The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

Li, Yufeng; Dong, Wenyue; Shan, Xijin; Hong, Hui; Liu, Yan; Liu, Yankun; Lu, Xiaohui; Zhang, Xiaojun; Zhang, Jinghua

doi:10.3892/ol.2018.8314

Cited by 17 publications

(18 citation statements)

References 48 publications

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“…It may be involved in cervical cancer pathogenesis and might serve as a biomarker of cervical SCC in the future [7]. In our and others studies, Mfn2 could induce Hela cells into mitochondrial apoptosis [8], pancreatic cancer into cell autophagy [9], and breast cancer into DNA methylation [10], as a tumour suppressor in many cancers. Mfn-2 is a mitochondrial outer-membrane protein with GTPase activity involved in mitochondrial fusion and fission and apoptosis regulation [11–13].…”

Section: Introductionmentioning

confidence: 91%

Mfn2 inhibits proliferation and cell-cycle in Hela cells via Ras-NF-κB signal pathway

et al. 2019

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Background Mitofusin 2 (Mfn2) is outer membrane protein, as the inhibitor of Ras protein. This study aimed to investigate the effect of Mfn2 on cell proliferation, and cell-cycle in Hela cervical carcinoma cell lines. Methods After treated with Adv-mfn2 or Adv-control for 48 h and 60 h, the RNA and protein of Mfn2 in Hela cells were detected by qRT-PCR and western blot. The immunofluorescence assay was performed to observe the expression and sub-location of Mfn2 in Hela cells. The flow cytometry was performed to detect the cell cycle of Hela cells, while western blots were performed to observe the Ras-NF-κB signal pathway. Then, the xenografted cervix carcinoma mouse model was used to confirm the effect of Mfn2 in Hela cells in vivo and the expression of Ras-NF-κB signaling pathway in vivo. Results In immunofluorescence detection, Mfn2 was located in cytoplasmic, not in the nucleus. In addition, Mfn2 inhibited cell proliferation of Hela cells through reducing PCNA protein expression. Mfn2 induced arrest in G0/G1 phase of the cell cycle in Hela cells. Meanwhile, Mfn2 reduced Cyclin D1 protein expression. Moreover, Mfn2 decreased the Ras signal pathway proteins such as Myc, NF-κB p65, STAT3 in a dose-dependent manner. Then, the in vivo experiment also confirmed that Mfn2 could inhibit the tumor growth, and depress the Cyclin D1, Ras, Myc, NF-κB p65, Erk1/2 and mTOR protein expression. Conclusions Mfn2 could significantly inhibit cell proliferation in Hela cells. It might be acted as an potential anti-cancer target through inducing cell cycle arrest in human cervical carcinoma cells.

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Section: Introductionmentioning

confidence: 91%

Mfn2 inhibits proliferation and cell-cycle in Hela cells via Ras-NF-κB signal pathway

et al. 2019

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“…Recently, it was reported that MFN2 plays an essential role in mitochondrial fusion, which regulates mitochondrial morphology and function in multiple cell types . Meanwhile, MFN2 has been demonstrated to be low expressed in various types of human malignant tumours, such as gastric cancer, hepatocellular cancer, colorectal cancer and breast cancer . Apart from its role in cancer, clinical evidence revealed that dysfunction of MFN2 is also involved in the pathophysiology of several cardiovascular diseases including hypertension, restenosis after angioplasty, cardiac hypertrophy and cardiac oxidative stress injury .…”

Section: Introductionmentioning

confidence: 99%

“…6 Meanwhile, MFN2 has been demonstrated to be low expressed in various types of human malignant tumours, such as gastric cancer, hepatocellular cancer, colorectal cancer and breast cancer. 7,8 Apart from its role in cancer, clinical evidence revealed that dysfunction of MFN2 is also involved in the pathophysiology of several cardiovascular diseases including hypertension, restenosis after angioplasty, cardiac hypertrophy and cardiac oxidative stress injury. 9,10 Intriguingly, MFN2 was found to exert an anti-proliferative effect by inducing more cells at the G0/G1 phase in cultured MCF-7 cells and a rat carotid artery balloon-injury model.…”

Section: Introductionmentioning

confidence: 99%

Aberrant MFN2 transcription facilitates homocysteine‐induced VSMCs proliferation via the increased binding of c‐Myc to DNMT1 in atherosclerosis

