Prolyl hydroxylase domain protein 3 and asparaginyl hydroxylase factor inhibiting HIF-1 levels are predictive of tumoral behavior and prognosis in hepatocellular carcinoma

Abstract

Hypoxia-inducible factors (HIFs) are key regulators in oxygen homeostasis. Their stabilization and activity are regulated by prolyl hydroxylase domain (PHD)-1, -2, -3 and factor inhibiting HIF (FIH). This study investigated the relation between these oxygen sensors and the clinical behaviors and prognosis of hepatocellular carcinoma (HCC). Tissue microarray and RT-PCR analysis of tumor tissues and adjacent non-tumor liver tissues revealed that mRNA and protein levels of both PHD3 and FIH were lower within tumors. The lower expression of PHD3 in tumor was associated with larger tumor size, incomplete tumor encapsulation, vascular invasion and higher Ki-67 LI (p < 0.05). The lower expression of FIH in tumor was associated with incomplete tumor encapsulation, vascular invasion, as well as higher TNM stage, BCLC stage, microvascular density and Ki-67 LI (p < 0.05). Patients with reduced expression of PHD3 or FIH had markedly shorter disease-free survival (DFS), lower overall survival (OS), or higher recurrence (p < 0.05), especially early recurrence. Patients with simultaneously reduced expression of PHD3 and FIH exhibited the least chance of forming tumor encapsulation, highest TNM stage (p < 0.0083), lowest OS and highest recurrence rate (p < 0.05). Multivariate analysis indicated that a lower expression of FIH independently predicted a poor prognosis in HCC. These findings indicate that downregulation of PHD3 and FIH in HCC is associated with more aggressive tumor behavior and a poor prognosis. PHD3 and FIH may be potential therapeutic targets for HCC treatment.

Erythropoietin promoted the proliferation of hepatocellular carcinoma through hypoxia induced translocation of its specific receptor

“…That means in the tumor region, which had a higher HIF-1α level, EPO also expressed higher and cells grew faster. Although the overexpression of HIF-1α in HCC had been observed previously by us and several other groups [ 2 , 5 ], this is the first time to reveal the correlation between EPO and hypoxia in HCC.…”

“…To score the immunostaining of target proteins as we published previously [ 2 ], the intensity of IHC was classified into four categories—0, 1, 2 and 3—corresponding to no staining, weak staining, moderate staining and strong staining, respectively. The percentage of positively staining tumor cells was classified into five categories—0, 1, 2, 3 and 4—which corresponding to < 10, 10–25, 26–50, 51–75 and > 75%, respectively.…”

“…HIF-1α was scored according to the presence of nuclear staining as previously published [ 2 ]. Only cells with completely and darkly stained nuclei were interpreted as positive expression.…”

“…Statistics have shown that the annual incidence of HCC in China alone contributes to 55% of global HCC cases. Previously, we have conducted a series of clinical and basic investigations into the mechanism and treatment of HCC [ 2 – 5 ]. Unfortunately, the tumor in most HCC patients is not suitable for surgical resection and carries a very poor prognosis.…”

Hypoxia-Inducible Factor Prolyl 4-Hydroxylases and Metabolism

“…Interestingly, HIF-P4H-3 expression seems to be a favorable prognostic marker for patients with HCC [102] since its downregulation in HCC was associated with more aggressive tumor behavior and poor prognosis [103]. Altogether, the mechanisms involved in the progression of fatty liver diseases to fibrosis/cirrhosis/HCC are many and involve not only the HIF system but also the crosstalk with various other signaling pathways.…”