CXCL12

Gene Summary

Gene:CXCL12; C-X-C motif chemokine ligand 12
Aliases: IRH, PBSF, SDF1, TLSF, TPAR1, SCYB12
Location:10q11.21
Summary:This antimicrobial gene encodes a stromal cell-derived alpha chemokine member of the intercrine family. The encoded protein functions as the ligand for the G-protein coupled receptor, chemokine (C-X-C motif) receptor 4, and plays a role in many diverse cellular functions, including embryogenesis, immune surveillance, inflammation response, tissue homeostasis, and tumor growth and metastasis. Mutations in this gene are associated with resistance to human immunodeficiency virus type 1 infections. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:stromal cell-derived factor 1
Source:NCBIAccessed: 14 March, 2017

Ontology:

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

Research Indicators

Publications Per Year (1992-2017)
Graph generated 14 March 2017 using data from PubMed using criteria.

Literature Analysis

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

  • Breast Cancer
  • Messenger RNA
  • Chromosome 10
  • Small Cell Lung Cancer
  • Apoptosis
  • Cell Movement
  • Tissue Array Analysis
  • Stromal Cells
  • Uveal Neoplasms
  • Lung Cancer
  • Gene Expression Profiling
  • Transcriptome
  • Transcriptional Activation
  • Wnt Signaling Pathway
  • Cervical Cancer
  • YY1 Transcription Factor
  • Protein Interaction Maps
  • siRNA
  • Ovarian Cancer
  • Vaccinia virus
  • Tunisia
  • Risk Factors
  • Vascular Endothelial Growth Factor C
  • gamma-Synuclein
  • Microfilament Proteins
  • Protein Kinases
  • Vitamin D
  • Biomarkers, Tumor
  • Single Nucleotide Polymorphism
  • Wound Healing
  • Western Blotting
  • Survival
  • Immunohistochemistry
  • Cancer Gene Expression Regulation
  • Eye Cancer
  • Chemokine CXCL12
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Repressor Proteins
  • Cell Proliferation
  • Staging
Tag cloud generated 14 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).

Latest Publications: CXCL12 (cancer-related)

Eiro N, Fernandez-Gomez J, Sacristán R, et al.
Stromal factors involved in human prostate cancer development, progression and castration resistance.
J Cancer Res Clin Oncol. 2017; 143(2):351-359 [PubMed] Related Publications
PURPOSE: To detect new predictive markers from the prostate cancer tissue, to study the expression by cultured cancer-associated fibroblasts (CAFs) of stromal factors implicated in prostate carcinogenesis, and to compare their expressions in localized, metastatic, castration-sensitive (CSCP), castration-resistant prostate tumors (CRCP) as well as in fibroblasts from benign prostatic hyperplasia (BPH).
MATERIALS AND METHODS: The genomic expression of 20 stroma-derived factors, including the androgen receptor (AR), growth factors (FGF2, FGF7, FGF10, HGF, TGFβ, PDGFB), protein implicated in invasion (MMP-2, MMP-9 and MMP-11), inflammation (IL-6, IL-17, STAT-3 and NFκB), stroma/epithelium interaction (CDH11, FAP, CXCL12 and CXCL14) and chaperones (HPA1A and HSF1), was evaluated in cultured fibroblasts both from BHP and prostate carcinomas (PCa). After isolation and culture of fibroblasts by biopsy specimens, RNA was isolated and genomic studies performed.
RESULTS: Finally, 5 BPH and 37 PCa specimens were selected: clinically localized (19), metastatic (5), CSCP (7) and CRPC (6). Interleukin-17 receptor (IL-17RB) was highly expressed in CAFs compared with fibroblasts from BPH. However, metalloproteinase-2 and chemokine ligand 14 (CXCL14) were expressed at higher levels by fibroblasts from BPH. The fibroblastic growth factor-7 was highly expressed by CAFs from localized tumors, but metalloproteinase-11 in metastatic tumors. MMP-11, androgen receptor (AR) and heat-shock-70kda-protein-1A (HSPA1A) expressions were significantly higher in CAFs from CRPC.
CONCLUSIONS: These results demonstrate a CAFs heterogeneity among prostate carcinomas with regard to some molecular profile expressions that may be relevant in tumor development (IL-17RB), progression (MMP-11) and castration resistance (AR, MMP-11 and HSPA1A).

Lv X, Li J, Yang B
Clinical effects of miR-101 on prognosis of hepatocellular carcinoma and carcinogenic mechanism of anti-miR-101.
Oncol Rep. 2016; 36(4):2184-92 [PubMed] Related Publications
The aim of this study was to verify whether anti-miR-101 participates in the treatment of hepatocellular carcinoma (HCC) as a small-molecule antitumor agent, and to explore the effect on phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Patients who received consecutive hepatectomies were followed-up, and miR-101 expressions in their tumor and paracancerous tissues were detected. Correlation between miR-101 expression and clinical pathological factors and prognosis was studied. High‑throughput sequencing was used to detect the genetic and microRNA (miRNA) levels of tumor tissues. Expression of anti-miR-101 in different HCC cell lines was determined, and those of desired genes and proteins were detected by qRT-PCR and western blotting to obtain the target gene. miR-101 was significantly upregulated in HCC patients compared with that in paracancerous tissues. High miR-101 expression, vascular invasion, tumor size ≥7 cm and late pathological stage were the risk factors of recurrence-free survival rate. High miR-101 expression was the independent prognostic factor of total and recurrence-free survival rates. CXCL12, IL6R, FOXO3 and PTEN were screened as desired genes, and only PTEN was expressed significantly differently in three cell lines. miR-101 could bind 3'-UTR of WT-PTEN with reduced fluorescent intensity, suggesting that PTEN was the target gene. SMMC-7721, HepG2 and Huh7 were eligible cell lines for miR-101 studies. miR-101 was an applicable molecular marker of HCC. Anti-miR-101 regulated the transcription of PTEN and may promote cell proliferation, differentiation and apoptosis by regulating downstream genes with PTEN. The regulatory effects of anti-miR-101 on PTEN provide valuable evidence for finding novel miRNA drugs.

Pan GZ, Zhai FX, Lu Y, et al.
RUNX3 plays an important role in As2O3‑induced apoptosis and allows cells to overcome MSC‑mediated drug resistance.
Oncol Rep. 2016; 36(4):1927-38 [PubMed] Related Publications
The interaction between bone marrow stromal cells and leukemia cells is critical for the persistence and progression of leukemia, and this interaction may account for residual disease. However, the link between leukemia cells and their environment is still poorly understood. In our study, runt‑related transcription factor 3 (RUNX3) was identified as a novel target gene affected by As2O3 and involved in mesenchymal stem cell (MSC)‑mediated protection of leukemia cells from As2O3‑induced apoptosis. We observed induction of RUNX3 expression and the translocation of RUNX3 into the nucleus after As2O3 treatment in leukemia cells. In K562 chronic myeloid leukemia cells, downregulation of endogenous RUNX3 compromised As2O3‑induced growth inhibition, cell cycle arrest, and apoptosis. In the presence of MSC, As2O3‑induced expression of RUNX3 was reduced significantly and this reduction was modulated by CXCL12/CXCR4 signaling. Furthermore, overexpression of RUNX3 restored, at least in part, the sensitivity of leukemic cells to As2O3. We conclude that RUNX3 plays an important role in As2O3‑induced cellular responses and allows cells to overcome MSC‑mediated drug resistance. Therefore, RUNX3 is a promising target for therapeutic approaches to overcome MSC‑mediated drug resistance.

