Research IndicatorsGraph generated 11 March 2017 using data from PubMed using criteria.
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 (6)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: ANXA2 (cancer-related)
Our previous study identified an elevated abundance of annexin A3 (Anxa3) as a novel prognostic biomarker of lung adenocarcinoma (LADC) through quantitative proteomics analysis. However, the biological functions of Anxa3 in LADC are not fully clear. In this study, in vitro and in vivo assays were performed to investigate the effects of Anxa3 downregulation on the growth, migration, invasion, metastasis, and signaling pathway activation of LADC cells. After Anxa3 downregulation, the growth of A549 and LTEP-a2 LADC cells was slowed and they showed decreased migration and invasion in vitro. Anxa3 knockdown significantly inhibited tumor formation by A549 cells in vivo; while many metastases were formed by control A549 cells, there were obvious reductions in the numbers of lung, liver, and brain metastases formed by Anxa3 knockdown in A549 cells. Furthermore, Anxa3 knockdown significantly decreased MMP-2 and N-cadherin expression and increased E-cadherin expression both in cell lines in vitro and in tumor nodules examined during in vivo tumorigenesis assays. Interestingly, Anxa3 downregulation reduced the phosphorylated levels of MEK and ERK. In summary, Anxa3 knockdown inhibited the growth, migration, invasion, and metastasis of LADC, decreased the activation of the MEK/ERK signaling pathway, and modulated the expression of MMP-2, E-cadherin, and N-cadherin.
Glioblastomas are characterized by transcriptionally distinct subtypes, but despite possible clinical relevance, their regulation remains poorly understood. The commonly used molecular classification systems for GBM all identify a subtype with high expression of mesenchymal marker transcripts, strongly associated with invasive growth. We used a comprehensive data-driven network modeling technique (augmented sparse inverse covariance selection, aSICS) to define separate genomic, epigenetic, and transcriptional regulators of glioblastoma subtypes. Our model identified Annexin A2 (ANXA2) as a novel methylation-controlled positive regulator of the mesenchymal subtype. Subsequent evaluation in two independent cohorts established ANXA2 expression as a prognostic factor that is dependent on ANXA2 promoter methylation. ANXA2 knockdown in primary glioblastoma stem cell-like cultures suppressed known mesenchymal master regulators, and abrogated cell proliferation and invasion. Our results place ANXA2 at the apex of a regulatory cascade that determines glioblastoma mesenchymal transformation and validate aSICS as a general methodology to uncover regulators of cancer subtypes.
Yamamoto T, Kudo M, Peng WX, et al.Identification of aldolase A as a potential diagnostic biomarker for colorectal cancer based on proteomic analysis using formalin-fixed paraffin-embedded tissue.
Tumour Biol. 2016; 37(10):13595-13606 [PubMed
] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is one of the most common cancers worldwide, and many patients are already at an advanced stage when they are diagnosed. Therefore, novel biomarkers for early detection of colorectal cancer are required. In this study, we performed a global shotgun proteomic analysis using formalin-fixed and paraffin-embedded (FFPE) CRC tissue. We identified 84 candidate proteins whose expression levels were differentially expressed in cancer and non-cancer regions. A label-free semiquantitative method based on spectral counting and gene ontology (GO) analysis led to a total of 21 candidate proteins that could potentially be detected in blood. Validation studies revealed cyclophilin A, annexin A2, and aldolase A mRNA and protein expression levels were significantly higher in cancer regions than in non-cancer regions. Moreover, an in vitro study showed that secretion of aldolase A into the culture medium was clearly suppressed in CRC cells compared to normal colon epithelium. These findings suggest that decreased aldolase A in blood may be a novel biomarker for the early detection of CRC.
Zhang Y, Song H, Guo T, et al.Overexpression of Annexin II Receptor-Induced Autophagy Protects Against Apoptosis in Uveal Melanoma Cells.
Cancer Biother Radiopharm. 2016; 31(4):145-51 [PubMed
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Uveal melanoma is the most common primary malignant intraocular tumor in adults and still lacks effective systemic therapies. Annexin A2 receptor (AXIIR), a receptor for Annexin II, was demonstrated to play an important role in multiple cells, but its role in uveal melanoma cells remains exclusive. Herein, the authors reported that overexpression of AXIIR was able to reduce cell viability and activate apoptosis apparently in the Mum2C uveal melanoma cell line. Meanwhile, overexpression of AXIIR could induce autophagy and increase autophagy flux. After autophagy was inhibited by chloroquine, enhanced apoptosis and cytotoxicity could be detected. In summary, these data highlighted the crucial role of AXIIR in reducing Mum2C cell viability through inducing apoptosis, while autophagy played a protective role in this process. Interference of this gene may be a promising method for uveal melanoma therapy and combination with specific inhibitor of autophagy may serve as a supplementary.
Flodrova D, Toporova L, Macejova D, et al.A comparative study of protein patterns of human estrogen receptor positive (MCF-7) and negative (MDA-MB-231) breast cancer cell lines.
Gen Physiol Biophys. 2016; 35(3):387-92 [PubMed
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In the present study, we analyzed the cell lysates of human tumour cell lines representing two major clinically different types of breast cancer. Our main goal was to show the differences between them on proteomic level. Gel electrophoresis followed by MALDI-TOF MS analysis was used for proteins determination. Exactly 98 proteins were unequivocally identified and 60 of them were expressed differentially between MDA-MB-231 and MCF-7 cell lines. Among the proteins reported here, some well-known breast cancer markers (e.g., annexin A1, annexin A2 and vimentin) were identified in the MDA-MB-231 cell line and thus we were able to distinguish both cell lines sufficiently.
Chan CK, Chan G, Awang K, Abdul Kadir HDeoxyelephantopin from Elephantopus scaber Inhibits HCT116 Human Colorectal Carcinoma Cell Growth through Apoptosis and Cell Cycle Arrest.
