Targeting Src-Hic-5 Signal Cascade for Preventing Migration of Cholangiocarcinoma Cell HuCCT1

Wen Sheng Wu, Chin Hsien Ling, Ming Che Lee, Chuan Chu Cheng, Rui Fang Chen, Chen Fang Lin, Ren In You, Yen Cheng Chen

Research output: Contribution to journalArticlepeer-review

Abstract

Cholangiocarcinoma (CCA) is the second most common primary liver cancer with poor prognosis. The deregulation of a lot of oncogenic signaling molecules, such as receptor tyrosine kinases (RTKs), has been found to be associated with CCA progression. However, RTKs-based target therapy showed limited improvement suggesting a need to search for alternative targets for preventing CCA progression. To address this issue, we screened the oncogenic signal molecules upregulated in surgical tissues of CCAs. Interestingly, over-expression of hydrogen peroxide in-ducible clone-5 (Hic-5) coupled with over-activation of Src, AKT, JNK were observed in 50% of the cholangiocarcinoma with metastatic potential. To investigate whether these molecules may work together to trigger metastatic signaling, their up-and-down relationship was examined in a well-established cholangiocarcinoma cell line, HuCCT1. Src inhibitors PP1 (IC50, 13.4 µM) and dasatinib (IC50, 0.1 µM) significantly decreased both phosphorylated AKT (phosphor-AKT Thr450) and Hic-5 in HuCCT1. In addition, a knockdown of Hic-5 effectively suppressed activation of Src, JNK, and AKT. These implicated a positive cross-talk occurred between Hic-5 and Src for triggering AKT activation. Further, depletion of Hic-5 and inhibition of Src suppressed HuccT1 cell migration in a dose-dependent manner. Remarkably, prior transfection of Hic-5 siRNA for 24 h followed by treatment with PP1 or dasatinib for 24 h resulted in additive suppression of HuCCT1 migration. This suggested that a promising combinatory efficacy can be achieved by depletion of Hic-5 coupled with inhibition of Src. In the future, target therapy against CCA progression by co-targeting Hic-5 and Src may be successfully developed in vivo.

Original languageEnglish
Article number1022
JournalBiomedicines
Volume10
Issue number5
DOIs
Publication statusPublished - May 2022

Keywords

  • cholangiocarcinoma
  • HuCCT1
  • hydrogen peroxide clone-5
  • migration assays
  • nonreceptor tyrosine kinase Src

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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