Mutation R273H confers p53 a stimulating effect on the IGF-1R-AKT pathway via miR-30a suppression in breast cancer

Guo, Fangdong; Chen, Hongshen; Chang, Jian; Zhang, Lin

doi:10.1016/j.biopha.2016.01.031

Cited by 16 publications

(13 citation statements)

References 21 publications

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“…The impact of miR-30a and miR-31 on the initial and progress of BC seems to be deeply investigated than that in miR-22's studies. Other than the favorable biological functions such as inhibition of cell proliferation and migration [35,36] and activation of the IGF1R/PI3K/AKT pathway [37], miR-31 influences the BC apoptosis by protein kinase C epsilon [38,44] and regulates stem cell self-renewal and tumorigenesis by Wnt/β-catenin signaling [39], which is consistent with our enrichment analysis. Among the potential miRNA genes in the present study, we found that overexpression of miR-493 has been negatively correlated with monitoring the fidelity of chromosome segregation by mitotic arrest deficient-2 (MAD2), which predicts the efficacy of taxane chemotherapy [40].…”

Section: Discussionsupporting

confidence: 86%

Identification of miRNA-Based Signature as a Novel Potential Prognostic Biomarker in Patients with Breast Cancer

Tang

Zeng³

et al. 2019

Disease Markers

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To identify the novel, noninvasive biomarkers to assess the outcome and prognosis of breast cancer (BC), patients with high sensitivity and specificity are greatly desired. Herein, the miRNA expression profile and matched clinical features of BC patients were extracted from The Cancer Genome Atlas (TCGA) database. The preliminary candidates were screened out by the univariate Cox regression test. Then, with the help of LASSO Cox regression analysis, the hsa-let-7b, hsa-mir-101-2, hsa-mir-135a-2, hsa-mir-22, hsa-mir-30a, hsa-mir-31, hsa-mir-3130-1, hsa-mir-320b-1, hsa-mir-3678, hsa-mir-4662a, hsa-mir-4772, hsa-mir-493, hsa-mir-556, hsa-mir-652, hsa-mir-6733, hsa-mir-874, and hsa-mir-9-3 were selected to construct the overall survival (OS) predicting signature, while the hsa-mir-130a, hsa-mir-204, hsa-mir-217, hsa-mir-223, hsa-mir-24-2, hsa-mir-29b-1, hsa-mir-363, hsa-mir-5001, hsa-mir-514a-1, hsa-mir-624, hsa-mir-639, hsa-mir-659, and hsa-mir-6892 were adopted to establish the recurrence-free survival (RFS) predicting signature. Referring to the median risk scores generated by the OS and RFS formulas, respectively, subgroup patients with high risk were strongly related to a poor OS and RFS revealed by Kaplan-Meier (K-M) plots. Meanwhile, receiver operating curve (ROC) analysis validated the accuracy and stability of these two signatures. When stratified by clinical features, such as tumor stage, age, and molecular subtypes, we found that the miRNA-based OS and RFS classifiers were still significant in predicting OS/RFS and showed the best predictive values than any other features. Besides, functional prediction analyses showed that these targeted genes of the enrolled miRNAs were enriched in cancer-associated pathways, such as MAPK/RTK, Ras, and PI3K-Akt signaling pathways. In summary, our observations demonstrate that the novel miRNA-based OS and RFS signatures are independent prognostic indicators for BC patients and worthy to be validated by further prospective studies.

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Section: Discussionsupporting

confidence: 86%

Identification of miRNA-Based Signature as a Novel Potential Prognostic Biomarker in Patients with Breast Cancer

Tang

Zeng³

et al. 2019

Disease Markers

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“…In this study, we have shown that targeting mutant TP53 downregulated IGF‐1R in osteosarcoma cells in vitro. It has been reported in breast cancers that mutant TP53 R273H released the inhibitory effect of miR‐30a on IGF‐1R expression, thus enhancing the activation of IGF‐1r/AKT signaling cascade . In addition to this, in hepatoma cells, mutant TP53 R249 was shown to enhance IGF‐IR signaling, which could be specifically prevented by an IGF‐IR antibody, alpha IR3, and lovastin in p53 negative cells …”

