Role of IL‐6 activated STAT3 and TNF expression in obesity‐associated hepatocellular carcinoma

Sirs, We read with interest the systematic review by Saunders et al.1 on the association between obesity and hepatocellular carcinoma (HCC). The authors reviewed the epidemiological evidence suggesting an increased HCC risk in obese and overweight individuals. Although the authors discussed comprehensively the possible links for this association, we would like to mention a novel mechanism relating to obesity and HCC, which, we think, may be important for a better understanding of the results presented in the authors’ report. In their review, the authors discussed the incidence and risk factors relating to obesity and HCC; they described the current concepts regarding the possible association between these two entities, which has mainly been attributed to insulin resistance. It is obvious that this scientific field is undergoing a rapid development, making possible the use of tools and techniques that are new and entirely different,7 opening the possibility of discovering new mechanisms of tumourigenesis at the cellular level. For this reason, we would like to draw attention to the possible role of IL-6-activated signal transducer and activator of transcription 3 (STAT3) and tumour necrosis factor (TNF) in the development of HCC, which could elucidate the risk factors associated with increased HCC in obese individuals. Obesity-associated liver inflammation and HCC being related to enhancement of IL-6 and TNF expression were first described by Park et al.2 They demonstrated that obesity, either dietary or genetic, was a potent bona fide HCC promoter in mice; it was dependent on enhanced production of the tumour-promoting cytokines IL-6 and TNF, leading to liver inflammation and activation of the oncogenic transcription factor STAT3, which is a well-known transcription factor that also plays a key role in body weight regulation and glucose homoeostasis and it has been linked to the proliferation, survival, invasion and angiogenesis of several human cancers, including HCC.3, 4 Inhibition of STAT3 with several agents has also been shown to lead to growth inhibition and enhanced chemo-sensitivity in HCC cells, supporting the role of STAT3 in HCC development.5–7 In conclusion, based on the above observations, it is reasonable to suggest a potential link between obesity and HCC via activation of STAT3. Although it is widely agreed that IL-6- and TNF-mediated STAT3 activation plays a major role in the development of HCC, the association with obesity still warrants further clinical investigation. Declaration of personal and funding interests: None.