Molecules. 2016; 21(3):385 [PubMed
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Deoxyelephantopin (DET), one of the major sesquiterpene lactones derived from Elephantopus scaber was reported to possess numerous pharmacological functions. This study aimed to assess the apoptosis inducing effects and cell cycle arrest by DET followed by elucidation of the mechanisms underlying cell death in HCT116 cells. The anticancer activity of DET was evaluated by a MTT assay. Morphological and biochemical changes were detected by Hoescht 33342/PI and Annexin V/PI staining. The results revealed that DET and isodeoxyelephantopin (isoDET) could be isolated from the ethyl acetate fraction of E. scaber leaves via a bioassay-guided approach. DET induced significant dose- and time-dependent growth inhibition of HCT116 cells. Characteristics of apoptosis including nuclear morphological changes and externalization of phosphatidylserine were observed. DET also significantly resulted in the activation of caspase-3 and PARP cleavage. Additionally, DET induced cell cycle arrest at the S phase along with dose-dependent upregulation of p21 and phosphorylated p53 protein expression. DET dose-dependently downregulated cyclin D1, A2, B1, E2, CDK4 and CDK2 protein expression. In conclusion, our data showed that DET induced apoptosis and cell cycle arrest in HCT116 colorectal carcinoma, suggesting that DET has potential as an anticancer agent for colorectal carcinoma.
Lokman NA, Pyragius CE, Ruszkiewicz A, et al.Annexin A2 and S100A10 are independent predictors of serous ovarian cancer outcome.
Transl Res. 2016; 171:83-95.e1-2 [PubMed
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Annexin A2, a calcium phospholipid binding protein, has been shown to play an important role in ovarian cancer metastasis. This study examined whether annexin A2 and S100A10 can be used as prognostic markers in serous ovarian cancer. ANXA2 and S100A10 gene expressions were assessed in publicly available ovarian cancer data sets and annexin A2 and S100A10 protein expressions were assessed by immunohistochemistry in a uniform cohort of stage III serous ovarian cancers (n = 109). Kaplan-Meier and Cox regression analyses were performed to assess the relationship between annexin A2 or S100A10 messenger RNA (mRNA) and protein expressions with clinical outcome. High ANXA2 mRNA levels in stage III serous ovarian cancers were associated with reduced progression-free survival (PFS; P = 0.023) and overall survival (OS; P = 0.0038), whereas high S100A10 mRNA levels predicted reduced OS (P = 0.0019). Using The Cancer Genome Atlas data sets, ANXA2 but not S100A10 expression was associated with higher clinical stage (P = 0.005), whereas both ANXA2 and S100A10 expressions were associated with the mesenchymal molecular subtype (P < 0.0001). Kaplan-Meier and Cox regression analyses showed that high stromal annexin A2 immunostaining was significantly associated with reduced PFS (P = 0.013) and OS (P = 0.044). Moreover, high cytoplasmic S100A10 staining was significantly associated with reduced OS (P = 0.027). Multivariate Cox regression analysis showed stromal annexin A2 (P = 0.009) and cytoplasmic S100A10 (P = 0.016) levels to be independent predictors of OS. Patients with high stromal annexin A2 and high cytoplasmic S100A10 expressions had a 3.4-fold increased risk of progression (P = 0.02) and 7.9-fold risk of ovarian cancer death (P = 0.04). Our findings indicate that together annexin A2 and S100A10 expressions are powerful predictors of serous ovarian cancer outcome.
Mehrian-Shai R, Yalon M, Moshe I, et al.Identification of genomic aberrations in hemangioblastoma by droplet digital PCR and SNP microarray highlights novel candidate genes and pathways for pathogenesis.
BMC Genomics. 2016; 17:56 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: The genetic mechanisms underlying hemangioblastoma development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays and droplet digital PCR analysis to detect copy number variations (CNVs) in total of 45 hemangioblastoma tumors.
RESULTS: We identified 94 CNVs with a median of 18 CNVs per sample. The most frequently gained regions were on chromosomes 1 (p36.32) and 7 (p11.2). These regions contain the EGFR and PRDM16 genes. Recurrent losses were located at chromosome 12 (q24.13), which includes the gene PTPN11.
CONCLUSIONS: Our findings provide the first high-resolution genome-wide view of chromosomal changes in hemangioblastoma and identify 23 candidate genes: EGFR, PRDM16, PTPN11, HOXD11, HOXD13, FLT3, PTCH, FGFR1, FOXP1, GPC3, HOXC13, HOXC11, MKL1, CHEK2, IRF4, GPHN, IKZF1, RB1, HOXA9, and micro RNA, such as hsa-mir-196a-2 for hemangioblastoma pathogenesis. Furthermore, our data implicate that cell proliferation and angiogenesis promoting pathways may be involved in the molecular pathogenesis of hemangioblastoma.
The acquisition of inappropriate migratory feature is crucial for tumor metastasis. It has been suggested that CD147 and Annexin A2 are involved in regulating tumor cell movement, while the regulatory mechanisms are far from clear. In this study, we demonstrated that CD147 physically interacted with the N-terminal domain of Annexin A2 and decreased Annexin A2 phosphorylation on tyrosine 23. In vitro kinase assay showed that the I domain of CD147 was indispensable for CD147-mediated downregulation of Annexin A2 phosphorylation by Src. Furthermore, we determined that p-Annexin A2 promoted the expression of dedicator of cytokinesis 3 (DOCK3) and DOCK3 blocked β-catenin nuclear translocation, resulting in inhibition of β-catenin signaling. In addition, DOCK3 inhibited lamellipodium dynamics and tumor cell movement. Also, we found that β-catenin signaling increased WAVE2 expression. Therefore, DOCK3 was characterized as a negative regulator of WAVE2 expression via inhibiting β-catenin signaling. Our study provides the first evidence that CD147 promotes tumor cell movement and metastasis via direct interaction with Annexin A2 and DOCK3-β-catenin-WAVE2 signaling axis.
