The role of the class I Wnt pathway antagonist sFRP4 in colorectal cancer

The Wnt/β-catenin signaling pathway exerts integral roles in embryogenesis and adult homeostasis. Aberrant activation of the pathway is implicated in growth-associated diseases and cancers, especially as a key driver in the initiation and progression of colorectal cancer (CRC). Loss or inactivation of Adenomatous polyposis coli (APC) results in constitutive activation of Wnt/β-catenin signaling, which is considered as an initiating event in the development of CRC. Increased Wnt/β-catenin signaling is observed in virtually all CRC patients, underscoring the importance of this pathway for therapeutic intervention. Prior studies have deciphered the regulatory networks required for the cytoplasmic stabilisation or degradation of the Wnt pathway effector, β-catenin. However, the mechanism whereby nuclear β-catenin drives or inhibits expression of Wnt target genes is more diverse and less well characterised. Here, we describe a brief synopsis of the core canonical Wnt pathway components, set the spotlight on nuclear mediators and highlight the emerging role of chromatin regulators as modulators of β-catenin-dependent transcription activity and oncogenic output.

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Nuclear Receptor Interacting Protein-2 Mediates the Stabilization and Activation of β-Catenin During Podocyte Injury

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.781792 ◽

2021 ◽

Vol 9 ◽

Author(s):

Qing Hou ◽

Weibo Le ◽

Shuyan Kan ◽

Jinsong Shi ◽

Yue Lang ◽

...

Keyword(s):

Colorectal Cancer ◽

Nuclear Receptor ◽

Protein Interactions ◽

Wnt Pathway ◽

Expression Data ◽

Podocyte Injury ◽

Interacting Protein ◽

Chemical Treatments ◽

Geo Dataset

Objective: Activation of β-catenin causes podocyte injury and proteinuria, but how β-catenin signalling is regulated during podocyte injury remains elusive. Nuclear receptor interacting protein 2 (NRIP2) modulates the Wnt pathway in colorectal cancer-initiating cells, but the role of NRIP2 in podocyte injury has not yet been investigated. We aimed to examine the interaction between NRIP2 and β-catenin signalling.Materials and Methods: Knockdown or overexpression of NRIP2 and β-catenin and chemical treatments were performed in cultured human podocytes. Immunoprecipitation, immunoblotting and immunofluorescence assays were used to assess protein interactions and expression. Data from the GEO dataset and kidney tissues from patients with focal segmental glomerulosclerosis (FSGS) and surgical nephrectomy were examined. An adriamycin (ADR) nephropathy model was established in NRIP2 knockout mice.Results: NRIP2 knockdown accelerated β-catenin degradation, which was reversed by MG132; specifically, NRIP2 bound β-catenin and stabilized it to prevent its degradation through the ubiquitin proteasomal pathway. Overexpression of NRIP2 led to β-catenin activation and Snail1 induction, and these effects were attenuated by β-catenin knockdown. NRIP2 knockdown blocked ADR-stimulated β-catenin activation. In ADR mice, genetic knockout of Nrip2 ameliorated podocyte injury and loss, glomerulosclerosis, and proteinuria by inhibiting β-catenin activation. Moreover, NRIP2 was significantly upregulated in podocytes of FSGS patients and colocalized with nuclear β-catenin.Conclusion: These results established NRIP2 as a stabilizer of β-catenin activation through the ubiquitin proteasomal pathway in podocyte injury.

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The Contemporary Role of Resection and Ablation in Colorectal Cancer Liver Metastases

Digestive Disease Interventions ◽

10.1055/s-0040-1715816 ◽

2020 ◽

Vol 04 (03) ◽

pp. 291-302

Author(s):

Mariam F. Eskander ◽

Christopher T. Aquina ◽

Aslam Ejaz ◽

Timothy M. Pawlik

Keyword(s):

Colorectal Cancer ◽

Portal Vein ◽

Surgical Oncology ◽

Portal Vein Ligation ◽

Safe Alternative ◽

Colorectal Cancer Liver Metastases ◽

Liver Remnant ◽

New Era ◽

Ablation Therapy

AbstractAdvances in the field of surgical oncology have turned metastatic colorectal cancer of the liver from a lethal disease to a chronic disease and have ushered in a new era of multimodal therapy for this challenging illness. A better understanding of tumor behavior and more effective systemic therapy have led to the increased use of neoadjuvant therapy. Surgical resection remains the gold standard for treatment but without the size, distribution, and margin restrictions of the past. Lesions are considered resectable if they can safely be removed with tumor-free margins and a sufficient liver remnant. Minimally invasive liver resections are a safe alternative to open surgery and may offer some advantages. Techniques such as portal vein embolization, association of liver partition with portal vein ligation for staged hepatectomy, and radioembolization can be used to grow the liver remnant and allow for resection. If resection is not possible, nonresectional ablation therapy, including radiofrequency and microwave ablation, can be performed alone or in conjunction with resection. This article presents the most up-to-date literature on resection and ablation, with a discussion of current controversies and future directions.

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