Section: Discussionmentioning

confidence: 79%

“…It has been reported in breast cancers that mutant TP53 R273H released the inhibitory effect of miR-30a on IGF-1R expression, thus enhancing the activation of IGF-1r/AKT signaling cascade. 38 In addition to this, in hepatoma cells, mutant TP53 R249 was shown to enhance IGF-IR signaling, which could be specifically prevented by an IGF-IR antibody, alpha IR3, and lovastin in p53 negative cells. 39 In this study, down-regulation of anti-apoptotic protein expression, including Bcl-2 and Survivin, after targeting mutant TP53 revealed the involvement of TP53 mutations in apoptotic signaling.…”

Section: Discussionmentioning

confidence: 89%

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

Tang

Seebacher

et al. 2019

Journal Orthopaedic Research

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Mutant TP53 is a promising therapeutic target in cancers. Considering the current challenges facing the clinical treatment of cancer, as well as the urgent need to identify novel therapeutic targets in osteosarcomas, we aimed to evaluate the clinical significance of mutant TP53 in osteosarcoma patients and to explore the therapeutic effect of targeting mutant TP53 in osteosarcomas. We performed a meta‐analysis to investigate the relationship between mutant TP53 and the overall survival of patients with osteosarcoma. A CRISPR‐Cas9 system and a TP53 inhibitor, NSC59984, were also used to specifically knock‐out and inhibit mutant TP53 in the human osteosarcoma cell lines, KHOS, and KHOSR2. The meta‐analysis demonstrated that mutations in the TP53 gene could be used to predict a poor 2‐year survival in osteosarcoma patients. We also demonstrated that the expression of mutant TP53 in human osteosarcoma cell lines can be efficiently knocked‐out using CRISPR‐Cas9, and this decreased the proliferation, migration, and tumor formation activity of these osteosarcoma cells. Moreover, drug sensitivity to doxorubicin was increased in these TP53 knock‐out osteosarcoma cells. NSC59984 also showed similar anti‐tumor effects as CRISPR‐Cas9 targeted TP53 in the osteosarcoma cells in vitro. We have also demonstrated that the knock‐out or inhibition of mutant TP53 decreased the expression of the oncogene IGF‐1R, anti‐apoptotic proteins Bcl‐2, and Survivin in osteosarcoma cells. Collectively, these results suggest that mutant TP53 is a promising therapeutic target in osteosarcomas. Therefore, further studies exploring novel strategies to target mutant TP53 may help improve the treatment outcomes of osteosarcoma patients in the clinic. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

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“…Aberrant dysregulation of phosphoinositide 3-kinase and Akt (PI3K/Akt) pathway plays a key role in many hallmarks of cancer and contributes to increase ROS levels through direct modulation of mitochondrial bioenergetics and activation of NOX, or through the generation of highly reactive metabolic by-products, as superoxide ions and H 2 O 2 [105][106][107]. Importantly, a number of studies demonstrated that mutant p53 stimulates PI3K/Akt activity, leading to a variety of oncogenic proprieties, such as cell survival, cell migration, metabolic re-wiring, and anoikis resistance [108][109][110].…”

Section: Regulation Of Akt/mtor Signaling By Mutant P53 Proteinsmentioning

confidence: 99%

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

et al. 2020

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The TP53 tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, regulating numerous signaling pathways linked to metabolism and cell growth. Tumor cells frequently display higher ROS levels compared to healthy cells as a result of their increased metabolism as well as serving as an oncogenic agent because of its damaging and mutational properties. Several studies reported that in contrast with the wild type protein, mutant p53 isoforms fail to exert antioxidant activities and rather increase intracellular ROS, driving a pro-tumorigenic survival. These pro-oxidant oncogenic abilities of GOF mutant p53 include signaling and metabolic rewiring, as well as the modulation of critical ROS-related transcription factors and antioxidant systems, which lead ROS unbalance linked to tumor progression. The studies summarized here highlight that GOF mutant p53 isoforms might constitute major targets for selective therapeutic intervention against several types of tumors and that ROS enhancement driven by mutant p53 might represent an “Achilles heel” of cancer cells, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing the mutant TP53 gene.

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Mutation R273H confers p53 a stimulating effect on the IGF-1R-AKT pathway via miR-30a suppression in breast cancer

Cited by 16 publications

References 21 publications

Identification of miRNA-Based Signature as a Novel Potential Prognostic Biomarker in Patients with Breast Cancer

Identification of miRNA-Based Signature as a Novel Potential Prognostic Biomarker in Patients with Breast Cancer

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

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