Pierscianek D, Wolf S, Keyvani K, et al.
Study of angiogenic signaling pathways in hemangioblastoma.
Neuropathology. 2017; 37(1):3-11 [PubMed] Related Publications
Hemangioblastoma (HB) is mainly located in the brain and the spinal cord. The tumor is composed of two major components, namely neoplastic stromal cells and abundant microvessels. Thus, hyper-vascularization is the hallmark of this tumor. Despite the identification of germline and/or epigenetic mutations of Von Hippel Lindau (VHL) gene as an important pathogenic mechanism of HB, little is known about the molecular signaling involved in this highly vascularized tumor. The present study investigated the key players of multiple angiogenic signaling pathways including VEGF/VEGFR2, EphB4/EphrinB2, SDF1α/CXCR4 and Notch/Dll4 pathways in surgical specimens of 22 HB. The expression of key angiogenic factors was detected by RT(2) -PCR and Western blot. Immunofluorescent staining revealed the cellular localization of these proteins. We demonstrated a massive upregulation of mRNA levels of VEGF and VEGFR2, CXCR4 and SDF1α, EphB4 and EphrinB2, as well as the main components of Dll4-Notch signaling in HB. An increase in the protein expression of VEGF, CXCR4 and the core-components of Dll4-Notch signaling was associated with an activation of Akt and Erk1/2 and accompanied by an elevated expression of PCNA. Immuofluorescent staining revealed the expression of VEGF and CXCR4 in endothelial cells as well as in tumor cells. Dll4 protein was predominantly found in tumor cells, whereas EphB4 immunoreactivity was exclusively detected in endothelial cells. We conclude that multiple key angiogenic pathways were activated in HB, which may synergistically contribute to the abundant vascularization in this tumor. Identification of these aberrant pathways provides potential targets for a possible future application of anti-angiogenic therapy for this tumor, particularly when a total surgical resection becomes difficult due to the localization or multiplicity of the tumor.

Zheng Q, Shuai X, Ye Y, et al.
The role of polymorphisms of stromal-derived factor-1 and CXC receptor 4 in acute myeloid leukemia and leukemia cell dissemination.
Gene. 2016; 588(2):103-8 [PubMed] Related Publications
BACKGROUND: Acute myeloid leukemia (AML) is a form of cancer characterized by infiltration of the bone marrow, blood, and other tissues by proliferative, clonal, abnormally differentiated cells of the hematopoietic system. Chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXC receptor 4 (CXCR4) play crucial roles in malignant cell invasion. Genetic polymorphisms may contribute to the differences in the expression level and activities associated with the SDF-1/CXCR4 pathway. This study aimed to determine the associations between the polymorphisms located on the SDF-1 (rs1801157, G>A) and CXCR4 (rs2228014, C>T) encoding genes and susceptibility and leukemia cell dissemination in AML.
METHODS: A total of 926 individuals, including 466 de novo AML patients and 460 healthy controls were genotyped for rs1801157 and rs2228014 using DNA Sanger sequencing.
RESULTS: Genotype distributions of CT and CT+TT for rs2228014 were significantly increased in AML patients compared with healthy controls [OR: 1.36, p=0.04; OR: 1.34, p=0.04; respectively]. However, rs1801157 demonstrated no significant differences in genotype distributions and allele frequency between AML patients and healthy controls. For the two combined SNPs, there was no significant proportional difference between the wild type GG-CC genotypes and non-GG-CC genotypes in AML patients and healthy controls. Additionally, peripheral blood leukemia-cell (PBLC) count was not statistically influenced by the genotypes of either rs1801157 or rs2228014.
CONCLUSION: Genotype CT of rs2228014 appeared to correlate with AML risk, but played no role in leukemia cells invading the bloodstream, while rs1801157 and the two combined SNPs were not associated with either increased AML risk or extramedullary leukemia-cell dissemination.

Łukaszewicz-Zając M, Mroczko B, Kozłowski M, Szmitkowski M
The Serum Concentrations of Chemokine CXCL12 and Its Specific Receptor CXCR4 in Patients with Esophageal Cancer.
Dis Markers. 2016; 2016:7963895 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: Recent investigations have suggested that upregulated levels of inflammatory biomarkers, such as chemokines, may be associated with development of many malignancies, including esophageal cancer (EC). Based on our knowledge, this study is the first to assess the serum concentration of chemokine CXCL12 and its specific receptor CXCR4 in the diagnosis of EC patients.
MATERIAL AND METHODS: The present study included 79 subjects: 49 patients with EC and 30 healthy volunteers. The serum concentrations of CXCL12 and CXCR4 and classical tumor markers such as carcinoembryonal antigen (CEA) and squamous cell cancer antigen (SCC-Ag) were measured using immunoenzyme assays, while C-reactive protein (CRP) levels were assessed by immunoturbidimetric method. Moreover, diagnostic criteria of all proteins tested and the survival of EC patients were assessed.
RESULTS: The serum concentrations of CXCL12 were significantly higher, while those of its receptor CXCR4 were significantly lower in EC patients compared to healthy controls. The diagnostic sensitivity, negative predictive value, and accuracy of CXCR4 were the highest among all analyzed proteins and increased for combined analysis with classical tumor markers and CRP levels.
CONCLUSION: Our findings suggest that serum CXCR4 may improve the diagnosis of EC patients, especially in combination with classical tumor markers.

Zheng L, Chen L, Zhang X, et al.
TMEM49-related apoptosis and metastasis in ovarian cancer and regulated cell death.
Mol Cell Biochem. 2016; 416(1-2):1-9 [PubMed] Related Publications
Ovarian cancer is one of the greatest causes of cancer death in women. The association of TMEM49 and ovarian cancer is poorly defined. Here, we reported that TMEM49 was significantly increased in ovarian tumor tissues compared to ovarian normal tissues. Furthermore, down-regulation of TMEM49 through RNA interference inhibited cell proliferation and arrested G1/S transition in two ovarian cancer cell lines, OVCAR3 and A2780. More importantly, TMEM49 silencing induced cell apoptosis. Additionally, down-regulation of TMEM49 in ovarian cancer notably repressed cell invasion and adhesion. Further gene set enrichment analysis suggested that apoptosis and metastasis up related signal pathways were associated with the TMEM49 expression. Western blot revealed that the expression of Caspase3, Bad, and Bax were increased, while expression of MMP2, KLF10, and CXCL12 were reduced by TMEM49 knockdown. Since expression of TMEM49 seems to be associated with the apoptosis and metastasis up signaling pathways of ovarian cancer, and suppression of its expression can inhibit cancer cell growth and metastasis, TMEM49 may be a potential therapeutic target in human ovarian cancer.

Mercurio L, Ajmone-Cat MA, Cecchetti S, et al.
Targeting CXCR4 by a selective peptide antagonist modulates tumor microenvironment and microglia reactivity in a human glioblastoma model.
J Exp Clin Cancer Res. 2016; 35:55 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The CXCL12/CXCR4 pathway regulates tumor cell proliferation, metastasis, angiogenesis and the tumor-microenvironment cross-talk in several solid tumors, including glioblastoma (GBM), the most common and fatal brain cancer. In the present study, we evaluated the effects of peptide R, a new specific CXCR4 antagonist that we recently developed by a ligand-based approach, in an in vitro and in vivo model of GBM. The well-characterized CXCR4 antagonist Plerixafor was also included in the study.
METHODS: The effects of peptide R on CXCR4 expression, cell survival and migration were assessed on the human glioblastoma cell line U87MG exposed to CXCL12, by immunofluorescence and western blotting, MTT assay, flow cytometry and transwell chamber migration assay. Peptide R was then tested in vivo, by using U87MG intracranial xenografts in CD1 nude mice. Peptide R was administered for 23 days since cell implantation and tumor volume was assessed by magnetic resonance imaging (MRI) at 4.7 T. Glioma associated microglia/macrophage (GAMs) polarization (anti-tumor M1 versus pro-tumor M2 phenotypes) and expressions of vascular endothelial growth factor (VEGF) and CD31 were assessed by immunohistochemistry and immunofluorescence.
RESULTS: We found that peptide R impairs the metabolic activity and cell proliferation of human U87MG cells and stably reduces CXCR4 expression and cell migration in response to CXCL12 in vitro. In the orthotopic U87MG model, peptide R reduced tumor cellularity, promoted M1 features of GAMs and astrogliosis, and hindered intra-tumor vasculature.
CONCLUSIONS: Our findings suggest that targeting CXCR4 by peptide R might represent a novel therapeutic approach against GBM, and contribute to the rationale to further explore in more complex pre-clinical settings the therapeutic potential of peptide R, alone or in combination with standard therapies of GBM.

Tang T, Xia QJ, Qiao X, Xi M
Expression of C-X-C chemokine receptor type 7 in otorhinolaryngologic neoplasms.
Singapore Med J. 2016; 57(3):157-60 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: C-X-C chemokine receptor type 7 (CXCR7) has recently been characterised as a novel receptor for the C-X-C motif chemokine 12 (CXCL12)/stromal cell-derived factor 1-alpha. CXCR7 has been thought to play an important role in the pathogenesis of chronic rhinosinusitis, angiogenesis and tumour metastasis. The present study aimed to examine the expression of CXCR7 in tissue samples of laryngeal cancer and maxillary sinus carcinoma to determine its role in the development of otorhinolaryngologic neoplasms.
METHODS: Samples of otorhinolaryngologic neoplasms were obtained from 17 patients with either nasal polyps (n = 7), laryngeal cancer (n = 5) or maxillary sinus carcinoma (n = 5), and who underwent surgical resection at West China Hospital of Sichuan University. Total RNA was isolated and CXCR7 mRNA expression was examined and quantified by relative real-time reverse transcription polymerase chain reaction. A one-way analysis of variance was performed using SPSS Statistics version 11.0 (SPSS Inc, Chicago, IL, USA) to compare the CXCR7 mRNA levels among the three groups of patients.
RESULTS: All samples tested positive for CXCR7 mRNA. The quantitative results showed that the CXCR7 mRNA levels were highest in laryngeal cancer and lowest in maxillary sinus carcinoma neoplasms, although there was no significant difference among the three samples.
CONCLUSION: CXCL12 and its receptor CXCR7 may contribute to eosinophilic inflammation in patients with chronic sinusitis and nasal polyps. Our results also suggest that CXCR7 may play a role in the progression, metastasis and angiogenesis of otorhinolaryngologic tumours.

Fan Y, Xu LL, Shi CY, et al.
MicroRNA-454 regulates stromal cell derived factor-1 in the control of the growth of pancreatic ductal adenocarcinoma.
Sci Rep. 2016; 6:22793 [PubMed] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant carcinoma with an extremely high lethality. We recently reported that hypoxia-inducible factor 1 (HIF-1) targets quiescin sulfhydryl oxidase 1 to facilitate PDAC cell growth and invasion. Here, we analyzed the control of another HIF-1 target, stromal cell derived factor-1 (SDF-1), in PDAC cells. We detected significantly more CD68+ macrophages in the PDAC, compared to normal human pancreas (NT). Since macrophages are recruited to the tissue through their expression of CXCR4 in response to SDF-1, we thus examined the SDF-1 levels in the PDAC specimens. Surprisingly, the SDF-1 protein but not mRNA significantly increased in PDAC, compared to NT. Moreover, a SDF-1-targeting microRNA, miR-454, was found to decrease in PDAC. Promoter luciferase assay confirmed that bindings of miR-454 to 3'-UTR of SDF-1 mRNAs inhibited SDF-1 protein translation. Co-culture of bone marrow derived macrophages and miR-454-modified PDAC cells in a transwell migration experiment showed that macrophages migrated less towards miR-454-overexpressing PDAC cells, and migrated more towards miR-454-depleted cells. Implanted miR-454-depleted PDAC cells grew significantly faster than control, while implanted miR-454-overexpressing PDAC cells grew significantly slower than control. Together, our data suggest that miR-454 may regulate SDF-1 in the control of the growth of PDAC.

Bakkar A, Alshalalfa M, Petersen LF, et al.
microRNA 338-3p exhibits tumor suppressor role and its down-regulation is associated with adverse clinical outcome in prostate cancer patients.
Mol Biol Rep. 2016; 43(4):229-40 [PubMed] Related Publications
MicroRNAs (miRNAs) are small non-coding RNAs that function in transcriptional and post-transcriptional regulation of gene expression. Several miRNAs have been implicated in regulating prostate cancer (PCa) progression. Deregulations of miRNA regulatory networks have been reported in ERG positive PCa, which accounts for ~50 % of PCa and have been suggested to affect tumor aggressiveness. The function of miR338-3p, its prognostic significance, and its association with ERG positive PCa has not been fully investigated. Using microarray expression profiling, we identified miRNA338-3p as among the top deregulated miRNAs associated with ERG status in PCa. We investigated miR338-3p function using in vitro and in vivo experimental models and its expression was assessed and validated in clinical samples and a public cohort of localized and metastatic prostate cancer. miR338-3p was significantly down-regulated with disease progression from benign prostate tissue to primary and metastatic lesions. In localized disease, patients with lower miR338-3p expression levels showed increased association to biochemical recurrence and several adverse pathological parameters compared to patients with higher miRNA338-3p tissue expression levels. Using in vitro PCa cell models, overexpression of miR338-3p resulted in a decrease in cell invasion and expression of chemokine signalling genes CXCL12, CXCR4, and CXCR7. In vivo, orthotropic implantation of PC3 cells stably expressing miR338-3p was associated with a significant decrease in tumor weights compared to control cells. miR338-3p has anti-proliferative and anti-invasive properties. It affects CXCR4 axis, and its down-regulation is associated with adverse clinical outcomes in PCa patients.

