WIPF1 antagonizes the tumor suppressive effect of miR-141/200c and is associated with poor survival in patients with PDAC

Pan, Yu; Lü, Fang; Xiong, Ping; Pan, Maoen; Zhang, Zheyang; Lin, Xianchao; Pan, Minggui; Huang, Heguang

doi:10.1186/s13046-018-0848-6

Cited by 29 publications

(19 citation statements)

References 43 publications

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“…All these observations also support the pro-tumoral role of WIP by endowing some cancer cells with anchorage-independent growth and higher motility [6,10]. In fact, a high WIP expression correlates with poor prognosis in patients with pancreatic ductal adenocarcinoma [11], lung cancer [12], colorectal cancers, breast cancer, and gliomas [13].…”

Section: Introductionsupporting

confidence: 53%

WIP Modulates Oxidative Stress through NRF2/KEAP1 in Glioblastoma Cells

et al. 2020

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Due to their high metabolic rate, tumor cells produce exacerbated levels of reactive oxygen species that need to be under control. Wiskott–Aldrich syndrome protein (WASP)-interacting protein (WIP) is a scaffold protein with multiple yet poorly understood functions that participates in tumor progression and promotes cancer cell survival. However, its participation in the control of oxidative stress has not been addressed yet. We show that WIP depletion increases the levels of reactive oxygen species and reduces the levels of transcription factor NRF2, the master regulator of redox homeostasis. We found that WIP stabilizes NRF2 by restraining the activity of its main NRF2 repressor, the E3 ligase adapter KEAP1, because the overexpression of a NRF2ΔETGE mutant that is resistant to targeted proteasome degradation by KEAP1 or the knock-down of KEAP1 maintains NRF2 levels in the absence of WIP. Mechanistically, we show that the increased KEAP1 activity in WIP-depleted cells is not due to the protection of KEAP1 from autophagic degradation, but is dependent on the organization of the Actin cytoskeleton, probably through binding between KEAP1 and F-Actin. Our study provides a new role of WIP in maintaining the oxidant tolerance of cancer cells that may have therapeutic implications.

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Section: Introductionsupporting

confidence: 53%

WIP Modulates Oxidative Stress through NRF2/KEAP1 in Glioblastoma Cells

et al. 2020

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“…WIP controls tumor growth through stabilization of the YAP/TAZ complex via forming the endocytic/endosomal system in glioma 24 . WIP also promotes PDAC cell invasion, metastasis and predicts poor prognosis in PDAC patients 25 . In addition, it has shown that WIP induces EMT in lung cancer A549 cells by regulating RhoA 26 .…”

Section: Introductionmentioning

confidence: 99%

PD-L1 promotes tumor growth and progression by activating WIP and β-catenin signaling pathways and predicts poor prognosis in lung cancer

et al. 2020

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PD-L1 is overexpressed in tumor cells and contributes to cancer immunoevasion. However, the role of the tumor cell-intrinsic PD-L1 in cancers remains unknown. Here we show that PD-L1 regulates lung cancer growth and progression by targeting the WIP and β-catenin signaling. Overexpression of PD-L1 promotes tumor cell growth, migration and invasion in lung cancer cells, whereas PD-L1 knockdown has the opposite effects. We have also identified WIP as a new downstream target of PD-L1 in lung cancer. PD-L1 positively modulates the expression of WIP. Knockdown of WIP also inhibits cell viability and colony formation, whereas PD-L1 overexpression can reverse this inhibition effects. In addition, PD-L1 can upregulate β-catenin by inhibiting its degradation through PI3K/Akt signaling pathway. Moreover, we show that in lung cancer cells β-catenin can bind to the WIP promoter and activate its transcription, which can be promoted by PD-L1 overexpression. The in vivo experiments in a human lung cancer mouse model have also confirmed the PD-L1-mediated promotion of tumor growth and progression through activating the WIP and β-catenin pathways. Furthermore, we demonstrate that PD-L1 expression is positively correlated with WIP in tumor tissues of human adenocarcinoma patients and the high expression of PD-L1 and WIP predicts poor prognosis. Collectively, our results provide new insights into understanding the pro-tumorigenic role of PD-L1 and its regulatory mechanism on WIP in lung cancer, and suggest that the PD-L1/Akt/β-catenin/WIP signaling axis may be a potential therapeutic target for lung cancers.

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“…However, the picture is seemingly more complex for PDAC. miR-200 family members are frequently overexpressed in precursor lesions 24 and PDAC,18, 25 where they may act as oncogenes 26 or as suppressor genes 27 . A complex crosstalk between miR-200 and ZEBs has been suggested.…”

Section: Introductionmentioning

confidence: 99%

Expression and Role of MicroRNAs from the miR-200 Family in the Tumor Formation and Metastatic Propensity of Pancreatic Cancer

Díaz‐Riascos

Ginestà

Fabregat

et al. 2019

Molecular Therapy - Nucleic Acids

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MicroRNAs from the miR-200 family are commonly associated with the inhibition of the metastatic potential of cancer cells, following inhibition of ZEB transcription factors expression and epithelial-to-mesenchymal transition. However, previous studies performed in pancreatic adenocarcinoma revealed a more complex picture challenging this canonical model. To gain better insights into the role of miR-200 family members in this disease, we analyzed the expression of miR-200a, miR-200b, miR-200c, miR-141, miR-429, and miR-205, and ZEB1, ZEB2, and CDH1 in pancreatic tumors and matching normal adjacent parenchyma and patient-derived xenografts. We found that miR-200a, miR-429, and miR-205 are frequently overexpressed in pancreatic tumors, whereas CDH1 is downregulated, and ZEB1 and ZEB2 levels remain unchanged. Furthermore, we measured a positive correlation between miR-200 family members and CDH1 expression, and a negative correlation between ZEB1 and miR-200c, miR-141, and miR-205 expression, respectively. Interestingly, we identified significant changes in expression of epithelial-to-mesenchymal transition regulators and miR-200 members in patient-derived xenografts. Lastly, functional studies revealed that miR-141 and miR-429 inhibit the tumorigenic potential of pancreatic cancer cells. Taken together, this comprehensive analysis strongly suggests that miRNAs from the miR-200 family, and in particular miR-429, may act as a tumor suppressor gene in pancreatic cancer.

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WIPF1 antagonizes the tumor suppressive effect of miR-141/200c and is associated with poor survival in patients with PDAC

Cited by 29 publications

References 43 publications

WIP Modulates Oxidative Stress through NRF2/KEAP1 in Glioblastoma Cells

WIP Modulates Oxidative Stress through NRF2/KEAP1 in Glioblastoma Cells

PD-L1 promotes tumor growth and progression by activating WIP and β-catenin signaling pathways and predicts poor prognosis in lung cancer

Expression and Role of MicroRNAs from the miR-200 Family in the Tumor Formation and Metastatic Propensity of Pancreatic Cancer

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