Abstract
BackgroundCisplatin has been used in the treatment of many cancers, including laryngeal cancer; however, its efficacy can be reduced due to the development of drug resistance. This study aimed to investigate whether interleukin-6 (IL-6) knockdown may enhance the efficacy of cisplatin in laryngeal cancer stem cells (CSC) and the potential involvement of the signal transducer and activator of transcription 3 (STAT3) and hypoxia-inducible factor 1 (HIF1) in this effect.MethodsThe ALDH+ and CD44+ CSC in Hep2 human laryngeal squamous cancer cells were identified by the fluorescence-activated cell sorting technique. IL-6, STAT3 and HIF1 mRNA and protein expressions were examined with quantitative real-time polymerase chain reaction and Western blot, respectively. Cell proliferation was measured by MTT assay. Tumorigenicity was measured by a colony formation assay and invasion was determined by a cell invasion assay. Apoptotic cells were counted by flow cytometry. Immunohistochemistry was performed to detect immunoreactive IL-6, STAT3 and HIF1 cells in xenografts.ResultsThe mRNA and protein levels of IL-6, STAT3 and HIF1 were significantly increased in Hep2-CSC as compared with those from Hep2 cells. Application of siRNA-IL-6 to knockdown IL-6 resulted in significantly decreased IL-6, STAT3 and HIF1 mRNA and protein levels. IL-6 knockdown reduced cell proliferation, tumorigenicity and invasion and increased apoptosis within CSC. Enhanced degrees of suppression in these parameters were observed when IL-6 knockdown was combined with cisplatin in these CSC. Results from the xenograft study showed that the combination of IL-6 knockdown and cisplatin further inhibited the growth of xenografts as compared with that obtained in the cisplatin-injected group alone. Immunoreactive IL-6, STAT3 and HIF1 cell numbers were markedly reduced in IL-6 knockdown tumor tissues. IL-6, STAT3 and HIF1 immunoreactive cell counts were further reduced in tissue where IL-6 knockdown was combined with cisplatin treatment as compared with tissue receiving cisplatin alone.ConclusionsIL-6 knockdown can increase chemo-drug efficacy of cisplatin, inhibit tumor growth and reduce the potential for tumor recurrence and metastasis in laryngeal cancer. The IL-6/STAT3/HIF1 pathway may represent an important target for investigating therapeutic strategies for the treatment of laryngeal cancer.
Highlights
Head and neck cancers represent the seventh most common cancer worldwide [1]
IL‐6, signal transducer and activator of transcription 3 (STAT3) and hypoxia-inducible factor 1 (HIF1) mRNA and protein expressions in Hep2‐cancer stem cells (CSC) Similar to our previous study [36], a high yield of aldehyde dehydrogenase (ALDH)+/CD44+ was obtained in this current study
IL-6, STAT3 and HIF1 mRNA levels in Hep2-CSC were significantly increased as compared to the IL-6, STAT3 and HIF1 mRNA expression levels in Hep2 cells and Hep2-derived tumor tissue, which were obtained from the tumor tissue after Hep2-cells were injected into dorsal area of nude mice (p < 0.001, Fig. 1a–c)
Summary
Head and neck cancers represent the seventh most common cancer worldwide [1]. In particular, head and neck squamous cell carcinoma (HNSCC) is the eighth leading cause of cancer mortality [2], with laryngeal squamous carcinoma (LSCC) being the most common type of HNSCC or head and neck cancer [3]. The recurrence and metastasis of head and neck cancer are often accompanied with chemo-drug resistance generated during the cancer therapy, with the result that therapeutic outcomes are unsatisfactory. Cancer stem cells (CSC) have become a theoretical foundation for chemo-resistance and cancer recurrence studies. CSC can mutate or experience abnormal differentiation, which may lead to tumor recurrence and metastasis and serve as the basis for drug resistance [12, 13]. Cisplatin has been used in the treatment of many cancers, including laryngeal cancer; its efficacy can be reduced due to the development of drug resistance. This study aimed to investigate whether interleukin-6 (IL-6) knockdown may enhance the efficacy of cisplatin in laryngeal cancer stem cells (CSC) and the potential involvement of the signal transducer and activator of transcription 3 (STAT3) and hypoxia-inducible factor 1 (HIF1) in this effect
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