Aspirin Use for Primary Prevention of HCC: Friend or Foe?

Corresponding author: Raffaella Mormile, Division of Pediatrics and Neonatology, Moscati Hospital, Aversa, Italy, Via A. Gramsci-81031, Italy. E-mail: raffaellamormile@alice.it Aspirin use has been suggested to reduce the risk of hepatocellular carcinoma (HCC).1 It has been reported that aspirin may have beneficial effect as a chemopreventive or adjuvant chemotherapeutic agent in HCC.2 The benefit of aspirin in reducing HCC risk has been proposed to be doserelated and apparent after 5 or more years of use.1 However, it is still unclear whether aspirin administration should be recommended to different populations of patients at risk for HCC.2 According to studies in animal models, it has been hypothesized that the mechanism of cancer preventive action of aspirin against HCC may be related to its antiplatelet and anti-inflammatory activities.2 HCC represents one of the most aggressive malignancies, whose prognosis is extremely poor, mainly due to its high propensity of invasion and metastasis.3 To date, an effective therapeutic approach against invasive or/and metastatic HCC still remains rare.3 Vascular invasion is particularly common in patients with HCC given that liver is an organ rich in blood vessels.3 It has been recognized that microRNA 126 (miR126) exerts a protective role against HCC.3,4,5 microRNAs (miRNAs) have emerged to be linked to human cancer onset and progression having an impact on invasion and metastasis.3 miR-126 belongs to the most abundantly expressed miRNAs in endothelial cells where it is responsible for vascular development.4 Both strands of miR-126: miR-126-3p and miR-126-5p, appear to be biologically active.4 Overexpression of miR-126 in nude mice has been tested to result in reduced weight and less new blood vessels in HCC.6 It has been verified that microRNA-126 (miR-126) is aberrantly downregulated and plays a critical role in carcinogenesis in several cancers, including HCC.5 It has been detected that miR-126 functions as a tumor suppressor in human HCC.5 miR126-3p has been demonstrated to counteract invasion and metastasis in HCC.3 Increasing evidence has revealed that miR-126 is markedly reduced in HCC cell lines and tissues as well as negatively connected with clinic-pathologic parameters.5 Low expression levels of miR-126 have been connected with a poor overall survival, late TNM stage, and the presence of recurrence in HCC.5 Inhibition of miR-126 has been proved to reduce cell apoptosis, and enhanced cell proliferation and tumor angiogenesis.6 Over-expression of miR126 has been shown to significantly reduce cell proliferation metastasis and promote apoptosis in vitro.5 miR-126 represents one of the most copious miRNAs in human platelets.7 miR-126 has been linked to platelet function and reactivity.4 Platelets have been discovered to supply important amounts of miR-126 upon activation into the surrounding plasma in vitro.7 Platelets and platelet microvesicles have been identified to discharge high levels of miR126 contributing largely to the pool of circulating miR-126.7 Aspirin treatment appears to lead to decreased levels of platelet-associated miR-126.7 It has been found that activation of healthy ex-vivo platelets appears to promote the release of miR126 from intracellular stores and that this event is inhibited by aspirin.7 When the activation of platelets is blocked by aspirin, the release of miR-126 has been observed to be withdrawn.7 Taken together, I speculate that aspirin use might therefore not exert a protective effect against HCC as a result of its negative impact on circulating miR-126 levels. On the contrary, I suppose that aspirin might contribute to the onset of HCC by downregulation of miR126 expression via its antiplatelet activity. Thus, I assume that further clinical trials are warranted to define whether aspirin may be utilized as a safe and efficacious repositioned drug against HCC.