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). 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)

[1]  O. Shaker,et al.  Single-nucleotide polymorphism in the promoter region of the osteopontin gene at nucleotide -443 as a marker predicting the efficacy of pegylated interferon/ribavirin-therapy in Egyptians patients with chronic hepatitis C. , 2012, Human immunology.

[2]  J. Marrero,et al.  Identification of osteopontin as a novel marker for early hepatocellular carcinoma , 2012, Hepatology.

[3]  Laura Straub.  Beyond the Transcripts: What Controls Protein Variation? , 2011, PLoS biology.

[4]  Hidenori Ojima,et al.  High-resolution characterization of a hepatocellular carcinoma genome , 2011, Nature Genetics.

[5]  M. Stratton.  Exploring the Genomes of Cancer Cells: Progress and Promise , 2011, Science.

[6]  V. Bansal,et al.  The importance of phase information for human genomics , 2011, Nature Reviews Genetics.

[7]  R. Makino,et al.  Cyclooxygenase‐2 gene promoter polymorphisms affect susceptibility to hepatitis C virus infection and disease progression , 2010, Hepatology research : the official journal of the Japan Society of Hepatology.

[8]  Q. Ye,et al.  Thrombin is a therapeutic target for metastatic osteopontin‐positive hepatocellular carcinoma , 2010, Hepatology.

[9]  E. Liu,et al.  A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci , 2010, Nature Genetics.

[10]  S. Juo,et al.  The impact of osteopontin promoter polymorphisms on the risk of calcium urolithiasis. , 2010, Clinica chimica acta; international journal of clinical chemistry.

[11]  Kuo-Wei Chang,et al.  The implication of osteopontin (OPN) expression and genetic polymorphisms of OPN promoter in oral carcinogenesis. , 2010, Oral oncology.

[12]  G. Kundt,et al.  The functional −443T/C osteopontin promoter polymorphism influences osteopontin gene expression in melanoma cells via binding of c‐Myb transcription factor , 2009, Molecular carcinogenesis.

[13]  Jie Chen,et al.  Lentiviral‐mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma , 2008, Hepatology.

[14]  Xin Tong,et al.  Down-regulation of osteopontin suppresses growth and metastasis of hepatocellular carcinoma via induction of apoptosis. , 2008, Gastroenterology.

[15]  R. Weinberg,et al.  Systemic Endocrine Instigation of Indolent Tumor Growth Requires Osteopontin , 2008, Cell.

[16]  Q. Ye,et al.  Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. , 2007, Journal of hepatology.

[17]  K. Kleesiek,et al.  SPP1 promoter polymorphisms: identification of the first modifier gene for pseudoxanthoma elasticum. , 2007, Clinical chemistry.

[18]  Chien-Jen Chen,et al.  Elevated plasma osteopontin associated with gastric cancer development, invasion and survival , 2006, Gut.

[19]  F. Campbell,et al.  The regulation and role of osteopontin in malignant transformation and cancer. , 2006, Cytokine & growth factor reviews.

[20]  S. Cho,et al.  Elevated Plasma Osteopontin Levels in Patients with Hepatocellular Carcinoma , 2006, The American Journal of Gastroenterology.

[21]  V. Bramwell,et al.  Serial Plasma Osteopontin Levels Have Prognostic Value in Metastatic Breast Cancer , 2006, Clinical Cancer Research.

[22]  P. Nelson,et al.  Increased expression of osteopontin contributes to the progression of prostate cancer. , 2006, Cancer research.

[23]  M. Nagano,et al.  SNPs in the promoter region of the osteopontin gene as a marker predicting the efficacy of interferon-based therapies in patients with chronic hepatitis C , 2005, Journal of Gastroenterology.

[24]  R. Ravazzolo,et al.  Two single-nucleotide polymorphisms in the 5' and 3' ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus. , 2005, Arthritis and rheumatism.

[25]  M. Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[26]  R. Ravazzolo,et al.  Polymorphisms in the osteopontin promoter affect its transcriptional activity. , 2004, Physiological genomics.

[27]  G. Gores,et al.  Diagnosis and staging of hepatocellular carcinoma. , 2004, Gastroenterology.

[28]  M. Nagano,et al.  Genetic polymorphims in promoter region of osteopontin gene may be a marker reflecting hepatitis activity in chronic hepatitis C patients. , 2004, Biochemical and biophysical research communications.

[29]  X. Wang,et al.  Predicting hepatitis B virus–positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning , 2003, Nature Medicine.

[30]  L. Qin,et al.  High‐lose and long‐term therapy with interferon‐alfa inhibits tumor growth and recurrence in nude mice bearing human hepatocellular carcinoma xenografts with high metastatic potential , 2000, Hepatology.

[31]  T. Ishida,et al.  Structure of the Osteopontin Gene and Its Promoter a , 1995, Annals of the New York Academy of Sciences.

[32]  O. Mcbride,et al.  cDNA cloning, mRNA distribution and heterogeneity, chromosomal location, and RFLP analysis of human osteopontin (OPN). , 1990, Genomics.

[33]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[34]  D. Woodfield.  Hepatocellular carcinoma. , 1986, The New Zealand medical journal.

[35]  M. Stephens,et al.  Accounting for Decay of Linkage Disequilibrium in Haplotype Inference and Missing-data Imputation , 2022 .