信号转导与转录激活因子3（STAT3）阻断通过根除头颈部类干细胞样癌细胞增强传统化疗药物的疗效。

STAT3 blockade enhances the efficacy of conventional chemotherapeutic agents by eradicating head neck stemloid cancer cell.

作者信息

Bu Lin-Lin, Zhao Zhi-Li, Liu Jian-Feng, Ma Si-Rui, Huang Cong-Fa, Liu Bing, Zhang Wen-Feng, Sun Zhi-Jun

机构信息

The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, Wuhan, China.

Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.

出版信息

Oncotarget. 2015 Dec 8;6(39):41944-58. doi: 10.18632/oncotarget.5986.

DOI:10.18632/oncotarget.5986

PMID:26556875

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4747200/

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.

摘要

信号转导子和转录激活子3（STAT3）与癌症干细胞（CSCs）作为治疗靶点已备受关注，因为有证据表明它们可能是肿瘤起始和放化疗耐药的病因根源。在此，我们研究了头颈部鳞状细胞癌（HNSCC）中STAT3的高磷酸化状态（p-STAT3）及其与自我更新标志物的相关性。发现在化疗后的HNSCC组织中p-STAT3的过表达有所增加。我们表明，阻断p-STAT3可在体外消除具有CSCs特征的实体瘤细胞和侧群（SP）细胞。使用小分子S3I-201抑制p-STAT3可显著延迟小鼠自发性HNSCC的肿瘤发生。将p-STAT3阻断与细胞毒性药物顺铂、多西他赛、5-氟尿嘧啶（TPF）联合使用可增强体外和体内的抗肿瘤作用，减少肿瘤球形成和SP细胞。综上所述，我们的结果表明，阻断p-STAT3与传统化疗药物联合使用可通过改善HNSCC中CSCs的清除来提高疗效。