Metformin prevents liver tumourigenesis by attenuating fibrosis in a transgenic mouse model of hepatocellular carcinoma

Shankaraiah, Ram C.; Callegari, Elisa; Guerriero, Paola; Rimessi, Alessandro; Pinton, Paolo; Gramantieri, Laura; Silini, Enrico Maria; Sabbioni, Silvia; Negrini, Massimo

doi:10.1038/s41388-019-0942-z

Cited by 60 publications

(55 citation statements)

References 55 publications

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“…MET (p.o) was administered at 300 mg/kg in drinking water. This can be translated to the human equivalent dose using the Reagan‐Shaw method . By the end of the experiment and after the rats were anesthetized, the trunk blood samples were collected from each rat.…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway

Sun

Zhai²,

et al. 2019

Cancer Medicine

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Hepatocellular carcinoma (HCC) is a devastating and highly metastatic cancer worldwide. Metformin (MET) is the priority drug for treatment of type 2 diabetes; however, it possesses multiple biological effects like anticancer and hepatoprotective activity. Herein, we examined the effects of aloin (barbaloin) and MET as well as combination treatment in HCC cell line in vitro and in vivo. As a result, aloin and MET alone exhibited inhibitory effects on proliferation and invasion of HepG2 and Bel‐7402 cells. Specially, combination treatment of aloin and MET showed enhanced inhibitory effects in vitro. Aloin and MET alone induced apoptosis and autophagy in vitro. Similarly, aloin and MET cooperated to promote apoptosis and autophagy in HepG2 and Bel‐7402 cells. In the HepG2 xenograft models, aloin in combination with MET confine tumor growth and facilitate apoptosis and autophagy. Both the in vitro and in vivo results showed that aloin and MET alone as well as combination treatment activated the PI3K/AKT/mTOR pathway. Overall, our research demonstrated that the concomitant treatment with aloin and MET enhances the antitumor effect by inhibiting the growth and invasion as well as inducing apoptosis and autophagy in HCC through PI3K/AKT/mTOR pathway.

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Section: Methodsmentioning

confidence: 99%

RETRACTED: Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway

Sun

Zhai²,

et al. 2019

Cancer Medicine

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show abstract

“…Metabolic therapies targeting certain metabolism processes provide alternatives for chemoresistant patients. For example, it has been reported that metformin can prevent liver carcinogenesis (Shankaraiah et al , ) and treatment with metformin is associated with favorable prognosis in patients with HCC (Schulte et al , ). Determining the responders of metabolic therapies has proven to be challenging (Rosario et al , ).…”

Section: Discussionmentioning

confidence: 99%

Metabolism‐associated molecular classification of hepatocellular carcinoma

et al. 2020

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Hepatocellular carcinoma (HCC) is a disease with unique management complexity because it displays high heterogeneity of molecular phenotypes. We herein aimed to characterize the molecular features of HCC by the development of a classification system that was based on the gene expression profile of metabolic genes. Integrative analysis was performed with a metadata set featuring 371 and 231 HCC human samples from the Cancer Genome Atlas and the International Cancer Genome Consortium, respectively. All samples were linked with clinical information. RNA sequencing data of 2752 previously characterized metabolism‐related genes were used for non‐negative matrix factorization clustering, and three subclasses of HCC (C1, C2, and C3) were identified. We then analyzed the metadata set for metabolic signatures, prognostic value, transcriptome features, immune infiltration, clinical characteristics, and drug sensitivity of subclasses, and compared the resulting subclasses with previously published classifications. Subclass C1 displayed high metabolic activity, low α‐fetoprotein (AFP) expression, and good prognosis. Subclass C2 was associated with low metabolic activities and displayed high expression of immune checkpoint genes, demonstrating drug sensitivity toward cytotoxic T‐lymphocyte‐associated protein‐4 inhibitors and the receptor tyrosine kinase inhibitor cabozantinib. Subclass C3 displayed intermediate metabolic activity, high AFP expression level, and bad prognosis. Finally, a 90‐gene classifier was generated to enable HCC classification. This study establishes a new HCC classification based on the gene expression profiles of metabolic genes, thereby furthering the understanding of the genetic diversity of human HCC.

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“…Type 2 diabetes patients treated with metformin have a lower risk for HCC development compared with those taking other antidiabetic drugs in a large populationbased prospective clinical epidemiological survey (1). Besides, metformin alone or combined with other drugs obviously counteracts malignant features of HCC through multiple mechanisms (2)(3)(4)(5), suggesting an obvious antitumor role of metformin in HCC development and progression. Similar to other chemotherapy drugs, metformin may be also developed into drug tolerance and resistance in HCC during long-term treatment.…”

Section: Introductionmentioning

confidence: 99%

Matrix Stiffness-Upregulated MicroRNA-17-5p Attenuates the Intervention Effects of Metformin on HCC Invasion and Metastasis by Targeting the PTEN/PI3K/Akt Pathway

et al. 2020

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Background: Metformin, a traditional first-line anti-hyperglycemic agent for diabetes, recently exhibits better antitumor effect in hepatocellular carcinoma (HCC). However, its resistance and tolerance mechanism in HCC remains largely unknown. Here, we investigated whether increased matrix stiffness attenuated the intervention effects of metformin on HCC invasion and metastasis, and explored its underlying molecular mechanism. Methods: FN-coated gel substrates with 6, 10, and 16 kPa, which simulated the stiffness of normal, fibrotic, and cirrhotic liver tissues respectively, were established to evaluate matrix stiffness-mediated effects on HCC cells. Alterations in morphology, proliferation, motility, and invasive/metastatic-associated genes (PTEN, MMP2, MMP9) of HCC cells grown on different-stiffness substrates were comparatively analyzed before and after metformin intervention. Subsequently, the underlying molecular mechanism by which higher matrix stiffness attenuates antitumor effects of metformin in HCC was further elucidated. Results: Metformin significantly inhibited proliferation, migration, and invasion of HCC cells. Compared with the controls on lower-stiffness substrate, HCC cells grown on higher-stiffness substrate exhibited an obvious resistance to intervention effects of metformin on proliferation, migration, invasion and metastasis. High stiffness stimulation significantly activated the miR-17-5p/PTEN/PI3K/Akt signaling pathway in HCC cells via integrin β1 and in turn resulted in MMP2 and MMP9 upregulation. Meanwhile, integrin β1 knockdown or PI3K inhibitor partially reversed the activation of the above signaling molecules. For HCC cells grown on the same-stiffness substrate, metformin remarkably upregulated PTEN expression and suppressed the activation of the PI3K/Akt/MMP pathway, but no effect on integrin β1 expression. Importantly, the increase in fold of PTEN expression and decrease in folds of Akt phosphorylation level and MMP2

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Metformin prevents liver tumourigenesis by attenuating fibrosis in a transgenic mouse model of hepatocellular carcinoma

Cited by 60 publications

References 55 publications

RETRACTED: Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway

RETRACTED: Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway

Metabolism‐associated molecular classification of hepatocellular carcinoma

Matrix Stiffness-Upregulated MicroRNA-17-5p Attenuates the Intervention Effects of Metformin on HCC Invasion and Metastasis by Targeting the PTEN/PI3K/Akt Pathway

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