Inhibition of Kelch-like epichlorohydrin-related protein 1 promotes the progression and drug resistance of lung adenocarcinoma

Hong Gao; Peipei Tang; Kejie Ni; Lun Zhu; Song Chen; Yulong Zheng; Yufeng Wan

doi:10.7717/peerj.11908

Inhibition of Kelch-like epichlorohydrin-related protein 1 promotes the progression and drug resistance of lung adenocarcinoma

PeerJ. 2021 Aug 19:9:e11908. doi: 10.7717/peerj.11908. eCollection 2021.

Authors

Hong Gao^#¹, Peipei Tang^#², Kejie Ni¹, Lun Zhu³, Song Chen², Yulong Zheng¹, Yufeng Wan¹

Affiliations

¹ Department of Respiratory Diseases, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China.
² Institute of Medicinal Biotechnology, Jiangsu College of Nursing, Huai'an, Jiangsu, China.
³ Department of Pathology, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China.

^# Contributed equally.

Abstract

Background: Lung cancer is a common malignant carcinoma of respiratory system with high morbidity and mortality. Kelch-like epichlorohydrin-related protein 1 (Keap1), a member of the BTB-Kelch protein family, has been reported as an important molecule in several cancers. However, its potential role in tumor is still controversial. Here we aim to clarify the effect of Keap1 on the biological characteristics and chemotherapy resistance in lung adenocarcinoma (LUAD).

Methods: Immunohistochemistry was conducted to compare Keap1 expression in lung adenocarcinoma tissues and matched non-cancerous tissues, and the correlation between Keap1 expression and clinicopathological features was analyzed. Subsequently, the stable A549 and H1299 cell lines with Keap1 knockdown or overexpression were constructed using lentivirus. The roles of Keap1 on the cell proliferation, migration, invasion and drug resistance were investigated by colony formation assay, cell proliferation assay, wound scratch test, transwell invasion assay and drug sensitivity assay, respectively.

Results: Keap1 was lowly expressed in tumor tissues compared to matched non-cancerous tissues, and its expression was correlated with TNM stage and lymph node metastasis. Early stage (I) tumors without lymph node metastasis had higher levels of Keap1 expression compared with late-stage tumors (II, III) with the presence of lymphatic metastasis. Colony formation assays showed that Keap1 knockdown promoted the proliferation of A549 and H1299 cells, and the cell growth curves further confirmed this feature. In contrast, wound scratch and transwell invasion experiments showed that Keap1 overexpression inhibited cell migration and invasive malignancy. The IC50 for cisplatin and paclitaxel were significantly increased by Keap1 knockdown in A549 and H1299 cell lines.

Conclusion: Keap1 knockdown promotes tumor cell growth, proliferation, invasion, metastasis and chemotherapy resistance in LUAD. It may be a potential tumor marker to guide the staging and treatment of lung cancer.

Keywords: Drug resistance; Keap1; LUAD; Progression.

Grants and funding

The current study was supported by grants from the Natural Science Foundation of Huaian, Jiangsu, China (No. HAB202073 and No. HABZ201808). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.