Abstract
Purpose: To evaluate the role of signal transducer and activator of transcription 3 (STAT3) and mucin 1(MUC1) in non-small cell lung carcinoma (NSCLC) and the use of their inhibitors to reduce chemoresistance. Methods: Cisplatin or vinblastine was provided either with or without STAT3 inhibitor and evaluated for chemoresistance in NSCLC cells and a xenograft mice tumor model. Immunohistochemistry and Kaplan-Meier method of survival analysis were used to determine chemoresistance trends in patients. STAT3 inhibitor treatment, RNAi or ectopic overexpression of STAT3 or MUC1 in NSCLC cells were used to determine their inter-molecular relation and for modulating stemness-related genes. Results: A major subset of chemoresistance patients exhibited a combined aberration of both STAT3 and MUC1 and exhibited a significantly reduced median overall survival ( p = 0.008). Subsequent in vitro experiments in NSCLC cells showed that STAT3 levels modulate MUC1 expression ( p < 0.01) and increase stemness gene expressions such as AKT (3-fold), OCT4 (4-fold), SOX2 (2-fold) and CXCR4 levels (2 -fold). In addition, co-treatment of STAT3 inhibitor with cisplatin or vinblastine enhanced drug efficiency in viability and invasion assays ( p < 0.01) and in a xenograft mouse model ( p < 0.05). Conclusion: STAT3 inhibitor co-treatment with chemotherapy drugs increases drug efficacy and reduced tumor growth, and therefore, may improve outcomes in patients on NSCLC chemotherapies. Keywords: STAT3, Non-small cell lung carcinoma, Mucin 1, Chemoresistance, Chemotherapy
Highlights
Non-small cell lung carcinoma (NSCLC) accounts for > 80 % of all lung cancers including lung adenocarcinoma and squamous cell carcinoma [1,2,3,4]
Our results showed that both squamous cell carcinoma and adenocarcinoma types exhibited high levels of signal transducer and activator of transcription 3 (STAT3) or MUC1 expression (Figure 1B), which indicate a role for these proteins in tumor progression [13,23]
Our results showed that median overall survival (OS) for STAT3 and MUC1 over-expression patients were 78 and 75 months respectively, while it is reduced to 46 months (p < 0.008) in patients with the combined
Summary
Non-small cell lung carcinoma (NSCLC) accounts for > 80 % of all lung cancers including lung adenocarcinoma and squamous cell carcinoma [1,2,3,4]. Treatment options such as surgical resection, radiotherapy, and chemotherapy are widely used for disease management [4,5,6,7]. Developing tailor-made chemotherapeutic options based on cancer subtypes and the underlying facilitating mechanism for the chemoresistance has been proposed as an alternate strategy to improve outcomes [11]. Chemotherapy options for lung cancers could be improved by synergistically treating with drugs that block tumor survival pathways
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