Hypoxia-inducible enhancer/alpha-fetoprotein promoter-driven RNA interference targeting STK15 suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells.
STK15 (Aurora A/BTAK) is an oncogenic serine/threonine kinase that plays a role in centrosome separation and in the formation of the mitotic bipolar spindle. It is highly expressed and constitutively activated in various human tumors including hepatocellular carcinoma (HCC). To investigate its possibility as a molecular target for future therapies directed against hepatocellular carcinoma, we constructed a tissue-specific RNA interference (RNAi) system mediated by hypoxia-inducible (HI) enhancer/alpha-fetoprotein (AFP) promoter and employed it to downregulate exogenous reporters (LUC and EGFP) and endogenous STK15 gene expression and analyzed the phenotypical changes in HCC cells. Results showed that the expression of exogenous reporters (LUC and EGFP) was specifically downregulated in hepatoma cells but not in non-hepatoma cells. Moreover, the specific downregulation of STK15 expression in hepatocellular carcinoma cells (HepG2) significantly inhibited in vitro cellular proliferation and in vivo tumorigenicity. Furthermore, we also found that the downregulation of STK15 expression led to cell arrest in the G(2)/M phase and finally apoptosis induction of HepG2 cells. Thus, the HI enhancer/AFP promoter-mediated RNAi targeting STK15 may be a potential therapeutic strategy for the treatment of hepatocellular carcinoma with tumor specificity and high efficacy.
Gao
Ping
P
Laboratory Department, Tangdu Hospital, Fourth Millitary Medical University, Xi'an, Shaanxi Province, China.
Wang
Rui
R
Shen
Jian-Jun
JJ
Lin
Fang
F
Wang
Xi
X
Dong
Ke
K
Zhang
Hui-Zhong
HZ
D000818:Animals; D017209:Apoptosis; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D014407:Tumor Cells, Cultured; D000509:alpha-Fetoproteins / Q000235:genetics*
D051793:Hypoxia-Inducible Factor 1; D000509:alpha-Fetoproteins; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases