Onishi Hideya, Nakamura Katsuya, Nagai Shuntaro, Yanai Kosuke, Yamasaki Akio, Kawamoto Makoto, Imaizumi Akira, Morisaki Takashi
Departments of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Departments of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Anticancer Res. 2017 Sep;37(9):4987-4992. doi: 10.21873/anticanres.11910.
BACKGROUND/AIM: Previously we have shown that tropomyosin-related kinase B (TRKB) and Hedgehog (Hh) signalling pathways induce malignant phenotypes in many cancer types. However, results from small cell lung cancer (SCLC) clinical trials using TRK and Hh inhibitors have been disappointing. One reason for this may be the existence of crosstalk between TRKB and Hh signalling pathways. In this study, we detected negative crosstalk between the TRKB and Hh-GLI1 signalling pathways.
The human small cell lung carcinoma cell line, SBC-5, was used. Using small interfering RNA to inhibit TRKB and Hh signalling, whether TRKB and Hh signaling contribute to proliferation and invasiveness in SBC-5 cells were investigated.
TRKB expression in GLI1 siRNA-transfected SBC-5 cells was higher than that of control cells. GLI1-knockdown alone did not affect invasiveness of SBC-5 cells. However, combined knockdown of TRKB and GLI1 significantly decreased invasiveness. Moreover, combined TRKB and GLI1 knockdown inhibited proliferation and migration to a greater extent than when either was inhibited alone.
These results suggest that Hh inhibition increases TrkB expression to counter tumor suppression in SBC-5 cells. The combined use of TRKB and Hh inhibitors may, therefore, be useful for the treatment of refractory SCLC.
背景/目的：此前我们已表明，原肌球蛋白相关激酶B（TRKB）和刺猬信号通路（Hh）在多种癌症类型中诱导恶性表型。然而，使用TRK和Hh抑制剂的小细胞肺癌（SCLC）临床试验结果令人失望。其原因之一可能是TRKB和Hh信号通路之间存在串扰。在本研究中，我们检测到TRKB与Hh-GLI1信号通路之间存在负串扰。
使用人小细胞肺癌细胞系SBC-5。利用小干扰RNA抑制TRKB和Hh信号，研究TRKB和Hh信号是否促进SBC-5细胞的增殖和侵袭。
在转染GLI1小干扰RNA的SBC-5细胞中，TRKB的表达高于对照细胞。单独敲低GLI1不影响SBC-5细胞的侵袭性。然而，联合敲低TRKB和GLI1可显著降低侵袭性。此外，联合敲低TRKB和GLI1比单独抑制二者中的任何一个更能抑制增殖和迁移。
这些结果表明，Hh抑制会增加TrkB表达以对抗SBC-5细胞中的肿瘤抑制作用。因此，联合使用TRKB和Hh抑制剂可能有助于治疗难治性SCLC。
