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Visualization of Endogenous p53-Mediated Transcription In vivo Using Sodium Iodide Symporter

Departments of ¹ Nuclear Medicine and ² Tumor Biology and ³ Laboratory of Molecular Imaging and Therapy of Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

Requests for reprints: June-Key Chung, Department of Nuclear Medicine, Seoul National University Hospital, 28, Yongon-dong, Jongno-gu, Seoul 110-744, Korea. Phone: 82-2-760-3376; Fax: 82-2-745-7690; E-mail: jkchung{at}plaza.snu.ac.kr.

Purpose: To develop a gamma camera imaging method for the determination of endogenous gene expression, we evaluated the expression of endogenous p53 gene using human sodium iodide symporter (hNIS) gene as reporter.

Experimental Design: We constructed cis-p53RE-hNIS reporter vector placed under control of an artificial enhancer (p53RE). Moreover, we transfected it into human hepatoma cell line SK-Hep1 by liposome. Geneticin was used for the selection of stable transfectant (SK-Hep1p53NIS). To evaluate the function of hNIS, the inhibition study was examined with 1 mmol/L potassium perchlorate. After treatment of Adriamycin with serial dose for 24 hours, we measured the uptake of ¹²⁵I and did Western blot analysis to evaluate expression of p53 protein. Tumor xenografts were produced in nude mice by s.c. injection of SK-Hep1p53NIS cells. After 7 days, scintigraphic images of nude mice before and after Adriamycin treatment were obtained using [^99mTc]-pertechnetate.

Results: In the SK-Hep1p53NIS cells, Adriamycin-treated cells accumulated up to three times higher than did nontreated cells. Potassium perchlorate inhibited completely the uptake of ¹²⁵I. As Adriamycin dose increased, radioiodide uptake was significantly correlated with activated p53 as well as total p53 protein level. When Adriamycin (2 mg/kg) was treated in the same mice, a significantly higher uptake of [^99mTc]-pertechnetate was observed in SK-Hep1p53NIS xenografts compared with nontreated xenografts (P < 0.05, unpaired t test).

Conclusions: These results suggest that p53 expression level can be monitored by NIS gene expression using cis-p53RE-hNIS system in vitro and in vivo.

Key Words: Sodium iodide symporter • Transcriptional activation • p53 • Endogenous gene • Imaging reporter gene • Molecular imaging

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