Mego M, Cholujova D, Minarik G, et al.
CXCR4-SDF-1 interaction potentially mediates trafficking of circulating tumor cells in primary breast cancer.
BMC Cancer. 2016; 16:127 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cytokines are involved in cancer invasion and metastasis. Circulating tumor cells (CTCs) play key role in tumor dissemination and are an independent survival predictor in breast cancer patients. The aim of this study was to assess correlation between CTCs and plasma cytokines in primary breast cancer (PBC) patients.
METHODS: This study included 147 chemotherapy naïve PBC patients. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoetic cells using RossetteSep™ negative selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (Twist1, Snail1, Slug, Zeb1) and epithelial (Ck19) gene transcripts by qRT-PCR. The concentrations of 51 plasma cytokines were measured using multiplex bead arrays.
RESULTS: CTCs were detected in 25.2% patients. CTCs exhibiting only epithelial markers (CTC_EP) and only EMT markers (CTC_EMT) were present evenly in 11.6% patients, while CTCs co-expressing both markers were detected in 2.0% patients. Patients with presence of CTC_EP in peripheral blood had significantly elevated levels of plasma IFN-α2, IL-3, MCP-3, β-NGF, SCF, SCGF-β, TNF-β and SDF-1 compared to patients without CTC_EP. CTC_EP exhibited overexpression of SDF-1 receptor and CXCR4, but not other corresponding cytokine receptor, and in multivariate analysis SDF-1 was independently associated with CTC_EP. There was an inverse correlation between CTC_EMT and plasma cytokines CTACK, β-NGF and TRAIL, while presence of either subtype of CTCs was associated with increased level of TGF-β2.
CONCLUSION: Using cytokine profiling, we identified cytokines associated with CTCs subpopulations in peripheral blood of PBC. Our data suggest that CXCR4-SDF-1 axis is involved in mobilization and trafficking of epithelial CTCs.

Dong S, Jin M, Li Y, et al.
MiR-137 acts as a tumor suppressor in papillary thyroid carcinoma by targeting CXCL12.
Oncol Rep. 2016; 35(4):2151-8 [PubMed] Related Publications
Accumulating evidence has shown that aberrantly expressed microRNAs (miRs) are extensively involved in tumorigenesis. microRNA-137 (miR-137) has been reported as a tumor suppressor in various types of cancer. However, the biological function and underlying molecular mechanism of miR-137 in papillary thyroid carcinoma (PTC) remain largely unknown. Therefore, the present study aimed to investigate the expression pattern of miR-137 and its functional significance in PTC. Quantitative RT-PCR (qRT-PCR) assay showed that miR-137 expression was significantly downregulated in human PTC tissues, and its expression was significantly negatively correlated with tumor-node-metastasis (TNM) stage and lymph node metastasis. Functional assays showed that forced expression of miR-137 in PTC cells significantly inhibited proliferation, colony formation, migration and invasion in vitro. Importantly, on the basis of bioinformatic analysis and luciferase reporter assay, we found that miR-137 directly targeted the 3'-untranslated region (3'-UTR) of C-X-C motif chemokine 12 (also known as SDF-1) (CXCL12). qRT-PCR and western blot analysis further verified the results and demonstrated that miR-137 could downregulate CXCL12 expression in PTC cells. We also confirmed that CXCL12 expression was increased in PTC tissues and was inversely correlated with miR-137. In addition, our results also showed that downregulation of CXCL12 mimicked the effects of miR-137 overexpression, and upregulation of CXCL12 partially reversed the inhibitory effects of miR-137 in PTC cells. These results showed that miR-137 may function as a tumor suppressor in PTC by targeting CXCL12, suggesting that miR-137 may act as a potential target for PTC treatment.

Flüh C, Hattermann K, Mehdorn HM, et al.
Differential expression of CXCR4 and CXCR7 with various stem cell markers in paired human primary and recurrent glioblastomas.
Int J Oncol. 2016; 48(4):1408-16 [PubMed] Related Publications
The chemokine CXCL12 (also termed SDF-1, stromal cell-derived factor-1) and its receptors CXCR4 and CXCR7 are known to play a pivotal role in tumor progression including glioblastomas (GBM). Previous investigations focused on the expression and functional roles of CXCR4 and CXCR7 in different GBM cell subpopulations, but comparative analysis in matched primary versus recurrent GBM samples are still lacking. Thus, here we investigated the expression of CXCR4 and CXCR7 on mRNA and protein level using matched primary and recurrent GBM pairs. Additionally, as GBM CXCR4-positive stem-like cells are supposed to give rise to recurrence, we compared the expression of both receptors in primary and recurrent GBM cells expressing either neural (MUSASHI-1) or embryonic stem cell markers (KLF-4, OCT-4, SOX-2, NANOG). We were able to show that both CXCR4 and CXCR7 were expressed at considerable mRNA and protein levels. CXCR7 was downregulated in relapse cases, and different groups regarding CXCR4/CXCR7 expression differences between primary and recurrent samples could be distinguished. A co-expression of both receptors was rare. In line with this, CXCR4 was co-expressed with all investigated neural and embryonic stem cell markers in both primary and recurrent tissues, whereas CXCR7 was mostly found on stem cell marker-negative cells, but was co-expressed with KLF-4 on a distinct GBM cell subpopulation. These results point to an individual role of CXCR4 and CXCR7 in stem cell marker-positive GBM cells in glioma progression and underline the opportunity to develop new therapeutic tools for GBM intervention.

