The GAPs between hepatocellular carcinoma and RAS

Abstract

A landmark work of Jennifer Harvey in the 600s demonstrated that viruses have the capacity to induce tumours in mice [1]. Twenty years later, homologue genes of these tumourigenic viruses were found encrypted in the human genome, retaining the potential of transforming fibroblasts when over-expressed [2,3]. These first oncogenes were named Ha-Ras and Ki-Ras honouring their initial discoverers Jennifer Harley and Werner Kirsten. Since then, hundreds of studies have associated Ras over-activation with human cancer. In fact, an estimated 30% of all human tumours display mutations in Ras [4]. However, the abnormal activation of Ras in liver cancer is just now coming into light. Liver cancer is the third most common cause for cancer related death just after lung and stomach cancer [5]. Abnormal activation of the RAS and JNK pathways were recently identified in human hepatocellular carcinoma [6]. In this issue of the Journal of Hepatology, Calvisi et al., take a further step in understanding the molecular mechanisms of oncogenic transformation that leads to human liver cancer. While RAS guanine nucleotide exchange factors (GEF’s) activate RAS by exchanging GDP for GTP, the GTPase activating proteins (GAPs) inactivate RAS by enhancing its GTPase activity thereby stabilizing the inactive GDP-bound form of RAS. In the current issue, Calvisi et al., show that the down-regulation of GAPs might play a fundamental role in liver tumour aggressiveness by activating the RAS pathway [7]. Epigenetic silencing of the Ras GTPase-activating-like protein (RASAL1) has recently been identified as a novel mechanism contributing to the activation of RAS in human cancers including HCC [8]. However, a systematic analysis of the growing number of RAS GTPases in liver cancer formation has not previously been reported. Such an analysis has now been conducted on a significant number of HCC and the surrounding normal liver tissue [7]. The study shows that in the absence of RAS mutations, at least one of the RAS GAPs (RASAL1, DAP2IP, or NF1) is down-regulated in human HCC. In addition, PITX1 suppression was associated with HCC (42%), specifically with HCC of poor prognosis (81%). PITX1 is amemberof thePitx1 subfamilyof transcription factors that regulate RAS activity through RASAL1 and its suppressionwas previously associated with prostate and bladder tumours [9]. The