OBJECTIVEThis review focuses on the state-of-the-art of CXCL12/CXCR4 signaling axis in pancreatic cancer and its role in tumor progression.

DATA SOURCESRelevant articles published in English were identified by searching in Pubmed from 1997 to 2013, with keywords "CXCL12", "CXCR4" and "pancreatic cancer". Important references from selected articles were also retrieved.

STUDY SELECTIONArticles about CXCL12/CXCR4 signaling axis in pancreatic cancer and relevant mechanisms were selected.

RESULTSPancreatic cancer has been one of the most lethal human malignancies, with median survival less than one year and overall 5-year survival only 6%. Tumor cells from pancreatic cancer express high level of CXCR4. CXCL12, the ligand for CXCR4, is extensively secreted by neighboring stromal cells and other distant organs. CXCL12 primarily binds to CXCR4, induces intracellular signaling through several divergent pathways, which are involved in progression and metastasis of pancreatic cancer.

CONCLUSIONSCXCL12/CXCR4 signaling axis may play an important role in the communication between pancreatic cancer cells and their microenvironment, which may have effect on tumor proliferation, invasion, angiogenesis, metastasis and chemoresistance. CXCL12/CXCR4 signaling axis may serves as a novel therapeutic target for pancreatic cancer.

Chemokine CXCL12 ; genetics ; metabolism ; Humans ; Pancreatic Neoplasms ; genetics ; metabolism ; Receptors, CXCR4 ; genetics ; metabolism ; Signal Transduction ; genetics ; physiology

OBJECTIVE: To investigate the role of IL-17A in promoting the activation of lung fibroblasts and the secretion of chemokine CXCL12, and to explore the possible mechanism. METHODS: Lung tissues of BALB/c mice were collected after intraperitoneal injection of recombinant mouse IL-17A (rmIL-17A). Real-time RT-PCR and Western blotting were used to detect the expression levels of α-smooth muscle actin (α-SMA) and collagen I in lung tissues, and immunohistochemical staining and real-time RT-PCR were used to determine the expression of CXCL12. Normal mouse primary lung fibroblasts were isolated and cultured, and identified by immunofluorescence staining with optical microscopy. Cells and supernatant of culture medium were collected after stimulation with rmIL-17A at different concentrations. mRNA levels of α-SMA, collagen I, and CXCL12 in the cells were determined by real-time RT-PCR, and the levels of collagen I and CXCL12 in the supernatant of culture medium were determined by ELISA. RESULTS: The mRNA and protein levels of α-SMA and collagen I in the lung tissue of mice injected with rmIL-17A were significantly increased compared with the control group (all CONCLUSIONS s: IL-17A can promote the activation of lung fibroblasts and translation into myofibroblast. The secretion of collagen is increased, which promote the deposition of extracullular matrix, and leads to the occurrence and development of lung fibrosis. CXCL12, a chemokine secreted by activated fibroblasts, may be involved in this process.
Actins/genetics* ; Animals ; Cells, Cultured ; Chemokine CXCL12/metabolism* ; Fibroblasts/metabolism* ; Interleukin-17/pharmacology* ; Lung/metabolism* ; Mice ; Mice, Inbred BALB C