Kong L, Guo S, Liu C, et al.
Overexpression of SDF-1 activates the NF-κB pathway to induce epithelial to mesenchymal transition and cancer stem cell-like phenotypes of breast cancer cells.
Int J Oncol. 2016; 48(3):1085-94 [PubMed] Related Publications
The formation of EMT and EMT-induced CSC-like phenotype is crucial for the metastasis of tumor cells. The stromal cell-derived factor-1 (SDF-1) is upregulated in various human carcinomas, which is closely associated with proliferation, migration, invasion and prognosis of malignancies. However, limited attention has been directed towards the effect of SDF-1 on epithelial to mesenchymal transition (EMT) or cancer stem cell (CSC)-like phenotype formation in breast cancer cells and the related mechanism. In the present study, we screened MCF-7 cells with low SDF-1 expression level for the purpose of evaluating whether SDF-1 is involved in EMT and CSC-like phenotype formation in MCF-7 cells. The pEGFP-N1-SDF-1 plasmid was transfected into MCF-7 cells, and the stably overexpressed SDF-1 in MCF-7 cells was confirmed by real-time PCR and western blot analysis. Colony formation assay, MTT, wound healing assay and Transwell invasion assay demonstrated that overexpression of SDF-1 significantly boosted the proliferation, migration and invasion of MCF-7 cells compared with parental (P<0.05). Flow cytometry analysis revealed a notable increase of CD44+/CD24- subpopulation in SDF-1 overexpressing MCF-7 cells (P<0.001), accompanied by the apparently elevated ALDH activity and the upregulation of the stem cell markers OCT-4, Nanog, and SOX2 compared with parental (P<0.01). Besides, western blot analysis and immunofluorescence assay observed the significant decreased expression of E-cadherin and enhanced expression of slug, fibronectin and vimentin in SDF-1 overexpressed MCF-7 cells in comparison with parental (P<0.01). Further study found that overexpression of SDF-1 induced the activation of NF-κB pathway in MCF-7 cells. Conversely, suppressing or silencing p65 expression by antagonist or RNA interference could remarkably increase the expression of E-cadherin in SDF-1 overexpressed MCF-7 cells (P<0.001). Overall, the above results indicated that overexpression of SDF-1 enhanced EMT by activating the NF-κB pathway of MCF-7 cells and further induced the formation of CSC-like phenotypes, ultimately promoting the proliferation and metastasis of MCF-7 cells. Therefore, SDF-1 may further be assessed as a potential target for gene therapy of breast cancer.

Yang DL, Xin MM, Wang JS, et al.
Chemokine receptor CXCR4 and its ligand CXCL12 expressions and clinical significance in bladder cancer.
Genet Mol Res. 2015; 14(4):17699-707 [PubMed] Related Publications
It is well known that chemokine receptors and their ligands play important roles in mediating the invasion and metastasis of malignant tumors. This aim of this study was to investigate the expression and clinical significance of chemokine receptor CXCR4 and its ligand CXCL12 in bladder tumor tissues. Cancerous and adjacent normal bladder tissues were collected from 42 patients. The expressions of CXCR4 and CXCL12 proteins were then detected by immunohistochemistry, and the expressions of CXCR4 and CXCL12 mRNAs were detected by RT-PCR. Bladder cancer tissues showed higher positive expressions of CXCR4 and CXCL12 than those in normal bladder mucosal tissues (z = 7.332, 6.758, P < 0.001). Positive expressions of CXCR4 and CXCL12 were related to the differentiation degree and invasive depth of cancer tissues (z = 2.598-4.594, P < 0.05), but not to patient gender or age (z = 0.273-0.554, P > 0.05). The expression of CXCR4 was positively correlated to CXCL12 expression in bladder cancer tissues (r = 0.661, P < 0.05). RT-PCR revealed that CXCR4 and CXCL12 mRNAs were not expressed in normal tissues. Moreover, with increased depth of invasion, CXCR4 and CXCL12 mRNA expressions gradually increased in bladder cancer tissues and showed significant intergroup differences (F = 56.642, 67.928, P < 0.01). Taken together, these results indicate that the chemokine receptor CXCR4 and its ligand CXCL12 play important roles in the occurrence and development of bladder cancer.

Landry B, Gül-Uludağ H, Plianwong S, et al.
Targeting CXCR4/SDF-1 axis by lipopolymer complexes of siRNA in acute myeloid leukemia.
J Control Release. 2016; 224:8-21 [PubMed] Related Publications
In spite of high complete remission rates in Acute Myeloid Leukemia (AML), little progress has been made in the long-term survival of relapsing AML patients, urging for the development of novel therapies. The CXCR4/SDF-1 axis is a potential therapeutic target in AML to reduce the enhanced survival and proliferation of leukemic cells, with current drug development efforts focusing on antagonists and blocking antibodies. The RNAi technology mediated by siRNA is a promising alternative; however, further development of clinically relevant siRNA carriers is needed since siRNA on its own is an incompetent silencing agent. Here, we report on lipid-substituted polymeric carriers for siRNA delivery to AML cells, specifically targeting CXCR4. Our results demonstrate an effective suppression of CXCR4 protein with the polymeric siRNA delivery in AML THP-1 cells. The suppression of CXCR4 as well as its ligand, SDF-1 (CXCL12), decreased THP-1 cell numbers due to reduced cell proliferation. The reduced proliferation was also observed in the presence of human bone marrow stromal cells (hBMSC), suggesting that our approach would be effective in the protective bone marrow microenvironment. The combination of CXCR4 silencing and cytarabine treatment resulted in more effective cytotoxicity when the cells were co-incubated with hBMSC. We observed a decrease in the toxicity of the lipopolymer/siRNA complexes when THP-1 cells were treated in the presence of hBMSC but this effect did not negatively affect CXCR4 silencing. In addition, siRNA delivery to mononuclear cells derived from AML patients led to significant CXCR4 silencing in 2 out of 5 samples, providing a proof-of-concept for clinical translation. We conclude that decreasing CXCR4 expression via lipopolymer/siRNA complexes is a promising option for AML therapy and could provide an effective alternative to current CXCR4 inhibition strategies.

Wu W, Qian L, Chen X, Ding B
Prognostic significance of CXCL12, CXCR4, and CXCR7 in patients with breast cancer.
Int J Clin Exp Pathol. 2015; 8(10):13217-24 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The chemokine CXCL12 and its receptors CXCR4 and CXCR7 play important roles in cancer invasion and metastasis. This study investigated the mRNA expressions of CXCL12, CXCR4, and CXCR7 to illustrate the role of these biomarkers in breast cancer metastasis and prognosis.
METHODS: The mRNA expressions of CXCL12, CXCR4, and CXCR7 in 115 primary breast cancer and regional lymph node specimens were detected by quantitative reverse-transcription polymerase chain reaction. Survival time was analyzed by Kaplan-Meier survival curves using log-rank test. Univariable and multivariable Cox regression analyses were performed to assess independent prognostic factors for survival.
RESULTS: The expression levels of CXCR4 and CXCR7 in breast cancer tissues were significantly higher than that in adjacent normal tissues (P=0.022 and P<0.001, respectively), while the expression level of CXCL12 in breast cancer tissues did not differ from that in adjacent normal tissues (P=0.156). Furthermore, CXCL12 exhibited significant differences in expression between primary tumor and lymph node metastasis tumor (P=0.039). CXCR4 and CXCR7 expressions in metastasis tumor were also higher, although no significant difference was observed (P=0.067 and P=0.054, respectively). Kaplan-Meier survival analysis revealed that patients exhibiting high CXCR4 and CXCR7 expression experienced a shorter survival period compared with those with low expression. When analyzed with a Cox regression model, the expressions of CXCL12, CXCR4 and CXCR7 were independent prognostic factors for overall survival.
CONCLUSIONS: The mRNA expressions of CXCL12, CXCR4, and CXCR7 play important roles in the progression and metastasis of breast cancer and may act as predictive factors significantly affecting the prognosis.

