Characterization and mechanisms of radioresistant lung squamous cell carcinoma cell lines

Author:

Pan Lifang1,Wu Qiong2,Wang Yuqing3,Ma Shenglin14,Zhang Shirong3ORCID

Affiliation:

1. Department of the Fourth Clinical Medical College Zhejiang Chinese Medical University Hangzhou China

2. Department of Integrated Chinese and Western Medicine The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) Hangzhou China

3. Department of Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou China

4. Department of Oncology, Affiliated Hangzhou Cancer Hospital Zhejiang University School of Medicine Hangzhou China

Abstract

AbstractBackgroundRadiotherapy is an important clinical treatment for patients with lung squamous cell carcinoma (LUSC), and resistance to radiotherapy is an important cause of recurrence and metastasis in LUSC. The aim of this study was to establish and explore the biological characteristics of radioresistant LUSC cells.Materials and methodsThe LUSC cell lines NCI‐H2170 and NCI‐H520 were irradiated (4 Gy × 15Fraction). Radiosensitivity, cell apoptosis, cell cycle, and DNA damage repair were measured by clonogenic survival assay, flow cytometry, immunofluorescence for γ‐H2AX foci, and Comet assay, respectively. Activation of p‐ATM(Ser1981), p‐CHK2(Th68), p‐DNA‐PKcs (Ser2056), and Ku70/Ku80 was measured by western blot. Proteomics was used to explore the differential genes and enriched signaling pathways between radioresistant cell lines and parental lines. In vivo nude mouse xenograft experiments further verified the feasibility of the radioresistant LUSC cell lines.ResultsAfter fractionated irradiation (total dose of 60 Gy), radioresistant cells had decreased radiosensitivity, increased G0/G1 phase arrest, enhanced DNA damage repair ability, and through the ATM/CHK2 and DNA‐PKcs/Ku70 pathways regulated double strands break. The upregulated differential genes in radioresistant cell lines were mainly enriched in biological pathways such as cell migration and extracellular matrix (ECM)‐receptor interaction. In vivo verification of decreased radiosensitivity of radioresistant cellsConclusionsRadioresistant LUSC cell lines were established by fractional radiotherapy, which regulates IR‐induced DNA damage repair through ATM/CHK2 and DNA‐PKcs/Ku70. Tandem Mass Tags (TMT) quantitative proteomics found that the biological process pathway of cell migration and ECM‐receptor interaction are upregulated in LUSC radioresistant cells.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Pulmonary and Respiratory Medicine,Oncology,General Medicine

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