Autophagy and epithelial–mesenchymal transition: an intricate interplay in cancer

Gugnoni, Mila; Sancisi, Valentina; Manzotti, Gloria; Gandolfi, Greta; Ciarrocchi, Alessia

doi:10.1038/cddis.2016.415

Cited by 163 publications

(159 citation statements)

References 124 publications

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“…Vimentin is essential to the progression and prognosis of cancer through the EMT, a critical event in the invasion, progression and metastasis of epithelial cancers [25,26]. In the present study, we found that FOXD1 expression was related to increased expression of Vimentin.…”

Section: Discussionsupporting

confidence: 60%

FOXD1 Promotes Cell Growth and Metastasis by Activation of Vimentin in NSCLC

Fan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Forkhead box D1 (FOXD1) has a well-established role in early embryonic development and organogenesis and functions as an oncogene in several cancers. However, the clinical significance and biological roles of FOXD1 in non-small cell lung cancer (NSCLC) remain largely unknown. Methods: A total of 264 primary NSCLC tissue samples were collected. The expression levels of FOXD1 in these samples were examined by immunohistochemical staining. The expression of FOXD1 was knocked down by lentiviral shRNA. The relative expression of FOXD1 was determined by qRT-PCR, Western blotting and immunofluorescence image. The functional roles of FOXD1 in NSCLC were demonstrated cell viability CCK-8 assay, colony formation, cell invasion and migration assays, and cell apoptosis assay in vitro. In vivo mouse xenograft and metastasis models were used to assess tumorigenicity and metastatic ability. The Chi-square test was used to assess the correlation between FOXD1 expression and the clinicopathological characteristics. Survival curves were estimated by Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used for univariate and multivariate analyses. Results: We determined that higher levels of FOXD1 were present in NSCLC tissues, especially in metastatic NSCLC tissues. FOXD1 was also higher in all NSCLC cells compared with normal human bronchial epithelial cells. A higher expression level of FOXD1 was associated with malignant behavior and poor prognosis in NSCLC patients. Knockdown of FOXD1 significantly inhibited proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo, and it increased the apoptosis rates of NSCLC cells. Mechanistic analyses revealed that FOXD1 expressed its oncogenic characteristics through activating Vimentin in NSCLC. Multivariate Cox regression analysis indicated that FOXD1 was an independent prognostic factor both for overall survival (OS) and disease-free survival (DFS) in NSCLC patients. Conclusion: Our results indicated that FOXD1 might be involved in the development and progression of NSCLC as an oncogene, and thereby might be a potential therapeutic target for NSCLC patients.

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Section: Discussionsupporting

confidence: 60%

FOXD1 Promotes Cell Growth and Metastasis by Activation of Vimentin in NSCLC

Fan

et al. 2018

Cell Physiol Biochem

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“…Autophagy is a dual function player in cancer progression. On one hand autophagy plays oncosuppressive functions by the clearance of potentially harmful components; on the other hand it facilitates to overcome cellular stress during cancer progression (26). The core pathway of autophagy involves at least five molecular components regulated by a panel of proteins such as Atg1, Atg8, Atg9, Atg12, Beclin 1 and LC3 (28).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we demonstrated that miR-221 inhibited autophagy activity and thereby promoted cell survival in CRC. Autophagy is a cellular degradation process by eliminating damaged or superfluous proteins, and unnecessary or dysfunctional cellular components (26,27). Autophagy is a dual function player in cancer progression.…”

