• The Journal of the Korean bone and joint tumor society
• /
• v.18 no.1
• /
• pp.20-27
• /
• 2012

Purpose: The chemokine receptor CXCR4 has been reported to be aberrantly expressed in human cancer and has been shown to participate in cancer metastasis. We compared the expression of CXCR4 in conventional high-grade and low-grade central osteosarcomas, and determined if an association between CXCR4 expression and prognosis could be made. Materials and Methods: We performed the immunohistochemistry for CXCR4 in a total of 63 patients with osteosarcoma and determined the relationships according to the clinicopathologic variables and overall survival rates. Results: CXCR4 was detected in 76.3% of conventional high-grade osteosarcoma patients and in 36% of low-grade central osteosarcomas. Diffuse expression was noted in 47.4% of the high-grade osteosarcomas and all low-grade cases were focal positive. CXCR4 expression was significantly correlated with histologic grade (p<0.0001). While overall survival rate was reduced significantly with increased CXCR4 expression (p=0.0058), higher histologic grade (p<0.0001), and younger age (p=0.0140), survival rate did not correlate with gender, tumor size, or AJCC stage. Conclusion: Our results suggest that CXCR4 expression is associated with higher-grade tumors and with poor prognosis for osteosarcoma patients.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.17
• /
• pp.7201-7205
• /
• 2014

Chemokine and chemokine receptor expression by tumor cells contributes to tumor growth and angiogenesis and thus these factors may be considered as tumor markers. Here we aimed to characterize cells directly extracted from glioma, meningioma, and secondary brain tumors as well as non-tumoral cells in vitro. Cells were isolated from brain tissues using 0.2% collagenase and characterized by flow cytometry. Expression of SDF-1, CXCR4, CXCR7, RANTES, CCR5, MCP-1 and IP-10 was defined using flow cytometry and qRT-PCR methods. Brain tissue isolated cells were observed as spindle-shaped cell populations. No significant differences were observed for expression of SDF-1, CXCR4, CXCR7, RANTES, CCR5, and IP-10 transcripts. However, the expression of CXCR4 was approximately 13-fold and 110-fold higher than its counterpart, CXCR7, in meningioma and glioma cells, respectively. CXCR7 was not detectable in secondary tumors but CXCR4 was expressed. In non tumoral cells, CXCR7 had 1.3-fold higher mRNA expression than CXCR4. Flow cytometry analyses of RANTES, MCP-1, IP-10, CCR5 and CXCR4 expression showed no significant difference between low and high grade gliomas. Differential expression of CXCR4 and CXCR7 in brain tumors derived cells compared to non-tumoral samples may have crucial impacts on therapeutic interventions targeting the SDF-1/CXCR4/CXCR7 axis.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.12
• /
• pp.4893-4896
• /
• 2014

Background: Recent reports have shown that C-X-C chemokine receptor 4 (CXCR4) plays an important role in metastasis. Despite a clear understanding of the protein's structure and properties, its functional role remains elusive. We conducted the present study to evaluate the expressions of CXCR4 in pancreatic cancer, and to investigate its relationship with clinicopathological parameters, especially perineural invasion(PNI). Materials and Methods: The association between CXCR4 expression and perineural invasion was determined by immunohistochemistry in pancreatic cancer patients (n=51). Results: CXCR4 expression was correlated with the existence of PNI and the type of PNI (p=0.042, p=0.040). TIMP-2 expression was also correlated with the existence, the pathway and degree of PNI (p=0.000, p=0.006, p=0.000). Conclusions: Our results suggest an association between PNI and expression of CXCR4 and TIMP-2 in pancreatic cancer. CXCR4 may promote the occurrence of PNI in pancreatic cancer cells by decreasing the inhibition of TIMPs on MMP.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.9
• /
• pp.4077-4080
• /
• 2015

The chemokine receptor 4 (CXCR4) has been widely used in diagnosis and prognosis of colorectal cancer (CRC). However, there is no current consensus on the impact of CXCR4 on CRC patients. The purpose of this study was to evaluate the prognostic and clinicopathological importance of CXCR4 in CRC patients. Databases, such as PubMed, Cochrane library, CBM and EMBASE updated to 2014 were searched to include eligible articles. We analysed correlations between CXCR4 expression and clinicopathological features and overall survival (OS). A total of 1, 055 CRC patients from twelve studies were included in the study. The pooled odds ratios (ORs) which indicated CXCR4 expression was likely to be associated with TNM stage (OR=0.43, CI=0.34-0.55, P<0.00001), lymph node status (OR=2.23, CI=1.23-4.05, P=0.008) and vascular invasion (OR=2.21, CI=1.11-4.39, P=0.02). Poor overall survival of CRC cancer was found to be significantly related to CXCR4 overexpression (hazard ratio (HR) 1.36 CI=1.17-1.59, P<0.0001), whereas combined ORs revealed that CXCR4 expression had no correlation with gender or differentiation. Based on the published studies, CXCR4 overexpression in patients w ith CRC indicates poor survival outcome and clinicopathological factors.

