Autophagy inhibition suppresses pulmonary metastasis of HCC in mice via impairing anoikis resistance and colonization of HCC cells

Peng, Yuan‐Fei; Shi, Ying‐Hong; Ding, Zhen–Bin; Ke, Ai–Wu; Gu, Chengyu; Hui, Bo; Zhou, Jian; Qiu, Shuang–Jian; Dai, Zhi; Fan, Jia

doi:10.4161/auto.26398

Cited by 246 publications

(210 citation statements)

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“…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. Thus, autophagy may play a critical role in the benign-to-malignant transition that is central to the initiation of metastasis.…”

Section: Introductionmentioning

confidence: 99%

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

Xiao

Liu

et al. 2015

Autophagy

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(2015) MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation, Autophagy, 11:12, 2213-2232, DOI: 10.1080/15548627.2015 LG, low glucose; MAP1LC3B/LC3B, microtubuleassociated protein 1 light chain 3B; MU, mutation; NC, negative control; NSC, neural stem cell; oe, overexpressing; OS, overall survival; PFS, progression-free survival; qRT-PCR, quantitative real-time reverse transcription polymerase chain reaction; SNAI2, Slug (snail family zinc finger 2); SNAI1, snail (snail family zinc finger 1); TEM, transmission electron microscopy; TMZ, temozolomide; VIM, vimentin; WT, wild type; ZEB1, zinc finger E-box binding homeobox 1.The epithelial-to-mesenchymal (-like) transition (EMT), a crucial embryonic development program, has been linked to the regulation of glioblastoma (GBM) progression and invasion. Here, we investigated the role of MIR517C/miR-517c, which belongs to the C19MC microRNA cluster identified in our preliminary studies, in the pathogenesis of GBM. We found that MIR517C was associated with improved prognosis in patients with GBM. Furthermore, following treatment with the autophagy inducer temozolomide (TMZ) and low glucose (LG), MIR517C degraded KPNA2 (karyopherin alpha 2 [RAG cohort 1, importin alpha 1]) and subsequently disturbed the nuclear translocation of TP53 in the GBM cell line U87 in vitro. Interestingly, this microRNA could inhibit autophagy and reduce cell migration and infiltration in U87 cells harboring wild-type (WT) TP53, but not in U251 cells harboring mutant (MU) TP53. Moreover, the expression of epithelial markers (i.e., CDH13/T-cadherin and CLDN1 [claudin 1]) increased, while the expression of mesenchymal markers (i.e., CDH2/N-cadherin, SNAI1/Snail, and VIM [vimentin]) decreased, indicating that the EMT status was blocked by MIR517C in U87 cells. Compared with MIR517C overexpression, MIR517C knockdown promoted infiltration of U87 cells to the surrounding structures in nude mice in vivo. The above phenotypic changes were also observed in TP53 +/+ and TP53 -/-HCT116 colon cancer cells. In summary, our study provided support for a link between autophagy and EMT status in WT TP53 GBM cells and provided evidence for the signaling pathway (MIR517C-KPNA2-cytoplasmic TP53) involved in attenuating autophagy and eliminating the increased migration and invasion during the EMT.

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Section: Introductionmentioning

confidence: 99%

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

Xiao

Liu

et al. 2015

Autophagy

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“…These results suggest that, once the tumor cells are present in the lung, autophagy is not essential for survival. An earlier study of hepatocellular carcinoma demonstrated that autophagy was required for lung colonization due to anoikis resistance; however, the authors also noted that autophagic activity was more apparent in early-stage lesions (Peng et al, 2013).…”

Section: Autophagy Inhibition Delays Early Metastatic Disease Discussionmentioning

confidence: 97%

“…Autophagy is induced in detached breast cancer epithelial cells and is necessary for their continued survival (Fung et al, 2008). In a model of hepatocellular carcinoma, autophagy inhibition did not alter invasion or migration, but could attenuate anchorageindependent growth (Peng et al, 2013). Additionally, autophagy levels appeared highest in early metastatic lesions, and autophagy was only necessary in the lung-colonization stage.…”

Section: Introductionmentioning

confidence: 99%

Autophagy Inhibition Delays Early but Not Late-Stage Metastatic Disease

Barnard

Regan

Hansen

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The autophagy pathway has been recognized as a mechanism of survival and therapy resistance in cancer, yet the extent of autophagy's function in metastatic progression is still unclear. Therefore, we used murine models of metastatic cancer to investigate the effect of autophagy modulation on metastasis development. Pharmacologic and genetic autophagy inhibition were able to impede cell proliferation in culture, but did not impact the development of experimentally induced 4T1 and B16-F10 metastases. Similarly, autophagy inhibition by adjuvant chloroquine (CQ) treatment did not delay metastasis in an orthotopic 4T1, tumor-resection model. However, neoadjuvant CQ treatment or genetic autophagy inhibition resulted in delayed metastasis development, whereas stimulation of autophagy by trehalose hastened development. Cisplatin was also administered either as a single agent or in combination with CQ.The combination of cisplatin and CQ was antagonistic. The effects of autophagy modulation on metastasis did not appear to be due to alterations in the intrinsic metastatic capability of the cells, as modulating autophagy had no impact on migration, invasion, or anchorage-independent growth in vitro. To explore the possibility of autophagy's influence on the metastatic microenvironment, bone marrow-derived cells (BMDCs), which mediate the establishment of the premetastatic niche, were measured in the lung and in circulation. Trehalose-treated mice had significantly more BMDCs than either vehicle-or CQ-treated mice. Autophagy inhibition may be most useful as a treatment to impede early metastatic development. However, modulating autophagy may also alter the efficacy of platinum-based therapies, requiring caution when considering combination therapies.

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“…Investigation of HCC has been done conducted at the level of genes, ribonucleic acid (RNA), proteins, cells, and animals [10][11][12][13][14]. The resultant development of animal models and monitoring methods has improved the effectiveness of guidelines provided to researchers working with preclinical HCC models.…”

Section: Introductionmentioning

confidence: 99%

Establishment of Animal Models with Orthotopic Hepatocellular Carcinoma

Lee

Kim

et al. 2014

Nucl Med Mol Imaging

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Hepatocellular carcinoma (HCC) is one of the most serious health problems worldwide. Many researchers have investigated HCC at the level of genes, ribonucleic acid, proteins, cells, and animals. The resultant development of animal models and monitoring methods has improved the effectiveness of guidelines provided to researchers working with preclinical HCC models. HCC in animal models and clinical patients is monitored by various current imaging modalities such as ultrasound (US) imaging, computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET) and bioluminescence imaging (BLI). These techniques are currently used for both preclinical and clinical assessment, and provide valuable diagnostic information. In this article, we have mainly reviewed the established animal models and the assessment of orthotopic HCC using imaging modalities. Additionally, we have introduced a method of orthotopic HCC rat model developed in our laboratory. We have furthermore evaluated the occurrence of tumor mass using molecular imaging techniques.

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Autophagy inhibition suppresses pulmonary metastasis of HCC in mice via impairing anoikis resistance and colonization of HCC cells

Abstract: (2013) Autophagy inhibition suppresses pulmonary metastasis of HCC in mice via impairing anoikis resistance and colonization of HCC

Cited by 246 publications

References 36 publications

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

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

Autophagy Inhibition Delays Early but Not Late-Stage Metastatic Disease

Establishment of Animal Models with Orthotopic Hepatocellular Carcinoma

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