BACKGROUND: There is growing evidence that 5-fluorouracil (5-FU) combined with therapeutic trauma can effectively induce skin repigmentation in vitiligo patients who are unresponsive to conventional treatments. Previous studies have mainly focused on identifying the antimitotic activity of 5-FU for the treatment of skin cancer, but few studies have investigated its extra-genotoxic actions favoring melanocyte recruitment. METHODS: We utilized the full thickness excisional skin wound model in Dct-LacZ transgenic mice to dynamically assess the migration of melanocytes in the margins of wounds treated with or without 5-FU. The in-situ expression of CXCL12 was examined in the wound beds using immunofluorescence staining. Quantitative real-time polymerase chain reaction and Western blotting analyses were performed to detect the expression levels of CXCL12 mRNA and protein in primary mouse dermal fibroblasts treated with or without 5-FU. Transwell assays and fluorescein isothiocyanate (FITC)-phalloidin staining were used to observe cell migration and filamentous actin (F-actin) changes of melan-a murine melanocytes. RESULTS: Whole mount and cryosection X-gal staining showed that the cell numbers of LacZ-positive melanocytes were much higher in the margins of dorsal and tail skin wounds treated with 5-FU compared with the controls. Meanwhile, CXCL12 immunostaining was significantly increased in the dermal compartment of wounds treated with 5-FU (control vs. 5-FU, 22.47 ± 8.85 vs. 44.69 ± 5.97, P < 0.05). Moreover, 5-FU significantly upregulated the expression levels of CXCL12 mRNA (control vs. 5-FU, 1.00 ± 0.08 vs. 1.54 ± 0.06, P < 0.05) and protein (control vs. 5-FU, 1.00 ± 0.06 vs. 2.93 ± 0.10, P < 0.05) in cultured fibroblasts. Inhibition of the CXCL12/CXCR4 axis suppressed melanocyte migration in vitro using a CXCL12 small interfering RNA (siRNA) or a CXCR4 antagonist (AMD3100). CONCLUSION 5-FU possesses a pro-pigmentary activity through activation of the CXCL12/CXCR4 axis to drive the chemotactic migration of melanocytes.
Animals ; Cell Movement ; Cell Proliferation ; Chemokine CXCL12/genetics* ; Fibroblasts ; Fluorouracil/therapeutic use* ; Humans ; Mice ; RNA, Messenger ; Receptors, CXCR4

OBJECTIVETo explore the association of CCR5δ32, CCR2-64I and SDFl-3 A gene polymorphisms with HIV-1-infection in Chinese population.

METHODSA meta-analysis was performed to identify case-control studies of CCR5δ32, CCR2-64I and SDFl-3 A polymorphisms from the literatures.

RESULTSFourteen studies of CCR5δ32 were found, involving a total of 1607 cases and 1632 controls. Compared with the wild-type homozygote wt/wt, the pooled odds ratios (95%CI) of wt/mt, mt/mt, and wt/mt+mt/mt genotypes of CCR5δ32 gene polymorphisms were 1.156 (0.808, 1.654), 0.997 (0.198, 5.022), and 1.149 (0.808, 1.634), respectively. Twelve studies of CCR2-64I were identified, including 1415 cases and 1239 controls. Compared with the wild-type homozygote wt/wt, the pooled odds ratios (95%CI) of wt/mt, mt/mt, and wt/mt+mt/mt genotypes of CCR2-64I gene polymorphisms were 1.005 (0.844, 1.197), 1.191 (0.808, 1.754), and 1.028 (0.870, 1.214), respectively. Ten studies of SDFl-3 A were found, involving 1179 cases and 1003 controls. Compared with the wild-type homozygote wt/wt, the pooled odds ratios (95%CI) of wt/mt, mt/mt, and wt/mt + mt/mt genotypes of SDF1-3 A gene polymorphisms were 1.010 (0.830, 1.228), 1.188 (0.860, 1.643), and 1.038 (0.861, 1.250).

CONCLUSIONCCR5δ32, CCR2-64I and SDFl-3 A gene polymorphisms do not show strong correlations to HIV-1-infection in Chinese population. These 3 genes may not have protective effect against HIV-1 infection in Chinese population, suggesting the susceptibility of Chinese population to the infection.

Alleles ; Asian Continental Ancestry Group ; genetics ; Chemokine CXCL12 ; genetics ; Gene Frequency ; Genotype ; HIV Infections ; genetics ; HIV-1 ; Humans ; Polymorphism, Genetic ; Receptors, CCR2 ; genetics ; Receptors, CCR5 ; genetics

