The effect of metformin usage on survival outcomes for hepatocellular carcinoma patients with type 2 diabetes mellitus after curative therapy

Yuan, Bo; Ma, Jichun; Wang, Jing; Hao, Jinyong

doi:10.3389/fendo.2022.1060768

Cited by 8 publications

(6 citation statements)

References 26 publications

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“…The main mechanism for the antitumour activity of metformin may be the inhibition of mitochondrial respiration, leading to intracellular energy consumption. 29 Recently, Yuan et al 30 found that metformin therapy can significantly prolong the survival of HCC patients with T2D and reduce the recurrence rate, indicating the pivotal role of metformin in the treatment of HCC. In parallel, IL-8, a chemotactic cytokine, has been demonstrated to assist HCC progression by regulating self-renewal of tumour-initiating cells and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Low-dose metformin suppresses hepatocellular carcinoma metastasis via the AMPK/JNK/IL-8 pathway

Zhao,

Zheng,

et al. 2024

Int J Immunopathol Pharmacol

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Background and objectives Metformin, an oral hypoglycemic drug, has been suggested to possess antitumour activity in several types of cancers. Additionally, interleukin-8 (IL-8) has been reported to be involved in the development and metastasis of many cancers. However, the effect of metformin on IL-8 expression in hepatocellular carcinoma (HCC) remains unclear. Therefore, this study aimed to investigate whether metformin could inhibit IL-8 expression to exert an inhibitory effect on HCC progression. Materials and methods The IL-8 levels were measured in the plasma of 159 HCC patients (86 men, 73 women; average age 56 years) and in the culture supernatant of HCC cells (Hep3B and HuH7) using flow cytometry. In addition, the protein expression levels of IL-8 were also validated by the Human Protein Atlas (HPA) database. The prognostic value of IL-8 was evaluated using the Kaplan–Meier Plotter database. The association between IL-8 expression and immune checkpoints was estimated using the TIMER and The Cancer Genome Atlas (TCGA) databases. What’s more, bioinformatics analysis, western blotting, and transwell assays were conducted to illustrate the molecular mechanism of metformin (≤1 mM) on IL-8 in HCC. Results IL-8 expression was found to be increased in the plasma of HCC patients, which is consistent with the expression of IL-8 in HCC cells and tissues. High expression of IL-8 was significantly related to poor prognosis. In addition, IL-8 was positively correlated with immune checkpoints in HCC. Notably, we found that low-dose metformin could inhibit the secretion of IL-8 by HCC cells and the migration of HCC cells. Mechanistically, low-dose metformin significantly suppresses HCC metastasis mainly through the AMPK/JNK/IL-8/MMP9 pathway. Conclusion The results indicate that low-dose metformin can inhibit HCC metastasis by suppressing IL-8 expression. Targeting the AMPK/JNK/IL-8 axis may be a promising treatment strategy for patients with HCC metastasis.

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Section: Discussionmentioning

confidence: 99%

Low-dose metformin suppresses hepatocellular carcinoma metastasis via the AMPK/JNK/IL-8 pathway

Zhao,

Zheng,

et al. 2024

Int J Immunopathol Pharmacol

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“…70 Moreover, another report of meta-analysis also revealed that treatment with metformin significantly extended overall survival (OS) and progression-free survival compared with other antihyperglycemic agents in HCC patients with T2DM after curative HCC treatment. 71,81 Prediagnostic use of metformin ≤1500 mg/day has also been shown to be associated with longer OS in elderly DM HCC patients. 72 The beneficial effects of metformin for anti-HCC can be exerted by plentiful molecular mechanisms.…”

Section: Biguanidesmentioning

confidence: 99%

The Role of Type 2 Diabetes Mellitus–Related Risk Factors and Drugs in Hepatocellular Carcinoma

Mai,

Meng,

Deng

et al. 2024

JHC

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With changes in modern lifestyles, type 2 diabetes mellitus (T2DM) has become a global epidemic metabolic disease, and hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. T2DM is a complex metabolic disorder and has been considered an independent risk factor for HCC. Growing evidence supports that T2DM-related risk factors facilitate hepatocarcinogenesis via abundant mechanisms. With the wide implementation of microbiomics, transcriptomics, and immunotherapy, the understanding of the complex mechanisms of intestinal flora and immune cell subsets have advanced tremendously in T2DM-related HCC, uncovering new findings in T2DM-related HCC patients. In addition, reports have indicated the different effects of anti-DM drugs on the progression of HCC. In this review, we summarize the effects of major T2DM-related risk factors (including hyperglycemia, hyperinsulinemia, insulin, chronic inflammation, obesity, nonalcoholic fatty liver disease, gut microbiota and immunomodulation), and anti-DM drugs on the carcinogensis and progression of HCC, as well as their potential molecular mechanisms. In addition, other factors (miRNAs, genes, and lifestyle) related to T2DM-related HCC are discussed. We propose a refined concept by which T2DM-related risk factors and anti-DM drugs contribute to HCC and discuss research directions prompted by such evidence worth pursuing in the coming years. Finally, we put forward novel therapeutic approaches to improve the prognosis of T2DM-related HCC, including exploiting novel diagnostic biomarkers, combination therapy with immunocheckpoint inhibitors, and enhancement of the standardized management of T2DM patients.

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“…Several meta-analyses have been conducted recently analyzing the effects of metformin in the overall survival (OS) of DM patients with HCC [ 20 ], the HCC risk [ 55 ], the OS of DM patients after hepatectomy with a curative intent [ 56 ], the HCC risk in patients also receiving aspirin [ 57 ] and the HCC risk in patients with chronic hepatitis B infection [ 58 ].…”

Section: Clinical Significance Of Metforminmentioning

confidence: 99%

“…Additionally, the use of metformin was associated with a decrease in the recurrence rate at 1 year (OR = 1.31, 95% CI: 1.08–1.59, p = 0.007), 3 years (OR = 1.88, 95% CI: 1.48–2.37, p = 0.000) and 5 years (OR = 1.83, 95% CI: 1.40–2.40, p = 0.000). In conclusion, the study suggested that metformin can significantly improve the OS and decrease the recurrence rate in patients with HCC and T2DM who have undergone curative therapy for HCC [ 56 ]. Finally, Campbell et al assessed the risk factors associated with the progression to HCC in individuals with chronic HBV infection [ 58 ].…”

Section: Clinical Significance Of Metforminmentioning

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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The effect of metformin usage on survival outcomes for hepatocellular carcinoma patients with type 2 diabetes mellitus after curative therapy

Cited by 8 publications

References 26 publications

Low-dose metformin suppresses hepatocellular carcinoma metastasis via the AMPK/JNK/IL-8 pathway

Low-dose metformin suppresses hepatocellular carcinoma metastasis via the AMPK/JNK/IL-8 pathway

The Role of Type 2 Diabetes Mellitus–Related Risk Factors and Drugs in Hepatocellular Carcinoma

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

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