0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop

Xia, Caixia; Shui, Liyan; Lou, Guohua; Ye, Bingjue; Zhu, Wenhe; Wang, Jing; Wu, Shanshan; Xu, Xiao; Mao, Long; Xu, Wanhong; Chen, Zhi; Liu, Yanning; Zheng, Ming‐Hua

doi:10.1038/s41598-017-04487-x

Cited by 15 publications

(12 citation statements)

References 26 publications

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“…Previous research showed that TP53 had the highest prevalence of protein-altering mutations in HCC [37,38]. Several studies have shown that tumor drugs can suppress the proliferation of liver cancer cells by activating the P53/miR-34a/SIRT1 positive feedback loop [39,35]. In our study, we show that the P53/miR-34a/SIRT1 positive feedback loop is de cient in the P53-de cient Hep3B and P53-mutated Huh7 cell lines.…”

Section: Discussionsupporting

confidence: 61%

T-β-MCA Regulates the Termination of Liver Regeneration via the P53/miR-34a/SIRT1 Positive Feedback Loop by Suppressing the FXR/SHP Signaling Pathway.

Yuan¹,

Chen²,

Wu³

et al. 2020

Preprint

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Background The capacity of the liver to restore its architecture and function assures good prognoses of patients who suffer serious hepatic injury or cancer resection. In our previous study, we initially found that the P53/miR-34a/SIRT1 positive feedback loop has a remarkable negative regulatory effect, which is related to the termination of liver regeneration. Here, we described how P53/miR-34a/SIRT1 positive feedback loop controls liver regeneration and its possible relationship with liver cancer.Method We performed partial hepatectomy (PH) in mice transfected with adenovirus (Ade) overexpressing P53 and adenovirus-associated virus (AAV) knock-downing miR-34a. LR was analyzed by liver weight/body weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were investigated. Bile acid (BA) levels during LR were analyzed by metabolomics of bile acids. Results We found that the P53/miR-34a/SIRT1 positive feedback loop was activated in the late phase of LR. Overexpression of P53 terminated LR early and enhanced P53/miR-34a/SIRT1 positive feedback loop expression and its proapoptotic effect. Mice from the Ade-P53 group showed smaller livers and higher levels of serum ALT and AST than control mice. While knock-down of miR-34a abolished P53/miR-34a/SIRT1 positive feedback loop during LR. Mice from anti-miR-34a group showed larger livers and lower levels of PCNA-positive cells than control mice. T-β-MCA increased gradually during LR and peaked at 7 days after PH. T-β-MCA inhibited cell proliferation and promoted cell apoptosis via facilitating the P53/miR-34a/SIRT1 positive feedback loop during LR by suppressing FXR/SHP. Conclusion The P53/miR-34a/SIRT1 positive feedback loop plays an important role in the termination of LR. Our findings shed light on the molecular and metabolic mechanisms of LR termination and provide a potential therapeutic alternative for treating P53-wild-type HCC patients.

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Section: Discussionsupporting

confidence: 61%

T-β-MCA Regulates the Termination of Liver Regeneration via the P53/miR-34a/SIRT1 Positive Feedback Loop by Suppressing the FXR/SHP Signaling Pathway.

Yuan¹,

Chen²,

Wu³

et al. 2020

Preprint

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“…Ito et al found that miR-34a increased with age in endothelial cells in senescent human umbilical cord vein endothelial cells and in the hearts and spleens of older mice [ 31 ]. The regulation of miR-34a-5p/SIRT 1 pathway was investigated in multiple disease and aging models for its effect on aging and oxidative damage [ 33 – 35 ]. In the present research, our data demonstrated that the expression level of miR-34a-5p in the oxidized HLE-B3 cells is 2.59 fold higher compared to the control group.…”

Section: Discussionmentioning

confidence: 99%

Identification of H2O2 induced oxidative stress associated microRNAs in HLE-B3 cells and their clinical relevance to the progression of age-related nuclear cataract

