MDM2–p53 Pathway in Hepatocellular Carcinoma

Meng, Xuan; Franklin, David S.; Dong, Jiahong; Zhang, Yanping

doi:10.1158/0008-5472.can-14-1446

Cited by 178 publications

(140 citation statements)

References 61 publications

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“…E3 ubiquitin ligases are important regulators of a variety of biological processes including cell cycle regulation, cell proliferation, and apoptosis [27, 28]. The TRIM family of genes has been widely studied due to their key roles in development, differentiation and host cell antiviral defenses; however, roles in cancer biology are emerging [29].…”

Section: Discussionmentioning

confidence: 99%

TRIM11, a direct target of miR-24-3p, promotes cell proliferation and inhibits apoptosis in colon cancer

Yin

Zhong

et al. 2016

Oncotarget

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TRIM11 (tripartite motif-containing protein 11) is an E3 ubiquitin ligase recently identified as an oncogene in malignant glioma and lung cancer. In the present study, we report that expression of TRIM11 was increased in colon cancer (CC) tissue relative to paired normal tissues and that higher TRIM11 levels predicted poor overall survival (OS) and disease-free survival (DFS) in CC patients. Mechanistically, we showed that miR-24-3p downregulation contributes to TRIM11 upregulation in CC. We also demonstrated that TRIM11 overexpression promotes cell proliferation and colony formation and inhibits apoptosis in CC, while knocking down TRIM11 using CRISPR/Cas9-mediated genome editing inhibited cell proliferation and induced apoptosis. Silencing TRIM11 in vivo decreased tumor growth. These findings indicate that TRIM11 facilitates CC progression by promoting cell proliferation and inhibiting apoptosis and that the novel miR-24-3p/TRIM11 axis may be a useful new target for treating patients with CC.

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Section: Discussionmentioning

confidence: 99%

TRIM11, a direct target of miR-24-3p, promotes cell proliferation and inhibits apoptosis in colon cancer

Yin

Zhong

et al. 2016

Oncotarget

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“…An E3-ubiquitin ligase murine double-minute 2 (MDM2) also regulates the tumor suppressor p53. MDM2 overexpression promotes ubiquitylation and proteasomal degradation of p53, which plays a crucial role in tumor progression [14]. Conversely, inhibition of MDM2 re-sensitized rapamycin-resistant renal cancer cells RCC4 and A549 via p53 activation [15].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

You

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Renal tubular epithelial cells and fibroblasts are the main sources of myofibroblasts, and these cells produce the extracellular matrix during tubulointerstitial fibrosis (TIF). Histone deacetylases (HDAC) inhibitors exert an antifibrogenic effect in the skin, liver and lung. Sirtuin 2 (SIRT2), which is a class III HDAC, is an important member of NAD⁺-dependent protein deacetylases. The current study evaluated the role of SIRT2 in renal TIF. Methods: Immunohistochemical staining and Western blot were performed to evaluate SIRT2 expression in TIF patients and unilateral urethral obstruction (UUO) mice. Western blot was used to assess the protein levels of SIRT2, α-SMA, collagen III, fibronectin, and MDM2 in tubular epithelial cells and fibroblasts. The specific inhibitor AGK2 was used to inhibit SIRT2 activity, and targeted siRNA was used to suppress SIRT2 expression. Results: SIRT2 expression increased in the tubulointerstitium of TIF patients and UUO mice. SIRT2 inhibition ameliorated TIF in UUO mice. SIRT2 expression in tubular cells was unchanged after exposure to TGF-β1. The SIRT2-specifc inhibitor AGK2 did not attenuate TGF-β1-induced tubular epithelial-mesenchymal transition. However, SIRT2 was upregulated in fibroblasts, and fibroblasts were activated after TGF-β1 treatment. Genetic knockdown and chemical inhibition of SIRT2 attenuated TGF-β1-induced fibroblast activation. We also explored the downstream signaling of SIRT2 during fibroblast activation. Genetic knockdown and chemical inhibition of SIRT2 suppressed TGF-β1-induced increase in MDM2 expression, and inhibition of the MDM2-p53 interaction using Nutlin-3 did not suppress SIRT2 upregulation. Conclusion: Our results suggest that SIRT2 participates in the activation of fibroblasts and TIF, which is mediated via regulation of the MDM2 pathway, and the downregulation of SIRT2 may be a therapeutic strategy for renal fibrosis.

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“…Understanding of the molecular mechanisms underlying HCC is important for the development of effective treatment strategies, and deregulations of oncogenes or tumor suppressors have been demonstrated to be involved in the development and progression of HCC [3, 4]. …”

Section: Introductionmentioning

confidence: 99%

MicroRNA-98 acts as a tumor suppressor in hepatocellular carcinoma via targeting SALL4

et al. 2016

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MicroRNAs (miRs) are involved in the development and progression of hepatocellular carcinoma (HCC), but the regulatory mechanism of miR-98 in HCC still remains unclear. Here we found that miR-98 was significantly downregulated in HCC tissues compared to matched adjacent normal tissues (ANTs). Low miR-98 expression was associated with tumor size, metastasis, portal vein tumor embolus, and poor overall survival. Ectopic expression of miR-98 decreased the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of HCC cells. SALL4 was identified as a novel target of miR-98, and the protein expression of SALL4 was inhibited by miR-98 in HCC cells. Overexpression of SALL4 reversed the suppressive effects of miR-98 on the malignant phenotypes of HCC cells. Besides, SALL4, upregulated in HCC tissues compared to the matched ANTs, was inversely correlated to the miR-98 levels in HCC tissues. In addition, overexpression of miR-98 markedly suppressed the tumor growth as well as tumor-induced death in nude mice. In summary, miR-98 plays a suppressive role in the proliferation, migration, invasion and EMT of HCC cells, partly at least, via directly inhibition of SALL4. Therefore, the miR-98/SALL4 axis may become a promising therapeutic target for HCC.

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MDM2–p53 Pathway in Hepatocellular Carcinoma

Cited by 178 publications

References 61 publications

TRIM11, a direct target of miR-24-3p, promotes cell proliferation and inhibits apoptosis in colon cancer

TRIM11, a direct target of miR-24-3p, promotes cell proliferation and inhibits apoptosis in colon cancer

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

MicroRNA-98 acts as a tumor suppressor in hepatocellular carcinoma via targeting SALL4

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