Osteopontin promoter polymorphisms at locus -443 significantly affect the metastasis and prognosis of human hepatocellular carcinoma.
Osteopontin (OPN) plays a crucial role in hepatocellular carcinoma (HCC) metastasis. However, little is known about the impact of OPN polymorphisms on cancer progression. In this study, we first identified the single nucleotide polymorphisms (SNPs) in the OPN promoter region by direct sequencing in 30 HCCs, and then evaluated the prognostic values of the selected ones in two large cohorts of 826 HCC patients. The identified SNPs were functionally analyzed using in vitro and in vivo assays and their correlations with OPN levels were also evaluated. Only SNP at locus -443 and their related haplotypes (Ht2: -1748A/-616G/-443T/-155* [*indicates base deletion]; Ht3: -1748A/-616G/-443C/-155*) were significantly associated with overall survival (OS) and time to recurrence (TTR). The patients with the -443TT/TC genotype or Ht2 had a shorter OS and TTR compared with those with -443CC genotype or Ht3. This was further confirmed in the validation cohort. Moreover, this correlation remained significant in patients with small HCCs (≤5 cm). Multivariate analyses indicated that the prognostic performance of the -443 genotypes (OS, P=0.031; TTR, P=0.005) and their related haplotypes (OS, P=0.002; TTR, P=0.001) was independent of other clinicopathological factors. The Ht2 and -443TT genotype could significantly increase the promoter transcriptional activity and expression level of OPN compared with the Ht3 or -443CC genotype, and lead to an obvious increase in both in vitro invasion and in vivo tumor growth and lung metastasis of HCC cells (P<0.05).


CONCLUSIONS
The genetic variation at locus -443 of the OPN promoter plays important roles in the regulation of OPN expression and cancer progression of HCCs, which is a novel determinant and target for HCC metastasis and prognosis.
Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China.
Qiong-Zhu
QZ
Dong
Xiao-Fei
XF
Zhang
Yue
Y
Zhao
Hu-Liang
HL
Jia
Hai-Jun
HJ
Zhou
Chun
C
Dai
Hai-Jing
HJ
Sun
Yi
Y
Qin
Wei-De
WD
Zhang
Ning
N
Ren
Qing-Hai
QH
Ye
Lun-Xiu
LX
Qin
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000556:secondary*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D053495:Osteopontin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics
C506895:SPP1 protein, human; D053495:Osteopontin