Hepatocellular carcinoma(HCC) ranks as the fifth most common malignant cancer and the third leading cause of cancer-related death worldwide(1). Despite the remarkable achievements that have been attained in the treatment of hepatocellular carcinoma, the prognosis of HCC patients is generally very poor(2). Although a large number of molecules and signaling pathways involved in the development of HCC have been identified(3-6), the molecular mechanisms underlying the tumorigenesis and proliferation of HCC are still poorly understood.
Enoyl-CoA hydratase short chain 1 (ECHS1) is a critical enzyme that catalyzes the hydration of 2-trans-enoylcoenzyme A (CoA) intermediates to L-3-hydroxyacyl-CoAs, which constitutes the second step in β-oxidation pathway of fatty acid metabolism(7). Apart from its crucial roles in regulation of fatty acid metabolism, several researches have demonstrated that ECHS1 might be involved in tumor development. It has been shown that ECHS1 was frequently deleted in metastatic conjunctival melanomas(8). Several studies have reported that the expression level of ECHS1 decreases in cancer cell lines and carcinoma tissues(9-11). Downregulation of ECHS1 potentiates PP2-induced apoptosis in MCF-7 cells(12). Proteomic analysis confirmed ECHS1 as a candidate prostate cancer biomarker in prostate needle-biopsy specimens(13). ECHS1 was also identified as a candidate gene involved in human colorectal carcinogenesis(14, 15). Yan et al. identified that ECHS1 interacts with STAT3 and negatively regulates STAT3 signaling by inhibiting STAT3 phosphorylation, transcriptional activity and the subsequent target genes expression(16). Our group preciously confirmed ECHS1 as a novel binding protein of HBs and the interaction enhances HepG2 cell apoptosis by decreasing mitochondrial membrane potential (MMP) and we also screened the potential role of ECHS1 involved in HCC(17). However, the detailed molecular mechanism of ECHS1 in HCC progression remains largely unknown.
Extensive studies over past years have identified aberrant activation of epidermal growth factor receptor(EGFR) involved in pathogenesis of HCC, which causes significant changes in downstream cellular signaling cascades including PI3K/Akt/mTOR pathway, Raf/MEK/ERK pathway and alter gene expression resulting in hepatoma formation because of increased proliferation, cell-cycle progression, and apoptosis resistance(18-21). However, underlying molecular mechanism remains to be determined. In this study, our present investigation reveals that ECHS1 promotes cell proliferation of HCC dependent on EGFR pathway activation involved the PI3K/Akt and MEK/ERK signaling in vitro and vivo.
Materials and Methods
This study was approved by the Ethics Committee (No:20081009) of Zhongshan Hospital, affiliated with Xiamen University in Xiamen, Fujian Province, China. Written consent was obtained from all participants who were involved in the study. All procedures involving...