Shan S, Lv Q, Zhao Y, et al.
Wnt/β-catenin pathway is required for epithelial to mesenchymal transition in CXCL12 over expressed breast cancer cells.
Int J Clin Exp Pathol. 2015; 8(10):12357-67 [PubMed] Free Access to Full Article Related Publications
CXCL12 is positively associated with the metastasis and prognosis of various human malignancies. Cancer-associated fibroblasts (CAFs), the main cells secreting CXCL12, are capable of inducing epithelial to mesenchymal transition (EMT) of breast cancer cells. However, it has not been completely understood whether CXCL12 is involved in EMT of breast cancer cells and the underlying mechanisms. The present study aimed to investigate the effects of CXCL12 on the EMT and cancer stem cell (CSC)-like phenotypes formation by transfecting pEGFP-N1-CXCL12 plasmid into MCF-7 cells. Real time-PCR and Western blot analysis demonstrated the successful over expression of CXCL12 in MCF-7 cells. Cell counting kit-8 assay, wound healing assay and Transwell invasion analysis confirmed that over expression of CXCL12 significantly promoted the proliferation, migration and invasion in MCF-7 cells (P<0.05). In addition, ALDH activity was dramatically enhanced compared with parental (P<0.001), accompanied by the notably elevated mRNA and protein levels of OCT-4, Nanog, and SOX2 in CXCL12 overexpressed-MCF-7 cells (P<0.001). Furthermore, we observed the down regulation of E-cadherin and up regulation of vimentin, N-cadherin, and α-SMA in CXCL12 overexpressed-MCF-7 cells (P<0.01). Meanwhile, western blot and immunofluorescence assay showed that over expression of CXCL12 activated Wnt/β-catenin pathway to induce EMT of MCF-7 cells, as evidenced by the increased expression of E-cadherin after silencing β-catenin by siRNA interference (P<0.001). Collectively, our findings suggested that over expression of CXCL12 could trigger EMT by activating Wnt/β-catenin pathway and induce CSC-like phenotypes formation to promote the proliferation and metastasis in MCF-7. Hence, CXCL12 may become a promising candidate for breast cancer therapy.

Qiao N, Wang L, Wang T, Li H
Inflammatory CXCL12-CXCR4/CXCR7 axis mediates G-protein signaling pathway to influence the invasion and migration of nasopharyngeal carcinoma cells.
Tumour Biol. 2016; 37(6):8169-79 [PubMed] Related Publications
This study explored whether the migration, invasion, and apoptosis of nasopharyngeal carcinoma (NPC) cells were affected by the CXCR4/CXCR7-CXCL12 axis and if this mechanism was related to G-protein signaling pathway. A total of 72 NPC patients admitted in our hospital between April 2013 and February 2015 were incorporated in this study. Immunohistochemistry was performed to compare the expression levels of CXCR4, CXCR7, and CXCL12 between NPC tissues and adjacent normal tissues. Then, the correlation analysis was implemented to assess the association among CXCR4, CXCR7, and CXCL12 expressions. Jellyfish glow protein experiment was carried out after the cultivation of CNE-2Z cell lines in order to observe the intracellular calcium mobilization resulted from G-protein activation contributed by CXCR4/CXCR7-CXCL12 axis. The impact of CXCR4/CXCR7-CXCL12 axis on the migration and invasion of NPC cells was explored using transwell experiments. Finally, the anti-apoptosis effects of CXCR4/CXCR7-CXCL12 axis on NPC cells were investigated by the splicing of poly ADP-ribose polymerase (PARP). Compared to NPC patients with low-grade (stage I-II) tumor node metastasis (TNM) and those without lymph node metastasis, the expression of CXCR4, CXCR7, and CXCL12 were significantly higher in NPC patients with high-grade (stage III-IV) TNM and those with lymph node metastasis (P < 0.05). Moreover, there was significant positive correlation between the expression level of CXCL12 and CXCR7 (r s = 0.484, P < 0.001) as well as the expression level of CXCL12 and CXCR4 (r s = 0.414, P < 0.001). As suggested by cellular experiments using CNE-2Z, the calcium mobilization degree induced by CXCR4-CXCL12 axis in activating G proteins seemed to be slightly more effective than that induced by CXCR4/CXCR7-CXCL12 axis, while the CXCR7-CXCL12 axis could hardly activate calcium mobilization. Furthermore, the transwell experiment showed that CXCR4/CXCR7-CXCL12 axis could exacerbate the migration and invasion of NPC cells (P < 0.05). The transwell experiment also suggested that the CXCR4/CXCR7-CXCL12 axis was associated with the expression of matrix metallo proteinase 9 (MMP9) which is a substance in the downstream of G-protein pathways (P < 0.05). Results from PARP shear zone also indicated that the CXCR4/CXCR7-CXCL12 axis could suppress NPC cell apoptosis (P < 0.05). The expressional levels of CXCR4, CXCR7, and CXCL12 significantly varied with clinical stages and status of lymph node metastasis of NPC patients. This revealed potential indicators which can be used for NPC prognosis. Additionally, the CXCR4/CXCR7-CXCL12 axis may regulate the expression of downstream proteins (e.g., MMP-9) through the activation of G-protein signaling pathways. These conclusions may provide key evidence for NPC aetiology which can be further investigated to develop novel molecular targets for NPC treatments.

Weidle UH, Birzele F, Kollmorgen G, Rüger R
Molecular Mechanisms of Bone Metastasis.
Cancer Genomics Proteomics. 2016 Jan-Feb; 13(1):1-12 [PubMed] Related Publications
Metastasis of breast and prostate cancer as well as multiple myeloma to the bones represents a significant medical problem. We herein discuss the molecular basis of the creation of pre-metastatic niches, the process of bone metastasis and the phenomenon of tumor dormancy in the bone marrow as well as its regulation. We describe the identification and validation of genes mediating bone metastasis by use of pre-clinical models of bone metastasis. Additionally, we discuss the role of small integrin binding N-linked glycoproteins (SIBLINGS), the chemokine/chemokine receptor CXCL12/CXCR4 pathway and the role of micro RNAs (miRNAs) as mediators of bone metastasis. Finally, we summarize clinical achievements for the treatment of bone metastases.

