Research Papers:

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

Chia-Lin Liu _, Su-Feng Chen, Min-Zu Wu, Shu-Wen Jao, Yaoh-Shiang Lin, Chin-Yuh Yang, Tsai-Yu Lee, Lian-Wu Wen, Guo-Lun Lan and Shin Nieh

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Oncotarget. 2016; 7:14279-14290. https://doi.org/10.18632/oncotarget.7306

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Chia-Lin Liu1, Su-Feng Chen2,*, Min-Zu Wu3, Shu-Wen Jao4, Yaoh-Shiang Lin5, Chin-Yuh Yang6, Tsai-Yu Lee4, Lian-Wu Wen7, Guo-Lun Lan7, Shin Nieh1,7,*

1Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan

2Department of Dental Hygiene, China Medical University, Taichung, Taiwan

3Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA

4Institute of Environmental and Occupational Health Sciences, School of Medicine & Division of Colon and Rectum Surgery, Department of Surgery, National Yang-Ming University & National Defense Medical Center, Tri-Service General Hospital Songshan Branch, Taipei, Taiwan

5Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Dentistry, Cheng Hsin Hospital & Taipei Medical University, Taipei, Taiwan

7Department of Pathology, National Defense Medical Center & Tri-Service General Hospital, Taipei, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Shin Nieh, e-mail: [email protected]

Su-Feng Chen, e-mail: [email protected]

Keywords: cisplatin-based chemotherapy, drug-resistant sphere, lung cancer, heat shock protein 27, treatment strategy

Received: November 17, 2015     Accepted: January 29, 2016     Published: February 10, 2016


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.

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