Wnt signaling pathway and lung disease

Scoyk, Michelle Van; Randall, Jessica A.; Sergew, Amen; Williams, Lisa; Tennis, Meredith A.; Winn, Robert A.

doi:10.1016/j.trsl.2007.12.011

Cited by 56 publications

(51 citation statements)

References 57 publications

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“…Other key mediators of the Wnt pathway are TCF4 (also called transcription factor 7-like 2 (TCF7L2)) and TCF1 (also called transcription factor 7 (TCF7)) both of which form a complex with ␤-catenin and regulate the expression of many downstream Wnt-responsive genes (2). The Wnt pathway also plays a significant role in other cancer types, such as lung, gastric, thyroid, and prostate cancer (3)(4)(5), and it has been shown to be involved in the regulation of RNA splicing as well (6).…”

Section: Most Colorectal Cancers (Crc)mentioning

confidence: 99%

Alternative Splicing of SLC39A14 in Colorectal Cancer is Regulated by the Wnt Pathway

Thorsen

Mansilla

Schepeler

et al. 2011

Molecular & Cellular Proteomics

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Alternative splicing is a crucial step in the generation of protein diversity and its misregulation is observed in many human cancer types. By analyzing 143 colorectal samples using exon arrays, SLC39A14, a divalent cation transporter, was identified as being aberrantly spliced in tumor samples. SLC39A14 contains two mutually exclusive exons 4A and 4B and the exon 4A/4B ratio was significantly altered in adenomas (p ‫؍‬ 3.6 ؋ 10 ؊10 ) and cancers (p ‫؍‬ 9.4 ؋ 10 ؊11 ), independent of microsatellite stability status. The findings were validated in independent exon array data sets and by quantitative real-time reverse-transcription PCR (qRT-PCR). Aberrant Wnt signaling is a hallmark of colorectal tumorigenesis and is characterized by nuclear ␤-catenin. Experimental inactivation of Wnt signaling in DLD1 and Ls174T cells by knockdown of ␤-catenin or overexpression of dominant negative TCFs (TCF1 and TCF4) altered the 4A/4B ratio, indicating that SLC39A14 splicing is regulated by the Wnt pathway. An altered 4A/4B ratio was also observed in gastric and lung cancer where Wnt signaling is also known to be aberrantly activated. The splicing factor SRSF1 and its regulator, the kinase SRPK1, were found to be deregulated upon Wnt inactivation in colorectal carcinoma cells. SRPK1 was also found up-regulated in both adenoma samples (p ‫؍‬ 1.5 ؋ 10 ؊5 ) and cancer samples (p ‫؍‬ 5 ؋ 10 ؊4 ). In silico splicing factor binding analysis predicted SRSF1 to bind predominantly to the cancer associated exon 4B, hence, it was hypothesized that SRPK1 activates SRSF1 through phosphorylation, followed by SRSF1 binding to exon 4B and regulation of SLC39A14 splicing. Indeed, siRNA-mediated knockdown of SRPK1 and SRSF1 in DLD1 and SW480 colorectal cancer cells led to a change in the 4A/4B isoform ratio, supporting a role of these factors in the regulation of SLC39A14 splicing. In conclusion, alternative splicing of SLC39A14 was identified in colorectal tumors and found to be regulated by the Wnt pathway, most likely through regulation of SRPK1 and SRSF1. Molecular &

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Section: Most Colorectal Cancers (Crc)mentioning

confidence: 99%

Alternative Splicing of SLC39A14 in Colorectal Cancer is Regulated by the Wnt Pathway

Thorsen

Mansilla

Schepeler

et al. 2011

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

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“…In the lung, Wnt signaling is crucial for lung development (Bonner et al, 2003;Daniel et al, 2006). However, unscheduled reactivation of this embryonic signaling pathway in adult cells can lead to inflammatory diseases, such as pulmonary fibrosis and cancer transformation (Morrisey, 2003;Polakis, 2007;Klaus and Birchmeier, 2008;Van Scoyk et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

EMMPRIN regulates the canonical Wnt/β-catenin signaling pathway, a potential role in accelerating lung tumorigenesis

et al. 2010

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Advances in the field of tumor biology have identified that tumor cells co-opt developmental signaling pathways of embryonic stem cells and thus gain the ability to proliferate, differentiate and alter cell-cell interactions. One such pathway is the Wnt/b-catenin signaling pathway. High levels of EMMPRIN expression have been shown to correlate with poor prognosis and metastasis in a broad range of tumors. Although a variety of functions are attributed to EMMPRIN in tumorigenesis, the specific mechanism(s) through which it can exert its effects have not been elucidated, until now. In this study, we identify EMMPRIN as a novel regulator of the canonical Wnt/ b-catenin signaling pathway in lung cancer. Increasing EMMPRIN expression levels in lung cancer epithelial cells upregulated the b-catenin signaling pathway and silencing EMMPRIN inhibited b-catenin signaling, cell migration, proliferation, anchorage-independent growth and tumor growth in a mouse tumor xenograft model. These results provide a compelling rationale for targeting EMMPRIN for anticancer therapies. Understanding the molecular mechanisms driving EMMPRIN-induced lung tumorigenesis will provide enormous benefits in developing new therapeutic treatments for this and other forms of cancer.

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“…Wnt/β-catenin signaling is an early developmental pathway that plays an important role in airway and vascular smooth muscle cell development (8)(9)(10). Wnt signaling has been shown to be upregulated in the lungs of adult patients with idiopathic lung fibrosis and PH (11)(12)(13).…”

mentioning

confidence: 99%

Inhibition of LRP5/6-mediated Wnt/β-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats

et al. 2013

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Background: Hyperoxia-induced neonatal lung injury is associated with activation of Wnt/β-catenin signaling. Lowdensity lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are Wnt coreceptors that bind to Wnt ligands and mediate canonical Wnt/β-catenin signaling. We hypothesized that inhibition of LRP5/6 by their universal inhibitor, Mesd, would attenuate hyperoxia-induced lung injury. Methods: Newborn rat pups were randomly exposed to normoxia or hyperoxia at 90% FiO 2 and injected intraperitoneally with placebo or Mesd every other day for 14 d. On day 15, phosphorylation of LRP5/6 (pLRP5/6), expression of Wnt/ β-catenin target genes, cyclin D1 and Wnt-induced signaling protein-1 (WISP-1), right-ventricular systolic pressure (RVSP), right-ventricular hypertrophy (RVH), pulmonary vascular remodeling, alveolarization, and vascularization were measured. results: Hyperoxia exposure markedly induced pLRP5/6, cyclin D1, and WISP-1 expression in the lungs of placebo animals, but they were significantly attenuated by the administration of Mesd. Mesd also significantly attenuated hyperoxiainduced pulmonary hypertension (PH) and pulmonary vascular remodeling. However, there was no effect on alveolarization or vascularization after Mesd administration. conclusion: This study demonstrates that LRP5/6 mediates pulmonary vascular remodeling and PH in hyperoxia-induced neonatal lung injury, thereby suggesting a potential therapeutic target to alleviate PH in neonates with severe bronchopulmonary dysplasia.

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Wnt signaling pathway and lung disease

Cited by 56 publications

References 57 publications

Alternative Splicing of SLC39A14 in Colorectal Cancer is Regulated by the Wnt Pathway

Alternative Splicing of SLC39A14 in Colorectal Cancer is Regulated by the Wnt Pathway

EMMPRIN regulates the canonical Wnt/β-catenin signaling pathway, a potential role in accelerating lung tumorigenesis

Inhibition of LRP5/6-mediated Wnt/β-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats

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