Li Y, Zhao L, Shi B, et al.
Functions of miR-146a and miR-222 in Tumor-associated Macrophages in Breast Cancer.
Sci Rep. 2015; 5:18648 [PubMed] Free Access to Full Article Related Publications
Tumor-associated macrophages (TAMs) play critical roles in promoting tumor progression and invasion. However, the molecular mechanisms underlying TAM regulation remain to be further investigated and may make significant contributions to cancer treatment. Mammalian microRNAs (miRNAs) have recently been identified as important regulators of gene expression that function by repressing specific target genes mainly at the post-transcriptional level. However, systematic studies of the functions and mechanisms of miRNAs in TAMs in tumor tissues are rare. In this study, miR-146a and miR-222 were shown to be significantly decreased in TAMs associated with the up-regulated NF-κB p50 subunit. miR-146a promoted the expression of some M2 macrophage phenotype molecules, and miR-146a antagomir transfected RAW264.7 monocyte-macrophage cells inhibited 4T1 tumor growth in vivo. Meanwhile, overexpression of miR-222 inhibited TAM chemotaxis, and miR-222 in TAMs inhibited 4T1 tumor growth by targeting CXCL12 and inhibiting CXCR4. These data revealed that miRNAs influence breast tumor growth by promoting the M2 type polarization or regulating the recruitment of TAMs. These observations suggest that endogenous miRNAs may exert an important role in controlling the polarization and function of TAMs in breast cancer.

Hu Y, Li S
Survival regulation of leukemia stem cells.
Cell Mol Life Sci. 2016; 73(5):1039-50 [PubMed] Related Publications
Leukemia stem cells (LSCs) are a subpopulation cells at the apex of hierarchies in leukemia cells and responsible for disease continuous propagation. In this article, we discuss some cellular and molecular components, which are critical for LSC survival. These components include intrinsic signaling pathways and extrinsic microenvironments. The intrinsic signaling pathways to be discussed include Wnt/β-catenin signaling, Hox genes, Hh pathway, Alox5, and some miRNAs, which have been shown to play important roles in regulating LSC survival and proliferation. The extrinsic components to be discussed include selectins, CXCL12/CXCR4, and CD44, which involve in LSC homing, survival, and proliferation by affecting bone marrow microenvironment. Potential strategies for eradicating LSCs will also discuss.

Long P, Sun F, Ma Y, Huang Y
Inhibition of CXCR4 and CXCR7 for reduction of cell proliferation and invasion in human endometrial cancer.
Tumour Biol. 2016; 37(6):7473-80 [PubMed] Related Publications
As one of the most common malignant cancers in female reproductive tract, endometrial cancer accounts for 20-30 % of the most frequent gynecological malignancy, which is originated from endometrial epithelial. The molecular mechanisms for the generation of endometrial cancer are up to now unclear, hindering the development of corresponding therapy. CXCR4 and CXCR7 were receptors of CXCL12 chemokine ligand, which could regulate critical procedures of neoplastic transformation, including proliferation, invasion, and apoptosis of the cells. The messenger RNA (mRNA) and protein expression levels of CXCR4 and CXCR7 in human endometrial adenocarcinoma cancer, as well as in Ishikawa and HEC-1-A cell line, were analyzed by using reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting. In order to explore the biological function of CXCR4 and CXCR7 in endometrial tumor, small interference RNAs of CXCR4 and CXCR7 fragments were designed, synthesized, and transfected into Ishikawa and HEC-1-A by using Lipofectamine2000. The influence of RNA interference (RNAi)-mediated silencing CXCR4 and CXCR7 on the cell proliferation was investigated under CCK-8. The invasion assay was performed transwell, and cell apoptosis was tested by FCM. Higher mRNA and protein expression levels of CXCR4 and CXCR7 were investigated in endometrial adenocarcinomas. The expression levels of CXCR4 and CXCR7 could be inhibited by RNA interference, reducing the cell proliferation, invasion in Ishikawa and HEC-1-A cells. In this study, we also observed that treated with CXCR4 and CXCR7 small interfering RNA (siRNA) arrested cells in S phase. CXCL12/CXCR4 and CXCL12/CXCR7 receptor ligand systems affect the invasion of endometrial carcinoma cell line into Ishikawa and HEC-1-A. CXCR4 and CXCR7 were silenced by RNAi, which can inhibit the invasion of Ishikawa and HEC-1-A cell lines. Hence, CXCR4 and CXCR7 are expected to become two target genes for the treatment of endometrial carcinoma.

Gao Q, Chen CF, Dong Q, et al.
Establishment of a neuroblastoma mouse model by subcutaneous xenograft transplantation and its use to study metastatic neuroblastoma.
Genet Mol Res. 2015; 14(4):16297-307 [PubMed] Related Publications
The aim of this study was to establish a metastatic human neuroblastoma (NB) mouse model by xenograft in order to study the metastatic mechanisms of NB. A human NB cell line was obtained from a 5-year-old patient and cultured in vitro. A suspension of these cells was subcutaneously inoculated into nude mice at the right flank next to the forelimb. The biological characteristics of the developed subcutaneous and metastatic tumors were analyzed by hematoxylin and eosin staining. The expression of the tumor marker neuron-specific enolase was determined by immunohistochemistry, and the invasive ability of metastatic tumors was examined by a Matrigel invasion assay. DNA microarray analyses were performed to examine the metastasis-related gene expression. Our results showed that tumors grew in 75% of the mice injected with NB cells and the rate of metastasis was 21%. The xenograft tumors retained the morphological and biological characteristics of the NB specimen from the pediatric patient. Neuron-specific enolase was highly expressed in both subcutaneous and metastatic tumors. The metastatic tumor cells possessed a higher invasive capability than the primary NB cells. The expression of 25 metastasis-related genes was found to be significantly altered in metastatic tumors compared to primary tumors, including RECK, MMP2, VEGF, MMP3, and CXCL12. In conclusion, we successfully established a human NB xenograft model with high tumor-bearing and metastatic rates in nude mice, providing an ideal animal model for the in vivo study of NB.

Guo J, Yu X, Gu J, et al.
Regulation of CXCR4/AKT-signaling-induced cell invasion and tumor metastasis by RhoA, Rac-1, and Cdc42 in human esophageal cancer.
Tumour Biol. 2016; 37(5):6371-8 [PubMed] Related Publications
CXC chemokines and their cognate receptors have been implicated wildly in cancer pathogenesis. In the present study, we report a critical cause relationship between CXCR4 expression and tumorigenesis in the setting of human esophageal squamous cell carcinoma (ESCC). In ESCC cells, CXCR4 expression was significantly higher than in human esophageal epithelial cells (HEEC). Reduction of CXCR4 in ESCC cells reduced cell proliferation and invasion in vitro and tumor growth in vivo. Among the potential downstream targets of CXCR4-CXCL12 are RhoA, Rac-1, and Cdc42, which are likely to contribute to the invasiveness of ESCC cells. Finally, we found that CXCR4-CXCL12/AKT axis regulates RhoA, Rac-1, and Cdc42 to modulate cell invasion and tumor metastasis. Together, these results demonstrate a role for CXCR4 in ESCC metastasis and progression and suggest potential targets for therapeutic intervention.