The aim of this study was to further our understanding of the transformation process by identifying differentially expressed proteins in melanocytes compared with melanoma cell lines. Tandem mass spectrometry incorporating iTRAQ reagents was used as a screen to identify and comparatively quantify the expression of proteins in membrane-enriched samples isolated from primary human melanocytes or three melanoma cells lines. Real-time PCR was used to validate significant hits. Immunohistochemistry was used to validate the expression of proteins of interest in melanocytes in human skin and in melanoma-infiltrated lymph nodes. Publically available databases were examined to assess mRNA expression and correlation to patient outcome in a larger cohort of samples. Finally, preliminary functional studies were carried out using siRNAs to reduce the expression of a protein of interest in primary melanocytes and in a keratinocyte cell line. Two proteins, AHNAK and ANXA2, were significantly downregulated in the melanoma cell lines compared with melanocytes. Downregulation was confirmed in tumor cells in a subset of human melanoma-infiltrated human lymph nodes compared with melanocytes in human skin. Examination of Gene Expression Omnibus database data sets suggests that downregulation of AHNAK mRNA and mutation of the AHNAK gene are common in metastatic melanoma and correlates to a poor outcome. Knockdown of AHNAK in primary melanocytes and in a keratinocyte cell line led to a reduction in detectable cadherin-1. This is the first report that we are aware of which correlates a loss of AHNAK with melanoma and poor patient outcome. We hypothesize that AHNAK is required for the expression of functional cadherin-1.
Zhang J, Cheng J, Zeng Z, et al.Comprehensive profiling of novel microRNA-9 targets and a tumor suppressor role of microRNA-9 via targeting IGF2BP1 in hepatocellular carcinoma.
Oncotarget. 2015; 6(39):42040-52 [PubMed
] Free Access to Full Article Related Publications
MicroRNA-9 (miR-9) dysregulation is implicated in a variety of human malignancies including hepatocellular carcinoma (HCC), but its role remains contradictory. In this study, we explored the expression and methylation status of miR-9 in HCC samples, as well as the tumor-related functions of miR-9 in vitro. Bioinformatics analysis, array-based RNA expression profile, and literature retrieval were used to identify miR-9 targets in HCC. The potential downstream candidates were then validated by luciferase reporter assay, real-time quantitative PCR, and western blot or enzyme linked immunosorbent assay (ELISA). The expression status and clinicopathologic significances of miR-9 target genes in clinical samples were further explored. The results showed that miR-9 was frequently downregulated in primary HCC. Its silencing was largely contributed by a high frequency (42.5%) of mir-9-1 hypermethylation, which was correlated with bigger tumor size (P = 0.0234). In vitro functional studies revealed that miR-9 restoration retarded HCC cell proliferation and migration. IL-6, AP3B1, TC10, ONECUT2, IGF2BP1, MYO1D, and ANXA2 were confirmed to be miR-9 targets in HCC. Among them, ONECUT2, IGF2BP1, and ANXA2 were confirmed to be aberrantly upregulated in HCC. Moreover, upregulation of ONECUT2, IGF2BP1, and IL-6 were significantly associated with poor post-surgery prognosis (P = 0.0458, P = 0.0037 and P = 0.0461, respectively). Mechanically, miR-9 plays a tumor suppressive role partially through a functional miR-9/IGF2BP1/AKT&ERK axis. Our study suggests that miR-9 functions as a tumor suppressor in HCC progression by inhibiting a series of target genes, including the newly validated miR-9/IGF2BP1/AKT&ERK axis, thus providing potential therapeutic targets and novel prognostic biomarkers for HCC patients.
Gopalakrishnapillai A, Kolb EA, Dhanan P, et al.Disruption of Annexin II /p11 Interaction Suppresses Leukemia Cell Binding, Homing and Engraftment, and Sensitizes the Leukemia Cells to Chemotherapy.
PLoS One. 2015; 10(10):e0140564 [PubMed
] Free Access to Full Article Related Publications
The bone marrow microenvironment plays an important role in acute lymphoblastic leukemia (ALL) cell proliferation, maintenance, and resistance to chemotherapy. Annexin II (ANX2) is abundantly expressed on bone marrow cells and complexes with p11 to form ANX2/p11-hetero-tetramer (ANX2T). We present evidence that p11 is upregulated in refractory ALL cell lines and patient samples. A small molecule inhibitor that disrupts ANX2/p11 interaction (ANX2T inhibitor), an anti-ANX2 antibody, and knockdown of p11, abrogated ALL cell adhesion to osteoblasts, indicating that ANX2/p11 interaction facilitates binding and retention of ALL cells in the bone marrow. Furthermore, ANX2T inhibitor increased the sensitivity of primary ALL cells co-cultured with osteoblasts to dexamethasone and vincristine induced cell death. Finally, in an orthotopic leukemia xenograft mouse model, the number of ALL cells homing to the bone marrow was reduced by 40-50% in mice injected with anti-ANX2 antibody, anti-p11 antibody or ANX2T inhibitor compared to respective controls. In a long-term engraftment assay, the percentage of ALL cells in mouse blood, bone marrow and spleen was reduced in mice treated with agents that disrupt ANX2/p11 interaction. These data show that disruption of ANX2/p11 interaction results in reduced ALL cell adhesion to osteoblasts, increased ALL cell sensitization to chemotherapy, and suppression of ALL cell homing and engraftment.
Bao P, Chen SC, Xiao KQDynamic equilibrium of endogenous selenium nanoparticles in selenite-exposed cancer cells: a deep insight into the interaction between endogenous SeNPs and proteins.
Mol Biosyst. 2015; 11(12):3355-61 [PubMed
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Elemental selenium (Se) was recently found to exist as endogenous nanoparticles (i.e., SeNPs) in selenite-exposed cancer cells. By sequestrating critical intracellular proteins, SeNPs appear capable of giving rise to multiple cytotoxicity mechanisms including inhibition of glycolysis, glycolysis-dependent mitochondrial dysfunction, microtubule depolymerization and inhibition of autophagy. In this work, we reveal a dynamic equilibrium of endogenous SeNP assembly and disassembly in selenite-exposed H157 cells. Endogenous SeNPs are observed both in the cytoplasm and in organelles. There is an increase in endogenous SeNPs between 24 h and 36 h, and a decrease between 36 h and 72 h according to transmission electron microscopy results and UV-Vis measurements. These observations imply that elemental Se in SeNPs could be oxidized back into selenite by scavenging superoxide radicals and ultimately re-reduced into selenide; then the assembly and disassembly of SeNPs proceed simultaneously with the sequestration and release of SeNP high-affinity proteins. There is also a possibility that the reduction of elemental Se to selenide pathway may lie in selenite-exposed cancer cells, which results in the assembly and disassembly of endogenous SeNPs. Genome-wide expression analysis results show that endogenous SeNPs significantly altered the expression of 504 genes, compared to the control. The endogenous SeNPs induced mitochondrial impairment and decreasing of the annexin A2 level can lead to inhibition of cancer cell invasion and migration. This dynamic flux of endogenous SeNPs amplifies their cytotoxic potential in cancer cells, thus provide a starting point to design more efficient intracellular self-assembling systems for overcoming multidrug resistance.
