tumor types, is emerging as a novel potent macrophage immune checkpoint for cancer immunotherapy. In this review, we highlight the prominent role of CD47 as a 'don't-eat-me' signal that inhibits macrophage phagocytosis for immune evasion of a tumor and presents the opportunities and challenges for CD47 inhibitors both as monotherapy and in combination treatments for hematological cancers and solid tumors; some of these agents are currently in clinical trials.

Ji J, Yu Y, Li ZL, et al.
XIAP Limits Autophagic Degradation of Sox2 and Is A Therapeutic Target in Nasopharyngeal Carcinoma Stem Cells.
Theranostics. 2018; 8(6):1494-1510 [PubMed] Free Access to Full Article Related Publications

Casey SC, Baylot V, Felsher DW
The MYC oncogene is a global regulator of the immune response.
Blood. 2018; 131(18):2007-2015 [PubMed] Free Access to Full Article Related Publications
The MYC proto-oncogene is a gene product that coordinates the transcriptional regulation of a multitude of genes that are essential to cellular programs required for normal as well as neoplastic cellular growth and proliferation, including cell cycle, self-renewal, survival, cell growth, metabolism, protein and ribosomal biogenesis, and differentiation. Here, we propose that MYC regulates these programs in a manner that is coordinated with a global influence on the host immune response. MYC had been presumed to contribute to tumorigenesis through tumor cell-intrinsic influences. More recently, MYC expression in tumor cells has been shown to regulate the tumor microenvironment through effects on both innate and adaptive immune effector cells and immune regulatory cytokines. Then, MYC was shown to regulate the expression of the immune checkpoint gene products CD47 and programmed death-ligand 1. Similarly, other oncogenes, which are known to modulate MYC, have been shown to regulate immune checkpoints. Hence, MYC may generally prevent highly proliferative cells from eliciting an immune response. MYC-driven neoplastic cells have coopted this mechanism to bypass immune detection. Thus, MYC inactivation can restore the immune response against a tumor. MYC-induced tumors may be particularly sensitive to immuno-oncology therapeutic interventions.

Bagrezaei F, Hassanshahi G, Mahmoodi M, et al.
Expression of Inhibitor of Apoptosis Gene Family Members in Bladder Cancer Tissues and the 5637 Tumor Cell Line
Asian Pac J Cancer Prev. 2018; 19(2):529-532 [PubMed] Free Access to Full Article Related Publications
Background: Apoptosis is suppressed in cancer tissues and tumor cell lines because anti-apoptosis genes are overexpressed. The inhibitor of apoptosis proteins (IAP) gene family contributes to control of apoptosis. The expression profile of eight genes of the IAP family in biopsies from patients with a history of bladder cancer and normal bladder tissues, as well as a bladder tumor cell line (5637), was assessed in the present study. Methods: Cancer tissue samples were obtained at surgery and the 5637 tumor cell line was cultured in RPMI1640 medium. Beyond tumor margins were selected as normal tissue. Expressional profile of interested genes was obtained by using specific primers and the real-time PCR method. Results: The results showed that expression of seven of the studied genes was up-regulated in cancer tissues and the cell line whereas BIRC4 (XIAP) was down-regulated in both. Conclusions: The results showed that these genes were expressed to a greater extent in cancer tissue and cancer cells than in normal tissues. The data suggested that over-expression of anti-apoptotic genes such as IAP family members, can trigger cells to escape from apoptosis.

