Up-regulated expression of sulfatases (SULF1 and SULF2) as prognostic and metastasis predictive markers in human gastric cancer.
Gastric cancer (GC) is the fourth most common cancer worldwide. In spite of the mortality incidence associated with GC, no reliable prognostic biomarkers are currently available for this malignancy. The sulfatases (or SULFs), SULF1 and SULF2, play a critical role in the pathogenesis of a variety of human cancers. We sought to evaluate the potential of SULFs as biomarkers for GC. Thirty pairs of GC and corresponding normal tissues were analysed for the expression and methylation status of SULFs. Furthermore, the functional role of SULF overexpression was investigated in GC cell lines and tumour xenograft animal models. Lastly, we validated the expression of SULF1 protein in a large cohort of 450 GC patients. GC tissues showed conspicuously higher expression of SULF1 (p = 0.0002) and SULF2 (p = 0.001) compared to normal mucosa, which was correlated with its promoter hypomethylation. Furthermore, high expression of SULFs caused marked acceleration in the growth of xenograft tumours in nude mice. The expression of SULF1 protein significantly correlated with higher recurrence rates (p = 0.0002) and worse overall survival (p < 0.0001) in GC patients. Multivariate analysis revealed that SULF1 is an independent prognostic (p = 0.0123) and lymph node metastasis predictive factor (p = 0.0003) in patients with GC. We provide novel evidence that hypomethylation of promoter CpG islands within SULF genes imparts them with oncogenic potential in GC. Moreover, our data suggest that SULF1 may serve as a promising biomarker for patients with GC.
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Keun
K
Hur
Tae-Su
TS
Han
Eun-Jung
EJ
Jung
Jieun
J
Yu
Hyuk-Joon
HJ
Lee
Woo Ho
WH
Kim
Ajay
A
Goel
Han-Kwang
HK
Yang
D000230:Adenocarcinoma / Q000175:diagnosis / Q000201:enzymology* / Q000401:mortality; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008875:Middle Aged; D009367:Neoplasm Staging; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology; D011379:Prognosis; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000401:mortality; D013429:Sulfatases; D015238:Sulfotransferases / Q000378:metabolism*; D015996:Survival Rate; D046888:Tissue Array Analysis; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D014408:Biomarkers, Tumor; C470791:SULF1 protein, human; D015238:Sulfotransferases; C470792:SULF2 protein, human; D013429:Sulfatases