Platelet-derived growth factor may be a potential diagnostic and prognostic marker for cholangiocarcinoma.
Our previous report showed that platelet-derived growth factor (PDGF) and related genes were upregulated in a Syrian hamster model and could be detected in all human cholangiocarcinoma (CCA) tissues. We therefore hoped that PDGF could be used as a diagnostic and prognostic marker. We analyzed 78 samples of human CCA and adjacent tissues for PDGF and related gene expression, and localized PDGF protein expression. The mechanism of anti-cancer drugs on PDGF and related genes or proteins in CCA cell lines (OCA17, M156, and KKU100) was studied through MTT cell viability assay, quantitative real-time PCR, and immunoblotting. Mutagenesis of the PDGFRA coding region was analyzed. Moreover, the PDGFRA in sera of CCA patients and healthy controls was investigated. PDGFA was found to be upregulated in CCA tissue (84.6 %). Positive PDGFA immunohistochemical staining was significantly correlated with status (P = 0.000), stage of CCA (P = 0.013), metastasis (P = 0.017), and short survival rate (P = 0.005), and the multivariate analysis confirmed that PDGFA positive immunostaining had a higher likelihood of the risk of death (HR = 2.907, P = 0.016). For DNA point mutation of the PDGFRA sequence, silent mutations were found at tyrosine kinase 2 V824V (exon 18) and A603A (exon 13), and a missense mutation in S478P (exon 10); there was only a missense mutation in S478P (29 %) that has significant correlation with the histopathological grading (P = 0.037) and positive immunoreactive PDGFA (P = 0.021). In vitro cell line study by immunowestern blotting found that sunitinib malate had an inhibitory effect on the PDGFA pathway by decreasing p-PDGFRA, AKT, and p-AKT expression. The serum level of PDGFA in CCA patients was significantly higher than those of healthy control by 1.4-fold (P = 0.014). The present results suggest that PDGFA and PDGFRA may be used for CCA prognosis and/or as diagnostic candidate markers.
Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
Sirintip
S
Boonjaraspinyo
Thidarut
T
Boonmars
Zhiliang
Z
Wu
Watcharin
W
Loilome
Paiboon
P
Sithithaworn
Isao
I
Nagano
Somchai
S
Pinlaor
Puangrat
P
Yongvanit
Phuangphaka Sadee
PS
Nielsen
Chawalit
C
Pairojkul
Narong
N
Khuntikeo
D000368:Aged; D001483:Base Sequence; D001650:Bile Duct Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009889:Opisthorchiasis / Q000150:complications; D010982:Platelet-Derived Growth Factor / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011758:Pyrroles / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077210:Sunitinib
D014408:Biomarkers, Tumor; D007211:Indoles; D010982:Platelet-Derived Growth Factor; D011758:Pyrroles; C075278:platelet-derived growth factor A; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000077210:Sunitinib