In our case, the rate of HBV infection

is 86.3% for cohort 1 and 84% for cohort 2. There were 31 non-HBV patients in cohort 1, and among them 11 and 20 belong to the high PROX1 level group and low PROX1 level group, respectively. Interestingly, there is no statistical significance for the differences in OS and TTR between these two groups (Supporting Fig. S5). Nevertheless, it is premature to reach a conclusion because the number of non-HBV patients in cohort 1 is rather small. Third, a relatively small number of HCC patients (n = 52) were included in the previous study, although statistical significance was strong (P = 0.014).[18] PROX1-mediated up-regulation of HIF-1α expression in HCC cells occurs at two levels: the activation of HIF-1α transcription and the stabilization of HIF-1α protein through prevention of HIF-1α acetylating. Although it contains a DNA binding domain located at the carboxyl Selumetinib mw terminal MK-8669 chemical structure one-third, PROX1 does not usually regulate transcription by directly binding to target gene promoter DNA. Instead,

PROX1 often serves as a coregulator for transcription factors.[22, 33] HIF-1α transcription is activated by nuclear factor kappa B (NF-κB),[34] which is, to date, not known to partner with PROX1. Therefore, how PROX1 activates HIF-1α transcription remains an interesting topic for future study. On the other hand, recruitment of HDAC1 to stabilize HIF-1α has been reported to be employed by metastasis-associated protein 1 (MTA1) in breast cancer cells.[10] Interestingly, MTA1 belongs to a family of proteins associated with tumor metastasis. The similarity between PROX1 and MTA1 in HDAC1 recruitment click here to stabilize HIF-1α suggests a possible common strategy cancer cells may utilize to achieve metastasis. Given the extremely

poor prognosis of HCC, biomarkers for improving HCC prognosis and intervention are urgently needed. According to our ROC curve analysis, tumor size and TNM stage are the most effective predictors of survival and early recurrence among postoperative HCC patients. The combination of PROX1 and HDAC1 levels appears a potentially useful predictor for survival and early recurrence. Since a high PROX1 level is an independent risk factor for poor OS and shortened TTR (Table 1), we speculate that combining PROX1/HDAC1 levels with tumor size and TNM stage may increase the predictive power. This hypothesis should be tested in a prospective study with postoperative HCC patients. From a therapeutic viewpoint, the concurrent increase in HDAC1 protein expression in HCCs with high PROX1 level suggests that inhibitors of HDAC1 might be potent drugs against HCC metastasis. On the other hand, elucidation of the molecular mechanism leading to high PROX1 expression in certain HCC patients and discovery of the means to suppress PROX1 activity may provide novel therapies for preventing HCC metastasis. Additional Supporting Information may be found in the online version of this article.