Shetty P, Bargale A, Patil BR, et al.Cell surface interaction of annexin A2 and galectin-3 modulates epidermal growth factor receptor signaling in Her-2 negative breast cancer cells.
Mol Cell Biochem. 2016; 411(1-2):221-33 [PubMed
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Overexpression and activation of tyrosine kinase receptors like EGFR and Src regulate the progression and metastasis of Her-2 negative breast cancer. Recently we have reported the role of cell membrane interaction of phospholipid-binding protein annexin A2 (AnxA2) and EGFR in regulating cellular signaling in the activation of angiogenesis, matrix degradation, invasion, and cancer metastasis. Beta-galactoside-specific animal lectin galectin-3 is an apoptosis inhibitor, and cell surface-associated extracellular galectin-3 also has a role in cell migration, cancer progression, and metastasis. Similar expression pattern and membrane co-localization of these two proteins made us to hypothesize in the current study that galectin-3 and AnxA2 interaction is critical for Her-2 negative breast cancer progression. By various experimental analyses, we confirm that glycosylated AnxA2 at the membrane surface interacts with galectin-3. N-linked glycosylation inhibitor tunicamycin treatment convincingly blocked AnxA2 membrane translocation and its association with galectin-3. To analyze whether this interaction has any functional relevance, we tried to dissociate this interaction with purified plant lectin from chickpea (Cicer arietinum agglutinin). This highly specific 30 kDa plant lectin could dissociate AnxA2 from endogenous lectin galectin-3 interaction at the cell surface. This dissociation could down-regulate Bcl-2 family proteins, cell proliferation, and migration simultaneously triggering cell apoptosis. Targeting this interaction of membrane surface glycoprotein and its animal lectin in Her-2 negative breast cancer may be of therapeutic value.
BACKGROUND: Migration and invasion enhancer 1 (MIEN1) is a novel gene found to be abundantly expressed in breast tumor tissues and functions as a critical regulator of tumor cell migration and invasion to promote systemic metastases. Previous studies have identified post-translational modifications by isoprenylation at the C-terminal tail of MIEN1 to favor its translocation to the inner leaflet of plasma membrane and its function as a membrane-bound adapter molecule. However, the exact molecular events at the membrane interface activating the MIEN1-driven tumor cell motility are vaguely understood.
METHODS: MIEN1 was first studied using in-silico analysis on available RNA sequencing data of human breast tissues and its expression was ascertained in breast cells. We performed several assays including co-immunoprecipitation, wound healing, western blotting and immunofluorescence to decipher the molecular events involved in MIEN1-mediated tumor cell migration.
RESULTS: Clinically, MIEN1 is predominantly overexpressed in Her-2 and luminal B subtypes of breast tumors, and its increased expression correlates with poor disease free survival. Molecular studies identified a phosphorylation-dependent activation signal in the immunoreceptor tyrosine based activation motif (ITAM) of MIEN1 and the phosphorylation-deficient MIEN1-mutants (Y39F/50 F) to regulate filopodia generation, migration and invasion. We found that ITAM-phosphorylation of MIEN1 is significantly impaired in isoprenylation-deficient MIEN1 mutants indicating that prenylation of MIEN1 and membrane association is required for cross-phosphorylation of tyrosine residues. Furthermore, we identified MIEN1 as a novel interactor of Annexin A2 (AnxA2), a Ca(2+) -dependent phospholipid binding protein, which serves as an extracellular proteolytic center regulating plasmin generation. Fluorescence resonance energy transfer (FRET) confirmed that MIEN1 physically interacts with AnxA2 and functional studies revealed that they mutually cooperate to accentuate tumor cell motility. Interestingly, our study identified that ectopic overexpression of MIEN1 significantly enhances Tyr23-phosphorylation on AnxA2, thereby stimulating cell surface translocation of AnxA2 and catalyzing the activation of its proteolytic activity.
CONCLUSION: Our data show that the presence and interaction of both MIEN1 and AnxA2 in breast tumors are crucial drivers of cell motility. Our study has now deciphered a novel regulatory network governing the vicious process of breast tumor cell invasion-metastasis, and findings suggest MIEN1-AnxA2 as prospective targets to counter the deadly disease.
Zhang F, Wang Z, Yuan J, et al.RNAi-mediated silencing of Anxa2 inhibits breast cancer cell proliferation by downregulating cyclin D1 in STAT3-dependent pathway.
Breast Cancer Res Treat. 2015; 153(2):263-75 [PubMed
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Although the upregulated expression of Anxa2 has been implicated in carcinogenesis, cancer progression, and poor prognosis of cancer patients, the detailed molecular mechanisms involved in these processes remain unclear. In this study, we investigated the effect of Anxa2 downregulation with small interference RNA on breast cancer proliferation. To explore molecular mechanisms underlying Anxa2-mediated cancer cell proliferation. We analyzed cell cycle distribution and signaling pathways using semi-quantitative real-time PCR and Western blotting. Anxa2 depletion in breast cancer cells significantly inhibited cell proliferation by decelerating cell cycle progression. The retarded G1-to-S phase transition in Anxa2-silenced cells was attributed to the decreased levels of cyclin D1, which is a crucial promoting factor for cell proliferation because it regulates G1-to-S phase transition during cell cycle progression. We provided evidence that Anxa2 regulates epidermal growth factor-induced phosphorylation of STAT3. The reduced expression of phosphorylated STAT3 is the main factor responsible for decreased cyclin D1 levels in Anxa2-silenced breast cancer cells. Our results revealed the direct relationship between Anxa2 and activation of STAT3, a key transcription factor that plays a pivotal role in regulating breast cancer proliferation and survival. This study provides novel insights into the functions of Anxa2 as a critical molecule in cellular signal transduction and significantly improves our understanding of the mechanism through which Anxa2 regulates cell cycle and cancer cell proliferation.
