Chemokine receptor CXCR4 expression, function, and clinical implications in gastric cancer.
The chemokine receptor CXCR4 is associated with the biological behavior of cancer, but few studies have addressed the expression and function of CXCR4 in human gastric cancer and its impact on disease prognosis. We studied the expression of CXCR4 using RT-PCR, Western blotting, flow cytometry, and confocal microscopy in five gastric cancer cell lines. We also examined cell proliferation, migration, and anti-apoptotic activity in response to stromal cell-derived factor (SDF)-1alpha and evaluated SDF-1alpha/CXCR4 signaling pathways. Furthermore, we investigated the correlation between CXCR4 expression and the clinical features of 221 gastric cancer tissue samples. CXCR4 transcripts and proteins were detectable in all five gastric cancer cell lines. However, MKN-28, MKN-45, MKN-74, and SNU16 cells did not express membrane CXCR4. In contrast, KATO III cells expressed membrane CXCR4. In these cells, SDF-1alpha-induced migration was observed and was blocked by AMD3100, a specific inhibitor of CXCR4. SDF-1alpha induced rapid phosphorylation of Erk1/2 MAPK but did not promote phosphorylation of Stat3 or Akt. Gastric cancer tissue samples expressed CXCR4 with variable intensities. Strong CXCR4 expression was significantly associated with lymph node metastases (P=0.028) and higher stages III/IV (P=0.047), and further tended to be correlated with a reduced 5-year survival rate (42.6% vs. 53.9%; P=0.1). In conclusion, CXCR4 expression is associated with gastric cancer cell migration in vitro, and strong expression of CXCR4 by gastric cancer cells is significantly associated with lymphatic metastasis in patients with gastric cancer, suggesting that CXCR4 plays an important role during gastric cancer progression.
Lee
Hyo Jin
HJ
Department of Internal Medicine, Chungnam National University College of Medicine, Chungnam National University Hospital, Daejeon, Korea.
Kim
Seong Woo
SW
Kim
Ha Yon
HY
Li
Shengjin
S
Yun
Hwan Jung
HJ
Song
Kyu Sang
KS
Kim
Samyong
S
Jo
Deog Yeon
DY
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000368:Aged; D015153:Blotting, Western; D002455:Cell Division; D045744:Cell Line, Tumor; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D014407:Tumor Cells, Cultured
C527276:CXCR4 protein, human; D017931:DNA Primers; D019718:Receptors, CXCR4