MDM2 induces EMT via the B‑Raf signaling pathway through 14‑3‑3

Ou, Mengting; Xu, Xichao; Chen, Ying; Li, Li; Zhang, Lu; Liao, Yi; Sun, Weichao; Quach, Christine; Feng, Jianguo; Tang, Liling

doi:10.3892/or.2021.8071

Cited by 7 publications

(3 citation statements)

References 78 publications

(160 reference statements)

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“…The data presented here implies that MDM2 regulates the expression of ZEB factors in HCC. Consistent with this, MDM2 overexpression has been found to enhance the expression of EMT markers, such as ZEB1, via the B‐Raf signaling pathway in glioma, lung cancer, and breast cancer cells [ 63 ]. In addition, recent evidence has been published suggesting that MDM2 can regulate ZEB1 and ZEB2 by activating Smad2 and Smad3, resulting in EMT progression [ 50 ].…”

Section: Discussionmentioning

confidence: 71%

Functional role and epithelial to mesenchymal transition of the miR-590-3p/MDM2 axis in hepatocellular carcinoma

2023

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Background There is considerable evidence that microRNAs (miRNAs) regulate several key tumor-associated genes/pathways and may themselves have a dual regulatory function either as tumor suppressors or oncogenic miRNA, depending on the tumor type. MicroRNA-590-3p (miR-590-3p) is a small non-coding RNA involved in the initiation and progression of numerous tumors. However, its expression pattern and biological role in hepatocellular carcinoma (HCC) are controversial. Results In the current work, computational and RT-qPCR analysis revealed that HCC tissues and cell lines exhibited miR-590-3p downregulation. Forced expression of miR-590-3p attenuated HepG2 cells proliferation, migration, and repressed EMT-related gene expression. Bioinformatic, RT-qPCR, and luciferase assays revealed that MDM2 is a direct functional target of miR-590-3p. Moreover, the knockdown of MDM2 mimicked the inhibitory effect of miR-590-3p in HepG2 cells. Conclusion We have identified not only novel targets for miR-590-3p in HCC, but also novel target genes for miR590-3p/MDM2 pathway in HCC like SNAIL, SLUG, ZEB1, ZEB2, and N-cadherin. Furthermore, these findings demonstrate a crucial role for MDM2 in the regulatory mechanism of EMT in HCC.

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Section: Discussionmentioning

confidence: 71%

Functional role and epithelial to mesenchymal transition of the miR-590-3p/MDM2 axis in hepatocellular carcinoma

2023

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“…Gemcitabine treatment can enhance the expression of MDM2 and increase mesenchymal properties in pancreatic and breast cancer ( Ahmad et al, 2020 ). Recent studies have demonstrated that MDM2 promotes the EMT via MDM2/p53/14-3-3 signaling mediated by v-raf murine sarcoma viral oncogene homolog B1 (B-raf) activity ( Ou et al, 2021 ). It may also be enhanced by MDM2/protein kinase B (Akt)/androgen receptor signaling, suggesting another pathway linking MDM2 and the EMT to drug resistance ( Singh et al, 2013 ).…”

Section: The Rationale For Targeting Mdm2 For Molecular Targeted Therapymentioning

confidence: 99%

MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future

Wang,

Albadari,

et al. 2024

Pharmacol Rev

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Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated. Significance Statement Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.

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“…The process of epithelial to mesenchymal transition (EMT) is widely believed to act as a trigger for cancer metastasis, as it empowers cells to migrate and invade the stroma [ 28 ]. Research suggests that MDM2 can stimulate the EMT process by enhancing the expression of EMT-related transcription factors through the activation of the B-Raf signaling pathway [ 29 ]. As a result, this process can promote the metastasis of tumor cells, thereby compromising the effectiveness of treatment modalities such as anticancer immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Targeting MDM2 in malignancies is a promising strategy for overcoming resistance to anticancer immunotherapy

Sun,

Qian,

et al. 2024

J Biomed Sci

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MDM2 has been established as a biomarker indicating poor prognosis for individuals undergoing immune checkpoint inhibitor (ICI) treatment for different malignancies by various pancancer studies. Specifically, patients who have MDM2 amplification are vulnerable to the development of hyperprogressive disease (HPD) following anticancer immunotherapy, resulting in marked deleterious effects on survival rates. The mechanism of MDM2 involves its role as an oncogene during the development of malignancy, and MDM2 can promote both metastasis and tumor cell proliferation, which indirectly leads to disease progression. Moreover, MDM2 is vitally involved in modifying the tumor immune microenvironment (TIME) as well as in influencing immune cells, eventually facilitating immune evasion and tolerance. Encouragingly, various MDM2 inhibitors have exhibited efficacy in relieving the TIME suppression caused by MDM2. These results demonstrate the prospects for breakthroughs in combination therapy using MDM2 inhibitors and anticancer immunotherapy.

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MDM2 induces EMT via the B‑Raf signaling pathway through 14‑3‑3

Cited by 7 publications

References 78 publications

Functional role and epithelial to mesenchymal transition of the miR-590-3p/MDM2 axis in hepatocellular carcinoma

Functional role and epithelial to mesenchymal transition of the miR-590-3p/MDM2 axis in hepatocellular carcinoma

MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future

Targeting MDM2 in malignancies is a promising strategy for overcoming resistance to anticancer immunotherapy

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