Most patients with pancreatic ductal adenocarcinoma (PDA) present with metastatic disease at the time of diagnosis or will recur with metastases after surgical treatment. Semaphorin-plexin signaling mediates the migration of neuronal axons during development and of blood vessels during angiogenesis. The expression of the gene encoding semaphorin 3D (Sema3D) is increased in PDA tumors, and the presence of antibodies against the pleiotropic protein annexin A2 (AnxA2) in the sera of some patients after surgical resection of PDA is associated with longer recurrence-free survival. By knocking out AnxA2 in a transgenic mouse model of PDA (KPC) that recapitulates the progression of human PDA from premalignancy to metastatic disease, we found that AnxA2 promoted metastases in vivo. The expression of AnxA2 promoted the secretion of Sema3D from PDA cells, which coimmunoprecipitated with the co-receptor plexin D1 (PlxnD1) on PDA cells. Mouse PDA cells in which SEMA3D was knocked down or ANXA2-null PDA cells exhibited decreased invasive and metastatic potential in culture and in mice. However, restoring Sema3D in AnxA2-null cells did not entirely rescue metastatic behavior in culture and in vivo, suggesting that AnxA2 mediates additional prometastatic mechanisms. Patients with primary PDA tumors that have abundant Sema3D have widely metastatic disease and decreased survival compared to patients with tumors that have relatively low Sema3D abundance. Thus, AnxA2 and Sema3D may be new therapeutic targets and prognostic markers of metastatic PDA.
Cai J, Shen G, Liu S, Meng QDownregulation of HMGA2 inhibits cellular proliferation and invasion, improves cellular apoptosis in prostate cancer.
Tumour Biol. 2016; 37(1):699-707 [PubMed
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Prostate cancer is the most commonly diagnosed cancer among men and is the second leading cause of cancer-associated deaths among men in the world. Unfortunately, treatment failures are common due to the metastasis and chemoresistance, but the underlying molecular mechanism remains unclear. Accumulating evidence has indicated that the deregulation of DNA-binding protein High Mobility Group A2 (HMGA2) is associated with the development and progression of cancer. This study aimed to explore the expression of HMGA2 in prostate cancer tissues and its correlation to the clinical pathology of prostate cancer, and to discuss the role of HMGA2 in the development of prostate cancer. The results showed that the expression of HMGA2 messenger RNA (mRNA) in the prostate cancer tissues and cells was significantly higher than that in normal prostate tissues and cells (p < 0.05), and the positive expression rate of HMGA2 mRNA in the prostate cancer tissues from patients with positive lymph node metastasis or with high Gleason grade was significantly higher than that from patients with negative lymph node metastasis or with low Gleason grade (p < 0.05). In order to explore the role of HMGA2 in prostate cancer, the expression of HMGA2 in the human prostate cancer PC3 cell line was downregulated by RNA interference. Then, the changes in proliferation, apoptosis, invasion, and migration of PC3 cells were examined by MTT test, PI staining, Annexin V-FITC staining, and Transwell chamber assay. Results showed that the abilities of proliferation, invasion, and migration were suppressed in HMGA2 knockdown PC3 cells, and the abilities of apoptosis were enhanced in HMGA2 knockdown PC3 cells. The expression of cyclin A and vimentin was downregulated in HMGA2 knockdown PC3 cells, and the expression of caspase 3 and E-cadherin was upregulated in HMGA2 knockdown PC3 cells. Taken together, the overexpression of HMGA2 in prostate cancer might be related to the tumorigenesis, invasion, and metastasis of prostate cancer, the downregulation of HMGA2 could inhibit cellular proliferation, invasion, and metastasis, and improve cellular apoptosis in prostate cancer, which might be a potential target for the treatment of prostate cancer.
Nymoen DA, Hetland Falkenthal TE, Holth A, et al.Expression and clinical role of chemoresponse-associated genes in ovarian serous carcinoma.
Gynecol Oncol. 2015; 139(1):30-9 [PubMed
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OBJECTIVE: To validate our earlier observation that 11 chemoresistance-associated mRNAs are molecular markers of poor overall survival in ovarian serous carcinoma.
METHODS: Ovarian serous carcinomas (n=112) and solid metastases (n=63; total=175) were analyzed for mRNA expression of APC, BAG3, EGFR, S100A10, ITGAE, MAPK3, TAP1, BNIP3, MMP9, FASLG and GPX3 using quantitative real-time PCR. mRNA expression was studied for association with clinicopathologic parameters and survival. Tumor heterogeneity was assessed in 20 cases with >1 specimen per patient. APC, BAG3, S100A10 and ERK1 protein expression by immunohistochemistry was analyzed in 58 specimens (38 primary carcinomas, 20 metastases).
RESULTS: BAG3 (p=0.013), TAP1 (p=0.014), BNIP3 (p<0.001) and MMP9 (p=0.036) were overexpressed in primary tumors, whereas S100A10 (p=0.027) and FASLG (p=0.006) were overexpressed in metastases. Analysis of patient-matched primary carcinomas and metastases showed overexpression of APC (p=0.022), MAPK3 (p=0.002) and BNIP3 (p=0.004) in the former. In primary carcinomas, higher APC (p=0.003) and MAPK3 (p=0.005) levels were related to less favorable chemoresponse. Higher S100A10 (p=0.029) and MAPK3 (p=0.041) levels were related to primary chemoresistance. Higher BAG3 (p=0.026) and APC (p=0.046) levels in primary carcinomas were significantly related to poor overall survival in univariate, though not in multivariate survival analysis. S100A10 protein expression was related to poor chemoresponse (p=0.002) and shorter overall (p=0.005) and progression-free (p<0.001) survival, the latter finding retained in multivariate analysis (p=0.035).
CONCLUSIONS: Our data provide evidence of heterogeneity in ovarian serous carcinoma and identify APC, MAPK3, BAG3 and S100A10 as potential biomarkers of poor chemotherapy response and/or poor outcome in this cancer.
