title: Autophagy inhibition suppresses pulmonary metastasis of HCC in mice via impairing anoikis resistance and colonization of HCC cells.
abstract: Metastasis is one of the main causes of poor prognosis for hepatocellular carcinoma (HCC), which has been linked to cell-death resistance. Autophagy is an important survival mechanism under conditions of cell stress. We hypothesized that autophagy may play a role in HCC metastasis due to its prosurvival effect. Highly metastatic HCC cell lines with stable autophagy inhibition were established via lentivirus-mediated silencing of BECN1 and ATG5 genes. Mouse models of pulmonary metastasis were then developed using the cells with or without autophagy inhibition. The analysis of lung metastasis by histopathological examination and small animal imaging showed that autophagy inhibition significantly decreased the incidence of pulmonary metastases in vivo. Further invasion, migration, detachment, lung colonization, and epithelial-mesenchymal transition (EMT) assays indicated that autophagy inhibition did not affect cell invasiveness, migration or EMT but attenuated the anoikis-resistance and lung colonization of HCC cells. Investigation of the molecular mechanisms underlying showed that the autophagy-inhibition-mediated anoikis-resistance attenuation was associated with the regulation of apoptotic signaling. As autophagy inhibition was shown to be able to suppress HCC metastasis, an autophagy-based HCC tissue-specific target therapy system (AFP-Cre/LoxP-shRNA) was constructed. In vitro and in vivo analyses showed that the system was able to efficiently inhibit autophagy of HCC cells and tissue in a tissue-specific manner. Further in vivo metastasis assay showed that intratumoral administration of the system could significantly suppress lung metastasis. Together, our findings suggest that autophagy may be involved in HCC metastasis through facilitating anoikis resistance and lung colonization of HCC cells. Autophagy-based HCC tissue-specific target therapy may be a new strategy for the management of HCC metastasis.
authors.affiliation: Department of Liver Surgery; Liver Cancer Institute; Zhongshan Hospital; Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education; Shanghai, China.
authors.forename: Yuan-Fei
authors.initials: YF
authors.lastname: Peng
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Shi
authors.forename: Zhen-Bin
authors.initials: ZB
authors.lastname: Ding
authors.forename: Ai-Wu
authors.initials: AW
authors.lastname: Ke
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Gu
authors.forename: Bo
authors.initials: B
authors.lastname: Hui
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: Shuang-Jian
authors.initials: SJ
authors.lastname: Qiu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Dai
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
mesh_terms: D000818:Animals; D023102:Anoikis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D008175:Lung Neoplasms / Q000235:genetics / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering
keywords: autophagy; hepatocellular carcinoma; metastasis; target therapy; tissue-specific