Hao

et al. 2019

J Cellular Molecular Medi

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It is well‐established that homocysteine (Hcy) is an independent risk factor for atherosclerosis. Hcy can promote vascular smooth muscle cell (VSMC) proliferation, it plays a key role in neointimal formation and thus contribute to arteriosclerosis. However, the molecular mechanism on VSMCs proliferation underlying atherosclerosis is not well elucidated. Mitofusin‐2 (MFN2) is an important transmembrane GTPase in the mitochondrial outer membrane and it can block cells in the G0/G1 stage of the cell cycle. To investigate the contribution of aberrant MFN2 transcription in Hcy‐induced VSMCs proliferation and the underlying mechanisms. Cell cycle analysis revealed a decreased proportion of VSMCs in G0/G1 and an increased proportion in S phase in atherosclerotic plaque of APOE −/− mice with hyperhomocystinaemia (HHcy) as well as in VSMCs exposed to Hcy in vitro. The DNA methylation level of MFN2 promoter was obviously increased in VSMCs treated with Hcy, leading to suppressed promoter activity and low expression of MFN2. In addition, we found that the expression of c‐Myc was increased in atherosclerotic plaque and VSMCs treated with Hcy. Further study showed that c‐Myc indirectly regulates MFN2 expression is duo to the binding of c‐Myc to DNMT1 promoter up‐regulates DNMT1 expression leading to DNA hypermethylation of MFN2 promoter, thereby inhibits MFN2 expression in VSMCs treated with Hcy. In conclusion, our study demonstrated that Hcy‐induced hypermethylation of MFN2 promoter inhibits the transcription of MFN2, leading to VSMCs proliferation in plaque formation, and the increased binding of c‐Myc to DNMT1 promoter is a new and relevant molecular mechanism.

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“…MFN2 promotes cellular apoptosis and inhibits cell proliferation [ 17 , 18 ]. Studies showed that the expression of MFN2 in colorectal cancer tissues and breast cancer tissues is significantly lower than that in normal adjacent tissues [ 19 , 20 ]. These results suggest that MFN2 plays an important role in the occurrence and development of malignant tumors.…”

Section: Introductionmentioning

confidence: 99%

Mitofusin-2 acts as biomarker for predicting poor prognosis in hepatitis B virus related hepatocellular carcinoma

Wang

Liu

Sun

et al. 2018

Infect Agents Cancer

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ObjectiveTo investigate the expression of Mitofusin-2 (MFN2) in HCC tissues and its role in the development of HCC.MethodsA total of 107 HCC specimens were collected for tissue microarray analysis and immunohistochemistry (IHC) analysis. The relationship between MFN2 expression and clinical features of patients with HCC was analyzed.ResultsExpression level of MFN2 in HCC tissues was 0.92 ± 0.78, significantly lower than that of matched paracancerous liver tissues (1.25 ± 0.75). Patients with low expression of MFN2 had significantly higher rates of cirrhosis than those with high expression of MFN2 (P = 0.049). Kaplan-Meier survival analysis showed that HCC patients with low expression of MFN2 had a worse prognosis in overall survival than HCC patients with high expression of MFN2 (P = 0.027). Patients with high expression of MFN2 had a better prognosis in disease-free survival compared with HCC patients with low expression of MFN2 (P = 0.047). Vascular invasion and MFN2 expression were shown to be prognostic variables for overall survival in patients with HCC. Multivariate analysis showed that vascular invasion (P < 0.001) and MFN2 expression (P = 0.045) were independent prognostic factors for overall survival. Vascular invasion (P < 0.001) and MFN2 expression (P = 0.042) were independent risk factors associated with disease-free survival.ConclusionOur data revealed that MFN2 expression was decreased in HCC samples. High MFN2 expression was correlated with longer survival times in patients with HCC and served as an independent factor for better outcomes. Our study therefore provides a promising biomarker for the prognostic prediction of HCC and a potential therapeutic target for the disease.

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The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

Cited by 17 publications

References 48 publications

Mfn2 inhibits proliferation and cell-cycle in Hela cells via Ras-NF-κB signal pathway

Mfn2 inhibits proliferation and cell-cycle in Hela cells via Ras-NF-κB signal pathway

Aberrant MFN2 transcription facilitates homocysteine‐induced VSMCs proliferation via the increased binding of c‐Myc to DNMT1 in atherosclerosis

Mitofusin-2 acts as biomarker for predicting poor prognosis in hepatitis B virus related hepatocellular carcinoma

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