New mechanism of transforming growth factor-beta signaling in hepatoma: Dramatic up-regulation of tumor initiating cells and epidermal growth factor receptor expression.

Abstract

AIM:

Transforming growth factor-beta (TGF-beta) has dual activity in tumor cells. We studied the effect of TGF-beta on tumor-initiating cells (TICs), which are similar in self-renewal and differentiation features to normal adult stem cells.

METHODS:

We used side population (SP) cells that exclude DNA binding dye Hoechst 33342 to obtain TICs, studied the differences in the kinetics of the SP cell response to TGF-beta treatment between hepatic tumor cell lines, and performed gene analysis.

RESULTS:

SP cells from all cell lines have higher proliferative ability compared to non-SP cells and they are drug resistant. TGF-beta treatment increased the percentage of SP cells (%SP) and the survival rate; chemotherapeutic drug resistance developed only in K-251 SP cells. Gene analysis showed that TGF-beta up-regulated epidermal growth factor receptor (EGFR) only in K-251 cells. There were no EGFR mutations in K-251, which had been reported in lung cancer. Knockdown of Smad4 using the small-interfering RNA technique in K-251 cells inhibited EGFR overexpression and significantly decreased the %SP. In contrast, the JNK inhibitor had little effect on EGFR expression or the %SP.

CONCLUSION:

TGF-beta treatment of K-251 cells causes tumor progression and the anti-cancer drug resistant phenotype by increasing SP.

• Authors: Takeshi Nishimura, Toshifumi Azuma, Akiko Yokoyama, Hiromi Ochiai, Hidetsugu Saito, Toshifumi Hibi
• Journal: Hepatology research : the official journal of the Japan Society of Hepatology (Hepatol Res) Vol. 39 Issue 5 Pg. 501-9 (May 2009) ISSN: 1386-6346 [Print] Netherlands
• PMID: 19261001 (Publication Type: Journal Article)