The expression of annexin A2 (ANXA2) in nasopharyngeal carcinoma (NPC) cells induces the immunosuppressive response in dendritic cells; however, the oncogenic effect and clinical significance of ANXA2 have not been fully investigated in NPC cells. Immunohistochemical staining for ANXA2 was performed in 61 patients and the association with clinicopathological status was determined. Short hairpin (sh)RNA knockdown of ANXA2 was used to examine cellular effects of ANXA2, by investigating alterations in cell proliferation, migration, invasion, adhesion, tube-formation assay, and chemo- and radiosensitivity assays were performed. RT-qPCR, Western blotting, and immunofluorescence were applied to determine molecular expression levels. Clinical association studies showed that the expression of ANXA2 was significantly correlated with metastasis (p = 0.0326) and poor survival (p = 0.0256). Silencing of ANXA2 suppressed the abilities of cell proliferation, adhesion, migration, invasion, and vascular formation in NPC cell. ANXA2 up-regulated epithelial-mesenchymal transition associated signal proteins. Moreover, ANXA2 reduced sensitivities to irradiation and chemotherapeutic drugs. These results define ANXA2 as a novel prognostic factor for malignant processes, and it can serve as a molecular target of therapeutic interventions for NPC.
El-Abd N, Fawzy A, Elbaz T, Hamdy SEvaluation of annexin A2 and as potential biomarkers for hepatocellular carcinoma.
Tumour Biol. 2016; 37(1):211-6 [PubMed
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Hepatocellular carcinoma (HCC) ranks as the fifth most common malignancy worldwide. Early detection of HCC is difficult due to the lack of reliable markers. We aimed to assess the diagnostic role of annexin A2 (ANXA2) and follistatin as serum markers for HCC patients. This study included 50 patients with confirmed diagnosis of HCC, 30 patients with chronic liver disease, and 20 normal persons. Subjects performed thorough assessment and laboratory investigations. Serum levels of alpha fetoprotein (AFP), annexin A2, and follistatin were measured using ELISA technique. Annexin A2 significantly increased in the sera of HCC patients (median, 69.6 ng/ml) compared to chronic liver disease patients (median, 16.8 ng/ml) and control group (median, 9.5 ng/ml) (p < 0.001). Follistatin was higher in sera of HCC patients (median, 24.4 ng/ml) compared to the control group (median, 4.2 ng/ml) (p = 0.002) while no such significant difference was achieved between HCC and chronic liver disease patients. At a cutoff level 29.3 ng/ml, area under the receiver-operating characteristic curve for ANXA2 was 0.910 (95 % confidence interval (CI) 0.84-0.97). For follistatin, it was 0.631 (95 % confidence interval 0.52-0.74) at cutoff level 15.7 ng/ml. Combining both annexin A2 and AFP increased the diagnostic efficiency (98 % specificity, LR + 41 and 97.6 % PPV). Follistatin combined with AFP provided 92 % specificity while lower sensitivity (50 %) was observed. Serum ANXA2 is a promising biomarker for HCC, certainly when measured with AFP. Follistatin could not differentiate between HCC and chronic liver disease, but its combination with AFP improved the specificity for HCC diagnosis.
Zhang H, Yao M, Wu W, et al.Up-regulation of annexin A2 expression predicates advanced clinicopathological features and poor prognosis in hepatocellular carcinoma.
Tumour Biol. 2015; 36(12):9373-83 [PubMed
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Hepatic annexin A2 (ANXA2) orchestrates multiple biologic processes and clinical symptoms and plays a key role in development, metastasis, and drug resistance of lethal hepatocellular carcinoma (HCC). However, the prognostic significance of ANXA2 for HCC has not been elucidated up to now. In this study, ANXA2 was frequently found to be up-regulated in HCC tissues compared with benign liver disease (BLD) tissues, which was consistent with the results in serum samples and tissue specimens of patients with HCC. Furthermore, ANXA2 expression was significantly correlated with differentiated degree, intrahepatic metastasis, portal vein thrombus, and tumor node metastasis (TNM) staging. More importantly, increased ANXA2 level was first confirmed to be closely associated with shortened overall survival of HCC (χ (2) = 12.872, P = 0.005) and identified as an independent prognostic factor (hazard ratio 1.338, 95 % confidence interval (CI) 1.013 ~ 1.766, P = 0.040), suggesting that ANXA2 up-regulation might represent an acquired metastasis phenotype of HCC, help to screen out high-risk population for HCC, or more effectively treat a subset of postsurgical HCC patients positive for ANXA2.
BACKGROUND: Identification of tumour antigens is crucial for the development of vaccination strategies against hepatocellular carcinoma (HCC). Most studies come from eastern-Asia, where hepatitis-B is the main cause of HCC. However, tumour antigen expression is poorly studied in low-endemic, western areas where the aetiology of HCC differs.
METHODS: We constructed tissue microarrays from resected HCC tissue of 133 patients. Expression of a comprehensive panel of cancer-testis (MAGE-A1, MAGE-A3/4, MAGE-A10, MAGE-C1, MAGE-C2, NY-ESO-1, SSX-2, sperm protein 17), onco-fetal (AFP, Glypican-3) and overexpressed tumour antigens (Annexin-A2, Wilms tumor-1, Survivin, Midkine, MUC-1) was determined by immunohistochemistry.
RESULTS: A higher prevalence of MAGE antigens was observed in patients with hepatitis-B. Patients with expression of more tumour antigens in general had better HCC-specific survival (P=0.022). The four tumour antigens with high expression in HCC and no, or weak, expression in surrounding tumour-free-liver tissue, were Annexin-A2, GPC-3, MAGE-C1 and MAGE-C2, expressed in 90, 39, 17 and 20% of HCCs, respectively. Ninety-five percent of HCCs expressed at least one of these four tumour antigens. Interestingly, GPC-3 was associated with SALL-4 expression (P=0.001), an oncofetal transcription factor highly expressed in embryonal stem cells. SALL-4 and GPC-3 expression levels were correlated with vascular invasion, poor differentiation and higher AFP levels before surgery. Moreover, patients who co-expressed higher levels of both GPC-3 and SALL-4 had worse HCC-specific survival (P=0.018).
