Autophagy promotes hepatocellular carcinoma cell invasion through activation of epithelial–mesenchymal transition

Abstract

Ubiquitin-conjugating enzyme E2 J2 (UBE2J2) is an ubiquitin proteasome component that responds to proteotoxic stress. We found that UBE2J2 was highly expressed in cellular protrusions of HCCLM3 metastatic hepatocellular carcinoma (HC) cells. Immunohistochemical analyses showed that UBE2J2 was expressed at higher levels in HC patient tissues than in corresponding non-tumor tissues. Because cellular protrusions are important for cell invasion, we hypothesized that UBE2J2 promotes HC cell invasion. We used chip-based surface plasmon resonance (SPR) to assess possible mechanisms of UBE2J2-regulated HCCLM3 cell invasion. We found that p-EGFR interacted with UBE2J2, and this finding was confirmed by co-immunoprecipitation analysis. UBE2J2 overexpression activated endothelial-mesenchymal transition in the non-invasive SMMC7721 HC cell line, and promoted invasion. UBE2J2 silencing reduced HCCLM3 cell invasion and endocytosis, and downregulated p-EGFR expression. p-EGFR inhibition by lapatinib reduced UBE2J2-promoted cell invasion, suggesting p-EGFR is important for UBE2J2-mediated HCCLM3 cell invasion. These findings demonstrate that endocytosis by HC cells is closely related to invasion, and may provide new anti-HC therapeutic targets. UBE2J2 may also be a novel biomarker for clinical HC diagnosis.

MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

“…18,40 Some new studies have revealed the close relationship between autophagy and the EMT. For example, Li et al 16 report that starvation-induced autophagy is critical for cellular invasion through induction of the EMT in hepatocellular carcinoma cells. Furthermore, in breast carcinoma, Akalay et al 41 show that EMT-induced tumor cell resistance to cytotoxic Tlymphocytes (CTLs) is correlated with the induction of autophagy.…”

“…In hepatocellular carcinoma cells, starvationinduced autophagy is critical for cellular invasion through induction of the EMT. 16 Furthermore, in mouse models of pulmonary metastasis of hepatocellular carcinoma cells, inhibition of autophagy has been shown to significantly decrease the incidence of pulmonary metastases in vivo. 17 Inhibition of autophagy via knockdown of autophagy related 12 (ATG12) in glioma cells does not affect cell viability, proliferation, or migration, but significantly reduces cellular invasion in a 3-dimensional (3D) organotypic model.…”

Autophagy functions on EMT in gastrulation of avian embryo

“…Several reports demonstrated that autophagy was involved in the EMT progress of some cell lines or tumor tissues, [39][40][41][42] and the embryonic EMT was similar to the transformation of cell phenotype during carcinoma progression. 43 Thus, we did perform the evaluation of E-Cadherin, N-Cadherin and laminin expression following the treatment of RAPA and 3-MA (Figs.…”

Autophagic degradation of focal adhesions underlies metastatic cancer dissemination

“…1). In combination with other recent studies showing a role for autophagy in epithelial-to-mesenchymal transition (EMT) and tumor cell invasion, 5,10 this suggests that autophagy inhibition may reduce progression to invasive disease and metastatic dissemination by blocking tumor cell motility and invasion in patients with early non-disseminated disease, although this represents a small subset of patients given the difficulties of early detection in many solid tumor types. Moreover, the mechanism that we have identified likely represents the co-opting of a normal physiological function for autophagy through focal adhesion disassembly, adding to a growing body of literature indicating that the autophagy machinery has many functions beyond its classic role in promoting cellular homeostasis and survival.…”