Abstract
The phosphatidic acid phosphatase HTPAP has been defined as a metastatic suppressor of hepatocellular carcinoma (HCC), but little is known about its function or potential applications as a prognostic marker. In this study, we analyzed patterns of HTPAP genetic variation and gene expression in 864 patients who underwent HCC resection, assessing these patterns for correlations to tumor metastasis potential. Focusing on two tagSNPs that were selected (+357G/C and +1838A/G), we found that only the +357G/C genotype was significantly associated with HTPAP mRNA and protein expression levels and the probability of metastasis. In an independent cohort of 665 HCC patients, we determined that the +357G/C genotype was associated with shorter time to recurrence and overall survival. Together, these results indicated that the HTPAP tagSNP +357 GG+GC genotypes may influence HCC metastatic potential and clinical prognosis by down-regulating HTPAP expression. Extending these results, a global expression profiling analysis identified 41 genes including the pro-inflammatory genes IL-8 and TLR2 that were significantly overexpressed in the +357 GG+GC group, as possible coregulated markers with HTPAP. Together, our findings identify an HTPAP genotype and associated gene expression pattern that favors metastasis progression and that could be used to predict tumor metastasis and prognosis in HCC patients.
Highlights
Our previous studies demonstrating that chromosome 8p deletion was associated with hepatocellular carcinoma (HCC) metastasis [1,2,3,4] identified HTPAP gene as a suppressor of in vitro invasion and in vivo lung metastasis of HCC [5]
Metastasis is a complex process that is thought to be the result of multiple genetic changes that may be responsible for the increased abnormalities and selective survival advantages observed in metastatic lesions
Analysis of gene expression profiles demonstrate that activation of genes favoring HCC metastasis is initiated in primary HCCs, and the metastatic potential is predetermined in primary tumors [24]
Summary
Our previous studies demonstrating that chromosome 8p deletion was associated with hepatocellular carcinoma (HCC) metastasis [1,2,3,4] identified HTPAP gene as a suppressor of in vitro invasion and in vivo lung metastasis of HCC [5]. The official symbol of the HTPAP gene is phosphatidic acid phosphatase type 2 domain containing 1B (PPAPDC1B). HTPAP contains 7 exons and 8 introns; its full length is 4,459 bp with an 826-bp mRNA encoding a 175 amino acid protein. It is not known whether the presence of HTPAP genetic polymorphisms affects the prognosis of HCC patients.
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