The human <i>PKP2</i>/plakophilin‐2 gene is induced by Wnt/β‐catenin in normal and colon cancer‐associated fibroblasts

Niell, Núria; Larriba, María Jesús; Ferrer-Mayorga, Gemma; Sánchez‐Pérez, Isabel; Cantero, Ramón; Real, Francisco X.; Peso, Luis del; Múñoz, Alberto; González‐Sancho, José Manuel

doi:10.1002/ijc.31104

Cited by 30 publications

(28 citation statements)

References 55 publications

(102 reference statements)

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“…In this study, we rstly showed that WNT4 secreted by CRC cells could activate surrounding broblasts through the WNT4/βcatenin pathway. Furthermore, recent evidence suggests a signi cant role for EMT in brosis, including its involvement in tumor stroma activation [24,43]. In the current study, we showed that WNT4 prompted the nuclear translocation of β-catenin and increased the expression of α-SMA and bronectin in NFs, which subsequently enhanced reinforced cell contraction and microsphere formation.…”

Section: Discussionsupporting

confidence: 62%

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WNT4 secreted by tumor tissues promotes tumor progression in colorectal cancer by activation of the Wnt/β-catenin signalling pathway

Yang

Shang

et al. 2020

Preprint

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Background: Wingless and Int-related protein (Wnt) ligands are aberrantly expressed in patients with colorectal cancer (CRC). However, the aberrant level of Wnt ligands in serum have not been explored. Here, we aimed to identify the levels of WNT4 in serum and explored its oncogenic role in CRC Methods: The Oncomine database was used to analyze the relationship between WNT4 and the prognosis of CRC. ELISA was performed to measure WNT4 levels in serum and conditioned medium from fresh CRC tissues and adjacent normal tissues. Western blot and immunohistochemistry were carried out to measure the expression of WNT4 in human CRC tissues and adjacent normal tissues. The migration and invasion of CRC cells were determined by trans-well assay, and the effects of WNT4 on CRC invasion and metastasis in vivo were verified by tumor xenograft in nude mice. Cancer-associated fibroblasts (CAFs) and angiogenesis in subcutaneous nodules were detected by immunofluorescence (IF). In addition, the suspended spheres formation and tube formation assay were performed to explore the effects of WNT4 on CAFs and angiogenesis respectively. Results: WNT4 was significantly upregulated in serum of CRC patients, and CRC tissues were identified as an important source of elevated WNT4 levels in CRC patients. Interestingly, elevated levels of WNT4 in serum were downregulated after tumor resection. Furthermore, we found that WNT4 contributed to epithelial-to-mesenchymal transition (EMT) and activated fibroblasts by activating the WNT4/β-catenin pathway in vitro and in vivo. Moreover, angiogenesis was induced via the WNT4/β-catenin/Ang2 pathway. Those effects could be reversed by ICG-001, a β-catenin/TCF inhibitor. Conclusion: Our findings indicated that serum levels of WNT4 may be a potential biomarker for CRC. WNT4 secreted by colorectal cancer tissues promote the progression of CRC by inducing EMT, activate fibroblasts and promote angiogenesis through the canonical Wnt/β-catenin signalling pathway.

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Section: Discussionsupporting

confidence: 62%

“…The WNT/β-catenin pathway is known to play an important role in CRC-associated broblasts [24,25]. To interrogate the WNT4 signaling pathways operating in CAF activation, we rst assessed activation of the β-catenin-dependent pathway using immuno uorescence assay.…”

Section: Wnt4 Promotes Broblast Recruitment and Activationvia β-Catenmentioning

confidence: 99%

WNT4 secreted by tumor tissues promotes tumor progression in colorectal cancer by activation of the Wnt/β-catenin signalling pathway

Yang

Shang

et al. 2020

Preprint

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“…In this paper, we showed that WNT4 could activated surrounding broblasts through WNT4/β-catenin pathway. Furthermore, recent evidence suggests a signi cant role for EMT in brosis, including its involvement in tumor stroma activation [24,36]. In our current study, WNT4 prompted the nuclear translocation of β-catenin and increased the expression of α-SMA and bronectin in NFs, which subsequently enhanced reinforced cell contraction and microsphere formation.…”

Section: Discussionsupporting

confidence: 57%

“…The WNT/β-catenin pathway is known to play an important role in CRC-associated broblast [24,25]. To interrogate the WNT4 signaling pathways operating in CAF activation, we rst assessed the activation of the β-catenin-dependent pathway using immuno uorescence.…”

Section: Wnt4 Promotes Broblast Recruitment and Activationvia β-Catenmentioning

confidence: 99%

WNT4, a Potential Biomarker in Serum for Colorectal Cancer, Promotes Metastasis Through WNT4/β-Catenin Pathway

