Abstract
Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) plays an important role in lung cancer progression. Here, we examined the therapeutic efficacy of CEACAM6 gene silencing using an siRNA delivery platform targeting the acidic tumour microenvironment in a lung adenocarcinoma xenograft mouse model. An siRNA delivery vector was constructed by tethering the peptide nucleic acid form of an siRNA targeting CEACAM6 (siCEACAM6) to a peptide with a low pH-induced transmembrane structure (pHLIP) to transport siRNAs across the plasma membrane. Specific binding of the pHLIP-siCEACAM6 conjugate to A549 lung adenocarcinoma cells at low pH was demonstrated by flow cytometry. A549 cells incubated with pHLIP-siCEACAM6 at an acidic pH showed downregulated expression of endogenous CEACAM6 protein and reduced cell viability. The in vivo tumour-suppressing effects of pHLIP-siCEACAM6 in lung adenocarcinoma were assessed in a xenograft model generated by injecting BALB/c nude mice with A549 cells. pHLIP-siCEACAM6 treatment alone resulted in tumour growth inhibition of up to 35.5%. When combined with cisplatin treatment, pHLIP-siCEACAM6 markedly enhanced tumour growth inhibition by up to 47%. In conclusion, the delivery of siCEACAM6 to lung adenocarcinoma using the pHLIP peptide has therapeutic potential as a unique cancer treatment approach.
Highlights
Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for 80–85% of lung cancer cases[1]
Kaplan-Meier survival analysis showed that high levels of Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) mRNA expression were associated with poor overall survival in lung adenocarcinoma patients (P = 0.026) (Supplementary Fig. 1)[31]
A549 lung adenocarcinoma cells were transfected with non-target siRNA, GAPDH siRNA, and four different siCEACAM6 sequences
Summary
Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for 80–85% of lung cancer cases[1]. Other CEACAM family proteins, such as CEACAM1 and CEACAM5, are known to be dysregulated in lung adenocarcinoma as well, CEACAM6 is more highly expressed than CEACAM5 and is associated with poor clinical outcomes among lung adenocarcinoma patients[3,7,13,14,15,18,19] These data support a critical role of CEACAM6 in lung adenocarcinoma and suggest that it is an attractive therapeutic target. We report the results of a concept study in a lung adenocarcinoma preclinical model that demonstrated the efficacy of CEACAM6 silencing using pHLIP-mediated PNA siRNA delivery
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