Plasma exosomal miR-122 regulates the efficacy of metformin via AMPK in type 2 diabetes and hepatocellular carcinoma

Peng, Hui; Hou, Mei; Wu, Zixin; Wang, Jing; Zhou, Man; Zhuang, Xiangjin; Xing, Jiayu; Tao, Qianqian; Huang, Long; Zhou, Fuhai; Zhang, Shengming; Feng, Qiyu; Hou, Yilin; Yu, Qinsheng

doi:10.1016/j.heliyon.2022.e11503

Cited by 3 publications

(3 citation statements)

References 53 publications

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“…Even thou medications alter some miRNA cargo in EVs, it has been demonstrated in a very recent study that levels of EV-encapsulated miR-122 were not affected by metformin treatment. Consistent with our results, in metformin-insensitive T 2 D patients, Peng and collaborators found low levels of exosome miRNA-122, indicating miR-122 as biomarker of metformin insensitivity [ 79 ]. As important regulator of glucose and lipid metabolism as well [ 80 – 82 ], increased miR-122 showed a specific correlation with monounsaturated and saturated fatty acids within the lipid classes triacylglycerols and cholesterol esters.…”

Section: Resultssupporting

confidence: 91%

Microvesicle-associated and circulating microRNAs in diabetic dyslipidemia: miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 have biomarker potential

Nemecz,

Stefan,

Comarița

et al. 2023

Cardiovasc Diabetol

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Background Circulating MicroRNAs (miRNAs) carried by microvesicles (MVs) have various physiological and pathological functions by post-transcriptional regulation of gene expression being considered markers for many diseases including diabetes and dyslipidemia. We aimed to identify new common miRNAs both in MVs and plasma that could be predictive biomarkers for diabetic dyslipidemia evolution. Methods For this purpose, plasma from 63 participants in the study (17 type 2 diabetic patients, 17 patients with type 2 diabetes and dyslipidemia, 14 patients with dyslipidemia alone and 15 clinically healthy persons without diabetes or dyslipidemia) was used for the analysis of circulating cytokines, MVs, miRNAs and MV-associated miRNAs. Results The results uncovered three miRNAs, miR-218, miR-132 and miR-143, whose expression was found to be significantly up-regulated in both circulating MVs and plasma from diabetic patients with dyslipidemia. These miRNAs showed significant correlations with important plasma markers, representative of this pathology. Thus, MV/plasma miR-218 was negatively correlated with the levels of erythrocyte MVs, plasma miR-132 was positively connected with MV miR-132 and negatively with uric acid and erythrocyte plasma levels, and plasma miR-143 was negatively related with creatinine levels and diastolic blood pressure. Also, three miRNAs common to MV and plasma, namely miR-21, miR-122, and miR-155, were identified to be down-regulated and up-regulated, respectively, in diabetic dyslipidemia. In addition, MV miR-21 was positively linked with cholesterol plasma levels and plasma miR-21 with TNFα plasma levels, MV miR-122 was negatively correlated with LDL-c levels and plasma miR-122 with creatinine and diastolic blood pressure and positively with MV miR-126 levels, MV miR-155 was positively associated with cholesterol and total MV levels and negatively with HDL-c levels, whereas plasma miR-155 was positively correlated with Il-1β plasma levels and total MV levels and negatively with MV miR-223 levels. Conclusions In conclusion, miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 show potential as biomarkers for diabetic dyslipidemia, but there is a need for more in-depth studies. These findings bring new information regarding the molecular biomarkers specific to diabetic dyslipidemia and could have important implications for the treatment of patients affected by this pathology.

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Section: Resultssupporting

confidence: 91%

Microvesicle-associated and circulating microRNAs in diabetic dyslipidemia: miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 have biomarker potential

Nemecz,

Stefan,

Comarița

et al. 2023

Cardiovasc Diabetol

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“…Epigenetic alterations that play a role in HCC are DNA methylation, where a methyl group is added to a cytosine base in DNA, histone modifications that alter the chromatin structure and affect gene expression, noncoding RNA and chromatin remodeling [ 114 ]. Recent evidence has provided important insights into the mechanisms by which metformin alters DNA methylation [ 115 ] and regulates the expression of noncoding RNAs [ 116 ], with implications for the use of metformin in cancer therapy.…”

Section: Preclinical Evidence About Metformin Influence On Hcc Hallmarksmentioning

confidence: 99%

“…By regulating key molecules of related signaling pathways, miR-122 may produce similar therapeutic effects on glycemic control and tumor suppression as metformin. This offers new possibilities for developing therapeutic strategies for hepatocellular carcinoma based on miR-122 and metformin [ 116 ].…”

Section: Preclinical Evidence About Metformin Influence On Hcc Hallmarksmentioning

confidence: 99%

The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?

Papadakos

Ferraro

Carbone

et al. 2023

Cancers

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells’ exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.

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Suppression of colorectal cancer growth: Interplay between curcumin and metformin through DMT1 downregulation and ROS‐mediated pathways

Chuang,

Chan,

Shih

2024

BioFactors

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The rising incidence of colorectal cancer (CRC) poses significant healthcare challenges. This study explored the therapeutic potential of combined curcumin (CUR) and metformin (MET) treatment in CRC models. Our findings indicate that the combination treatment (COMB) effectively downregulates the expression of divalent metal transporter‐1 (DMT‐1), leading to a reduction in cell proliferation aligned with suppression of the pAKT/mTOR/Cyclin D1 signaling pathway. The COMB increased reactive oxygen species (ROS) production, triggering activation of the NRF2/KEAP1 pathway. This pathway elicits an antioxidant response to manage oxidative stress in CRC cell lines. Interestingly, the response of NRF2 varied between CT26 and HCT116 cells. Moreover, our study highlights the induction of apoptosis and autophagy, as evidenced by upregulations in Bax/Bcl‐2 ratios and autophagy‐related protein expressions. Notably, the COMB promoted lipid peroxidation and downregulated xCT levels, suggesting the induction of ferroptosis. Ferroptosis has been shown to activate autophagy, which helps eliminate cells potentially damaged by the increased oxidative stress. Furthermore, the COMB effectively diminished the migratory ability of CRC cells. In vivo experiments using CRC‐bearing mouse models, the results confirmed the anti‐tumor efficacy of the COMB, leading to substantial inhibition of tumor growth without inducing general toxicity. In conclusion, our study suggests that combining CUR with MET holds promise as a potential option for CRC treatment, with critical mechanisms likely involving ROS elevation, autophagy, and ferroptosis.

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Plasma exosomal miR-122 regulates the efficacy of metformin via AMPK in type 2 diabetes and hepatocellular carcinoma

Cited by 3 publications

References 53 publications

Microvesicle-associated and circulating microRNAs in diabetic dyslipidemia: miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 have biomarker potential

Microvesicle-associated and circulating microRNAs in diabetic dyslipidemia: miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 have biomarker potential

The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?

Suppression of colorectal cancer growth: Interplay between curcumin and metformin through DMT1 downregulation and ROS‐mediated pathways

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