AFP Promoter Enhancer Increased Specific Expression of the Human Sodium Iodide Symporter (hNIS) for Targeted Radioiodine Therapy of Hepatocellular Carcinoma

Abstract

The sodium iodide symporter (NIS) present in the membranes of thyroid cells is responsible for the capacity of the thyroid to concentrate iodide. This allows treatment of thyroid cancers with ¹³¹I. We propose to enlarge the therapeutic strategy to hepatocellular carcinomas by using hepatoma-specific promoter and enhancer for targeted radiotherapy. We constructed a recombinant adenovirus encoding hNIS gene under the control of AFP promoter and enhancer (AdPLEN). After being infected with AdPLEN, HepG2 cells (high AFP-expression hepatoma cells) showed 6 times greater perchlorate-sensitive ¹²⁵I uptake than did SMMC7721 cells (low/no AFP-expression hepatoma cells), 30 times higher than Hela (human cervix tumor cells), and noninfected HepG2 cells. These results demonstrate that the AdPLEN vector can function in high AFP expression hepatoma cells. In addition, AdPLEN-infected tumor cells were selectively killed by exposure to ¹³¹I, as revealed by clonogenic assays. To assess the efficiency of this target gene therapy strategy in vivo, we injected the AdPLEN vector in human tumors (HepG2 cells) established in nude mice. Western blotting analysis confirmed the expression of the NIS protein in the tumor. Two days after intratumoral injection, AdPLEN-treated tumors could specifically accumulate ¹³¹I, as revealed by imaging experiments. Altogether, these data indicate that AdPLEN is very efficient in triggering and enlarging significant iodide uptake by hepatocellular carcinomas, outlining the potential of this novel cancer gene therapy approach for a targeted radiotherapy.

Keywords:

• α-fetoprotein (AFP)
• Human sodium iodide symporter (hNIS)
• Targeted radioiodine therapy
• Hepatocellular carcinoma (HCC)
• 131I