CONCLUSIONS: We describe a panel of four tumour antigens with excellent coverage and good tumour specificity in a western area, low-endemic for hepatitis-B. The association between GPC-3 and SALL-4 is a novel finding and suggests that GPC-3 targeting may specifically attack the tumour stem-cell compartment.
BACKGROUND: NBPF1 (Neuroblastoma Breakpoint Family, member 1) was originally identified in a neuroblastoma patient on the basis of its disruption by a chromosomal translocation t(1;17)(p36.2;q11.2). Considering this genetic defect and the frequent genomic alterations of the NBPF1 locus in several cancer types, we hypothesized that NBPF1 is a tumor suppressor. Decreased expression of NBPF1 in neuroblastoma cell lines with loss of 1p36 heterozygosity and the marked decrease of anchorage-independent clonal growth of DLD1 colorectal carcinoma cells with induced NBPF1 expression further suggest that NBPF1 functions as tumor suppressor. However, little is known about the mechanisms involved.
METHODS: Expression of NBPF was analyzed in human skin and human cervix by immunohistochemistry. The effects of NBPF1 on the cell cycle were evaluated by flow cytometry. We investigated by real-time quantitative RT-PCR the expression profile of a panel of genes important in cell cycle regulation. Protein levels of CDKN1A-encoded p21(CIP1/WAF1) were determined by western blotting and the importance of p53 was shown by immunofluorescence and by a loss-of-function approach. LC-MS/MS analysis was used to investigate the proteome of DLD1 colon cancer cells with induced NBPF1 expression. Possible biological interactions between the differentially regulated proteins were investigated with the Ingenuity Pathway Analysis tool.
RESULTS: We show that NBPF is expressed in the non-proliferative suprabasal layers of squamous stratified epithelia of human skin and cervix. Forced expression of NBPF1 in HEK293T cells resulted in a G1 cell cycle arrest that was accompanied by upregulation of the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) in a p53-dependent manner. Additionally, forced expression of NBPF1 in two p53-mutant neuroblastoma cell lines also resulted in a G1 cell cycle arrest and CDKN1A upregulation. However, CDKN1A upregulation by NBPF1 was not observed in the DLD1 cells, which demonstrates that NBPF1 exerts cell-specific effects. In addition, proteome analysis of NBPF1-overexpressing DLD1 cells identified 32 differentially expressed proteins, of which several are implicated in carcinogenesis.
CONCLUSIONS: We demonstrated that NBPF1 exerts different tumor suppressive effects, depending on the cell line analyzed, and provide new clues into the molecular mechanism of the enigmatic NBPF proteins.
ALK is a receptor tyrosine kinase with an oncogenic role in various types of human malignancies. Despite constitutive activation of the kinase through gene alterations, such as chromosomal translocation, gene amplification or mutation, treatments with kinase inhibitors invariably lead to the development of resistance. Aiming to develop new tools for ALK targeting, we took advantage of our previous demonstration identifying ALK as a dependence receptor, implying that in the absence of ligand the kinase-inactive ALK triggers or enhances apoptosis. Here, we synthesized peptides mimicking the proapoptotic domain of ALK and investigated their biological effects on tumor cells. We found that an ALK-derived peptide of 36 amino acids (P36) was cytotoxic for ALK-positive anaplastic large-cell lymphoma and neuroblastoma cell lines. In contrast, ALK-negative tumor cells and normal peripheral blood mononuclear cells were insensitive to P36. The cytotoxic effect was due to caspase-dependent apoptosis and required N-myristoylation of the peptide. Two P36-derived shorter peptides as well as a cyclic peptide also induced apoptosis. Surface plasmon resonance and mass spectrometry analysis of P36-interacting proteins from two responsive cell lines, Cost lymphoma and SH-SY5Y neuroblastoma, uncovered partners that could involve p53-dependent signaling and pre-mRNA splicing. Furthermore, siRNA-mediated knockdown of p53 rescued these cells from P36-induced apoptosis. Finally, we observed that a treatment combining P36 with the ALK-specific inhibitor crizotinib resulted in additive cytotoxicity. Therefore, ALK-derived peptides could represent a novel targeted therapy for ALK-positive tumors.
Zhang F, Liu Y, Wang Z, et al.A novel Anxa2-interacting protein Ebp1 inhibits cancer proliferation and invasion by suppressing Anxa2 protein level.
Mol Cell Endocrinol. 2015; 411:75-85 [PubMed
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Anxa2 is dysregulated in many types of carcinomas and implicated in several pivotal biological functions, such as angiogenesis, cell proliferation, invasion, and metastasis. We previously demonstrated that upregulation of Anxa2 enhances the proliferation and invasion of breast cancer cells. However, the detailed mechanism remains unclear. In this study, co-immunoprecipitation and LC-MS/MS-based interactome approach were employed to screen potential Anxa2 binding proteins. A total of 312 proteins were identified as candidate Anxa2 interacting partners. Using Gene Ontology, pathway annotation, and protein-protein interaction analyses, we constructed a connected network for Anxa2 interacting proteins, and Ebp1 may function as a "hub" in the Anxa2 interaction network. Moreover, Ebp1 knockdown resulted in enhanced cell proliferation and invasion, as well as increased expression of Anxa2. Furthermore, the abundance of cyclin D1 and the phosphorylation of Erk1/2 were increased in Ebp1 inhibited cells. This finding is consistent with a previous study, in which upregulation of Anxa2 results in an increased cyclin D1 expression and Erk1/2 activation. Our results suggest a novel function of Ebp1 as a binding protein and negative regulator of Anxa2. The functional association between Anxa2 and EBP1 may also participate in regulating cancer cell proliferation and invasion, thereby contributing to cancer progression.
Yamashita K, Nagai H, Toyokuni SReceptor role of the annexin A2 in the mesothelial endocytosis of crocidolite fibers.
