Abstract
Epithelial-mesenchymal transition (EMT) plays a fundamental role in cancer metastasis. The ubiquitin ligase FBXW7, a general tumor suppressor in human cancer, has been implicated in diverse cellular processes, however, its role in cholangiocarcinoma (CCA) metastasis has not been identified. Here, we report a crucial role of FBXW7 in CCA metastasis by regulating EMT. Loss of FBXW7 expression was detected in CCA cells and clinical specimens. Clinicopathological analysis revealed a close correlation between FBXW7 deficiency and metastasis, TNM stage and differentiation in intrahepatic CCA and perihilar CCA. Moreover, FBXW7 silencing in CCA cells dramatically promoted EMT, stem-like capacity and metastasis both in vitro and in vivo. Conversely, FBXW7 overexpression attenuated these processes. Mechanistically, treatment with rapamycin, a mTOR inhibitor, inhibited EMT, stem-like capacity and metastasis induced by FBXW7 silencing both in vitro and in vivo. Furthermore, the expression of EMT regulating transcription factors, snail, slug and ZEB1, were also decreased markedly with rapamycin treatment. In addition, silencing ZEB1 inhibited EMT and metastasis of both CCA cells and FBXW7 deficient CCA cells, which implicated the potential role of ZEB1 in FBXW7/mTOR signaling pathway related CCA metastasis. In conclusion, our findings defined a pivotal function of FBXW7 in CCA metastasis by regulating EMT.
Highlights
Cholangiocarcinoma (CCA), the second most common primary hepatobiliary malignancy, is an epithelial cell malignancy originating from the bile ducts
FBXW7 expression deficiency correlates with IHCC and PHCC metastasis
FBXW7 is regarded as a general tumor suppressor in human cancer
Summary
Cholangiocarcinoma (CCA), the second most common primary hepatobiliary malignancy, is an epithelial cell malignancy originating from the bile ducts. The most contemporary classification based on anatomical location includes intrahepatic (IHCC), perihilar (PHCC), and distal (DCC) CCA [1]. 5-year survival for CCA patients is disappointing, the median survival is only 15 months [3] and more than two thirds of CCA patients are diagnosed with advanced stage. Dissecting the molecular mechanisms of CCAs is urgent for identifying early diagnosis and effective chemotherapy markers for CCA patients. FBXW7 (or hCdc4), a member of the F-box family of proteins, is a substrate recognition component of the Skp1-Cul1-F box protein (SCF) ubiquitin ligase complex [4, 5]. It has been shown to mediate the ubiquitin-dependent proteolysis of several well-known oncoproteins, including Notch, cyclin E1, mammalian target of rapamycin (mTOR), c-Myc, and c-Jun [6]
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