TMPRSS4 Drives Angiogenesis in Hepatocellular Carcinoma by Promoting HB‐EGF Expression and Proteolytic Cleavage

Abstract

Background and Aims Heparin‐binding epidermal growth factor (HB‐EGF), a member of the epidermal growth factor family, plays a pivotal role in the progression of several malignancies, but its role and regulatory mechanisms in hepatocellular carcinoma (HCC) remain obscure. Here, we report that transmembrane protease serine 4 (TMPRSS4) significantly enhanced the expression and proteolytic cleavage of HB‐EGF to promote angiogenesis and HCC progression. Approach and Results A mechanistic analysis revealed that TMPRSS4 not only increased the transcriptional and translational levels of HB‐EGF precursor, but also promoted its proteolytic cleavage by enhancing matrix metallopeptidase 9 expression through the EGF receptor/Akt/mammalian target of rapamycin/ hypoxia‐inducible factor 1 α signaling pathway. In addition, HB‐EGF promoted HCC proliferation and invasion by the EGF receptor/phosphoinositide 3‐kinase/Akt signaling pathway. The level of HB‐EGF in clinical samples of serum or HCC tissues from patients with HCC was positively correlated with the expression of TMPRSS4 and the microvessel density, and was identified as a prognostic factor for overall survival and recurrence‐free survival, which suggests that HB‐EGF can serve as a potential therapeutic target for HCC. More importantly, we provide a demonstration that treatment with the HB‐EGF inhibitor cross‐reacting material 197 alone or in combination with sorafenib can significantly suppress angiogenesis and HCC progression. Conclusions HB‐EGF can be regulated by TMPRSS4 to promote HCC proliferation, invasion, and angiogenesis, and the combination of the HB‐EGF inhibitor cross‐reacting material 197 with sorafenib might be used for individualized treatment of HCC.

Role of the E3 Ubiquitin Ligase TRIM4 in Predicting the Prognosis of Hepatocellular Carcinoma

“…Traditionally, E3 ubiquitin ligases have been categorized into two classes of RING/U-box ligases and HECT ligases. Both types of ligases have been reported to lead to positive or negative regulation of multiple cancer-related signal pathways and maybe potential novel targets for anticancer therapies [13,19].…”

“…The inclusion and exclusion criteria of the patient cohorts included (a) having a distinctive pathologic diagnosis of HCC, (b) having no anticancer treatment before liver resection, (c) having curative liver resection, (d) having suitable formalin-fixed, paraffin-embedded tissues and (e) having complete clinicopathologic and follow-up data. All patients were followed regularly in the outpatient clinic and were monitored prospectively for recurrence according to a standard protocol as previously described [13][14][15].…”

“…Tissue microarray (TMA) was constructed as described in our previous studies [13][14][15]. Immunohistochemical staining for TRIM4 was performed on formalin-fixed sample sections from the TMA.…”

“…Cases were scored independently based on the intensity of cellular staining and the proportion of stained tumour cells. The product of the intensity and proportion scores was used to determine the level of TRIM4, as described in our previous studies [13,14].…”

CircMEMO1 modulates the promoter methylation and expression of TCF21 to regulate hepatocellular carcinoma progression and sorafenib treatment sensitivity

“…Quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis, dot blot analysis, immunohistochemistry (IHC) and immunofluorescence assay QRT-PCR, western blot analysis, dot blot analysis, IHC and immunofluorescence assays were performed as described previously [13,14]. The primers for miR-106-5p during qRT-PCR were purchased from GeneCopoeia, Rockville, Maryland.…”