c‐Fos separation from Lamin A/C by GDF15 promotes colon cancer invasion and metastasis in inflammatory microenvironment

Ding, Youxiang; Hao, Kun; Li, Zhaohe; Ma, Rong; Zhou, You; Zhou, Zhou; Wei, Mian; Liao, Yan; Dai, Yanjun; Yang, Yue; Zhang, Xiaobo; Zhao, Li

doi:10.1002/jcp.29317

Cited by 37 publications

(39 citation statements)

References 45 publications

(63 reference statements)

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“…In d, patients are clustered into three groups using the expression profiles of all genes, as well as with somatic mutations associated with them and the expression profiles of miRNAs targeting the genes Smad2/3 pathway via binding to the TGF-β receptor [45]. GDF15 has been shown to be activated c-Fos [46], an AP-1 component, which is consistent with the altered expression noted in JunD knockdown cells. Another gene involved in TGF-β signaling [47], MGAT5, has been linked to tumor growth [48,49] and invasion [50,51], as well as maintenance of colon cancer stem cells [49].…”

Section: Characterization Of Tf "Regulons" Underlying Crc Progressionmentioning

confidence: 62%

An integrated multi-omics approach to identify regulatory mechanisms in cancer metastatic processes

et al. 2021

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Background Metastatic progress is the primary cause of death in most cancers, yet the regulatory dynamics driving the cellular changes necessary for metastasis remain poorly understood. Multi-omics approaches hold great promise for addressing this challenge; however, current analysis tools have limited capabilities to systematically integrate transcriptomic, epigenomic, and cistromic information to accurately define the regulatory networks critical for metastasis. Results To address this limitation, we use a purposefully generated cellular model of colon cancer invasiveness to generate multi-omics data, including expression, accessibility, and selected histone modification profiles, for increasing levels of invasiveness. We then adopt a rigorous probabilistic framework for joint inference from the resulting heterogeneous data, along with transcription factor binding profiles. Our approach uses probabilistic graphical models to leverage the functional information provided by specific epigenomic changes, models the influence of multiple transcription factors simultaneously, and automatically learns the activating or repressive roles of cis-regulatory events. Global analysis of these relationships reveals key transcription factors driving invasiveness, as well as their likely target genes. Disrupting the expression of one of the highly ranked transcription factors JunD, an AP-1 complex protein, confirms functional relevance to colon cancer cell migration and invasion. Transcriptomic profiling confirms key regulatory targets of JunD, and a gene signature derived from the model demonstrates strong prognostic potential in TCGA colorectal cancer data. Conclusions Our work sheds new light into the complex molecular processes driving colon cancer metastasis and presents a statistically sound integrative approach to analyze multi-omics profiles of a dynamic biological process.

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Section: Characterization Of Tf "Regulons" Underlying Crc Progressionmentioning

confidence: 62%

An integrated multi-omics approach to identify regulatory mechanisms in cancer metastatic processes

et al. 2021

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“…It has been previously reported that GDF15 could promote colon cancer invasion and metastasis by activating c-Fos ( 20 ). We investigated whether GDF15 played an additional role in EMT and metastasis of EC.…”

