Induction of hepatocyte growth factor activator gene expression under hypoxia activates the hepatocyte growth factor/c‐Met system via hypoxia inducible factor‐1 in pancreatic cancer

Abstract

Hepatocyte growth facor activator (HGFA) is a serine protease that converts hepatocyte growth factor (HGF) into its active form. Our previous study demonstrated that tumor-stromal interaction under hypoxia augments the aggressive invasive features of pancreatic cancer line PK8 through activated HGF/c-Met signaling. The present study investigated whether or not hypoxia increases HGFA expression in PK8 cells and promotes the processing of HGF, and leads to c-Met activation. Moreover, HGFA promoter assays were performed to define whether hypoxia inducible factor-1 alpha (HIF-1a) directly activates the HGFA promoter in a hypoxia-dependent fashion. As a result, hypoxia induced the HGFA mRNA and protein expression in PK8 and the elevation under hypoxia was inhibited by the transfection of HIF-1a siRNA, thus indicating HIF-1a-dependent induction of HGFA. The transfection of siRNA against HGFA to PK8 cells suppressed the conversion to the active HGF, which is secreted from fibroblast MRC5. H epatocyte growth factor (HGF) is a multifunctional cytokine produced from stromal cells, and it functions as a mitogen, motogen, and morphogen, and in angiogenesis.(1-3)The various effects of HGF are mediated through binding to the specific receptor, c-Met receptor tyrosine kinase, which is expressed on the cell surfaces of epithelial origin. HGF is mainly produced in cells of mesenchymal origin and secreted as a single-chain precursor form (pro-HGF). The proteolytic conversion of pro-HGF to the two-chain heterodimeric active form (mature HGF) is essential in its biological activity.(4) The most potent enzyme involved in the activation of pro-HGF is HGF activator (HGFA), a serine protease discovered in serum that is related to coagulation factor XIIa.(5) The liver is the main source of HGFA, and produces HGFA as an inactive form (pro-HGFA), which is converted to the active form by thrombin. (6) The extrahepatic expression of HGFA has also been reported, and recent studies have demonstrated HGFA to be involved in the activation of pro-HGF in several tumors. (7)(8)(9)(10) Hypoxia is a common feature of various solid tumors due to inadequacies in their vasculature.(11) The hypoxic environment, in which hypoxia-inducible factor-1 (HIF-1) plays a key role, might be associated with both malignant progression and a poor response to various treatments. (12,13) HIF-1 is a heterodimeric basic helix-loop-helix PER/ARNT/SIM (HLH-PAS) transcription factor that consists of HIF-1α and a constitutively expressed aryl hydrocarbon receptor nuclear translocator known as HIF-1β. Under normoxic conditions, HIF-1α is bound to the tumor suppressor Von Hippel-Lindau protein. This protein complex causes HIF-1α to be targeted by proteasomes, thus leading to rapid protein degradation. In contrast, under hypoxic condition, HIF-1α is stabilized and dimerized with HIF-1β, translocates to the nucleus, and transactivates expressions of various genes. (14,15) The hypoxia-responsive element (HRE) consists of a pair of consecutive transcription factor binding sites, ...

Anti-inflammatory cytokines hepatocyte growth factor and interleukin-11 are over-expressed in Polycythemia vera and contribute to the growth of clonal erythroblasts independently of JAK2V617F

“…This suggests that the HGF/c-MET pathway may exert a fundamental role in the maintenance of normalcy in dividing cells. Indeed, increased production of HGF is a common cellular response to hypoxia, frequent in the context of cancer and chronic inflammation (Tacchini et al, 2001;Kitajima et al, 2008). In addition Significantly different than PV with 450% JAK2V617F, P ¼ 0.0065.…”

Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling

“…In the vasculature, cMet activation through paracrine signalling by tumour cell-released HGF stimulates tumour angiogenesis by inducing proliferation, migration and survival of endothelial cells 13 . Expression of both cMet and HGF is induced by hypoxiainducible factor 1a, further providing evidence for an important role of the HGF/cMet axis in adverse microenvironment conditions to promote tumour angiogenesis 14,15 . Importantly, it has been reported in a preclinical model that HGF/cMet signalling can act as an alternative angiogenic pathway in sunitinib-resistant tumours 16 .…”

MET/HGF pathway activation as a paradigm of resistance to targeted therapies

“…In MET-driven cancer, the loss of tight regulation of these events leads to invasion and metastasis. Invasion can also be driven by hypoxia, which induces HGF and MET expression via HIF-1α, rendering cells more sensitive to further HGF stimulation and MET overexpression (23,24).…”