Abstract
Signaling transducer and activator 3 (STAT3) and cancer stem cells (CSCs) have garnered huge attention as a therapeutic focus, based on evidence that they may represent an etiologic root of tumor initiation and radio-chemoresistance. Here, we investigated the high phosphorylation status of STAT3 (p-STAT3) and its correlation with self-renewal markers in head neck squamous cell carcinoma (HNSCC). Over-expression of p-STAT3 was found to have increased in post chemotherapy HNSCC tissue. We showed that blockade of p-STAT3 eliminated both bulk tumor and side population (SP) cells with characteristics of CSCs in vitro. Inhibition of p-STAT3 using small molecule S3I-201 significantly delayed tumorigenesis of spontaneous HNSCC in mice. Combining blockade of p-STAT3 with cytotoxic drugs cisplatin, docetaxel, 5-fluorouracil (TPF) enhanced the antitumor effect in vitro and in vivo with decreased tumor sphere formation and SP cells. Taken together, our results advocate blockade of p-STAT3 in combination with conventional chemotherapeutic drugs enhance efficacy by improving CSCs eradication in HNSCC.
Highlights
Head neck squamous cell carcinoma (HNSCC), which has more than 600,000 newly diagnosed cases per year and a high mortality rate, is the sixth most common cancer worldwide [1]
Previous reports have shown that activation of Signaling transducer and activator 3 (STAT3) signaling was due to gene mutation and high level phosphorylation were widely expressed in HNSCC [17, 18], while the exact role of STAT3 in HNSCC cancer stem cells (CSCs) is unclear
On the basis of the increased expression of phosphorylation status of STAT3 (p-STAT3) in human HNSCC, which is consistent with previously study, we hypothesized that STAT3 may play an important role in maintaining HNSCC cancer stem cell properties
Summary
Head neck squamous cell carcinoma (HNSCC), which has more than 600,000 newly diagnosed cases per year and a high mortality rate, is the sixth most common cancer worldwide [1]. Despite significant advances in therapeutic approaches including reconstructive surgery, minimally invasive surgery, precisely targeted radiotherapy, chemotherapy, and monoclonal antibody therapy that have been achieved in the last three decades, little improvement has been achieved in the overall survival rates for HNSCC patients [2]. Accumulating evidence reveals that many types of tumors including HNSCC are frequently composed of heterogeneous cell types and that tumor initiation, growth, metastasis, chemoresistance, and recurrence after therapy are driven by a subpopulation of cells, termed cancer stem cells (CSC) or tumor-initiating cells [3]. The improvement of therapies targeting CSCs may raise hope for the treatment of HNSCC patient. Previous study identified CD44+ [7] and ALDH1+ [8] cell population as possible molecular biomarkers of cancer stemloid cells in HNSCC patient
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