Targeting AMPK, mTOR and β-Catenin by Combined Metformin and Aspirin Therapy in HCC: An Appraisal in Egyptian HCC Patients

Abdelmonsif, Doaa A.; Sultan, Ahmed; El-Hadidy, Wessam F.; Abdallah, Dina

doi:10.1007/s40291-017-0307-7

Cited by 29 publications

(19 citation statements)

References 60 publications

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“…According to the study of Hsieh et al (), activation of AMPK was induced by palbociclib, which inhibits HCC. In addition, targeting AMPK by combined metformin–aspirin treatment might serve as a therapeutic strategy for Egyptian HCC patients (Abdelmonsif, Sultan, El‐Hadidy, & Abdallah, ). Moreover, overexpression of miR‐1271 can induce activation of the AMPK signaling pathway and AMPK can suppress the mammalian target of the rapamycin complex 1 pathway to control cell growth and autophagy, and AMPK‐dependent activation of autophagy in HCC cells can combat tumor growth (Huang, Jiang, Cai, Qu, & Shen, ; Qu et al, ).…”

Section: Discussionmentioning

confidence: 99%

Retracted: MicroRNA‐1271 functions as a potential tumor suppressor in hepatitis B virus–associated hepatocellular carcinoma through the AMPK signaling pathway by binding to CCNA1

Yang

Zhao

Huang

et al. 2018

Journal Cellular Physiology

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Hepatocellular carcinoma (HCC) is mainly associated with hepatitis B virus (HBV) infection and characterized by metastasizing and infiltrating adjacent and distant tissues. Notably, microRNA-1271 (miR-1271) is a tumor suppressor in various cancers. Therefore, we evaluate the ability of miR-1271 to influence cell proliferation, migration, invasion, and apoptosis in HBV-associated HCC through the Adenosine monophosphate-activated protein kinase (AMPK) signaling pathway via targeting CCNA1. HBV-associated HCC and adjacent normal tissues were collected to identify the expression of miR-1271 and CCNA1. To verify the relationship between miR-1271 and CCNA1, we used bioinformatics prediction and the dual-luciferase reporter gene assay. The effects of miR-1271 on HBV-associated HCC cell behaviors were investigated by treatment of the miR-1271 mimic, the miR-1271 inhibitor, or small interfering RNA against CCNA1. The HBV-DNA quantitative assay, 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromid assay, scratch test, transwell assay, and flow cytometry were used to detect HBV-DNA replication, cell proliferation, invasion, migration, and apoptosis. MiR-1271 showed a low expression, whereas CCNA1 showed a high expression in HBV-associated HCC tissues. We identified that miR-1271 targeted and negatively regulated CCNA1. Upregulated miR-1271 and downregulated CCNA1 inhibited the HBV-associated HCC cell HBV-DNA replication, proliferation, migration, and invasion, while accelerating apoptosis by activating the AMPK signaling pathway. MiR-1271 promotes the activation of the AMPK signaling pathway by binding to CCNA1, whereby miR-1271 suppresses HBV-associated HCC progression. This study points to a potential therapeutic approach of downregulation of miR-1271 in HBV-associated HCC treatment. K E Y W O R D S AMPK signaling pathway, apoptosis, CCNA1, hepatitis B virus-associated hepatocellular carcinoma, invasion, microRNA-1271, migration, proliferation J Cell Physiol. 2019;234:3555-3569. wileyonlinelibrary.com/journal/jcp -1271 functions as a potential tumor suppressor in hepatitis B virus-associated hepatocellular carcinoma through the AMPK signaling pathway by binding to CCNA1.

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Section: Discussionmentioning

confidence: 99%

Retracted: MicroRNA‐1271 functions as a potential tumor suppressor in hepatitis B virus–associated hepatocellular carcinoma through the AMPK signaling pathway by binding to CCNA1

Yang

Zhao

Huang

et al. 2018

Journal Cellular Physiology

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“…Studies have shown that the recruitment of membranes for the formation of autophagosomes is investigated by BECLIN1, a downstream effecter in the process of autophagy [24,25]. Similarly, it has been found that DMBG can induce the phosphorylation of AMPK and inhibit the phosphorylation of mTOR [26], and mTOR kinase has been found to play an important role in several cancer-and metabolic disease-related pathways upon DMBG [27]. It has also been suggested that modulation of the mTOR signaling pathway can have a signi cant function in mediating the bene cial effects of DMBG.…”

Section: Discussionmentioning

confidence: 98%

AMPK/mTOR-mediated therapeutic effect of metformin on myocardial ischemia reperfusion injury in diabetic rat

Zhang¹,

Zhang²,

Guan³

et al. 2020

Preprint

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BACKGROUND: The autophagy associated signalling pathways such as AMPK/mTOR previously were suggested to play a crucial role in protecting from ischemia-reperfusion injury (IRI). The objective of this study was to evaluate the effect of metformin (DMBG) on autophagy during myocardial IRI with diabetes mellitus (DM). METHODS: The DM rat model was established using streptozocin, and further induced ischemia model via transitory ligation of the left anterior coronary artery and following reperfusion. The model rats were treated with 400 mg/kg/day DMBG for one week. Autophagosomes were investigated using transmission electron microscopy. Autophagy-associated signalling pathways were detected by western blot. RESULTS: The myocardial infarct size was shown to significantly increase in the DM rats exposed to IRI compared to negative control, but decrease in DMBG treated. The mature autophagosomes were elevated in infarction and marginal zones of DM+IRI+DMBG compared to DM+IRI. Furthermore, the increasing protein levels of LC3-II, BECLIN 1, autophagy related 5 (ATG5) and AMP-activated protein kinase suggested activated autophagy-associated intracellular signalling AMPK and mTOR pathways upon DMBG treated. CONCLUSIONS: Taken together, the outcomes demonstrated that DMBG could activate autophagy process to provide a cardio-protective effect against DM induced myocardial IRI.