Xu C, Liu Y, Xiao L, et al.
The involvement of anterior gradient 2 in the stromal cell-derived factor 1-induced epithelial-mesenchymal transition of glioblastoma.
Tumour Biol. 2016; 37(5):6091-7 [PubMed] Related Publications
In recent years, it has been widely identified that the stromal cell-derived factor 1 (SDF-1) and anterior gradient 2 (AGR2) were implicated in the development of epithelial-mesenchymal transition (EMT) in a variety of cancers. However, the involvement of SDF-1-AGR2 pathway in the EMT of glioblastoma has not been investigated. In the present study, the in vitro assays were used to investigate the role of AGR2 in cell cycle, migration, and invasion. We found that the expressions of AGR2 and chemokine (C-X-C motif) receptor 4 (CXCR4) were obviously upregulated in glioblastoma cells T98G, A172, U87, and U251 than those in normal human astrocytes (NHA) (all p < 0.01), among which both U87 and U251 cells presented the highest expression (p > 0.05). Western blot revealed that SDF-1 induced the expression of p-AKT, AGR2, and EMT markers (N-cadherin, matrix metalloproteinase-2 (MMP2), and Slug) in a dose-dependent manner in U87 and U251 cells. However, the depletion of AGR2 reversed SDF-1-induced upregulation of EMT markers rather than p-AKT. Furthermore, functional analysis identified that knockdown of AGR2 induced cell cycle arrest in G0/G1 phase and suppressed the migration and invasion of U87 and U251 cells. Taken together, SDF-1-CXCR4 pathway induced the expression of AGR2 to control the progression of EMT likely via AKT pathway in the development of glioblastoma. Our findings lay a promising foundation for the SDF-1-AGR2 axis-targeting therapy in patients with glioblastoma.

Lu L, Lu M, Pei Y, et al.
Down-regulation of SDF1-α expression in tumor microenvironment is associated with aspirin-mediated suppression of the pro-metastasis effect of sorafenib in hepatocellular carcinoma.
Acta Biochim Biophys Sin (Shanghai). 2015; 47(12):988-96 [PubMed] Related Publications
Sorafenib is considered to be the first-line therapy for advanced hepatocellular carcinoma (HCC). It significantly delays tumor progression time; however, it increases the invasive and metastatic potential of HCC. Recent studies have shown that aspirin is effective in preventing and treating tumors, and the combination treatment of aspirin and sorafenib significantly suppresses sorafenib-induced intrahepatic metastasis. However, the mechanism through which aspirin suppresses the sorafenib-induced intrahepatic metastasis is still unclear. In this study, we find that sorafenib markedly increases stromal-derived factor 1-alpha (SDF1-α) expression in paratumor and intratumor tissues, and aspirin attenuates sorafenib-induced increase of SDF1-α expression in paratumor and intratumor tissues. Further studies show that SDF1-α improves cell invasion potential of HCC cells, and that AMD3100, a specific inhibitor of SDF1-α receptor CXCR4, suppresses the elevated intrahepatic metastatic potential of HCC induced by sorafenib in vivo. Collectively, this study reveals that the sorafenib-induced increase of SDF1-α expression in paratumor and intratumor microenvironments is suppressed by aspirin, which is associated with aspirin-mediated suppression of the pro-metastasis effect of sorafenib in HCC.

Cutler MJ, Lowthers EL, Richard CL, et al.
Chemotherapeutic agents attenuate CXCL12-mediated migration of colon cancer cells by selecting for CXCR4-negative cells and increasing peptidase CD26.
BMC Cancer. 2015; 15:882 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recurrence of colorectal cancer (CRC) may arise due to the persistence of drug-resistant and cancer-initiating cells that survive exposure to chemotherapy. Proteins responsible for this recurrence include the chemokine receptor CXCR4, which is known to enable CRC metastasis, as well as the cancer-initiating cell marker and peptidase CD26, which terminates activity of its chemokine CXCL12.
METHODS: We evaluated the expression and function of CXCR4 and CD26 in colon cancer cell lines and xenografts following treatment with common chemotherapies using radioligand binding, flow cytometry, immunofluorescence, and enzymatic assays.
RESULTS: 5-Fluorouracil, oxaliplatin and SN-38 (the active metabolite of irinotecan), as well as cisplatin, methotrexate and vinblastine, each caused decreases in cell-surface CXCR4 and concomitant increases in CD26 on HT-29, T84, HRT-18, SW480 and SW620 CRC cell lines. Flow cytometry indicated that the decline in CXCR4 was associated with a significant loss of CXCR4+/CD26- cells. Elevations in CD26 were paralleled by increases in both the intrinsic dipeptidyl peptidase activity of CD26 as well as its capacity to bind extracellular adenosine deaminase. Orthotopic HT-29 xenografts treated with standard CRC chemotherapeutics 5-fluorouracil, irinotecan, or oxaliplatin showed dramatic increases in CD26 compared to untreated tumors. Consistent with the loss of CXCR4 and gain in CD26, migratory responses to exogenous CXCL12 were eliminated in cells pretreated with cytotoxic agents, although cells retained basal motility. Analysis of cancer-initiating cell CD44 and CD133 subsets revealed drug-dependent responses of CD26/CD44/CD133 populations, suggesting that the benefits of combining standard chemotherapies 5-fluoruracil and oxaliplatin may be derived from their complementary elimination of cell populations.
CONCLUSION: Our results indicate that conventional anticancer agents may act to inhibit chemokine-mediated migration through eradication of CXCR4+ cells and attenuation of chemokine gradients through elevation of CD26 activity.

Abe A, Yamamoto Y, Iba S, et al.
ETV6-LPXN fusion transcript generated by t(11;12)(q12.1;p13) in a patient with relapsing acute myeloid leukemia with NUP98-HOXA9.
Genes Chromosomes Cancer. 2016; 55(3):242-50 [PubMed] Related Publications
ETV6, which encodes an ETS family transcription factor, is frequently rearranged in human leukemias. We show here that a patient with acute myeloid leukemia with t(7;11)(p15;p15) gained, at the time of relapse, t(11;12)(q12.1;p13) with a split ETV6 FISH signal. Using 3'-RACE PCR analysis, we found that ETV6 was fused to LPXN at 11q12.1, which encodes leupaxin. ETV6-LPXN, an in-frame fusion between exon 4 of ETV6 and exon 2 of LPXN, did not transform the interleukin-3-dependent 32D myeloid cell line to cytokine independence; however, an enhanced proliferative response was observed when these cells were treated with G-CSF without inhibition of granulocytic differentiation. The 32D and human leukemia cell lines each transduced with ETV6-LPXN showed enhanced migration towards the chemokine CXCL12. We show here for the first time that LPXN is a fusion partner of ETV6 and present evidence indicating that ETV6-LPXN plays a crucial role in leukemia progression through enhancing the response to G-CSF and CXCL12.

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