The Wnt signaling pathway: Aging gracefully as a protectionist?

Maiese, Kenneth; Li, Faqi; Chong, Zhao Zhong; Shang, Yan

doi:10.1016/j.pharmthera.2008.01.004

Cited by 152 publications

(184 citation statements)

References 340 publications

(414 reference statements)

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“…WNT16 belongs to the WNT family of secreted proteins that are mainly involved in development and tumorigenesis (25). However, WNT proteins were recently described to be involved in aging and senescence (6,26,27). Thus, we hypothesized that WNT16 overexpression may play a role in replicative senescence.…”

Section: Resultsmentioning

confidence: 99%

WNT16B Is a New Marker of Cellular Senescence That Regulates p53 Activity and the Phosphoinositide 3-Kinase/AKT Pathway

et al. 2009

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Senescence is a tumor suppression mechanism that is induced by several stimuli, including oncogenic signaling and telomere shortening, and controlled by the p53/p21 WAF1 signaling pathway. Recently, a critical role for secreted factors has emerged, suggesting that extracellular signals are necessary for the onset and maintenance of senescence. Conversely, factors secreted by senescent cells may promote tumor growth. By using expression profiling techniques, we searched for secreted factors that were overexpressed in fibroblasts undergoing replicative senescence. We identified WNT16B, a member of the WNT family of secreted proteins. We found that WNT16B is overexpressed in cells undergoing stress-induced premature senescence and oncogene-induced senescence in both MRC5 cell line and the in vivo murine model of KRas V12 -induced senescence. By small interfering RNA experiments, we observed that both p53 and WNT16B are necessary for the onset of replicative senescence. WNT16B expression is required for the full transcriptional activation of p21 WAF1 . Moreover, WNT16B regulates activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Overall, we identified WNT16B as a new marker of senescence that regulates p53 activity and the PI3K/AKT pathway and is necessary for the onset of replicative senescence. [Cancer Res 2009;69(24):9183-91]

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Section: Resultsmentioning

confidence: 99%

WNT16B Is a New Marker of Cellular Senescence That Regulates p53 Activity and the Phosphoinositide 3-Kinase/AKT Pathway

et al. 2009

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“…Published reports and our previous studies have demonstrated that the Wnt signaling pathway significantly correlated with the invasion and proliferation of tumor cells (27). Wnts are a family of secreted glycoproteins that signal by binding the Frizzled family of receptors.…”

Section: Discussionmentioning

confidence: 98%

MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1

et al. 2012

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Abstract. The invasive behavior of glioblastoma multiforme (GBM) cells is one of the most important reasons for the poor prognosis of this cancer. For invasion, tumor cells must acquire an ability to digest the extracellular matrix and infiltrate the normal tissue bordering the tumor. Preventing this by altering effector molecules can significantly improve a patient's prognosis. Accumulating evidence suggests that miRNAs are involved in multiple biological functions, including cell invasion, by altering the expression of multiple target genes. The expression levels of miR-218 correlate with the invasive potential of GBM cells. In this study, we found that miR-218 expression was low in glioma tissues, especially in GBM. The data showed an inverse correlation in 60 GBM tissues between the levels of miR-218 and MMP mRNAs (MMP-2, -7 and -9). Additionally, ectopic expression of miR-218 suppressed the invasion of GBM cells whereas inhibition of miR-218 expression enhanced the invasive ability. Numerous members of the MMP family are downstream effectors of the Wnt/LEF1 pathway. Target prediction databases and luciferase data showed that LEF1 is a new direct target of miR-218. Importantly, western blot assays demonstrated that miR-218 can reduce protein levels of LEF1 and MMP-9. We, therefore, hypothesize that miR-218 directly targets LEF1, resulting in reduced synthesis of MMP-9. Results suggest that miR-218 is involved in the invasive behavior of GBM cells and by targeting LEF1 and blocking the invasive axis, miR-218-LEF1-MMPs, it may be useful for developing potential clinical strategies. IntroductionGBM (WHO-grade IV) is the most malignant and frequent brain tumor and has the worst prognosis of any cancer. Despite advances in treatment by surgery combined with radiotherapy or chemotherapy, patients with GBM have a mean survival of only 14.6 months (1). Therefore, new therapeutic targets are urgently needed. A formidable difficulty in treating GBM is that tumor cells diffuse and infiltrate the normal peripheral tissue, therefore it is not possible to completely dissect out and remove the tumor. Degradation of extracellular matrix (ECM) is the defining step in tumor cell invasion and members of the matrix metalloproteinase family (MMPs) have crucial roles in regulating this process (2-4). Thus, understanding and blocking the invasive process may be an effective strategy for treating GBM.The recent discovery of miRNAs is a major advance. Accumulating evidence suggests that miRNAs are involved in multiple biological functions, including cell invasion, by altering the expression of multiple target genes. They bind to the 3' untranslated region (UTR) of target messenger RNAs (mRNAs) to suppress translation or induce degradation of these mRNAs. The roles different miRNAs play have been recently expounded in numerous human tumors as detailed below.Accumulated evidence shows that downregulation of miR-218 can enhance tumor cell invasion and proliferation in several kinds of solid tumors (5,6). In this study, we have identifi...

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“…The Wnt pathway significantly has been found to correlate with the invasion and proliferation of tumor cells (44). Wnt proteins bind receptors of the Frizzled (Fz) family and regulate formation of the b-catenin-LEF1 complex in the nucleus, which activates many downstream target genes regulating cell invasion, migration, and proliferation.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-218 Inhibits Glioma Invasion, Migration, Proliferation, and Cancer Stem-like Cell Self-Renewal by Targeting the Polycomb Group Gene Bmi1

et al. 2013

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Malignant gliomas are the most common central nervous system tumors and the molecular mechanism driving their development and recurrence is still largely unknown, limiting the treatment of this disease. Here, we show that restoring the expression of miR-218, a microRNA commonly downregulated in glioma, dramatically reduces the migration, invasion, and proliferation of glioma cells. Quantitative reverse transcription PCR and Western blotting analysis revealed that expression of the stem cell-promoting oncogene Bmi1 was decreased after overexpression of miR-218 in glioma cells. Mechanistic investigations defined Bmi1 as a functional downstream target of miR-218 through which miR-218 ablated cell migration and proliferation. We documented that miR-218 also blocked the self-renewal of glioma stem-like cells, consistent with the suggested role of Bmi1 in stem cell growth. Finally, we showed that miR-218 regulated a broad range of genes involved in glioma cell development, including Wnt pathways that suppress glioma cell stem-like qualities. Taken together, our findings reveal miR-218 as a tumor suppressor that prevents migration, invasion, proliferation, and stemlike qualities in glioma cells. Cancer Res; 73(19); 6046-55. Ó2013 AACR.

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The Wnt signaling pathway: Aging gracefully as a protectionist?

Cited by 152 publications

References 340 publications

WNT16B Is a New Marker of Cellular Senescence That Regulates p53 Activity and the Phosphoinositide 3-Kinase/AKT Pathway

WNT16B Is a New Marker of Cellular Senescence That Regulates p53 Activity and the Phosphoinositide 3-Kinase/AKT Pathway

MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1

MicroRNA-218 Inhibits Glioma Invasion, Migration, Proliferation, and Cancer Stem-like Cell Self-Renewal by Targeting the Polycomb Group Gene Bmi1

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