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“…It is suitable for antipyretic and analgesic use and is widely used in the prevention of cardiovascular thrombosis [18]. Recent studies have found that the long-term regular use of aspirin can signi cantly reduce the incidence of colorectal cancer, gastric cancer, liver cancer and other malignant tumors and improve the survival of patients with its anticancer effects [46][47][48][49] [58,59]. Autophagy-related pathway: AMPK not only directly inhibits the mTOR signaling pathway but also regulates the activity of ULK1 through phosphorylation, which is related to activating autophagy.…”

Section: Discussionmentioning

confidence: 99%

Aspirin use is not associated with the risk or prognosis of bladder cancer: a case‐control study and meta-analytic assessment

Fan

Luo

Jin

et al. 2020

Preprint

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Background Aspirin, widely used for the prevention of cardiovascular disease, could reduce the risk of many types of cancer, including colorectal, breast, and pancreatic cancer. Concerns have also been linked to bladder cancer(BCa), but relevant studies on the effects of aspirin on the occurrence or prognosis of BCa are inconsistent or even controversial. Meanwhile, existing studies focusing on Chinese populations are relatively uncommon, especially for Northeast China. Therefore, this study aims to assess the association of aspirin use with the occurrence and prognosis of BCa in Northeast China. Methods First, we investigated the association between aspirin use and BCa risk in a retrospective cohort study including 1087 patients with BCa from 2002 to 2019 and 1100 healthy persons in the same period as controls. Subsequently, we quantificationally combined the results with those from the published literature evaluating aspirin intake and its effects on the occurrence and prognosis of BCa by meta-analysis after searching the PubMed, Embase, Cochrane Library, and Google Scholar databases up to March 1, 2020. Results The results of our case-control study demonstrated that the regular use of aspirin was not associated with a reduced incidence of BCa (OR = 1.17, p = 0.311). Stratified analyses of sex showed that aspirin intake did not lead to a lower risk of BCa in male patients (OR = 1.25, p = 0.230) or in female patients (OR = 0.90, p = 0.744). Significant correlations were not found in the age subgroup analysis dividing age into younger or greater than 65, with a pooled OR estimate of 1.25 (p = 0.230) and 0.899 (p = 0.744). In 230 patients who relapsed from the 1087 BCa patients above, no significant relationship was found in the aspirin group (RR = 1.19, p = 0.360), and the sex stratification resulted in the same conclusion; however, in people younger than 68, aspirin seemed to have protective effects (RR = 0.60, p = 0.030). In addition, we performed a meta-analysis after searching several databases, and 10 articles involving 12441 BCa cases met the eligibility criteria, contributing to the analysis of aspirin intake and the incidence of BCa. The combined results indicated that aspirin intake was not associated with the occurrence of BCa (OR = 1.03, p = 0.221). In the subgroup analysis, aspirin intake did not reduce the risk of BCa in male patients (OR = 1.08, p = 0.163), female patients (OR = 0.92, p = 0.441), Asian patients (OR = 1.07; p = 0.088), European patients (OR = 1.12, p = 0.390), or North American patients (OR = 0.99, p = 0.839). At the same time, the study type did not influence the lack of a connection between aspirin intake and the risk of BCa in the cohort study (OR = 1.05; p = 0.176) and case-control study (OR = 1.01; p = 0.797). To explore the impact of aspirin intake on the prognosis of patents with BCa, 8 articles involving 3250 BCa cases were eligible. The combined results showed that patients with aspirin intake did not have a significantly lower risk of BCa recurrence than those without aspirin intake (HR = 0.94, p = 0.718), and a consistent conclusion was also reached for overall survival (HR = 1.04, p = 0.879) and cancer-specific survival (HR = 0.98, p = 0.980) by subgroup analysis. Conclusions Both our retrospective study and literature meta-analysis suggested a lack of a relevant association between the use of aspirin and the risk and prognosis of BCa. Thus, additional long-term follow-up prospective research is warranted to clarify the association of aspirin with BCa incidence and prognosis.

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Targeting AMPK, mTOR and β-Catenin by Combined Metformin and Aspirin Therapy in HCC: An Appraisal in Egyptian HCC Patients

Abstract: Targeting AMPK, mTOR and β-catenin by combined metformin/aspirin treatment could be a promising therapeutic strategy for Egyptian HCC patients, and possibly other HCC patients.

Cited by 29 publications

References 60 publications

Retracted: MicroRNA‐1271 functions as a potential tumor suppressor in hepatitis B virus–associated hepatocellular carcinoma through the AMPK signaling pathway by binding to CCNA1

Retracted: MicroRNA‐1271 functions as a potential tumor suppressor in hepatitis B virus–associated hepatocellular carcinoma through the AMPK signaling pathway by binding to CCNA1

AMPK/mTOR-mediated therapeutic effect of metformin on myocardial ischemia reperfusion injury in diabetic rat

Aspirin use is not associated with the risk or prognosis of bladder cancer: a case‐control study and meta-analytic assessment

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