Sex Determining Region Y Box 9 Induces Chemoresistance in Pancreatic Cancer Cells by Induction of Putative Cancer Stem Cell Characteristics and Its High Expression Predicts Poor Prognosis
Sex Determining Region Y Box 9 Induces Chemoresistance in Pancreatic Cancer Cells by Induction of Putative Cancer Stem Cell Characteristics and Its High Expression Predicts Poor Prognosis
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DOI：
10.1097/mpa.0000000000000945
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发表时间：
2017-11-01
期刊：
影响因子：
2.9
通讯作者：
Miyazaki, Masaru
中科院分区：
文献类型：
--
作者：
Higashihara, Taku;Yoshitomi, Hideyuki;Miyazaki, Masaru
目的：胰腺癌是一种高度耐药的肿瘤，其机制尚不清楚。性别决定区Y盒9（Sox 9）是一种转录因子，在胰腺器官发生过程中对多能细胞的维持起重要作用。本研究旨在探讨Sox 9在胰腺癌中的作用。Sox 9的siRNA或shRNA抑制化疗敏感性，球体形成，干细胞标志物的表达，并在体内肿瘤形成率的影响，使用胰腺癌细胞株进行了检查。具有高Sox 9表达的细胞（PANC-1，Capan-1）显示出比具有低Sox 9表达的细胞（BxPC-3，MIA PaCa-2）更强的对吉西他滨的化学抗性。siRNA抑制Sox 9后PANC-1细胞对化疗药物的敏感性恢复（P < 0.05）。Sox 9抑制剂降低了球体形成率和CD 44（高）CD 24（高）细胞的比例。结论：Sox 9基因通过诱导胰腺癌细胞的干细胞性，在胰腺癌耐药中起重要作用。
Objectives: Pancreatic cancer is a highly chemoresistant tumor and underlying mechanisms are not well understood. Sex determining region Y box 9 (Sox9) is a transcription factor playing important roles on maintenance of pluripotent cells during pancreatic organogenesis. The purpose of this study is to evaluate the roles of Sox9 in pancreatic cancer.Methods: The Sox9 expression was evaluated by immunohistochemical analysis. Effects of Sox9 inhibition by siRNA or shRNA on chemosensitivity, sphere formation, stem cell markers expression, and in vivo tumor formation rate were examined using pancreatic cancer cell lines.Results: High expression of Sox9 in pancreatic cancer tissue is correlated with poor prognosis (P = 0.011). Cells with high Sox9 expression (PANC-1, Capan-1) showed stronger chemoresistance to Gemcitabine than cells with low Sox9 expression (BxPC-3, MIA PaCa-2). The chemosensitivity in PANC-1 was recovered by suppressing Sox9 using siRNA (P < 0.05). Both sphere formation rate and the proportion of CD44(high)CD24(high) cells were decreased by Sox9 inhibition. Tumor formation rate of Tet-on inducible Sox9 shRNA-transfected PANC-1 cells in KSN/Slc nude mice was decreased by induction of shRNA with doxycycline feeding (P < 0.05).Conclusion: Sox9 plays an important role in chemoresistance by the induction of stemness in pancreatic cancer cells.