SerpinB3 and Yap interplay increases Myc oncogenic activity

Abstract

Primary liver cancer, mainly hepatocellular carcinoma (HCC), is one of the leading causes of cancer-related death worldwide 1 and generally has a poor prognosis since it is often diagnosed at an advanced stage when treatment is not effective. Great efforts have been made to decipher the molecular mechanisms of HCC and gene expression profiling has been used to identify subgroups of patients according to etiological factors, early pre-neoplastic lesions, stage of the disease, rate of recurrence and survival [2][3][4][5] . Genetic analysis has revealed that Myc oncogene over-expression is present in up to 70% of viral and alcohol-related HCCs. Myc is a potent activator of tumorigenesis and its deregulation has been shown to contribute to a variety of cancers [6][7][8] . Increased Myc levels often correlate with the more advanced and aggressive tumour forms, providing a characteristic signature of cancer progenitor cells and suggesting that its overexpression plays some part in Myc-driven pathogenesis and tumor biology 9,10 . The Myc oncoprotein is a pleiotropic transcription factor belonging to the basic helix-loop-helix-leucine zipper family with a critical role in engaging and coordinating expression of the genes necessary for efficient and ordered proliferation of somatic cells. Myc expression is highly regulated being tightly controlled by a number of mechanisms involving many transcriptional regulatory motifs 11,12 . According to its well established predominant role Myc regulates up to 15% of human genes and is involved in cell growth, proliferation, metabolism, differentiation, and apoptosis 6 . According to data emerging from genome-wide gene expression profiling 13 Myc has been recently suggested to be at the centre of human liver tumor malignant conversion.As expected, given their broad role as transcriptional regulator, Myc family proteins are predominantly localized within nuclear compartment during proliferation, although emerging data indicate

Hypoxia‐inducible factor 2α drives nonalcoholic fatty liver progression by triggering hepatocyte release of histidine‐rich glycoprotein

“…To address the mechanisms by which hepatocyte HIF‐2α up‐regulation promotes inflammatory mechanisms in NAFLD, we focused our attention on the role of HRGP, a hepatocyte‐released mediator (i.e., hepatokine) that has been recently shown to support liver macrophage activation in experimental and clinical NAFLD/NASH . To investigate the possible hypoxia‐dependent and HIF‐2α‐dependent modulation of HRGP, we employed HepG2 cells, which are known to rapidly respond to hypoxia with HIF‐2α stabilization and the up‐regulation of HIF‐2α target genes . Incubation of HepG2 cells under hypoxic conditions, which is known to rapidly promote the nuclear translocation of HIF‐2α, was associated with an appreciable increase in HRGP synthesis (Fig.…”

“…(32) To investigate the possible hypoxia-dependent and HIF-2a-dependent modulation of HRGP, we employed HepG2 cells, which are known to rapidly respond to hypoxia with HIF-2a stabilization and the up-regulation of HIF-2a target genes. (28,33) Incubation of HepG2 cells under hypoxic conditions, which is known to rapidly promote the nuclear translocation of HIF-2a, (28) was associated with an appreciable increase in HRGP synthesis (Fig. 5A).…”

Performance of different biomarkers for the management of hepatocellular carcinoma

“…Furthermore, it was recently confirmed that its expression correlates with that of TGF-B1 and that in fact, SERPINB3 contributes to TGFB1 overexpression and release [42] . So, far from its antiprotease activity, and its biomarker possibilities, SERPINB3 was suggested to be an oncoprotein in as much as it protects the cells from apoptosis and induces epithelial-mesenchymal transition, cell invasiveness and proliferation [43] .…”

Pro-oncogenic role of SerpinB3 in hepatocellular carcinoma

“…[24] , 2014 mice transgenic for liver SerpinB3 showed higher liver regenerative ability compared to wild-type mice, supporting a role of this protein in promoting cell growth and proliferation [26] . Other mechanisms of tumor growth promotion induced by SerpinB3 include the up-regulation of Myc oncogene transcription with two different strategies [27] : the first mechanism is through the intracellular SerpinB3 antiprotease activity that blocks its cleavage exerted by Calpain, preventing the generation of the non-oncogenic cytoplasmic Mycnick form and allowing nuclear translocation of Myc with pro-oncogenic activity. The second one consists in the transcriptional induction of Myc, through the increase of Yap pathway [27] .…”

“…Other mechanisms of tumor growth promotion induced by SerpinB3 include the up-regulation of Myc oncogene transcription with two different strategies [27] : the first mechanism is through the intracellular SerpinB3 antiprotease activity that blocks its cleavage exerted by Calpain, preventing the generation of the non-oncogenic cytoplasmic Mycnick form and allowing nuclear translocation of Myc with pro-oncogenic activity. The second one consists in the transcriptional induction of Myc, through the increase of Yap pathway [27] . Furthermore, recent findings indicate that SerpinB3/SerpinB4 isoforms are a Ras-responsive factor that plays an important role in Rasassociated cytokine production and tumorigenesis [28] .…”