title: Autophagy promotes hepatocellular carcinoma cell invasion through activation of epithelial-mesenchymal transition.
abstract: Invasion of hepatocellular carcinoma (HCC) cells is a leading cause of intrahepatic dissemination and metastasis. Autophagy is considered to be an important mediator in the invasion of cancer cells. However, the precise contribution of autophagy to cancer cell invasion and underlying mechanisms remain unclear. Autophagy was induced in HepG2 and BEL7402 cells by starvation in Hank's balanced salt solution. Induction of autophagy inhibited the expression of epithelial markers and induced expression of mesenchymal markers as well as matrix metalloproteinase-9 stimulating cell invasion. Starvation-induced autophagy promoted the expression of epithelial-mesenchymal transition (EMT) markers and invasion in HepG2 and BEL7402 cells through a transforming growth factor-beta (TGF-β)/Smad3 signaling-dependent manner. The small interfering RNAs (siRNAs) for Atg3 or Atg7 and chloroquine inhibited autophagy of HepG2 and BEL7402 cells during starvation, resulting in suppression of EMT and diminished invasiveness of HCC cells. Administration of SIS3 also attenuated EMT and invasion of HepG2 and BEL7402 cells during starvation. Recombinant TGF-β1 was capable of rescuing EMT and invasion that was inhibited by siRNA for Atg3 and 7 in HepG2 and BEL7402 cells under starvation. These findings suggest that autophagy is critical for the invasion of HCC cells through the induction of EMT and that activation of TGF-β/Smad3-dependent signaling plays a key role in regulating autophagy-induced EMT. Inhibition of autophagy may represent a novel target for therapeutic interventions.
authors: Department of Breast Surgery, Cancer Hospital and Institute, Chongqing 400030, China.
authors: Jun
authors: J
authors: Li
authors: Bin
authors: B
authors: Yang
authors: Qi
authors: Q
authors: Zhou
authors: Yongzhong
authors: Y
authors: Wu
authors: Dan
authors: D
authors: Shang
authors: Yu
authors: Y
authors: Guo
authors: Zifang
authors: Z
authors: Song
authors: Qichang
authors: Q
authors: Zheng
authors: Jun
authors: J
authors: Xiong
mesh_terms: D001343:Autophagy / Q000187:drug effects; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D034622:RNA Interference; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics
chemical_list: D000071183:Autophagy-Related Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D002738:Chloroquine; D044763:Ubiquitin-Conjugating Enzymes; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; C455621:ATG3 protein, human