Osteopontin promoter polymorphisms at locus -443 significantly affect the metastasis and prognosis of human hepatocellular carcinoma

Abstract

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 5 0.031; TTR, P 5 0.005) and their related haplotypes (OS, P 5 0.002; TTR, P 5 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). Conclusion: 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. (HEPATOLOGY 2013;57:1024-1034 D uring the past decades, although much progress has been achieved in the clinical management of hepatocellular carcinoma (HCC), its prognosis remains dismal. 1,2 Thus, to develop effective individualized treatments based on molecular classification is pivotal to improve the prognosis of HCC patients.Osteopontin (OPN) is a secreted noncollagenous, sialic-acid-rich, chemokine-like extracellular matrix (ECM) protein. OPN binds to avb integrins and receptors of the CD44 family to promote cell adhesion, chemotaxis, ECM degradation, angiogenesis, prevention of apoptosis, and indolent tumor growth. 3 Moreover, it plays a crucial role in determining the oncogenic potential of various cancers, contributing to tumor invasion and metastasis. [4][5][6] In HCC increased OPN levels are associated with metastasis, poor prognosis, and early tumor recurrence. [7][8][9]

New insights into molecular diagnostic pathology of primary liver cancer: Advances and challenges

“…From that HCC can be divided into the following subgroups: high invasiveness and low invasiveness; high recurrent risk and low current risk; and short-term survival and long-term survival. Many genes or protein biomarkers that have abnormal expression in HCC tissues have been recently reported as shown in Table 1 [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

OPN -443C>T Genetic Polymorphism and Tumor OPN Expression are Associated with the Risk and Clinical Features of Papillary Thyroid Cancer in a Chinese Cohort

“…OPN gene polymorphisms are associated with susceptibility and clinicopatholigical characteristics of cervical cancer in a Chinese cohort [27]. OPN promoter polymorphisms at locus -443 significantly affect the metastasis and prognosis of human hepatocellular carcinoma [28]. However, no study regarding the role of OPN in PTC has been reported.…”

The OPN Gene Polymorphism Confers the Susceptibility and Response to Ara-C Based Chemotherapy in Chinese AML Patients

“…OPN plays a crucial role in hepatocellular carcinoma (HCC) metastasis. The genetic variation at locus -443 of the OPN promoter plays important roles in the regulation of OPN expression and cancerprogression of HCCs [28]. In this study, we found that the -443C>T OPN-443C>T gene polymorphism and the susceptibility and chemotherapy response of AML.…”