Yang

Shang

et al. 2020

SSRN Journal

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Background Wingless and Int-related protein (Wnt) ligands were aberrantly expressed in human diseases. However, the aberrant level of Wnt ligands have not been explored in serum. Here, we aimed to identify the WNT4 level in serum and explore its oncogenic role in colorectal cancer (CRC). Methods Serum samples from 40 CRC patients and 28 healthy donors were collected to measure the levels of WNT4. CRC tissue samples from patients were collected to explore the resource of WNT4. Further, we used CRC cells and xenograft mouse model to explore the oncogenic role of WNT4. Results WNT4 was signi cantly upregulated in serum of colorectal cancer (CRC) patients, and CRC tissues were identi ed as an important source of elevated WNT4 levels in CRC patients. Interestingly, the elevated WNT4 in serum was downregulated after tumor resection. Next, we found that WNT4 could contributed to epithelial-to-mesenchymal transition and activated broblasts by activating WNT4/β-catenin pathway in vitro and in vivo; besides, angiogenesis was also induced via WNT4/βcatenin/Ang2 pathway. Those effects could be reversed by ICG-001, a β-catenin/TCF inhibitor. Conclusion These data indicated that WNT4 may be a potential biomarker for CRC and provided evidence to support a critical role of WNT4 in promoting CRC cell metastasis by inducing epithelial-to-mesenchymal transition, activating broblasts and promoting angiogenesis in the colorectal tumor microenvironment.

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“…We only explored the regulatory network, functional mechanism and immune infiltration of PKP2/3 in OC subsequently. In terms of potential mechanism, PKP2 could regulate the activity of Wnt/β-catenin in colon cancer-associated fibroblasts [54], and PKP2 promoted the proliferation and migration of lung cancer by activating EGFR signaling pathway [38]. In addition, PKP3 regulated autophagy and invasion of ovarian cancer through MAPK/JNK/ERK1/2/mTOR signaling pathway [13,14].…”

Section: Casesmentioning

confidence: 99%

Identification of PKP 2/3 as potential biomarkers of ovarian cancer based on bioinformatics and experiments

Gao

Guo

et al. 2020

Cancer Cell Int

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Background Plakophilins (PKPs) are widely involved in gene transcription, translation, and signal transduction, playing a crucial role in tumorigenesis and progression. However, the function and potential mechanism of PKP1/2/3 in ovarian cancer (OC) remains unclear. It’s of great value to explore the expression and prognostic values of PKP1/2/3 and their potential mechanisms, immune infiltration in OC. Methods The expression levels, prognostic values and genetic variations of PKP1/2/3 in OC were explored by various bioinformatics tools and databases, and PKP2/3 were selected for further analyzing their regulation network and immune infiltration. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) enrichment were also conducted. Finally, the expression and prognosis of PKP2 were validated by immunohistochemistry. Results The expression level and prognosis of PKP1 showed little significance in ovarian cancer, and the expression of PKP2/3 mRNA and protein were upregulated in OC, showing significant correlations with poor prognosis of OC. Functional enrichment analysis showed that PKP2/3 and their correlated genes were significantly enriched in adaptive immune response, cytokine receptor activity, organization of cell–cell junction and extracellular matrix; KEGG analysis showed that PKP2/3 and their significantly correlated genes were involved in signaling pathways including cytokine-mediated signaling pathway, receptor signaling pathway and pathways in cancer. Moreover, PKP2/3 were correlated with lymphocytes and immunomodulators. We confirmed that high expression of PKP2 was significantly associated with advanced stage, poor differentiation and poor prognosis of OC patients. Conclusion Members of plakophilins family showed various degrees of abnormal expressions and prognostic values in ovarian cancer. PKP2/3 played crucial roles in tumorigenesis, aggressiveness, malignant biological behavior and immune infiltration of OC, and can be regarded as potential biomarker for early diagnosis and prognosis evaluation in OC.

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The human PKP2/plakophilin‐2 gene is induced by Wnt/β‐catenin in normal and colon cancer‐associated fibroblasts

Cited by 30 publications

References 55 publications

WNT4 secreted by tumor tissues promotes tumor progression in colorectal cancer by activation of the Wnt/β-catenin signalling pathway

WNT4 secreted by tumor tissues promotes tumor progression in colorectal cancer by activation of the Wnt/β-catenin signalling pathway

WNT4, a Potential Biomarker in Serum for Colorectal Cancer, Promotes Metastasis Through WNT4/β-Catenin Pathway

Identification of PKP 2/3 as potential biomarkers of ovarian cancer based on bioinformatics and experiments

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