The enforced expression of c-Myc in pig fibroblasts triggers mesenchymal-epithelial transition (MET) via F-actin reorganization and RhoA/Rock pathway inactivation

Shi, Junpeng; Liu, Wei; Zhang, Tingting; Wang, Shengchun; Lin, Xiaolin; Li, Jing; Jia, Jizeng; Sheng, Hong-Fen; Yao, Zhi-Fang; Zhao, Wentao; Zhao, Zunlan; Xie, Raoying; Yang, Sheng; Gao, Fei; Fan, Quan-Rong; Zhang, Mengya; Yue, Min; Yuan, Jingya; Gu, Wei; Yao, Kangde; Xiao, Dong

doi:10.4161/cc.24164

Cited by 41 publications

(37 citation statements)

References 38 publications

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“…They further showed that the induction of MET in fibroblasts decreased cell motility and increased cell adhesion. 30 This study indicated that mesenchymal characteristic is pivotal for CAFs function. In agreement with this, we found that KRT8 decreased mesenchymal markers in CAFs, meanwhile, cisplatin-induced KRT8 upregulation inhibited the enhancing effect of CAFs on metastasis.…”

Section: Discussionmentioning

confidence: 81%

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

Song¹,

Guo²,

Wang³

et al. 2020

OTT

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Background: Cancer-associated fibroblasts (CAFs) are an essential component of tumor microenvironment. They are attracting increasing attentions due to their crucial role in tumor growth, drug-resistance and metastasis. Cisplatin is a first-line chemotherapy drug applying in various types of cancer. There are intensive studies on cisplatin's effect on tumor cells, however, its effect on CAFs remains poorly understood. In the present study, we investigated the effect of cisplatin on CAFs. Methods: Cell migration was detected by wound healing assay. Cell invasion was performed by the transwell assay. mRNA expression was detected by quantitative PCR, and protein expression was detected by Western blotting. Tumor growth was measured using BALB/c nude mice tumor models. Results: Cisplatin attenuated the promoting capacity of CAFs on lung cancer cell migration and invasion, via suppressing CAFs' effect on metastasis-related genes including Twist1, vascular endothelial growth factor receptor (VEGFR), MMP2, and AKT signaling pathway. Keratin 8 (KRT8) was identified as a target of cisplatin. KRT8 upregulation in CAFs is responsible for the inhibitory effect of cisplatin on lung cancer cells metastasis potential through AKT pathway suppression. The stimulation of AKT by AKT activator SC79 reversed KRT8's effect on cell migration. Importantly, in vivo study also showed that CAFs enhanced tumor growth significantly, and cisplatin effectively abrogated the promoting effect of CAFs on tumor growth. Conclusion: Our results revealed a novel mechanism that cisplatin attenuated the metastasis promoting effect of CAFs via KRT8/AKT signaling pathway. This finding highlights KRT8 in CAFs as a potential therapeutic candidate for metastasis treatment.

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Section: Discussionmentioning

confidence: 81%

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

Song¹,

Guo²,

Wang³

et al. 2020

OTT

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“…There is evidence that strongly supports our novel findings: (i) knockdown of endogenous Smurf1 protein blocked the SND1-induced metastatic ability of breast cancer cells; (ii) the invasive phenotype correlated with SND1 hyperexpression was inhibited by blocking the proteasomal degradation of RhoA with proteasome inhibitor. This novel function of SND1 is similar to the proto-oncogene c-Myc, which is upregulated in many cancers causing cytoskeleton depolymerization and inhibition of the RhoA signaling pathway (39).…”

Section: Discussionmentioning

confidence: 96%

SND1 Acts Downstream of TGFβ1 and Upstream of Smurf1 to Promote Breast Cancer Metastasis

Liu

Cui

et al. 2015

Cancer Research

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SND1 is an AEG-1/MTDH/LYRIC-binding protein that is upregulated in numerous human cancers, where it has been assigned multiple functional roles. In this study, we report its association with the TGFb1 signaling pathway, which promotes epithelial-mesenchymal transition (EMT) in breast cancer. SND1 was upregulated in breast cancer tissues, in particular in primary invasive ductal carcinomas. Transcriptional activation of the SND1 gene was controlled by the TGFb1/Smad pathway, specifically by activation of the Smad2/Smad3 complex. The SND1 promoter region contained several Smad-specific recognition domains (RD motifs), which were recognized and bound by the Smad complex that enhanced the transcriptional activation of SND1. We found that SND1 promoted expression of the E3 ubiquitin ligase Smurf1, leading to RhoA ubiquitination and degradation. RhoA degradation in breast cancer cells disrupted F-actin cytoskeletal organization, reduced cell adhesion, increased cell migration and invasion, and promoted metastasis. Overall, our results define a novel role for SND1 in regulating breast tumorigenesis and metastasis. Cancer Res; 75(7); 1275-86. Ó2015 AACR.

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“…In support of this, morphological changes that occur with mouse 3T3-F442A preadipocyte differentiation are associated with a decrease in synthesis of cytoskeletal associated proteins [55] , [56] . Ectopic expression of MYC in pig fibroblasts has been reported to depolymerize the F-actin cytoskeleton, leading to reorganization of the cytoskeleton and the subsequent morphological changes reminiscent of an epithelial-to-mesenchymal transition (EMT) [57] . Interestingly, EMT was one pathway enriched in MYC knockdown samples as well.…”

Section: Discussionmentioning

confidence: 99%

MYC Is an Early Response Regulator of Human Adipogenesis in Adipose Stem Cells

et al. 2014

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Adipose stem cell (ASC) differentiation is necessary for the proper maintenance and function of adipose tissue. The procurement and characterization of multipotent ASCs has enabled investigation into the molecular determinants driving human adipogenesis. Here, the transcription factor MYC was identified as a significant regulator of ASC differentiation. Expression of MYC transcript and protein was found to accumulate during the initial course of differentiation. Loss-of-function analysis using siRNA mediated knockdown of MYC demonstrated inhibition of hormonally stimulated adipogenesis. MYC exhibited an early and sustained expression pattern that preceded down regulation of key suppressor genes, as well as induction of transcriptional and functional effectors. Glucocorticoid stimulation was identified as a necessary component for MYC induction and was found to impact adipogenesis in a concentration-dependent manner. Global gene expression analysis of MYC knockdown in ASC enriched for functional pathways related to cell adhesion, cytoskeletal remodeling, and transcriptional components of adipogenesis. These results identify a functional role for MYC in promotion of multipotent ASC to the adipogenic lineage.

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The enforced expression of c-Myc in pig fibroblasts triggers mesenchymal-epithelial transition (MET) via F-actin reorganization and RhoA/Rock pathway inactivation

Cited by 41 publications

References 38 publications

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

SND1 Acts Downstream of TGFβ1 and Upstream of Smurf1 to Promote Breast Cancer Metastasis

MYC Is an Early Response Regulator of Human Adipogenesis in Adipose Stem Cells

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