miR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in the rat liver and activated by disease severity in human non-alcoholic fatty liver disease

Castro, Rui E.; Ferreira, Duarte M. S.; Afonso, Marta B.; Borralho, Pedro M.; Machado, Mariana Verdelho; Cortez‐Pinto, Helena; Rodrigues, Cecília M. P.

doi:10.1016/j.jhep.2012.08.008

Cited by 310 publications

(277 citation statements)

References 36 publications

Supporting

Mentioning

256

Contrasting

Unclassified

Order By: Relevance

“…Following a decrease in its expression levels, or if gene mutation occurs, the p53 protein can no longer fulfill these roles, thus increasing the risk of cancer (23). Sirt1 may induce p53 loss-of-function through the deacetylation of p53 at the Lys382 residue, which is contained in the C-terminus, consequently losing the ability to suppress tumor formation (24). Furthermore, studies have also demonstrated that, under conditions of DNA damage and oxidative stress, the overexpression of Sirt1 may inhibit the p53-regulated cell cycle and lead to the arrest of cell replication and cell apoptosis (25).…”

Section: Discussionmentioning

confidence: 99%

Expression and clinical significance of Sirt1 in colorectal cancer

Jiang

Pan

et al. 2015

Oncology Letters

View full text Add to dashboard Cite

Abstract. The objective of the present study was to examine the expression of Silent information regulator 1 (Sirt1) in colorectal cancer and peritumoral normal mucosa tissue, and therefore analyze the role and molecular mechanism of Sirt1 in the pathogenesis of colorectal cancer. Colorectal cancer tissue specimens were employed as the experimental group, and adjacent normal mucosa tissues >5 cm from tumor lesions were used as the control group. The expression of Sirt1 was detected by the immunohistochemical streptavidin peroxidase detection method in paraffin-embedded sections, whilst Sirt1 protein expression was examined by western blot analysis in the fresh tissues. Sirt1 protein was primarily expressed in the nuclei of the tumor cells, and positive staining was brownish-yellow in color. The relative expression quantities of Sirt1 in the peritumoral normal rectal mucosa and rectal carcinoma were 1.15 and 2.62, and the differences between the two groups were statistically significant (P<0.05). The expression level of Sirt1 in colorectal carcinoma was significantly associated with the depth of tumor invasion, differentiation and tumor size (P<0.05). Sirt1 expression was also found to be associated with tumor tissue type, lymph node metastasis, Duke's stage and patient age. These characteristics combined may therefore be used as markers for the early diagnosis of colorectal cancer pathogenesis. IntroductionColorectal cancer occurs in the colorectal mucosa and colonic glands and is one of the most common types of malignant tumor of the digestive system (1,2). The worldwide incidence and mortality rates of colorectal cancer increased significantly between 2009 and 2013; in 2013, a total of 142,820 new cases were diagnosed and 50,830 mortalities occurred as a result of colorectal cancer (3). Thus, this malignancy presents a serious threat to human health (1,2). Clinical and pathological data of patients with colorectal cancer in China have demonstrated the following pathogenic characteristics: The number of patients in cities is higher than that in the countryside, indicating a clear urbanization trend; and patients <30 years of age account for >10% of the total number of patients, demonstrating a clear trend towards older age (4). Surgical resection is currently the main method used for the treatment of colorectal cancer. However, as significant symptoms are often not present in the early stages of the disease, patients are frequently diagnosed in the later stages; by this time, the optimal period for surgery has passed. Furthermore, metastasis or recurrence occurs in a large number of patients following surgical resection, affecting the prognosis of the patients. Therefore, the five-year survival rate is low (64%), posing a serious threat to patient health (5,6).The occurrence and pathogenesis of colorectal cancer is a complex, multistep process, regulated by a number of different genes (1). A total of 25% of patients with colorectal cancer have a genetic history, which is associated with familial adenomatous pol...