Wang

Guo

et al. 2018

BMC Ophthalmol

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BackgroundThis study is aimed to screen out the microRNAs (miRNAs) associated with H2O2 induced oxidative stress in human lens epithelial B3 (HLE-B3) cell lines and investigate their relations with the progression of age-related nuclear cataract.MethodsH2O2 was used to induce oxidative stress in HLE-B3 cells. A genome-wide expression profiling of miRNAs in HLE-B3 cells was performed to select the differentially expressed miRNAs before and after H2O2 treatment. The selected miRNAs were validated by RT-PCR and fluorescence in situ hybridization (FISH). Clinical specimens were divided into three groups according to the Lens Opacities Classification System III (LOCSIII) and the expression levels of the selected miRNAs were tested by RT-PCR in the three groups. Bioinformatics analyses were applied to predict the target genes of the miRNA hits and construct the miRNA regulatory network. The expression level of MAPK14 was analyzed by Western blot.ResultsThe H2O2 induced oxidative stress model of HLE-B3 cells was established. Nineteen upregulated and 30 downregulated miRNAs were identified as differentially expressed miRNAs. Seven of the total 49 were validated in the cell model. RT-PCR of the clinical samples showed that the expression levels of miR-34a-5p, miR-630 and miR-335-3p were closely related with the severity of nuclear opacity. The images taken from FISH confirmed the results of RT-PCR. There were 172 target genes of the three miRNAs clustered in the category of response to stress. The regulatory network demonstrated that 23 target genes were co-regulated by multiple miRNAs. MAPK14 was the target gene of three miRNAs and the result were verified by Western blot.ConclusionUp-regulation of miR-34a-5p and miR-630 and down-regulation of miR-335-3p are related with the progression of age-related nuclear cataract and the underlying mechanism awaits further functional research to reveal.

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“…As a key factor in inhibiting tumour formation, the p53 gene may be either wild-type or mutant type. The wild-type p53 gene may act as a tumour suppressor gene by repairing damaged DNA, blocking cell cycle, inhibiting cell proliferation and promoting apoptosis (31)(32)(33)(34). However, the mutant-type p53 promotes cell proliferation through negative regulation of the wild-type p53 protein, thereby protecting cells from apoptosis and promoting tumour development.…”

Section: Discussionmentioning

confidence: 99%

Role of the tumour protein P53 gene in human cervical squamous carcinoma cells: Discussing haematopoietic cell‑specific protein 1‑associated protein X‑1‑induced survival, migration and proliferation

et al. 2018

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The haematopoietic cell-specific protein 1-associated protein X-1 (HAX-1), as a mitochondrial membrane protein, induces cancer progression and metastasis. The present study aimed to investigate the role of HAX-1-induced survival, migration and proliferation of human cervical squamous carcinoma cells and to elucidate its potential molecular mechanisms. The level of HAX-1 was examined by quantitative polymerase chain reaction and western blot analyses. The survival, migration and proliferation of the human cervical squamous carcinoma SiHa cell line were measured by the water-soluble tetrazolium salt (WST-1) assay, Transwell assay and H-thymidine incorporation into DNA (H-TdR) assay, respectively. The intracellular reactive oxygen species (ROS) was estimated by the fluorescence of HDCFDA, and the mitochondrial membrane potential was tested using a JC-1 probe. The expression of the HAX-1 gene was significantly increased in human cervical carcinoma tissues relative to non-cancerous cervix tissues. Overexpression of HAX-1 increased the survival, migration and proliferation ability of SiHa cells, decreased the production of ROS, and maintained the integrity of the mitochondrial membrane and morphology. The effect brought on these cells could be abrogated by the addition of wild-type tumour protein P53 (p53) or carbonyl cyanide-p-trifluoro methoxyphenylhydrazone-induced mitochondrial dysfunction. In summary, these data support the notion that HAX-1 induced the survival, migration and proliferation of human cervical squamous carcinoma cells by inhibiting its downstream regulatory factor p53 in SiHa cells.

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0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop

Cited by 15 publications

References 26 publications

T-β-MCA Regulates the Termination of Liver Regeneration via the P53/miR-34a/SIRT1 Positive Feedback Loop by Suppressing the FXR/SHP Signaling Pathway.

T-β-MCA Regulates the Termination of Liver Regeneration via the P53/miR-34a/SIRT1 Positive Feedback Loop by Suppressing the FXR/SHP Signaling Pathway.

Identification of H2O2 induced oxidative stress associated microRNAs in HLE-B3 cells and their clinical relevance to the progression of age-related nuclear cataract

Role of the tumour protein P53 gene in human cervical squamous carcinoma cells: Discussing haematopoietic cell‑specific protein 1‑associated protein X‑1‑induced survival, migration and proliferation

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