FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells

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.

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

“…Recent studies also demonstrated that in CCA cells, the expression of FBXW7 is markedly lower compared with normal cholangiocytes. Furthermore, FBXW7 down-regulation was associated with the presence of metastasis, higher tumor stage and grade, and poor prognosis 126,127 . In CCA cells, FBXW7 loss results in increased expression and activation of its substrate mammalian target of rapamycin (mTOR), which eventually leads to increased cell migration/invasion via ZEB1-induced EMT 127,128 .…”

“…Furthermore, FBXW7 down-regulation was associated with the presence of metastasis, higher tumor stage and grade, and poor prognosis 126,127 . In CCA cells, FBXW7 loss results in increased expression and activation of its substrate mammalian target of rapamycin (mTOR), which eventually leads to increased cell migration/invasion via ZEB1-induced EMT 127,128 . Of note, mTOR involvement in EMT is a well-established concept 129,130 , and mTOR inhibition by the FDA-approved drug everolimus was actually reported to reduce CCA cell invasion, in vitro 131 .…”

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

“…Conversely, FBXW7 [127,128], thymosin β10 [129] and MAP3K4 [130] act as negative regulators of EMT through inhibition of mTOR, ERK1/2 and NFκB pathways, respectively.…”

FBXW7 Pathway Functions as a Promising Therapeutic Target of Cholangiocarcinoma

“…In an article published in Oncotarget, Yang et al [25] reported that FBXW7, a substrate recognition component of the SCF (complex of SKP1, CUL1 and F-box protein) complex, could suppress epithelialmesenchymal transition, stemness and metastatic potential of CCA cells. The expression of FBXW7 was deficient in CCA cell lines and tumor tissues compared with human intrahepatic biliary epithelial cell line and tumor adjacent tissues.…”

“…Furthermore, FBXW7 has been demonstrated to be a prognostic marker in colorectal cancer, gastric cancer, IHCC, hepatocellular carcinoma and T cell acute lymphoblastic leukemia [36][37][38][39][40], indicating FBXW7 may be measured perioperatively for making adjuvant therapeutic regimen and evaluating prognosis. Yang et al [25] demonstrated FBXW7 plays a pivotal role in suppressing CCA metastasis, which may serve as an essential clue for targeting FBXW7 pathway in CCA patients. mTOR is a well-known ubiquitination target of FBXW7 [41].…”