Role of FLT3 in the proliferation and aggressiveness of hepatocellular carcinoma

Abstract

Background/aim: Previously we showed that Fms-like tyrosine kinase (FLT3) changes its cellular localization upon partial hepatectomy, suggesting a role in liver regeneration. FLT3 was also shown to play an important function in cellular proliferation and activation of PI3K and Ras. Thus, we aimed to investigate the role of FLT3 in hepatocellular tumorigenesis utilizing in vitro and in vivo models. Materials and methods:We used Snu398 cells that express FLT3. We investigated these cells' in vitro proliferation and invasion abilities by treatment with the FLT3 inhibitor K-252a or by knocking-down with FLT3 shRNA,. Furthermore, the effect of blocking FLT3 activity and expression during in vivo tumorigenesis was assessed with xenograft models.Results: After K-252a treatment or stable knock-down, these cells' proliferation and migration abilities were highly diminished in vitro. In addition, significant diminution in tumorigenicity of Snu398 cells was also obtained in vivo. When FLT3 knocked-down Snu398 cells were injected into nude mice, we did not detect αSMA expression in these tumors, suggesting a role for FLT3 in in vivo invasiveness. Conclusion:Our data provided evidence that FLT3 has a crucial role both in hepatocarcinogenesis and its invasiveness. Therefore, targeting FLT3 and/or its activity may be a promising tool for combating hepatocellular carcinomas.

Novel FLT3/AURK multikinase inhibitor is efficacious against sorafenib-refractory and sorafenib-resistant hepatocellular carcinoma

“…Aydin et al [44] have reported that FLT3 was active and participatory in the proliferation response during progenitor-dependent liver regeneration in rats. The role of FLT3 in HCC tumorigenesis, proliferation, and invasion was demonstrated through the stable knockdown of FLT3 gene in the FLT3-expressing HCC cell line and the pharmacological inhibition of FLT3 kinase [45]. According to the Cancer Genome Atlas dataset [46], FLT3 gene expression level and copy number gain is associated with the low OS of patients with HCC, implying that FLT3 may play a key role in HCC progression.…”

Identification and Validation of Prognosis-Related Necroptosis Genes for Prognostic Prediction in Hepatocellular Carcinoma

“…The previous results showed that the mRNA expression of FLT3 was decreased in 64% of patients with HCC because of the loss of gene copy number; however, patients with high FLT3 expression benefit from sorafenib, which improves prognosis [ 34 ]. Therefore, the high expression of FLT3 promotes the proliferation and migration of HCC [ 35 ], which may be the reason for the high expression of FLT3 in vitro.…”