Type 2 diabetes–associated hepatocellular carcinoma: A molecular profile

Watch a video presentation of this article

Watch the interview with the author

Abbreviations

AOR

adjusted odds ratio

CI

confidence interval

HBV

hepatitis viral B

HCC

hepatocellular carcinoma

HCV

hepatitis viral C

HR

hazard ratio

IGF

insulin growth factor

IGFBP

IGF binding protein

IGF1R

IGF1 receptor

IL‐6

interleukin‐6

JNK1

c‐jun amino terminal kinase 1

LPS

lipopolysaccharide

MAPK

mitogen‐activated protein kinase

MS

metabolic syndrome

mTOR

mammalian target of rapamycin

NAFLD

nonalcoholic fatty liver disease

NF‐κB

nuclear factor‐κB

OR

odds ratio

ROS

reactive oxygen species

TNF‐α

tumor necrosis factor‐α

VEGF

vascular endothelial growth factor

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related deaths worldwide. HCC develops mainly on a background of chronic liver disease, with an incidence rate of 2% to 4% per year in cirrhotic patients. The main causative agents of the underlying liver disease and HCC are viral infections by hepatitis B virus (HBV) and hepatitis C virus (HCV), as well as alcohol abuse. Recently, new risk factors for HCC have emerged in developed countries, including nonalcoholic fatty liver disease (NAFLD) caused by metabolic syndrome (MS). Among the different components of the MS, type 2 diabetes, characterized by hyperglycemia, hyperinsulinemia, and insulin resistance, has been identified as an independent risk factor for HCC. The aim of this brief review is to describe the impact of insulin resistance and type 2 diabetes on the incidence of HCC, the underlying molecular defect linked to tumor development, and potential future therapeutic strategies identified by analysis of epidemiological studies and in vitro experiments.

Epidemiological Evidence

Epidemiological studies have revealed that type 2 diabetes plays an independent role in HCC development (Table 1). Diabetes has been associated with a 2‐ to 3‐fold increase in the risk for HCC occurrence; this risk did not differ between ethnic populations in the United States. The risk is even higher with duration of diabetes, with an odds ratio (OR) of 2.2 in patients having a longer than 10‐year duration (Table 1). New‐onset diabetes has also been significantly associated with higher incidence of HCC. Strong evidence also describes a synergistic interaction between type 2 diabetes and other risk factors for HCC, such as chronic HCV and HBV infection and alcohol abuse. In a prospective cohort of patients with HCV‐related cirrhosis, insulin resistance was also an independent risk factor for HCC development.1 Finally, a subset of HCC related to MS developed on noncirrhotic liver, suggesting a direct oncogenic mechanism.2

Table 1.

Risk for HCC and Type 2 Diabetes

Authors	Association	Description of the Study
Fu et al.11 Aliment Pharmacol Therapy 2015	HR 1798 (95% CI 1.194–2.707)	Cohort study New‐onset diabetes, patients with HBV
Raff et al.12 J Clin Transl Hepatol 2015	HR 3.0 (95% CI 1.3–6.9)	Cohort study Patients with NAFLD or alcoholic liver disease
Setiawan et al.13 J Natl Cancer Inst 2014	RR 2.62 (95% CI 2.13–3.23)	Cohort study Increased risk in all ethnic groups
Arase et al.14 Hepatology 2013	HR 1.73 (95% CI 1.3–2.3)	Cohort study Patients with HCV
Turati et al.15 Br J Cancer 2013	OR 4.33 (95% CI 1.89–9.86)	Case–control study
Koh et al.16 Br J cancer 2013	HR 2.14 (95% CI 1.69–2.71)	Cohort study
Schlesinger et al.17 Ann Oncol 2013	RR 2.17 (95% CI 1.36–3.47)	Cohort study
Atchison et al.18 Int J Cancer 2011	RR 1.95 (95% CI 1.82–20.9)	Cohort study
Hassan et al.19 Cancer 2010	AOR 4.2 (95% CI 3.0–5.9)	Case–control study Decreased risk for HCC using metformin
Veldt BJ et al.20 Hepatology 2008	HR 3.28 (95% CI 1.35–7.97)	Cohort study Patients with HCV
Rousseau et al.21 Int J cancer 2006	OR 3.1 (95% CI 1.1–8.8)	Case–control study
Davila et al.22 Gut 2005	OR 3.8 (95% CI 2.74–3.46)	Case–control study Increased risk regardless of other HCC risk factors
El‐Serag et al.23 Gastroenterology 2004	HR 2.16 (95% CI 1.86–2.52)	Cohort study Increased risk for chronic liver diseases
Hassan et al.24 Hepatology 2002	OR 4.3 (95% CI 1.9–9.9)	Case–control study Synergism with alcohol and viral hepatitis

AOR, adjusted odds ratio; CI, confidence interval; HR, hazard ratio.

Physiopathology and Molecular Pathways

In cellulo models, as well as mouse models, have helped to dissect the molecular pathway involved in liver carcinogenesis caused by insulin resistance and obesity (Fig. 1).

Figure 1.