show abstract

Section: Discussionmentioning

confidence: 99%

Expression and clinical significance of Sirt1 in colorectal cancer

Jiang

Pan

et al. 2015

Oncology Letters

View full text Add to dashboard Cite

show abstract

“…After isolation, hepatocytes were resuspended in Complete William's E medium (Sigma-Aldrich) ( 23 ) and plated on Primaria TM tissue culture dishes (BD Biosciences, San Jose, CA) at 5 × 10 4 cells/cm 2 . Cells were maintained at 37°C in a humidifi ed atmosphere of 5% CO 2 for 6 h to allow attachment.…”

Section: Cell Culture Isolation Of Rat Primary Hepatocytes and Rat mentioning

confidence: 99%

Deoxycholic acid modulates cell death signaling through changes in mitochondrial membrane properties

Sousa

Castro

Pinto

et al. 2015

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

“…Primary rat hepatocytes were isolated from male rats (100 to 150 g) by collagenase perfusion as previously described (19,20). After isolation, hepatocytes were resuspended in complete Williams E medium (Sigma-Aldrich Co., St. Louis, MO) (14) and plated on Primaria tissue culture dishes (BD Biosciences, San Jose, CA) at 5 ϫ 10 4 cells/cm 2 . Cells were maintained at 37°C in a humidified atmosphere of 5% CO 2 for 6 h, to allow attachment.…”

mentioning

confidence: 99%

“…Absorbance was measured at 490 nm, with 620 nm as reference, using a Bio-Rad model 680 microplate reader (Bio-Rad Laboratories). Hoechst labeling of attached cells was used to detect apoptotic nuclei by morphological analysis, as previously described (14). Finally, fluorescent transferase-mediated dUTP-digoxigenin nickend labeling (TUNEL) (EMD Millipore) was performed in rat liver sections according to the manufacturer's protocol.…”

mentioning

confidence: 99%

c-Jun N-Terminal Kinase 1/c-Jun Activation of the p53/MicroRNA 34a/Sirtuin 1 Pathway Contributes to Apoptosis Induced by Deoxycholic Acid in Rat Liver

Ferreira

Afonso

Rodrigues

et al. 2014

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

MicroRNAs (miRs) are increasingly associated with metabolic liver diseases. We have shown that ursodeoxycholic acid, a hydrophilic bile acid, counteracts the miR-34a/sirtuin 1 (SIRT1)/p53 pathway, activated in the liver of nonalcoholic steatohepatitis (NASH) patients. In contrast, hydrophobic bile acids, particularly deoxycholic acid (DCA), activate apoptosis and are increased in NASH. We evaluated whether DCA-induced apoptosis of rat hepatocytes occurs via miR-34a-dependent pathways and whether they connect with c-Jun N-terminal kinase (JNK) induction. DCA enhanced miR-34a/SIRT1/p53 proapoptotic signaling in a dose-and time-dependent manner. In turn, miR-34a inhibition and SIRT1 overexpression significantly rescued targeting of the miR-34a pathway and apoptosis by DCA. In addition, p53 overexpression activated the miR-34a/SIRT1/p53 pathway, further induced by DCA. DCA increased p53 expression as well as p53 transcriptional activation of PUMA and miR-34a itself, providing a functional mechanism for miR-34a activation. JNK1 and c-Jun were shown to be major targets of DCA, upstream of p53, in engaging the miR-34a pathway and apoptosis. Finally, activation of this JNK1/miR-34a proapoptotic circuit was also shown to occur in vivo in the rat liver. These results suggest that the JNK1/p53/miR-34a/SIRT1 pathway may represent an attractive pharmacological target for the development of new drugs to arrest metabolism-and apoptosis-related liver pathologies.

show abstract

miR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in the rat liver and activated by disease severity in human non-alcoholic fatty liver disease

Cited by 310 publications

References 36 publications

Expression and clinical significance of Sirt1 in colorectal cancer

Expression and clinical significance of Sirt1 in colorectal cancer

Deoxycholic acid modulates cell death signaling through changes in mitochondrial membrane properties

c-Jun N-Terminal Kinase 1/c-Jun Activation of the p53/MicroRNA 34a/Sirtuin 1 Pathway Contributes to Apoptosis Induced by Deoxycholic Acid in Rat Liver

Contact Info

Product

Resources

About