Lab Invest. 2015; 95(7):749-64 [PubMed
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Asbestos-induced mesothelioma is a worldwide problem. Parietal mesothelial cells internalize asbestos fibers that traverse the entire lung parenchyma, an action that is linked to mesothelial carcinogenesis. Thus far, vitronectin purified from serum reportedly enhances the internalization of crocidolite by mesothelial cells via integrin αvβ5. To reveal another mechanism by which mesothelial cells endocytose (phagocytose) asbestos, we first evaluated the effects of serum on asbestos uptake, which proved to be nonessential. Thereafter, we undertook a study to identify proteins on the surface of mesothelial cells (MeT5A) that act as receptors for asbestos uptake based on the assumption that receptors bind to asbestos with physical affinity. To this end, we incubated the membrane fraction of MeT5A cells with crocidolite or chrysotile and evaluated the adsorbed proteins using sodium dodecyl sulfate polyacrylamide gel analysis. Next, we extensively identified the proteins using an in-solution or in-gel digestion coupled with mass spectrometry. Among the identified proteins, annexin A2 (ANXA2) and transferrin receptor protein 1 (TFRC) were distinguished because of their high score and presence at the cell surface. Crocidolite uptake by MeT5A cells was significantly decreased by shRNA (short hairpin RNA)-induced knockdown of ANXA2 and direct blockade of cell surface ANXA2 using anti-ANXA2 antibody. In addition, abundant ANXA2 protein was present on the cell membrane of mesothelial cells, particularly facing the somatic cavity. These findings demonstrate that ANXA2 has a role in the mesothelial phagocytosis of crocidolite and may serve as its receptor.
BACKGROUND: Mounting evidence demonstrates a causal role for S100 proteins in tumourigenesis and several S100 isoforms have shown utility as biomarkers of several types of cancer. The S100 family is comprised of 21 small isoforms, many of them implicated in important cellular functions such as proliferation, motility and survival. Furthermore, in vivo experiments have proven the role of S100 proteins in tumour growth and disease progression, while other studies have shown their prognostic value and involvement in resistance to chemotherapy drugs. Taken together, all these aspects highlight S100 proteins as potential therapeutic targets and as a promising panel of cancer biomarkers. In this work, we have developed a mass spectrometry (MS)-based method for the multiplexed and specific analysis of the entire S100 protein family in tumour tissues and have applied it to investigate the expression of S100 isoforms in the context of thyroid cancer, the main endocrine malignancy.
METHODS: Selected Reaction Monitoring (SRM)-MS and stable isotope labelling/label-free analysis were employed to investigate the expression of the 21 S100 protein isoforms in thyroid tissue samples. Specimens included 9 normal thyroid tissues and 27 tumour tissues consisting of 9 follicular adenomas (FA), 8 follicular carcinomas (FTC) and 10 papillary carcinomas (PTC).
RESULTS: The multiplexed and targeted mass spectrometry method led to the detection of eleven S100 protein isoforms across all tissues. Label- and label-free analyses showed the same significant differences and results were confirmed by western blot. S100A6, S100A11 and its putative interaction partner annexin A1 showed the highest overexpression in PTC compared to normal thyroid. S100A13 was also elevated in PTC. Reduced S100A4 expression was observed in FA compared to all other tissues. FA and FTC showed reduction of S100A10 and annexin A2 expression.
CONCLUSIONS: Targeted mass spectrometry allows the multiplexed and specific analysis of S100 protein isoforms in tumour tissue specimens. It revealed S100A13 as a novel candidate PTC biomarker. Results show that S100A6, S100A11 and Annexin A1 could help discriminate follicular and papillary tumours. The diagnostic and functional significance of S100A4 and S100A10 reduction in follicular tumours requires further investigation.
Hajiahmadi S, Panjehpour M, Aghaei M, Shabani MActivation of A2b adenosine receptor regulates ovarian cancer cell growth: involvement of Bax/Bcl-2 and caspase-3.
Biochem Cell Biol. 2015; 93(4):321-9 [PubMed
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A2b adenosine receptor (A2bAR) acts as a potent regulator of cell growth in various cell lines. The present study was designed to understand the controlling mechanism of A2bAR agonist (NECA)-induced apoptosis in ovarian cancer cells. Real-time PCR and western blotting assays were used to evaluate the gene and protein expression profiles of A2bAR, respectively. MTT assay was used to study the cell proliferation effect of A2bAR agonist (NECA). Detection of apoptosis was conducted using annexin V-FITC/PI staining, caspase-3 activation assay, and the expression of Bax and Bcl-2 proteins analysis. The mitochondrial membrane potential (ΔΨM) was analyzed by employing JC-1 prob. The mRNA and protein expression levels of A2bAR in ovarian cancer cells were detected. NECA significantly reduced cell viability in a dose-dependent manner in OVCAR-3 and Caov-4 cell lines. The growth inhibition effect of NECA was related to the induction of cell apoptosis, which was manifested by annexin V-FITC staining, activation of caspase-3, and loss of mitochondrial membrane potentials (ΔΨm). In addition, downregulation of the regulatory protein Bcl-2 and upregulation of Bax protein by NECA were also observed. These findings demonstrated that NECA induces apoptosis via the mitochondrial signaling pathway. Thus, A2bAR agonists may be a potential agent for induction of apoptosis in ovarian cancer cells.
Zhang X, Pan JA novel clonal t(1;4)(p36.1;q31) translocation in acute promyelocytic leukaemia.
J Clin Pathol. 2015; 68(5):391-3 [PubMed
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The majority of patients with acute promyelocytic leukaemia (APL) carry the hallmark t(15;17)(q22;q21) translocation, involving the promyelocytic leukaemia/retinoic acid receptor-α (PML/RARα) fusion gene, and by sensitivity of blast cells to all-trans retinoic acid (ATRA) and/or arsenic trioxide therapy. The incidence and prognostic significance of additional chromosomal abnormalities in APL are still obscure. We reported a patient with APL with PML/RARα and clonal t(1;4)(p36.1;q31) positive, but t(15;17)(q22;q21) negative. She was initially treated with ATRA and idarubicin and got complete remission. Our report supports the suggestion that there are no differences in the clinical outcome between APL cases with classical t(15;17)(q22;q21) and those with additional chromosomal abnormality t(1;4)(p36.1;q31). To our knowledge, this is the first report of a patient with APL without classical t(15;17)(q22;q21), showing an additional clonal t(1;4)(p36.1;q31) and involving PML/RARα fusion gene. It will help us to understand the role of the clonal t(1;4)(p36.1;q31) translocation in the pathogenesis of APL when relevant genes involved in the clonal translocation have been identified.