Tyrosine metabolic enzyme HPD is decreased and predicts unfavorable outcomes in hepatocellular carcinoma

Abstract

BackgroundLiver is a major metabolic organ containing many metabolic enzymes. Disorders of liver-specific enzymes can cause liver dysfunction and tumorigenesis. Previous studies indicated that 4-Hydroxyphenylpyruvate dioxygenase (HPD) plays an essential role in catalyzing the tyrosinolytic metabolism of 4-hydroxyphenylpyruvate to homogeneous acids in liver tissues. However, the clinical significance of HPD in HCC has not been obtained. Here in our study, we aimed to identify the expression and the clinical significance of HPD in hepatocellular carcinoma (HCC). MethodsWestern Blotting and qRT-PCR were employed to evaluate the level of HPD in HCC cell lines and fresh samples. The expression of HPD was further confirmed by immunohistochemistry (IHC) using a tissue microarray (TMA) cohort with a total of 778 HCC patients. Furthermore, the mRNA expression of HPD in HCC was evaluated from TCGA and GEO public databases. Kaplan-Meier analysis and univariate and multivariate Cox regression analyses were used to determine the correlation between HPD expression with clinicopathological variables and survival rate of HCC patients. The cellular behaviors of transfected cells were respectively examined by CCK8 and Migration assay. ResultsThe expression of HPD is restricted in liver compared with other cancer types. HPD mRNA and protein expression was dramatically reduced in HCC cell lines and fresh tissue samples. IHC staining in HCC TMA further showed that the decreased of HPD in paraffin-imbedded HCC samples was linked to an adverse overall postoperative survival (p < 0.001). Clinicopathologically, low expression of HPD was correlated with larger tumor size, advanced TNM staging and poor differentiaion. In addition, multivariate analyses indicated that HPD was an independent predictive factor of HCC survival. Our study pioneering validates that knockdown of HPD increases HCC cell cell growth and cell motility. ConclusionOur results suggested that HPD may serve as a valuable prognostic marker, a tumor suppressor, and a potential therapeutic target for HCC patients.