The <i>TP73</i> complex network: Ready for clinical translation in cancer?

Soldevilla, Beatriz; Millán, Coral San; Bonilla, Félix; Domínguez, Gemma

doi:10.1002/gcc.22095

Cited by 16 publications

(17 citation statements)

References 172 publications

(206 reference statements)

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“…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. 46 In parallel, several studies have confirmed the convergence of p53 and the TGF-β network, 47 two major cancer regulators driving multiple cancer-associated pathways. In pancreatic cancer, their interplay seems to be associated with SMADs, 48 the deletion or mutation of which correlates with shorter survival and widespread metastasis.…”

Section: Discussionmentioning

confidence: 94%

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: 94%

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

et al. 2016

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“…19,20,23,24 Particularly in APL, TP53 mutations are uncommon, 25 which further highlights the relevance of the DNp73/TAp73 ratio to both survival advantage and failure to respond to chemotherapy. It is important to note that an intricate functional relationship between TP53 family members has been described 26 and, although speculative, it is conceivable that in patients with wild-type TP53, the overexpression of DNp73 protein would impair p53 tumorsuppressor functions. Thus, survival advantage would be the result of a high DNp73/TAp73 ratio, rather than TP53 mutations.…”

Section: Resultsmentioning

confidence: 99%

High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia

Lucena-Araújo

Kim

Thomé

et al. 2015

Blood

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Key Points• High DNp73/TAp73 expression ratio is associated with lower overall survival and higher cumulative incidence of relapse in APL.• DNp73/TAp73 expression ratio is an independent prognostic marker in APL.The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (DNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between DNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher DNp73/ TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high DNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P 5 .0035). Our data support the hypothesis that the DNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells. (Blood. 2015;126(20):2302-2306

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“…On the contrary, the over-expression of p73 gene was observed in several types of neoplasms, suggesting the oncogenic role of p73 gene in cancer development and progression [5]. The findings of either suppressor or oncogenic role of TP73 protein in carcinogenesis may be associated with different functions of several isoforms of the TP73 protein [4][5][6]. p73a mRNA variant encodes the longest protein isoform (69.6 kDa, 636aa) characterized by the occurrence of three domains: transactivation (TA), DNA-binding and proline-rich ones.…”

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confidence: 99%

Decreased expression of p73 in colorectal cancer

Kotulak

Wrońska

Godlewski

et al. 2016

Folia Histochem Cytobiol.

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Introduction. The colorectal cancer (CRC) is one of the most frequent cancer in Poland and worldwide. This disease is characterized by distinct genetic alterations. p73 belongs to the p53 gene family; however, its role in the pathogenesis of CRC has not been completely understood. p73 gene encodes several mRNA variants and protein isoforms with its longest and fully functional p73a (mRNA) and TAp73a (protein) isoform. The aim of the study was to investigate p73 gene expression at the mRNA (p73a) and protein (TAp73a) levels in CRC. Material and methods. Small sections of the CRC tumor tissue and macroscopically unchanged colon mucosa and submucosa from the dissection margin were collected from 23 patients diagnosed with CRC. p73 mRNA levels were measured by Real-time PCR (QPCR) method and the expression level of TAp73a protein was assessed by Western blotting (WB) and immunohistochemical (IHC) staining. Results. We found a 37% decrease in the level of p73a mRNA in neoplastically changed (tumor) compared with unchanged normal colon tissue from the surgical margin (p = 0.041). No correlations were found between mRNA levels in cancer tissue and clinical-pathological parameters. The semi-quantification of TAp73a protein revealed lower and higher TAp73a protein contents in 11/23 and 12/23 of tumor samples, respectively, when compared with the median value of TAp73a protein in normal colon tissue (p = 0.61). The level of TAp73a protein level was 5 times lower in poorly differentiated cancer cells (G3) in comparison to moderately differentiated ones (G2; p = 0.02). No statistically significant correlations were observed between the level of the TAp73a protein and clinical-pathological patients' characteristics. The IHC analysis of TAp73a protein presence in CRC samples showed decreased immunoreactivity when compared with matched sections of the unchanged colon wall in 4/9 patients, similar intensity of the IHC reaction in 4/9 patients and increased immunoreactivity in 1/9 patients. The TAp73a protein was localized mainly in the cytoplasm of the cancer cells. No statistically significant correlations between IHC results and clinical-pathological features of the patients were found. Conclusions. The obtained results suggest that the p73 gene may play a role as a tumor suppressor in the CRC progression.

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The TP73 complex network: Ready for clinical translation in cancer?

Cited by 16 publications

References 172 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

High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia

Decreased expression of p73 in colorectal cancer

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