Gowda P, Patrick S, Singh A, et al.
Mutant Isocitrate Dehydrogenase 1 Disrupts PKM2-β-Catenin-BRG1 Transcriptional Network-Driven CD47 Expression.
Mol Cell Biol. 2018; 38(9) [PubMed] Free Access to Full Article Related Publications
A gain-of-function mutation in isocitrate dehydrogenase 1 (IDH1) affects immune surveillance in gliomas. As elevated CD47 levels are associated with immune evasion in cancers, its status in gliomas harboring mutant IDH1 (IDH1-MT cells) was investigated. Decreased CD47 expression in IDH1-R132H-overexpressing cells was accompanied by diminished nuclear β-catenin, pyruvate kinase isoform M2 (PKM2), and TCF4 levels compared to those in cells harboring wild-type IDH1 (IDH1-WT cells). The inhibition of β-catenin in IDH1-WT cells abrogated CD47 expression, β-catenin-TCF4 interaction, and the transactivational activity of β-catenin/TCF4. The reverse effect was observed in IDH1-MT cells upon the pharmacological elevation of nuclear β-catenin levels. Genetic and pharmacological manipulation of nuclear PKM2 levels in IDH1-WT and IDH1-MT cells suggested that PKM2 is a positive regulator of the β-catenin-TCF4 interaction. The Cancer Genome Atlas (TCGA) data sets indicated diminished CD47, PKM2, and β-catenin levels in IDH1-MT gliomas compared to IDH1-WT gliomas. Also, elevated BRG1 levels with mutations in the ATP-dependent chromatin-remodeling site were observed in IDH1-MT glioma. The ectopic expression of ATPase-deficient BRG1 diminished CD47 expression as well as TCF4 occupancy on its promoter. Sequential chromatin immunoprecipitation (ChIP-re-ChIP) revealed the recruitment of the PKM2-β-catenin-BRG1-TCF4 complex to the TCF4 site on the CD47 promoter. This occupancy translated into CD47 transcription, as a diminished recruitment of this complex was observed in glioma cells bearing IDH1-R132H. In addition to its involvement in CD47 transcriptional regulation, PKM2-β-catenin-BRG1 cross talk affected the phagocytosis of IDH1-MT cells by microglia.

Liu F, Dai M, Xu Q, et al.
SRSF10-mediated IL1RAP alternative splicing regulates cervical cancer oncogenesis via mIL1RAP-NF-κB-CD47 axis.
Oncogene. 2018; 37(18):2394-2409 [PubMed] Free Access to Full Article Related Publications
High-risk human papillomavirus oncoproteins E6 and E7 are the major etiological factors of cervical cancer but are insufficient for malignant transformation of cervical cancer. Dysregulated alternative splicing, mainly ascribed to aberrant splicing factor levels and activities, contributes to most cancer hallmarks. However, do E6 and E7 regulate the expression of splicing factors? Does alternative splicing acts as an "accomplice" of E6E7 to promote cervical cancer progression? Here, we identified that the splicing factor SRSF10, which promotes tumorigenesis of cervix, was upregulated by E6E7 via E2F1 transcriptional activation. SRSF10 modulates the alternate terminator of interleukin-1 receptor accessory protein exon 13 to increase production of the membrane form of interleukin-1 receptor accessory protein. SRSF10-mediated mIL1RAP upregulates the expression of the "don't eat me" signal CD47 to inhibit macrophage phagocytosis by promoting nuclear factor-κB activation, which is pivotal in inflammatory, immune, and tumorigenesis processes. Altogether, these data reveal a close relationship among HPV infection, alternative splicing and tumor immune evasion, and also suggests that the SRSF10-mIL1RAP-CD47 axis could be an attractive therapeutic target for the treatment of cervical cancer.

Seo YS, Kang OH, Kong R, et al.
Polygalacin D induces apoptosis and cell cycle arrest via the PI3K/Akt pathway in non-small cell lung cancer.
Oncol Rep. 2018; 39(4):1702-1710 [PubMed] Related Publications
Polygalacin D (PGD) is a bioactive compound isolated from Platycodon grandiflorum (Jacq.) and it has a similar structure to platycodin D, which is a well known anticancer agent. In the present study, we investigated the anti-proliferative effects of PGD using NSCLC cell lines. We evaluated the effects of PGD on proliferation, apoptosis and cell cycle arrest in A549 and H460 cells. PGD significantly induced apoptosis and nuclear condensation in both cell lines. Furthermore, PGD upregulated the cleavage of apoptotic proteins such as caspase-3, -9 and PARP. Additionally, treatment with PGD suppressed the expression of the IAP family of proteins including survivin, cIAP-1 and cIAP-2. Furthermore, PGD induced G0/G1-phase arrest in both cell lines. After treatment with PGD, the expression of TIMP-1, CDK2, cyclin A and cyclin E was reduced at the protein level. In addition, PGD blocked the PI3K/Akt pathway by inhibiting the phosphorylation of GSK3β, Akt and the expression of PI3K. Our results indicated that the anti-proliferative properties of PGD may result from the regulation of the PI3K/Akt pathway, which plays a critical role in cell survival and growth.

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