Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness

Wan, Shan; Meyer, Anne S.; Weiler, Sofia M.E.; Rupp, Christian; Tóth, Marcell; Sticht, Carsten; Singer, Stephan; Thomann, Stefan; Roessler, Stephanie; Schorpp-Kistner, Marina; Schmitt, Julian; Gretz, Norbert; Angel, Peter; Tschaharganeh, Darjus F.; Marquardt, Jens U.; Schirmacher, Peter; Pinna, Federico; Breuhahn, Kai

doi:10.1002/hep.29669

Cited by 58 publications

(59 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We and others have demonstrated the importance of SCRIB and LANO in cancer development . In this study, we identified large protein complexes associated with these two paralogues and carried out for the first‐time a direct comparison of their associated protein complexes.…”

Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor SCRIB is a Negative Modulator of the Wnt/β‐Catenin Signaling Pathway

et al. 2019

View full text Add to dashboard Cite

SCRIB is a scaffold protein containing leucine‐rich repeats (LRR) and PSD‐95/Dlg‐A/ZO‐1 domains (PDZ) that localizes at the basolateral membranes of polarized epithelial cells. Deregulation of its expression or localization leads to epithelial defects and tumorigenesis in part as a consequence of its repressive role on several signaling pathways including AKT, ERK, and HIPPO. In the present work, a proteomic approach is used to characterize the protein complexes associated to SCRIB and its paralogue LANO. Common and specific sets of proteins associated to SCRIB and LANO by MS are identified and an extensive landscape of their associated networks and the first comparative analysis of their respective interactomes are provided. Under proteasome inhibition, it is further found that SCRIB is associated to the β‐catenin destruction complex that is central in Wnt/β‐catenin signaling, a conserved pathway regulating embryonic development and cancer progression. It is shown that the SCRIB/β‐catenin interaction is potentiated upon Wnt3a stimulation and that SCRIB plays a repressing role on Wnt signaling. The data thus provide evidence for the importance of SCRIB in the regulation of the Wnt/β‐catenin pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor SCRIB is a Negative Modulator of the Wnt/β‐Catenin Signaling Pathway

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Thus, EMT has been recognized as a prometastatic cellular event that promotes tumor cell invasion and malignant tumor progression [5]. Although recent studies have raised concerns about the actual contribution of EMT to metastasis in lung cancer [6] and pancreatic cancer [7], the experimental results acquired in HCC still support the idea that EMT plays a pivotal role in HCC metastasis [8][9][10][11]. Loss of E-cadherin, a typical marker of epithelial cells, is one of the key features of the EMT process and has been implicated in tumor metastasis [12].…”

Section: Introductionmentioning

confidence: 99%

TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin

et al. 2019

View full text Add to dashboard Cite

Metastasis is one of the main contributors to the poor prognosis of hepatocellular carcinoma (HCC). However, the underlying mechanism of HCC metastasis remains largely unknown. Here, we showed that TXNDC12, a thioredoxin-like protein, was upregulated in highly metastatic HCC cell lines as well as in portal vein tumor thrombus and lung metastasis tissues of HCC patients. We found that the enforced expression of TXNDC12 promoted metastasis both in vitro and in vivo. Subsequent mechanistic investigations revealed that TXNDC12 promoted metastasis through upregulation of the ZEB1mediated epithelial-mesenchymal transition (EMT) process. We subsequently showed that TXNDC12 overexpression stimulated the nuclear translocation and activation of β-catenin, a positive transcriptional regulator of ZEB1. Accordingly, we found that TXNDC12 interacted with β-catenin and that the thioredoxin-like domain of TXNDC12 was essential for the interaction between TXNDC12 and β-catenin as well as for TXNDC12-mediated β-catenin activation. Moreover, high levels of TXNDC12 in clinical HCC tissues correlated with elevated nuclear β-catenin levels and predicted worse overall and disease-free survival. In summary, our study demonstrated that TXNDC12 could activate β-catenin via protein-protein interaction and promote ZEB1-mediated EMT and HCC metastasis.

show abstract

“…Peritoneum was opened by incision and the remaining uid was collected by Pasteur pipette. After transfection, 1x107 Cells in cultured T75 cell culture ask were collected and incubated with formaldehyde/PBS (1%) for 12 minutes to allow cross-linking of DNA and protein according to a ChIP protocol previously described (13). Protein in the complex was diluted to 1 mg/ml with RIPA buffer and pre-cleared with 30 µl of Dynabeads Protein G (Nanoeast Biotech, Jiangsu, China).…”

Section: Mouse Experiments and Macrophage Isolationmentioning

confidence: 99%

MiR-7e-5p downregulation promotes malignant transformation of follicular lymphoma by modulating an immunosuppressive stroma through the upregulation of FasL in M1 macrophages

Lou¹,

Zhao³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Abstract Background In follicular lymphoma (FL), histologic transformation to high-grade FL and diffuse large B-cell lymphoma (DLBCL) is a critical adverse step in disease progression. Activation of the oncogene c-MYC and tumor microenvironment remodeling account for FL progression. A panel of miroRNA (miRNA) was downregulated in transformed FL. Methods Differentially expressed miRNAs were systematically analyzed in tissue samples from patients at different stages of disease. In FL cells, transcriptional regulation of the oncogene c-MYC on its target miR-7e-5p was revealed by Chromatin Immunoprecipitation (ChIP) assay. Exosome, carrying differentially expressed miR-7e-5p was isolated and visualized by transmission electron microscope and fluorescence tracing. The effect of miR-7e-5p on recipient macrophage was determined by target gene quantification, flow cytometry, and TUNEL method in a cocultured system with miR-7e-5p-mimics or inhibitor treatment. Expression of miR-7e-5p targets, macrophage proportions, and clinical parameters were included for correlation analysis. Results We determined that downregulation of miR-7e-5p, driven by c-MYC overexpression, was associated with poorer prognosis in FL patients. The decreased expression of miR-7e-5p in lymphoma cells led to a reduced exosomal transfer to surrounding macrophages. As a result, the target gene of miR-7e-5p, Fas ligand (FasL), was upregulated and activated the caspase signaling, which led to the apoptosis of M1 macrophages in tumor stroma. Finally, in transformed FL tissues, overexpression of FasL and activation of caspase proteins was detected in tumor stromal macrophages. Downregulation of miR-7e-5p was associated with poorer clinical outcomes. Conclusion Downregulation of exosomal miR-7e-5p induces stromal M1 macrophage apoptosis, which leads to immunosurveillance and transformation of FL.

show abstract

Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness

Cited by 58 publications

References 37 publications

The Tumor Suppressor SCRIB is a Negative Modulator of the Wnt/β‐Catenin Signaling Pathway

The Tumor Suppressor SCRIB is a Negative Modulator of the Wnt/β‐Catenin Signaling Pathway

TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin

MiR-7e-5p downregulation promotes malignant transformation of follicular lymphoma by modulating an immunosuppressive stroma through the upregulation of FasL in M1 macrophages

Contact Info

Product

Resources

About