Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway

Wang, Yifan; Liao, Ruocen; Chen, Xingyu; Ying, Xuhua; Chen, Guanping; Li, Mingqian; Dong, Chenfang

doi:10.1038/s41419-020-2725-4

Cited by 42 publications

(32 citation statements)

References 61 publications

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“…Moreover, YAP forms a TEAD/YAP/AP1 ternary complex to regulate activity of distal enhancers, whereas ZEB1 and YAP are part of a multimeric complex with AP1 factors independent of direct ZEB1 DNA binding to drive gene expression on a genome‐wide level (Zanconato et al , 2015 ; Feldker et al , 2020 ) (Fig 4B ). Wang and colleagues demonstrated that in breast cancer, also TWIST is involved in YAP/TAZ‐mediated EMT orchestrated by TWIST‐dependent activation of the GPCR member PAR1 (Wang et al , 2020 ).…”

Section: Non‐classical Emt Featuresmentioning

confidence: 99%

Dynamic EMT: a multi‐tool for tumor progression

et al. 2021

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The process of epithelial-mesenchymal transition (EMT) is fundamental for embryonic morphogenesis. Cells undergoing it lose epithelial characteristics and integrity, acquire mesenchymal features, and become motile. In cancer, this program is hijacked to confer essential changes in morphology and motility that fuel invasion. In addition, EMT is increasingly understood to orchestrate a large variety of complementary cancer features, such as tumor cell stemness, tumorigenicity, resistance to therapy and adaptation to changes in the microenvironment. In this review, we summarize recent findings related to these various classical and non-classical functions, and introduce EMT as a true tumorigenic multi-tool, involved in many aspects of cancer. We suggest that therapeutic targeting of the EMT process will-if acknowledging these complexities-be a possibility to concurrently interfere with tumor progression on many levels.

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Section: Non‐classical Emt Featuresmentioning

confidence: 99%

Dynamic EMT: a multi‐tool for tumor progression

et al. 2021

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“…In agreement, breast cancer TF/F3 is an independent prognostic factor for overall survival and has a predictive value for distant metastasis [ 52 ]. Moreover, previous pilot studies have suggested that PAR1 is upregulated in aggressive breast cancer [ 53 , 54 ], and mechanistic studies have demonstrated that PAR1 induction promotes breast cancer progression and metastasis [ 55 ]. PAR2 is highly expressed in infiltrative ductal breast cancer tissue [ 56 ] and has been shown to be associated with distant disease-free survival in a previous study on 221 breast cancer patients [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Syndecan-1 Promotes Angiogenesis in Triple-Negative Breast Cancer through the Prognostically Relevant Tissue Factor Pathway and Additional Angiogenic Routes

Nassar

Hassan

El-Ghonaimy

et al. 2021

Cancers

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Triple-negative breast cancer (TNBC) is characterized by increased angiogenesis, metastasis, and poor survival. Dysregulation of the cell surface heparan sulfate proteoglycan and signaling co-receptor Syndecan-1 is linked to poor prognosis. To study its role in angiogenesis, we silenced Syndecan-1 in TNBC cell lines using a 3D human umbilical vein endothelial cell (HUVEC) co-culture system. Syndecan-1 siRNA depletion in SUM-149, MDA-MB-468, and MDA-MB-231 cells decreased HUVEC tubule network formation. Angiogenesis array revealed reduced VEGF-A and tissue factor (TF) in the Syndecan-1-silenced secretome. qPCR independently confirmed altered expression of F3, F7, F2R/PAR1, F2RL1/PAR2, VEGF-A, EDN1, IGFBP1, and IGFBP2 in SUM-149, MDA-MB-231, and MDA-MB-468 cells. ELISA revealed reduced secreted endothelin-1 (SUM-149, MDA-MB-468) and TF (all cell lines) upon Syndecan-1 depletion, while TF pathway inhibitor treatment impaired angiogenesis. Survival analysis of 3951 patients demonstrated that high expression of F3 and F7 are associated with better relapse-free survival, whereas poor survival was observed in TNBC and p53 mutant basal breast cancer (F3) and in ER-negative and HER2-positive breast cancer (F2R, F2RL1). STRING protein network analysis revealed associations of Syndecan-1 with VEGF-A and IGFBP1, further associated with the TF and ET-1 pathways. Our study suggests that TNBC Syndecan-1 regulates angiogenesis via the TF and additional angiogenic pathways and marks its constituents as novel prognostic markers and therapeutic targets.

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“…In gastric and CRC cells, PAR-1 activation leads to upregulation of pro-EMT transcriptional factor Snail and Twist, respectively [ 28 , 67 ]. PAR-1 is also involved in the activation of YAP/TAZ [ 64 , 65 ]. Inhibition of PAR-1 suppresses YAP/TAZ-induced EMT, invasion, migration, cancer stem cell-like properties, tumour growth and metastasis of breast cancer cells [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1

et al. 2021

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Kallikrein-related peptidase 8 (KLK8) acts as an oncogene or anti-oncogene in various tumours, and the abnormal expression of KLK8 is involved in the carcinogenesis of several tumours. However, the role of KLK8 in colorectal cancer (CRC) and the underlying mechanism remain largely unclear. In this study, the carcinogenic effect of KLK8 was determined via CCK-8 and colony formation assays in vitro and a xenograft model in nude mice in vivo. The metastasis-promoting effect of KLK8 was investigated with transwell migration and invasion assays and wound-healing assay in vitro and a metastasis model in nude mice in vivo. Bioinformatics analyses and mechanistic experiments were conducted to elucidate the molecular mechanism. Herein, we reported that KLK8 had a promotive effect on the proliferation, migration and invasion of RKO and SW480 cells. Epithelial−mesenchymal transition (EMT) played an important role in the promotive effects of KLK8 on CRC. In addition, protease-activated receptor-1 (PAR-1) antagonist SCH79797 but not protease-activated receptor-2 (PAR-2) antagonist FSLLRY-NH2 attenuated the proliferation, migration and invasion of KLK8-upregulated RKO and SW480 cells. PAR-1 antagonist SCH79797 reduced the tumour volume of xenograft model and decreased the metastatic nodules in the livers of metastasis model. Furthermore, SCH79797 could reverse the positive impact of KLK8 on the EMT process in CRC both in vitro and in vivo. Taken together, these findings demonstrated for the first time that KLK8 promoted EMT and CRC progression, and this effect might be, at least partly mediated by PAR1-dependent pathway.

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Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway

Cited by 42 publications

References 61 publications

Dynamic EMT: a multi‐tool for tumor progression

Dynamic EMT: a multi‐tool for tumor progression

Syndecan-1 Promotes Angiogenesis in Triple-Negative Breast Cancer through the Prognostically Relevant Tissue Factor Pathway and Additional Angiogenic Routes

KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1

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