Abstract
Homeobox A9 (HOXA9) expression is associated with the aggressive growth of cancer cells and poor prognosis in lung cancer. Previously, we showed that HOXA9 can serve as a potential therapeutic target for the treatment of metastatic non-small cell lung cancer (NSCLC). In the present study, we have carried out additional studies toward the development of a peptide-based therapeutic agent. Vectors expressing partial DNA fragments of HOXA9 were used to identify a unique domain involved in the inhibition of NSCLC cell invasion. Next, we performed in vitro invasion assays and examined the expression of EMT-related genes in transfected NSCLC cells. The C-terminal fragment (HOXA9-C) of HOXA9 inhibited cell invasion and led to upregulation of CDH1 and downregulation of SNAI2 in A549 and NCI-H1299 cells. Reduced SNAI2 expression was consistent with the decreased binding of transcription factor NF-kB to the SNAI2 promoter region in HOXA9-C overexpressing cells. Based on the above results, we synthesized a cell-permeable peptide, CPP33-HADP (HOXA9 active domain peptide), for lung-specific delivery and tested its therapeutic efficiency. CPP33-HADP effectively reduced the invasion ability of NSCLC cells in both in vitro and in vivo mouse models. Our results suggest that CPP33-HADP has significant potential for therapeutic applications in metastatic NSCLC.
Highlights
Lung cancer is one of the most common types of cancer worldwide and contributed to about 12% of the total number of new cases diagnosed in 2020 [1]
We demonstrated that exogenous upregulation of Homeobox A9 (HOXA9) inhibited tumor cell invasion and migration and attenuated the expression of snail family zinc finger 2 (SNA12/SLUG) through repression of nuclear factor (NF)-kB activity and suggested that HOXA9 can serve as a potential target for developing anticancer agents [10]
We investigated the therapeutic efficacy of the sequence motif using the synthetic cell-penetrating peptide CPP33-HADP (HOXA9 active domain peptide) in in vitro and in vivo experimental models
Summary
Lung cancer is one of the most common types of cancer worldwide and contributed to about 12% of the total number of new cases diagnosed in 2020 [1]. HOX genes are reported to be transcriptional activators or repressors in the progression of various cancers [6]. Of these genes, HOXA9 is reported to be strongly associated with the aggressive growth of lung cancer cells. HOXA9 protein is downregulated in lung cancer tissues and plays the role of a tumor progression repressor [7,8]. A unique domain of the HOXA9 protein that negatively modulates the metastatic progression of NSCLC cells is currently not known. We investigated the therapeutic efficacy of the sequence motif using the synthetic cell-penetrating peptide CPP33-HADP (HOXA9 active domain peptide) in in vitro and in vivo experimental models
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