• BMB Reports
• /
• v.47 no.1
• /
• pp.33-38
• /
• 2014

The chemokine receptor 4 (CXCR4) plays an important role in the growth, angiogenesis and metastasis of various cancers, including epithelial ovarian cancer (EOC). However, the correlation between CXCR4 and the clinical response of EOC patients to chemotherapy remains unknown. 124 EOC patients were recruited to assess the relationship between CXCR4 and the response to cisplatin-based chemotherapy. The results showed that patients with a higher CXCR4 expression had a significantly lower chemosensitivity, a poorer progression-free survival and a lower overall survival than those with lower CXCR4 expression. In addition, knockdown of CXCR4 by small interfering RNA suppressed cell proliferation and resulted in G1/S arrest, increased apoptosis and chemosensitivity in both cisplatin-sensitive A2780 cells and cisplatin-resistant cell A2780/cis in vitro. Our data suggest that CXCR4 is one of the key molecules in cisplatin-based chemotherapy for EOC patients and that CXCR4 inhibition is a potential strategy to address the chemoresistance of EOC.

• Journal of Pathology and Translational Medicine
• /
• v.52 no.6
• /
• pp.369-377
• /
• 2018

Background: Chemokine receptor CXC chemokine receptor type 4 (CXCR4) and its ligand CXC motif chemokine 12 (CXCL12; stromal cell-derived factor-1) are implicated in tumor growth, metastasis, and tumor cell-microenvironment interaction. A number of studies have reported that increased CXCR4 expression is associated with worse prognosis in triple-negative breast cancer (TNBC), but its prognostic significance has not been studied in TNBC patients treated with adjuvant chemotherapy. Methods: Two hundred eighty-three TNBC patients who received adjuvant chemotherapy were retrospectively analyzed. Tissue microarray was constructed from formalin-fixed, paraffin-embedded tumor tissue and immunohistochemistry for CXCR4 and CXCL12 was performed. Expression of each marker was compared with clinicopathologic characteristics and outcome. Results: High cytoplasmic CXCR4 expression was associated with younger age (p=.008), higher histologic grade (p=.007) and lower pathologic stage (p=.045), while high CXCL12 expression was related to larger tumor size (p=.045), positive lymph node metastasis (p=.005), and higher pathologic stage (p=.017). The patients with high cytoplasmic CXCR4 experienced lower distant recurrence (p=.006) and better recurrence-free survival (RFS) (log-rank p=.020) after adjuvant chemotherapy. Cytoplasmic CXCR4 expression remained an independent factor of distant recurrence (p=.019) and RFS (p=.038) after multivariate analysis. Conclusions: High cytoplasmic CXCR4 expression was associated with lower distant recurrence and better RFS in TNBC patients treated with adjuvant chemotherapy. This is the first study to correlate high CXCR4 expression to better TNBC prognosis, and the underlying mechanism needs to be elucidated in further studies.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.3
• /
• pp.1073-1076
• /
• 2015

Background: To explore the relationship between CXCR4, CD133 co-expression and clinicopathological features as well as prognosis of patients with phase II~III colon cancer. Materials and Methods: Forty-nine paraffin-embedded samples of tumor tissue and epithelial tissue adjacent to cancer were collected from patients with colon cancer undergoing radical surgery in Baotou Cancer Hospital from January, 2010 to June, 2011. CXCR4 and CD133 expression was detected using immunohistochemistry and its relationship with clinicopathological features and the 3-year survival rate was analyzed. Results: In the tumor tissue and colonic epithelial tissue adjacent to cancer, the positive expression rates of CXCR4 were respectively 61.2% (30/49) and 8.16% (4/49), while those of CD133 being 36.7% (18/49) and 6.12% (3/49). CXCR4 and CD133 expression in tumor tissue was not related to patient age, gender, primary focal sites, tumor size, TNM staging, histological type, tumor infiltration depth and presence or absence of lymphatic metastasis, but CXCR4 and CD133 co-expression was associated with TNM staging and lymphatic metastasis. The 3-year survival rate of patients with CXCR4 and CD133 co-expression was 27.3% (3/11), and that of the remainderwas 76.3% (29/38), the difference being significant ($X^2=7.0206$, p=0.0081). Conclusions: CXCR4 and CD133 co-expression may be a risk factor for poor prognosis of patients with stage II~III colon cancer.

