4.2 Article

Possible role of combined therapy targeting MET and pro-HGF activation for renal cell carcinoma: analysis by human HGF-producing SCID mice

Journal

HUMAN CELL
Volume 36, Issue 2, Pages 775-785

Publisher

SPRINGER JAPAN KK
DOI: 10.1007/s13577-023-00857-y

Keywords

RCC; MET; HAI-2; HGF; TKI

Categories

Ask authors/readers for more resources

In this study, dual inhibition of MET phosphorylation and pro-HGF activation using a MET inhibitor and HAI-2 overexpression was attempted to inhibit the growth of RCC cells. Both in vitro and in vivo experiments showed that combined treatment with MET-TKI and HAI-2 had the strongest inhibitory effect on MET phosphorylation and cell proliferation. This study suggests that combined treatment with MET-TKI and HAI-2 could be a candidate for a new strong therapy for RCC.
MET is a high-affinity receptor tyrosine kinase of HGF (hepatocyte growth factor). HGF is secreted as an inactive single-chain precursor (pro-HGF), which requires proteolytic activation for conversion to an active form. HGF activator inhibitor (HAI)-2 is a transmembrane Kunitz-type serine protease inhibitor, which inhibits all pro-HGF-activating enzymes. In RCC, increased expression of MET and decreased expression of HAI-2 were reported to be poor prognostic factors. In the current study, we tried to inhibit the growth of RCC cells by dual inhibition of both MET phosphorylation and pro-HGF-activation using MET inhibitor and HAI-2 overexpression. A transgenic mouse model which expressed human HGF (HGF mouse) was used for in vivo analysis to evaluate the HGF/MET signaling axis accurately. Initially, doxycycline-induced HAI-2 overexpression RCC cells (786-O-HAI2) were prepared. The cells were cultured with pro-HGF, and inhibitory effect of MET inhibitor (SCC244) and HAI-2 was evaluated by phosphorylation of MET and cell proliferation. Next, the cells were subcutaneously implanted to HGF mice and the growth inhibition was determined by SCC244 and HAI-2. Single use of each inhibitor showed significant inhibition in MET phosphorylation, migration and proliferation of 786-O-HAI2 cells; however, the strongest effect was observed by combined use of both inhibitors. Although in vivo analysis also showed apparent downregulation of MET phosphorylation and growth inhibition in combined treatment, statistical significance was not observed compared with single use of MET inhibitor. Combined treatment with MET-TKI and HAI-2 suggested to consider as a candidate for new strong therapy for RCC.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.2
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available