Many studies have reported the relationship between CXCL12 G801A polymorphism and cancer risk, with conflicting results. In this study, we tried to clarify the possibility that this polymorphism may increase cancer risk by conducting an updated meta-analysis. PubMed and EMbase were searched for case-control studies regarding the association of the gene polymorphism and cancer risk. Data were extracted and odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of the association. Heterogeneity among articles and publication bias was also assessed. Significantly increased risk for cancer was found (A vs. G: OR=1.26, 95% CI=1.13-1.40, P<0.01; AA+AG vs. GG: OR=1.33, 95% CI=1.16-1.52, P<0.01). In subgroup analysis, statistically elevated cancer risk was found in both Asian and Caucasian populations (for Asian, AA+AG vs. GG: OR=1.74, 95% CI=1.22-2.47, P<0.01; for Caucasian, AA+AG vs. GG: OR=1.24, 95% CI=1.09-1.42, P<0.01). Our result indicated that CXCL12 G801A polymorphism is a risk factor for cancer. To validate the finding, further large-size case-control studies are warranted.
Asian Continental Ancestry Group ; genetics ; Chemokine CXCL12 ; genetics ; European Continental Ancestry Group ; genetics ; Genetic Predisposition to Disease ; Humans ; Neoplasms ; ethnology ; genetics ; pathology ; Odds Ratio ; Polymorphism, Single Nucleotide

The stromal cell-derived factor 1 (SDF-1) interacts with its receptor CXCR4 to transduction signals, playing important roles in most physiological and pathological processes. It is reported that CXCR4 is highly expressed in many kinds of hematological malignancies and closely related to the prognosis, drug resistance and relapse of diseases. The growth of tumor cells can be inhibited by the anti-SDF-1 antibody or anti- CXCR4 antibody, supporting a new way for the therapy against hematological malignancies. Their expression in relation with prognosis and drug resistance of hematological malignancies are summarized in this review.
Chemokine CXCL12 ; biosynthesis ; genetics ; Drug Resistance, Neoplasm ; genetics ; Hematologic Neoplasms ; metabolism ; pathology ; Humans ; Prognosis ; Receptors, CXCR4 ; biosynthesis ; genetics ; Signal Transduction ; Stromal Cells ; metabolism

This study was aimed to investigate the expression of SDF-1 mRNA in SDF-1 cDNA-modified human bone marrow mesenchymal stem cells (hBMSCs) before and after transfection. The hBMSCs were isolated, cultured and identified, the SDF-1-pIRES2-EGFP eukaryotic expressing vector was constructed, and then the hBMSCs were transfected with the vector encapsulated by lipofectamine 2000. The transfection efficiency was measured by observing the expression of green fluorescence protein and detecting the mRNA by RT-PCR. The results indicated that the expression of SDF-1 mRNA increased by about 20% after hBMSCs were transfected instantaneously by SDF-1-pIRES2-EGFP. It is concluded that SDF-1 cDNA eukaryotic expression vector can be instantly transfected into hBMSCs by lipofectamine 2000, but the efficiency was too low to obtain enough steady transferred hBMSCs. Other procedures should be trialed to improve the transfection efficiency.
Bone Marrow Cells ; cytology ; Chemokine CXCL12 ; genetics ; metabolism ; DNA, Complementary ; genetics ; Genetic Vectors ; Humans ; Mesenchymal Stromal Cells ; cytology ; RNA, Messenger ; genetics ; metabolism ; Transfection

OBJECTIVE: To investigate the association of CXCL12 and CXCR4 polymorphisms with the genetic risk and severity of coronary stenosis in patients with coronary artery disease (CAD). METHODS: Competitive allele specific PCR(KASP) was performed to identify the genotypes of rs2297630 and rs2322864 polymorphisms in 302 CAD patients and 302 age-and gender-matched healthy controls. The severity of CAD patients was assessed by the Gensini scoring system according to the results of coronary arteriography. The association of rs2297630 and rs2322864 polymorphisms with genetic risk of CAD and Gensini scores were analyzed by unconditional logistic regression and multivariate linear regression respectively. RESULTS: There were significant differences in the genotype and allele frequencies of both rs2297630 and rs2322864 between the CAD group and healthy control (all <0.01). Regression analysis showed that rs2297630 polymorphism was associated with genetic risk of CAD and Gensini scores (all <0.01). People who carried the AA genotype suffered higher risk of CAD susceptibility and more serious coronary stenosis (all <0.01), compared with GG genotype carriers. There was also significant association between rs2322864 polymorphism and genetic risk of CAD (<0.01); those who carried the CT genotype had higher risk of CAD (<0.01), compared with TT genotype carriers. However, rs2322864 polymorphism was not associated with the severity of coronary stenosis (>0.05). CONCLUSIONS Gene polymorphism of CXCL12 rs2297630 is associated with the genetic risk of CAD and the severity of coronary stenosis. Moreover, the gene polymorphism of CXCR4 rs2322864 is associated with genetic risk of CAD, but not with the severity of coronary stenosis.
Chemokine CXCL12 ; genetics ; Coronary Angiography ; Coronary Artery Disease ; complications ; Coronary Stenosis ; complications ; genetics ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Polymorphism, Genetic ; Receptors, CXCR4 ; genetics ; Risk Factors

