| 1.Background and Aims:Hepatocellular carcinoma (HCC) is one of the most prevalent malignant neoplasmsworld-wide，and the second leading cause of cancer-related deaths in China， HCCmortality ranks the first in some suburban areas in China. In the newly happened500-600thousand HCC per year in the world,42.5%occurred in China. Current standard practicesfor HCC treatment, which include surgical resection and liver transplantation, are less thansatisfactory due to high recurrence rates. Recently, several proteins and signaling pathwayshave been shown to correlate with the prognosis of HCC patients. Because the mechanismunderlying metastasis and recurrence is not thoroughly understood, the continued searchfor molecular markers that predict recurrence is essential.Fibroblast growth factor-inducible14(Fn14) is a14-kDA type I transmembranereceptor with its gene located at chromosome16p13. It belongs to the TNF receptorsuperfamily and has the shortest cytoplasmic domain: only28amino acids. Fn14andTNF-like weak inducer of apoptosis (TWEAK) are a TNF superfamily receptor-ligand pair;this pathway has pleiotropic effects, mediating pro-inflammatory and pro-angiogenicactivity as well as stimulating invasion, migration, and survival. Fn14lacks a death domain and contains the PIEET canonical TRAF (tumor necrosis factor receptor associatedfactors)-binding sequence that can recruit TRAF adapter proteins via the binding ofTRAF-1,2,3and5, and then activate the downstream signaling pathways of NF-κB aswell as the MAPK and AKT pathway. There is increasing evidence that Fn14expression iselevated in a variety of human tumors, such as breast cancer, malignant glioma, esophagealadenocarcinoma, and pancreatic cancer, and its overexpression is associated with poorclinical outcome. Fn14expression is enhanced in glioma cells migrating at the rimcompared with core cells and is up-regulated in patient-derived glioblastoma cells isolatedfrom the tumor rim compared with matched core; in addition, the role of Fn14in gliomacell motility was associated with the activation of Rac1and NF-κB signaling pathway.Moreover, Wang et al.reported that Fn14was one of the12genes that most specificallycorrelated with disease progression, with the highest levels of expression detected inesophageal adenocarcinoma. Willis et al.reported that a positive correlation was identifiedbetween Fn14expression and breast tumor metastasis, positive lymph node status, andHER2-positive/ER-negative breast tumors. In vitro, Fn14/TWEAK signaling pathwaycan protect glioma cells cultured with cytotoxic agents from apoptosis by inducing Bcl-2family members. It also promotes the invasion of breast tumors by up-regulating matrixexpression of MMP-9.As early as2000, a study reported that Fn14overexpression was mainly found in thepoorly differentiated HCC cell lines. Furthermore, another study reported that theTWEAK/Fn14pathway promoted the proliferation of multiple hepatocellular carcinoma cell lines in vitro. A recent investigation demonstrated that the TWEAK/Fn14pathway canstimulate liver progenitor cell (LPC) mitosis in the rapid growth phase of the LPC responseto choline-deficient, ethionine-supplemented (CDE) diet-induced injury and re-generationin vivo. The above data support the hypothesis that Fn14plays a role in tumor cell invasionin HCC. However, the correlation between Fn14expression level and the clinicalprognosis of HCC has not been examined. This study evaluates the clinical significance ofFn14in HCC patients after curative resection.2.Materials and Methods:Real-time PCR (RT-PCR) and western blot assays were performed to detect Fn14gene expression in paired liver samples to evaluate the difference in Fn14expressionbetween HCC and normal liver tissue. This study then employed a tissue microarraycontaining samples from260HCC patients with different types of portal vein tumorthrombosis (PVTT) to examine the expression of Fn14and its correlation with otherclinicopathological characteristics, tumor recurrence, and patient survival.3.Results:The expression of Fn14was markedly higher in HCC tumors than in normal livertissue. Particularly high Fn14expression was observed in tumors with high serum AFPlevels and multiple tumor nodes. A retrospective study of260patients undergoing curativeresection indicated that Fn14expression was an independent factor affecting recurrenceand survival. The clinical outcome was consistently worse for the Fn14highgroup than forthe Fn14lowgroup in the1-,3-and5-year overall survival rates (OS) and in the1-,3-and 5-year cumulative recurrence rates.4.Conclusions:Fn14overexpression in HCC is strongly correlated with poor surgical outcome, andthis molecule may be a candidate biomarker for prognosis as well as a target for therapy. |
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