TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity

Stantic, Marina; Sakil, Habib A. M.; Zirath, Hanna; Fang, Trixy; Sanz, Gema; Fernandez-Woodbridge, Alejandro; Marín, Ana V.; Susanto, Evelyn; Mak, Tak W.; Henriksson, Marie Arsenian; Wilhelm, Margareta

doi:10.1073/pnas.1421697112

Cited by 56 publications

(86 citation statements)

References 34 publications

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“…Inter and intra-PDA heterogeneity combined with a drastic genomic instability forces us to deepen our understanding on molecular events that drive the development and the evolution of tumor cells through critical pathways that are, at present, unusable in therapy. Previous studies reported the p53 homolog TAp73 as involved in cancer development through cell growth/death regulatory mechanisms and more recently in tumor angiogenesis 44 or metabolic adaptation. 45 Interestingly, although TAp73 has gained some importance within the cancer field, the significance of its altered expression in various cancers has not yet been clearly defined in terms of its clinical translation into cancer.…”

Section: Discussionmentioning

confidence: 99%

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

et al. 2016

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Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-β (TGF-β) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-β pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/ activity. Absence of TAp73 leads to activation of TGF-β signaling through a SMAD-independent pathway, favoring oncogenic TGF-β effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-β signaling. By suggesting TAp73 as a predictive marker for response to TGF-β inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-β inhibitors.

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Section: Discussionmentioning

confidence: 99%

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

et al. 2016

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“…However, the role of TAp73 in vasculogenesis remains contradictory and unclear. Some reports have suggested that TAp73 has a suppressive effect on angiogenesis (8,9). Conversely, other reports suggest that TAp73 is a proangiogenic factor.…”

Section: Discussionmentioning

confidence: 99%

“…However, the function of TAp73 in regulating angiogenesis in cancer is hotly debated (6,7). Some suggest that TAp73 suppresses angiogenesis (8,9). Conversely, others suggest that both the TAp73 and ΔNp73 forms are proangiogenic (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Association between TAp73, p53 and VASH1 expression in lung adenocarcinoma

Zhang

et al. 2018

Oncol Lett

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Abstract. TAp73 and p53 are involved in regulating tumor angiogenesis and vasohibin-1 (VASH1) is an anti-angiogenic factor. Whether TAp73 regulates angiogenesis positively or negatively is controversial. The status of P53 may determine the effect of TAp73 on angiogenesis. To the best of our knowledge it has not been previously reported whether TAp73, p53 and VASH1 are coexpressed in lung cancer. We profiled the association between TAp73 and p53 and VASH1 expression in lung adenocarcinoma (LAC) and investigated the function of TAp73 in regulating tumor angiogenesis. TAp73, p53 and VASH1 expression in 53 human LAC tissues and the adjacent normal tissues were evaluated using immunohistochemistry. The positive expression rates of p53, TAp73 and VASH1 were significantly higher (92.6, 97.7 and 67.4%, respectively) in LAC tissue compared with paraneoplastic lung tissue (7.4, 2.3 and 32.6%, respectively, P<0.01). Pearson's correlation coefficient showed a significant positive correlation between p53 and TAp73 (r= 0.474, P<0.01) and TAp73α and VASH1 (r= 0.367, P<0.01). The positive expression rate of p53 and VASH1 was almost significantly correlated (r= 0.187, P= 0.055). Similarly, p53 expression intensity had a significant positive correlation with TAp73α (r= 0.517, P<0.01) and with VASH1 (r= 0.277, P<0.01), as did TAp73α with VASH1 (r=0.351, P<0.01). TAp73, p53 (mutant) and VASH1 expression was significantly higher in LAC tissue compared with paraneoplastic lung tissue. The expression trends of the three proteins were significantly positively correlated with each other in LAC. These results suggest that TAp73 may suppress tumor angiogenesis in LAC.

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“…Synovial hypoxia frequently occurs in patients with RA, contributing to tendon rupture [8]. The cellular response to hypoxia is mainly driven by the transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) [9]. This is an upregulation of HIF-1α in RA patients [10].…”

Section: Introductionmentioning

confidence: 99%

Andrographolide inhibits the migration, invasion and matrix metalloproteinase expression of rheumatoid arthritis fibroblast-like synoviocytes via inhibition of HIF-1α signaling

Qin

2015

Life Sciences

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TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity

Cited by 56 publications

References 34 publications

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

Association between TAp73, p53 and VASH1 expression in lung adenocarcinoma

Andrographolide inhibits the migration, invasion and matrix metalloproteinase expression of rheumatoid arthritis fibroblast-like synoviocytes via inhibition of HIF-1α signaling

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