Section: Discussionmentioning

confidence: 99%

miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

Liao¹,

Li²,

Ye³

et al. 2017

Exp Ther Med

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Abstract. Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated mortalities worldwide. MicroRNAs (miRNAs/miRs) serve important roles in tumor development, progression and metastasis. miR-221 has been reported to modulate proliferation, apoptosis, cell cycle distribution and cell migration in a variety of cancers. However, the function of miR-221 in the autophagy of cancer is unclear. In the present study, the role of miR-221 in the autophagy of CRC cells was investigated and its associated target was identified. Survival analysis using The Cancer Genome Atlas data suggested that a higher expression of miR-221 was associated with poor survival in patients with CRC. A Cell Counting kit-8 assay revealed that miR-221 promoted CRC cell proliferation. Autophagy flux analyzed by microtubule-associated protein 1 light chain 3 (LC3) turnover indicated that miR-221 reduced autophagy in CRC cells using different protease inhibitors (E64d and pepstatin A; Bafilomycin A1) in nutrient-rich medium or under starvation conditions. Tumor protein 53-induced nuclear protein 1 (TP53INP1) was identified as a potential novel target of miR-221 by bioinformative prediction. The protein expression of TP53INP1 was inversely regulated by miR-221 in CRC cells. Furthermore, luciferase activity assays were performed and indicated that miR-221 may regulate the luciferase activity of wild-type TP53INP1 without interfering with the activity of mutant TP53INP1. These data suggested that miR-221 may promote the cell proliferation of CRC via the inhibition of autophagy and targeted TP53INP1. IntroductionColorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated death worldwide (1). The morbidity rates of CRC are increasing substantially in a number of countries within Eastern Asia and Eastern Europe which were previously at low risk (2). The multifactorial etiology of CRC involves lifestyle and dietary factors, such as smoking, red and processed meat consumption, and excessive alcohol consumption (3). Autophagy is a vital transformational switch among mechanisms that are involved in the pathogenesis of CRC (4). Autophagy may act as a suppressor during early stages and as a promoter during advanced stages of CRC (4,5). It is important to determine the regulative mechanisms of autophagy in CRC.Recent studies suggests that the post-transcription and translation regulation mediated by microRNAs (miRNAs/miRs) contribute significantly to autophagy in cancer (6). It is found that miR-23b-3p inhibits autophagy in gastric cancer cells (7) and miR-26 suppresses autophagy in hepatocellular carcinoma cells (8). Whereas miR-193b is suggested to induce autophagy in oesophageal cancer cells (9). It is interesting that different miRNAs play diverse roles in the regulation of autophagy through various targets.

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“…The multifunctional cytokine, TGF-β, is known to be one of the most potent activators of EMT during tumor progression [312, 314, 315]. TGF-β stimulation increases mitochondrial ROS and decreases mitochondrial membrane potential and intracellular glutathione levels.…”

Section: Mitochondria Information Transfer In Cancer Developmentmentioning

confidence: 99%

“…Studies also indicate that EMT and autophagy are linked in a complex relationship [315, 316], and that TGF-β is one of the major signaling pathways that converge on the regulation of these two processes [317–319]. It appears that during the early stages of tumor development, TGF-β promotes autophagy and cell death and suppresses tumor growth; later, when the tumor has settled, TGF-β restrains autophagy, induces EMT, and promotes metastatic spreading [315].…”

Section: Mitochondria Information Transfer In Cancer Developmentmentioning

confidence: 99%

Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome

Singh

Modica-Napolitano

Singh

2017

Seminars in Cancer Biology

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Mitochondria are complex intracellular organelles that have long been identified as the powerhouses of eukaryotic cells because of the central role they play in oxidative metabolism. A resurgence of interest in the study of mitochondria during the past decade has revealed that mitochondria also play key roles in cell signaling, proliferation, cell metabolism and cell death, and that genetic and/or metabolic alterations in mitochondria contribute to a number of diseases, including cancer. Mitochondria have been identified as signaling organelles, capable of mediating bidirectional intracellular information transfer: anterograde (from nucleus to mitochondria) and retrograde (from mitochondria to nucleus). More recently, evidence is now building that the role of mitochondria extends to intercellular communication as well, and that the mitochondrial genome (mtDNA) and even whole mitochondria are indeed mobile and can mediate information transfer between cells. We define this promiscuous information transfer function of mitochondria and mtDNA as “momiome” to include all mobile functions of mitochondria and the mitochondrial genome. Herein we review the “momiome” and explore its role in cancer development, progression, and treatment.

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Autophagy and epithelial–mesenchymal transition: an intricate interplay in cancer

Cited by 163 publications

References 124 publications

FOXD1 Promotes Cell Growth and Metastasis by Activation of Vimentin in NSCLC

FOXD1 Promotes Cell Growth and Metastasis by Activation of Vimentin in NSCLC

miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome

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