Section: Resultsmentioning

confidence: 99%

SCAP Mediated GDF15-Induced Invasion and EMT of Esophageal Cancer

et al. 2020

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Background: GDF15 is a potential biomarker for patients with esophageal cancer (EC). However, the mechanistic role of GDF15 in the invasion and metastasis of EC remains poorly understood. Methods: We determined the expression and function of GDF15 in esophageal cancer cells (ESCCs) and in patient tissue samples using western blotting, migration, and invasion assays, immunohistochemistry, Co-IP assays, and quantitative real-time-PCR. In addition, a pulmonary metastatic nude mouse model was used to determine the function of GDF15. We then supplemented our experimental results with database analysis to validate our findings. Results: GDF15 was upregulated in EC, and was associated with poor differentiation, high metastasis rates, and worse prognosis. GDF15 knock-down reduced the migration and invasion of ESCCs. Co-IP assays demonstrated its association with SCAP, while GDF15 knock-down decreased SCAP levels. SCAP overexpression reversed the migration, invasion and EMT in GDF15-siRNA ESCCs. However, after incubation with β-cyclodextrin (β-CD), the ability of migration and invasion was weakened, EMT was reversed again. Migration, invasion, and EMT were enhanced in GDF15-siRNA ESCCs cultured in the presence of cholesterol and were similar to GDF15-siRNA ESCCs overexpressing SCAP. In vivo , knockdown of GDF15 inhibited lung metastasis of ESCCs and was reversed by SCAP overexpression or high cholesterol diet. Increased lung metastasis after SCAP overexpression was partially suppressed by intraperitoneal injection of β-CD. In addition, we determined that GDF15 was a direct target of miR-1324, miR-1324 was down-regulated in EC tissues. MiR-1324 upregulation resulted in decreased GDF15 expression and metastasis in ESCCs. Conclusions: We demonstrated that SCAP mediated GDF15-induced the invasion and metastasis of EC by regulating cholesterol metabolism. In addition, GDF15 was shown to be a direct target of miR-1324.

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“…In our study, western blot results indicated that AA inhibited the phosphorylation of PI3K, AKT, and mTOR. NFATc1 has been reported as the dominating transcriptional regulator of osteoclast differentiation, which is activated by c‐fos and plays an important role in cell migration, adhesion, and osteoclast‐mediated bone resorption 27,28 . In osteoclasts, the sequential activation of PI3K, AKT, and mTOR involves c‐Fos and NFATc1 proteins.…”

Section: Discussionmentioning

confidence: 99%

Asperolide A prevents bone metastatic breast cancer via the PI3K/AKT/mTOR/c‐Fos/NFATc1 signaling pathway

Jiang¹,

Rixiati

Huang

et al. 2020

Cancer Medicine

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Background Breast cancer is the leading cause of death among women with malignant tumors worldwide. Bone metastasis is the main factor affecting the prognosis of breast cancer. Therefore, both antitumor and anti‐breast‐cancer‐induced osteolysis agents are urgently needed. Methods We examined the effect of Asperolide A (AA), a marine‐derived agent, on osteolysis and RANKL‐induced phosphoinositide 3‐kinase (PI3K)/AKT/mTOR/c‐FOS/nuclear factor‐activated T cell 1 (NFATc1) pathway activation, F‐actin ring formation, and reactive oxygen species (ROS) generation in vitro. We evaluated AA effect on breast cancer MDA‐MB‐231 and MDA‐MB‐436 cells in vitro through CCK8 assay, wound healing assay, transwell assay, Annexin V‐FITC/PI staining for cell apoptosis, and cell cycle assay. Furthermore, we assessed the effect of AA in vivo using a breast cancer‐induced bone osteolysis nude mouse model, followed by micro‐computed tomography, tartrate‐resistant acid phosphatase staining, and hematoxylin and eosin staining. Results Asperolide A inhibited osteoclast formation and differentiation, bone resorption, F‐actin belt formation, ROS activity, and osteoclast‐specific gene and protein expressions and prevented PI3K/AKT/mTOR/c‐FOS/NFATc1 signaling activation in a dose‐dependent manner in vitro. AA also inhibited breast cancer growth and breast cancer‐induced bone osteolysis by reducing osteoclast formation and function and inactivated PI3K/AKT/mTOR signaling in vivo. Conclusions Our study demonstrated that AA suppressed bone metastatic breast cancer. These findings indicate AA as a potential, novel curative drug candidate for patients with bone metastatic breast cancer.

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c‐Fos separation from Lamin A/C by GDF15 promotes colon cancer invasion and metastasis in inflammatory microenvironment

Cited by 37 publications

References 45 publications

An integrated multi-omics approach to identify regulatory mechanisms in cancer metastatic processes

An integrated multi-omics approach to identify regulatory mechanisms in cancer metastatic processes

SCAP Mediated GDF15-Induced Invasion and EMT of Esophageal Cancer

Asperolide A prevents bone metastatic breast cancer via the PI3K/AKT/mTOR/c‐Fos/NFATc1 signaling pathway

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