Abstract
Recent accumulating genomic and proteomic data suggested that decreased expression of phenazine biosynthesis-like domain-containing protein (PBLD) was frequently involved in hepatocellular carcinoma (HCC). However, there is lack of systematical investigation focusing on its expression pattern, clinical relevance, and biological function. Here, we found that PBLD was frequently decreased in HCC tissues relative to adjacent non-tumorigenic liver tissues. This decreased expression was significantly associated with poor tumor differentiation and advanced tumor stage. Kaplan-Meier analysis further showed that recurrence-free survival and overall survival were significantly worse among patients with low PBLD expression. Moreover, multivariate analyses revealed that PBLD was an independent predictor of OS and RFS. This prognostic value of PBLD was further validated in another independent cohort. We also found PBLD inhibited HCC cell growth and invasion in vitro and tumor growth in vivo. Furthermore, forced expression of PBLD influenced multiple downstream genes related to MAPK, NF-κB, EMT, and angiogenesis signaling pathways. PBLD deletion was an independent predictor of poor prognosis in patients with HCC. Elevated PBLD expression may reduce HCC cell growth and invasion via inactivation of several tumorigenesis-related signaling pathways.
Highlights
Hepatocellular carcinoma (HCC) ranks as the sixth most common cancer and the third leading cause of cancer-related mortality worldwide [1], accounting for approximately 75%-90% of malignant tumors in adult livers [2]
PBLD was frequently decreased in HCC tissues and this downregulation was significantly associated with poor prognosis of HCC patients
Using microarray analysis, we found that the antitumorigenic effects of PBLD overexpression were likely associated with the inhibition of multiple tumor progression–related signaling pathways, including vascular endothelial growth factor-A (VEGF-A), mitogen-activated protein kinase (MAPK), nuclear factor κB (NF-κB), epithelial-mesenchymal transition (EMT), angiogenesis and others, even if the precise mechanism of PBLD for tumor inhibition is yet not entirely clear and requires further study
Summary
Hepatocellular carcinoma (HCC) ranks as the sixth most common cancer and the third leading cause of cancer-related mortality worldwide [1], accounting for approximately 75%-90% of malignant tumors in adult livers [2]. As powerful molecular techniques at present, gene expression profiling and proteomics analysis have been extensively used to improve the identification of new biomarkers leading to early diagnosis and more effective therapies, and the definition of the mechanisms associated with HCC progression [6]. PBLD was significantly downregulated in HCC tissues with portal vein tumor thrombus (PVTT) and HCC recurrence compared with that without PVTT and recurrence in genomic and proteomic analyses [11, 12]. These findings suggested a potential role of PBLD in the carcinogenesis and progression of liver cancer
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