The molecular and clinical verification of therapeutic resistance via the p38 MAPK-Hsp27 axis in lung cancer

被引：36

作者：

Liu, Chia-Lin ^{[1
]}

Chen, Su-Feng ^{[2
]}

Wu, Min-Zu ^{[3
]}

Jao, Shu-Wen ^{[4
,5
,6
]}

Lin, Yaoh-Shiang ^{[7
]}

Yang, Chin-Yuh ^{[8
,9
]}

Lee, Tsai-Yu ^{[4
,5
,6
]}

Wen, Lian-Wu ^{[10
,11
]}

Lan, Guo-Lun ^{[10
,11
]}

Nieh, Shin ^{[1
,10
,11
]}

机构：

[1] Natl Def Med Ctr, Grad Inst Life Sci, Taipei, Taiwan

[2] China Med Univ, Dept Dent Hyg, Taichung, Taiwan

[3] Salk Inst Biol Studies, Gene Express Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA

[4] Natl Yang Ming Univ, Inst Environm & Occupat Hlth Sci, Sch Med, Taipei 112, Taiwan

[5] Natl Yang Ming Univ, Dept Surg, Div Colon & Rectum Surg, Taipei 112, Taiwan

[6] Natl Def Med Ctr, Triserv Gen Hosp, Songshan Branch, Taipei, Taiwan

[7] Kaohsiung Vet Gen Hosp, Dept Otolaryngol Head & Neck Surg, Kaohsiung, Taiwan

[8] Cheng Hsin Hosp, Dept Dent, Taipei, Taiwan

[9] Taipei Med Univ, Taipei, Taiwan

[10] Natl Def Med Ctr, Dept Pathol, Taipei, Taiwan

[11] Triserv Gen Hosp, Taipei, Taiwan

来源：

ONCOTARGET | 2016年 / 7卷 / 12期

关键词：

cisplatin-based chemotherapy; drug-resistant sphere; lung cancer; heat shock protein 27; treatment strategy; HEAT-SHOCK PROTEINS; TUMOR STEM-CELLS; DRUG-RESISTANCE; SIDE-POPULATION; EXPRESSION; CISPLATIN; HSP27; PHOSPHORYLATION; CARCINOMA; STRESS;

D O I：

10.18632/oncotarget.7306

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Treatment failure followed by relapse and metastasis in patients with non-small cell lung cancer is often the result of acquired resistance to cisplatin-based chemotherapy. A cancer stem cell (CSC)-mediated anti-apoptotic phenomenon is responsible for the development of drug resistance. The underlying molecular mechanism related to cisplatin resistance is still controversial, and a new strategy is needed to counteract cisplatin resistance. We used a nonadhesive culture system to generate drug-resistant spheres (DRSPs) derived from cisplatin-resistant H23 lung cancer cells. The expressions of drug-resistance genes, properties of CSCs, and markers of anti-apoptotic proteins were compared between control cells and DRSPs. DRSPs exhibited upregulation of cisplatin resistance-related genes. Gradual morphological alterations showing epithelial-to-mesenchymal transition phenomenon and increased invasion and migration abilities were seen during induction of DRSPs. Compared with control cells, DRSPs displayed increased CSC and anti-apoptotic properties, greater resistance to cisplatin, and overexpression of p-Hsp27 via activation of p38 MAPK signaling. Knockdown of Hsp27 or p38 decreased cisplatin resistance and increased apoptosis in DRSPs. Clinical studies confirmed that the expression of p-Hsp27 was closely associated with prognosis. Overexpression of p-Hsp27 was usually detected in advanced-stage patients with lung cancer and indicated short survival. Summary: DRSPs were useful for investigating drug resistance and may provide a practical model for studying the crucial role of p-Hsp27 in the p38 MAPK-Hsp27 axis in CSC-mediated cisplatin resistance. Targeting this axis using siRNA Hsp27 may provide a treatment strategy to improve prognosis and prolong survival in lung cancer patients.

引用

页码：14279 / 14290

页数：12

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