Pathogenesis of HCC developed on NAFLD. Hyperinsulinemia and obesity lead to NAFLD, cirrhosis, and finally, HCC development. However, a subset of NAFLD‐related HCC could also develop on noncirrhotic liver. Chronic liver inflammation, alteration of gut microbiota, lipotoxicity of free fatty acid, production of ROS, and activation of the IGF pathway and the JNK1 pathway promote NAFLD and HCC development. A polymorphism of PNPLA3 (Patatin‐like phospholipase domain containing 3, rs738409 c444C>G, I148M minor allele) increased the risk for NAFLD‐related cirrhosis and NAFLD‐related HCC. Abbreviation: LPS, lipopolysaccharide.

Hyperinsulinemia and obesity promote chronic liver inflammation and steatosis by the release of proinflammatory cytokines such as tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and nuclear factor‐κB (NF‐κB) (Fig. 1). This inflammatory state is a conjunction of the action of hepatocytes, Kupffer cells, and adipocytes.3 Moreover, MS increases the circulating level of leptin, a proinflammatory cytokine, but also decreases the production of adiponectin, an anti‐inflammatory polypeptide that also inhibits angiogenesis in animal models.4 Hyperglycemia leads to free fatty acid release that induces accumulation of reactive oxygen species (ROS) (Fig. 1). ROS promote carcinogenesis through uncontrolled liver inflammation, steatosis, and cell proliferation, and may induce cancer‐promoting mutations in tumor suppressor gene TP53.5 Moreover, free fatty acid production activates c‐jun amino terminal kinase 1 (JNK1) that induces cellular proliferation and inhibition of apoptosis.4

In human HCC, a subset of tumors have been shown to harbor activation of the insulin growth factor (IGF) pathway.6 IGF1 induces phosphorylation of insulin receptor substrate 1, leading to activation of AKT/mammalian target of rapamycin (MTOR) and mitogen‐activated protein kinase (MAPK) pathways that inhibit apoptosis and promote cell proliferation (Fig. 2).7 Upregulation of the IGF pathway by hyperinsulinemia is the consequence of overexpression of ligands such as IGF1 and aberrant expression of fetal IGF2.6 Concomitant downregulation of negative regulators of the pathway, such as the suppressor of cytokine signaling protein, is also observed in tumors, along with decreased production of IGF binding protein (IGFBP) type 1 and IGFBP2 that increases IGF1 bioavailability (Fig. 2). Consequently, the IGF axis is a key signaling pathway involved in liver carcinogenesis related to type 2 diabetes and obesity. Moreover, each human HCC is a unique combination of somatic genetic alterations, with a mean number of 40 to 60 mutations per tumor in the coding sequence.8 Somatic mutations in driver genes were also closely related to risk factors and etiology: TP53 mutations with HBV infection, the TP53 R249S mutation with aflatoxin B1 exposure, and ARID1A and CTNNB1 mutations with alcohol consumption.8 However, no clear association between genetic defects or nucleotide signatures and type 2 diabetes and MS have thus far been identified.

Figure 2.

Insulin signaling pathways in HCC. Different mechanisms (decreased circulating level of IGFBPs, increased circulating level of IGF1, reexpression of the foetal IGF2, overexpression of IGF1R, hyperinsulinemia, reexpression of the foetal form of the insulin receptor (IR) type A instead of the adult form IRB) lead to the activation of the IGF1 receptor (IGF1R) and insulin receptor signaling pathways. Most of the metabolic and proliferative consequences are mediated through the downstream activation of Akt/Mtor and ras/raf/map kinase signaling.

Insulin Resistance and Liver Carcinogenesis: A New Therapeutic Strategy

Human epidemiological studies have shown that statins confer protection against development of steatohepatitis, fibrosis, and HCC, mainly in patients with diabetes and obesity. El‐Serag et al.9 compared 1303 patients with diabetes and 5212 control subjects, and identified a 25% reduction in the risk for development of HCC in patients with diabetes using statins. Statins have no direct effect on insulin resistance, but the antitumor action could be explained by an anti‐inflammatory property mediated by inhibition of the JNK and MAPK pathways.

Moreover, in epidemiological studies performed on a general population, HBV‐ or HCV‐infected patients showed that metformin intake was also associated with a reduced incidence of HCC in a time‐ and dose‐dependent manner.10 Metabolic and antiangiogenic effects have been proposed as potential antitumor mechanisms. Metformin activated AMP‐activated protein kinase that inhibited the mTOR complex and fostered cell cycle arrest in vitro. Metformin also exhibited antiangiogenic effects through downregulation of vascular endothelial growth factor.4 Moreover, different signaling pathways such as Wnt/ß‐catenin or transcription factors such as Myc proto‐oncogene protein were shut down by metformin in cellulo.

Finally, an anti‐IGF1 receptor (anti‐IGF1R) antibody, cixutumumab, has been tested in patients with advanced HCC, as well as a small tyrosine kinase inhibitor, OSI‐906, targeting IGF1R/IR. However, they demonstrated no antitumor activity and have metabolic toxicities. An antibody against IGF2 is currently tested in solid cancers including HCC.7

In conclusion, type 2 diabetes and obesity are key players in NAFLD and HCC development. Chronic liver inflammation, modulation of the immune response, lipotoxicity, production of ROS, and activation of the IGF pathway are some of the mechanisms that promote tumorigenesis in this setting. Finally, epidemiological and in vitro studies suggested a chemopreventive effect of statin and metformin on HCC development. This will require confirmation by randomized controlled trials.