• apoptosis
• carcinogenesis
• liver

Hepatocellular carcinoma (HCC) represents a serious and urgent global health problem because of its increasing incidence and the limited therapeutic options.1 2 The standard treatment for patients with advanced HCC is the multikinase inhibitor sorafenib, which shows only modest survival improvement of approximately 2–3 months and remains associated with disease progression in a large number of patients.3 4 Therefore, to improve the survival of patients with advanced HCC, it is fundamental to understand the mechanisms of sorafenib resistance.

The antitumour efficacy of sorafenib is mainly based on the inhibition of the proliferative RAF/mitogen-activated protein kinase (MAPK) pathway, which is regulated by upstream RAS proteins.5 6 The majority of human HCCs shows an activation of this pathway, which is associated with shorter survival.6–9 In contrast to other human tumours, RAS activation in HCC occurs in the absence of RAS mutation, which is rare in this tumour entity.6 10 The pathomechanisms of enhanced activation of RAS and in particular of KRAS, the most important RAS isoform for carcinogenesis, in HCC as well as its implication for sorafenib resistance remain largely unclear.

There is increasing evidence that microRNAs …