Silencing of Jagged1 inhibits cell growth and invasion in colorectal cancer

Dai, Yun; Wilson, George S.; Huang, Bingqing; Peng, Meiyu; Teng, Guigen; Zhang, D; Zhang, R; Ebert, Matthias; Chen, Jierun; Wong, Benjamin C Y; Chan, Kwok Wah; George, Jacob; Qiao, Liang

doi:10.1038/cddis.2014.137

Cited by 72 publications

(62 citation statements)

References 52 publications

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“…It is worth underlining, however, that this work is based on conditional animal models, and the mutations were induced in the adult intestine and for a limited length of time, which might attenuate the phenotypes. In fact, increased Jag1 expression and its participation in intestinal Notch activity have clearly been established in pathological conditions, such as inflammation or cancer (Imaeda et al, 2011;Rodilla et al, 2009;Dai et al, 2014). Interestingly, Jag1 responds at the transcriptional level to different stimuli/transcription factors that are important for intestinal development and homeostasis, such as Wnt (Peignon et al, 2011;Rodilla et al, 2009) or HNF1α (D'Angelo et al, 2010.…”

Section: Discussionmentioning

confidence: 99%

The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine

et al. 2015

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Thyroid hormones control various aspects of gut development and homeostasis. The best-known example is in gastrointestinal tract remodeling during amphibian metamorphosis. It is well documented that these hormones act via the TR nuclear receptors, which are hormone-modulated transcription factors. Several studies have shown that thyroid hormones regulate the expression of several genes in the Notch signaling pathway, indicating a possible means by which they participate in the control of gut physiology. However, the mechanisms and biological significance of this control have remained unexplored. Using multiple in vivo and in vitro approaches, we show that thyroid hormones positively regulate Notch activity through the TRα1 receptor. From a molecular point of view, TRα1 indirectly controls Notch1, Dll1, Dll4 and Hes1 expression but acts as a direct transcriptional regulator of the Jag1 gene by binding to a responsive element in the Jag1 promoter. Our findings show that the TRα1 nuclear receptor plays a key role in intestinal crypt progenitor/stem cell biology by controlling the Notch pathway and hence the balance between cell proliferation and cell differentiation.

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Section: Discussionmentioning

confidence: 99%

The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine

et al. 2015

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“…Aberrations in cell cycle progression occur in the majority of human malignancies [16]. The cell cycle is a highly controlled process that involves tight regulation of key molecules that allow cells to progress between phases of the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

“…Cell migration was determined using the wound healing assay, as described previously [16]. Briefly, cells transfected with SiIF1 or SiCL were plated in 24-well plates at a density of 5,000 cells/well.…”

Section: Methodsmentioning

confidence: 99%

Silencing of ATPase Inhibitory Factor 1 Inhibits Cell Growth via Cell Cycle Arrest in Bladder Cancer

Wei¹,

Fukuhara²,

Kawada³

et al. 2015

Pathobiology

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Objective: The role of the ATPase inhibitory factor 1 (IF1) is inhibit the hydrolase activity of F₁F_o-ATPase when oxidative phosphorylation is impaired. It has been demonstrated that IF1 is overexpressed in various carcinomas and mediates tumor cell activities, but the detailed mechanisms of IF1-mediated tumor progression and the link between IF1 and cell cycle progression remain unclear. Herein, we aimed to investigate the potential role of IF1 in cell cycle progression of human bladder cancer (BCa). Methods: The expression of IF1 was analyzed by immunohistochemistry in tumor tissues. Western blot was used to detect protein expression in the cells. Cell proliferation was determined by MTT and colony formation assays. The cell cycle was analyzed using flow cytometry. Results: We firstly showed IF1 was overexpressed in BCa. Silencing of IF1 by small interfering RNA led to a significant decrease in cell proliferation and migration in T24 and UM-UC-3 cells. Importantly, IF1 knockdown caused cell cycle arrest at G₀/G₁ stage and decreased the protein level of cyclin E/cyclin-dependent kinases (cdk) 2 and/or cyclin D/cdk4/cdk6. Conclusion: These results suggest the inhibitory effect of IF1 knockdown on BCa cell proliferation is via the suppression of cyclins and cdks related to G₁/S transition and then induction of G₀/G₁ arrest, and firstly indicate IF1 mediates the tumor cell cycle. We concluded that IF1 may be a novel therapeutic target for BCa.

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“…Whereas Jagged1 overexpression appears to promote bone metastasis formation, Jagged1 knockdown or inhibition of Notch signaling by ␥-secretase inhibitors has been found to reduce bone metastasis in immunocompromised mice (6 ). Both strategies are hypothesized to also be efficient in humans and some agents are being tested currently in clinical trials (8,9 ). Taken together, these findings suggest that Jagged1 might serve as a poor-prognosis factor identifying patients at high risk of metastasis to the bone marrow and resistant to bone metastasis-specific treatments.…”

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confidence: 99%

Potential Involvement of Jagged1 in Metastatic Progression of Human Breast Carcinomas

et al. 2016

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BACKGROUND Jagged1, the ligand of Notch, has been shown to be involved in formation of bone metastases in an experimental study. Here, clinical relevance of Jagged1 expression in tumor progression was assessed in human breast carcinomas. METHODS Jagged1 expression was evaluated by immunohistochemistry in 228 tumor tissue samples and compared to clinicopathologic parameters and patients' outcomes. Furthermore, circulating tumor cells (CTCs) from peripheral blood of 100 unmatched metastatic cancer patients with progressive disease were enriched using Ficoll density gradient centrifugation and detected by pan-keratin/Jagged1/CD45 immunofluorescent staining. RESULTS Jagged1 expression was detected in 50% of 228 tumors. Jagged1 expression was correlated with higher tumor grade (P = 0.047), vascular invasion (P = 0.026), luminal B subtype (P = 0.016), overexpression of Her-2 (P = 0.001), high Ki-67 expression (P = 0.035), and aldehyde dehydrogenase 1 (ALDH1) positivity (P = 0.013). Jagged 1 expression indicated shorter disease-free survival (DFS) (P = 0.040) and metastasis-free survival (P = 0.048) in lymph node–negative breast cancer for which it was the only independent predictor of DFS (multivariate analysis, P = 0.046). Tumors characterized by the strongest Jagged1 staining intensity (7.5% of cases) correlated with lymph node positivity (P = 0.037), metastatic relapse (P = 0.049), and higher number of disseminated tumor cells in bone marrow aspirates (P = 0.041). Twenty-one unmatched metastatic breast cancer patients with progressive disease were positive for CTCs, and 85.7% of the CTCs also expressed Jagged1. The presence of Jagged1(+) CTCs was significantly associated with shorter progression-free survival in patients treated with bisphosphonates (P = 0.013). CONCLUSIONS Jagged1 expression characterizes more aggressive breast carcinoma and might be involved in tumor cell dissemination, metastatic progression, and resistance to bone-targeting therapy in breast cancer patients.

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Silencing of Jagged1 inhibits cell growth and invasion in colorectal cancer

Cited by 72 publications

References 52 publications

The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine

The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine

Silencing of ATPase Inhibitory Factor 1 Inhibits Cell Growth via Cell Cycle Arrest in Bladder Cancer

Potential Involvement of Jagged1 in Metastatic Progression of Human Breast Carcinomas

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