Therapeutic effects of STAT3 decoy oligodeoxynucleotide on human lung cancer in xenograft mice

Xulong Zhang, Jian Zhang, Lihua Wang, Haiming Wei, Zhigang Tian

Signal transducer and activator of transcription 3 (STAT3) is usually constitutively activated in a variety of malignancies. Therefore, STAT3 may be a promising target for treatment of tumor cells. To explore the possibility of a double-stranded decoy oligodeoxynucleotide (ODN) targeted blocking STAT3 over-activated tumor cells, we, here, evaluate the efficacy of STAT3 decoy ODN on human lung cancer cells in vitro and in vivo. A STAT3 decoy ODN was transfected into A549 lung cancer cell line in vitro by using lipofectamine. The flow cytometry and fluorescent microscopy were used to detect the transfection efficiency and the sub-cellular localization of STAT3 decoy ODN in A549 cells. Cell proliferation was determined by counting cell numbers and [3H]-thymidine uptake. Cell apoptosis was examined with Annexin V and propidum iodide by flow cytometry. The expression levels of STAT3 target genes were identified by RT-PCR and immunoblot. For in vivo experiment, A549 lung carcinoma-nude mice xenograft was used as a model to examine the effect of the STAT3 decoy by intratumoral injection. At the end of treatment, TUNEL and immunohistochemistry were used to examine the apoptosis and the expression levels of bcl-xl and cyclin D1 in tumor tissues. STAT3 decoy ODN was effectively transfected into A549 lung cancer cells and mainly located in nucleus. STAT3-decoy ODN significantly induced apoptosis and reduced [3H]-thymidine incorporation of A549 cells as well as down-regulated STAT3-target genes in vitro. STAT3 decoy ODN also dramatically inhibited the lung tumor growth in xenografted nude mice and decreased gene expression of bcl-xl and cyclin D1. STAT3 decoy ODN significantly suppressed lung cancer cells in vitro and in vivo, indicating that STAT3 decoy ODN may be a potential therapeutic approach for treatment of lung cancer.