• BMB Reports
• /
• v.49 no.9
• /
• pp.502-507
• /
• 2016

To examine the effect of TBMS1on breast cancer metastasis, and investigate the potential mechanism by which Tubeimoside-1 (TBMS1) inhibits the CXCR4 expression in breast cancer cells. The expression of CXCR4 in breast cancer cell lines was determined by immunoblotting and real-time PCR. The effect of TBMS1 on NF-κB binding activity was evaluated by EMSA assay and ChIP analysis. Cell proliferation and invasion were analyzed by MTT assay and transwell invasion assay, respectively. The effect of TBMS1 on breast cancer metastasis was further evaluated in a metastasis model of nude mice. TBMS1 suppressed the expression of CXCR4 through inhibition of NF-κB binding activity. TBMS1 inhibited CXCL12-induced invasion in breast cancer cells, while ectopic expression of CXCR4 abolished the inhibitive activity of TBMS1. TBMS1 suppressed breast cancer metastasis in the metastatic model of nude mice. TBMS1 suppressed the CXCR4-mediated metastasis of breast cancer by inhibiting NF-κB binding activity.

• Journal of Integrative Natural Science
• /
• v.10 no.4
• /
• pp.209-215
• /
• 2017

CXC chemokine receptor 2 (CXCR2) is a prominent chemokine receptor on neutrophils. CXCR2 antagonist may reduce the neutrophil chemotaxis and alter the inflammatory response because the neutrophilic inflammation in the lung diseases is found to be largely regulated through CXCR2 receptor. Hence, in the present study, Topomer based Comparative Molecular Field Analysis (Topomer CoMFA) was performed on a series of CXCR2 antagonist named pyrimidine-5-carbonitrile-6-alkyl derivatives. The best Topomer COMFA model was obtained with significant cross-validated correlation coefficient ($q^2$ = 0.487) and non cross-validated correlation coefficients ($r^2$ = 0.980). The model was evaluated with six external test compounds and its $r^2{_{pred}}$ was found to be 0.616. The steric and electrostatic contribution map show that presence of bulkier and electropositive group around cyclopropyl ring may contribute more for improving the biological activities of these compounds. The generated Topomer CoMFA model could be helpful for future design of novel and structurally related CXCR2 antagonists.

• Molecules and Cells
• /
• v.40 no.7
• /
• pp.476-484
• /
• 2017

C-X-C chemokine receptor 4 (CXCR4) stimulates cancer metastasis. NF-${\kappa}B$ regulates CXCR4 expression in cancer cells, and O-GlcNAc modification of NF-${\kappa}B$ promotes its transcriptional activity. Here, we determined whether CXCR4 expression is affected by O-GlcNAcylation of NF-${\kappa}B$ in lung metastasis of cervical cancer. We found elevated levels of O-linked-N-actylglucosamine transferase (OGT) and O-GlcNAcylation in cervical cancer cells compared to those in non-malignant epithelial cells and detected increased expression of NF-${\kappa}B$ p65 (p65) and CXCR4 in cervical cancer cells. Knockdown of OGT inhibited the O-GlcNAcylation of p65 and decreased CXCR4 expression levels in HeLa cells. Thiamet G treatment increased O-GlcNAcylated p65, which subsequently enhanced CXCR4 expression levels. Inhibition of O-GlcNAcylation by 6-Diazo-5-oxo-L-norleucine (DON) treatment decreased p65 activation, eventually inhibiting CXCR4 expression in HeLa cells. Lung tissues from mice engrafted with OGT-knockdown HeLa cells (shOGT) exhibited lower expression of Ki-67 and HPV E6 and E7 oncogenes compared to lung tissues from mice engrafted with control HeLa cells (shCTL). In addition, lung tissues from mice engrafted with shOGT cells exhibited lower p65 and CXCR4 immunoreactivity compared to tissues from mice engrafted with shCTL cells. Taken together, our data suggest that p65 O-GlcNAcylation promotes lung metastasis of cervical cancer cells by activating CXCR4 expression.