OBJECTIVETo explore the spatial genetic structure of two HIV-I-resistant polymorphisms (CCR2-64 I and SDF1-3'A) alleles in the population of Shandong Province, China.

METHODSUsing the techniques of spatial stratified sampling and spatial statistics, the spatial genetic structure of the locus (CCR2-64 I and SDF1-3'A), which was shown to be important co-receptor for HIV infection, was quantified from the populations of 36 sampled counties of Shandong Province, and a total of 3147 and 3172 samples were taken for testing CCR2-64I and SDF1-3'A respectively from individuals without known history of HIV-I infection and AIDS symptoms.

RESULTSThere were significantly spatial genetic structures of the two alleles at different spatial distance classes on the scale of populations, but on the scale of individuals, no spatial structure was found in either the whole area of Shandong Province or the area of each sampled county. Although the change of frequencies of the two alleles with geographic locations in Shandong Province both showed gradual increase trends, their changing directions were inverse. The frequency of CCR2-64I allele gradually increased from the southwest to the northeast, while the frequency of SDF1-3'A allele gradually increased from the northeast to the southwest. However the RH to AIDS of combined types of their different genotypes did not represent obvious geographic diversity on the whole area of the Province.

CONCLUSIONThe frequency of allele usually has some spatial genetic structures or spatial autocorrelation with different spatial distance classes, but the genotypes of individuals have random distribution in the same geographic area. Evaluating spatial distribution of the genetic susceptibility of HIV (AIDS) to CCR2-64I and SDF1-3'A alleles, should focus on the frequencies of combined genotypes of CCR2 and SDF1 based on the two-locus genotypes of each individual rather than the frequencies of CCR2-64I and SDF1-3'A alleles.

Acquired Immunodeficiency Syndrome ; epidemiology ; genetics ; Chemokine CXCL12 ; Chemokines, CXC ; genetics ; China ; epidemiology ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; HIV-1 ; Humans ; Immunity, Innate ; genetics ; Mutation ; Polymorphism, Genetic ; Receptors, CCR2 ; Receptors, Chemokine ; genetics

This study was aimed to investigate the expression level of stromal cell derived factor-1 gene (SDF-1) in bone marrow mesenchymal stem cells (MSC) of patients with myelodysplastic syndrome (MDS). The MSC from bone marrow samples of MDS patients were isolated, cultured and expanded, the morphology and immunophenotype of MSC were analyzed. The expression levels of SDF-1 and internal reference GAPDH in MSC of MDS patients were detected by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-RT-PCR) method and were compared with expression levels of healthy donors. The results showed that the expression levels of SDF-1 in MDS patients were significantly different from those in healthy donors (1.53 +/- 0.92 vs 5.51 +/- 0.99) (P < 0.01). SDF-1 gene expression levels in bone marrow MSC of MDS patients were significantly higher than that in MSC derived from healthy donors. It is concluded that the abnormal expression of SDF-1 gene in MSC may influence the regulation of hematopoiesis of the bone marrow microenvironment in MDS patients and it is worthy of further investigation for new clue on etiological mechanism and treatment of MDS.
Adult ; Aged ; Bone Marrow Cells ; metabolism ; pathology ; Cells, Cultured ; Chemokine CXCL12 ; biosynthesis ; genetics ; Female ; Humans ; Male ; Mesenchymal Stromal Cells ; metabolism ; pathology ; Middle Aged ; Myelodysplastic Syndromes ; genetics ; metabolism ; pathology