PEBP1 downregulation is associated to poor prognosis in HCC related to hepatitis B infection.
OBJECTIVE
Phosphatidylethanolamine-binding protein 1 (PEBP1, also RKIP) plays a pivotal role in cancer by regulating multiple cellular signaling processes and suppressing metastasis in animal models. We examined whether PEBP1 expression in hepatocellular carcinoma (HCC) correlated with the risk of recurrence and survival after resection.


METHODS
A randomly selected cohort of 240 Chinese HCC patients, predominantly hepatitis B related, formed the basis of the study. PEBP1 expression levels were evaluated by immunohistochemistry and real-time reverse-transcriptase PCR. Survival analysis was performed by univariate and multivariate analyses. The results were further validated in an independent series of 403 patients. The relevance of PEBP1 to phospho-ERK was determined by Western blot analysis on clinical samples and hepatoma cell lines.


RESULTS
PEBP1, prevalently down-regulated in HCC, was significantly associated with tumor invasive characteristics (such as vascular invasion, lack of encapsulation, poor differentiation and large size). Both PEBP1 protein and mRNA levels were independent predictors for tumor recurrence (hazard ratio (HR) = 1.877, p=0.001; HR = 2.633, p = 0.001; respectively), and patient survival (HR = 1.796, p = 0.004; HR = 1.730, p = 0.044; respectively). The prognostic value of PEBP1 was then confirmed in the validation cohort. In addition, Western blot suggested that loss of PEBP1 led to hyperactivity of MAPK signaling.


CONCLUSIONS
Down-regulation of PEBP1 in HCC indicated aggressive tumor behaviors and predicted a worse clinical outcome, which may be a useful biomarker to identify the patients at high risk of post-operative recurrence.
Xu
Yong-Feng
YF
Liver Cancer Institute, Zhong Shan Hospital, Fudan University, Shanghai, People's Republic of China.
Yi
Yong
Y
Qiu
Shuang-Jian
SJ
Gao
Qiang
Q
Li
Yi-Wei
YW
Dai
Chen-Xin
CX
Cai
Ming-Yan
MY
Ju
Min-Jie
MJ
Zhou
Jian
J
Zhang
Bo-Heng
BH
Fan
Jia
J
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000401:mortality; D045744:Cell Line, Tumor; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D006509:Hepatitis B / Q000150:complications*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000401:mortality; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000209:etiology; D049488:Phosphatidylethanolamine Binding Protein / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D011379:Prognosis
C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D048049:Extracellular Signal-Regulated MAP Kinases