J Cancer 2021; 12(4):976-987. doi:10.7150/jca.50234 This issue

Research Paper

JMJD8 Promotes Malignant Progression of Lung Cancer by Maintaining EGFR Stability and EGFR/PI3K/AKT Pathway Activation

Bo Zhang1, Yao Zhang1, Xizi Jiang1, Hongbo Su1, Qiongzi Wang1, Muli Wudu1, Jun Jiang1, Hongjiu Ren1, Yitong Xu1, Zongang Liu2, Xueshan Qiu1✉

1. Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.
2. Department of Thoracic Surgical, Shengjing Hospital Affiliated with China Medical University, Shenyang, China.

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Citation:
Zhang B, Zhang Y, Jiang X, Su H, Wang Q, Wudu M, Jiang J, Ren H, Xu Y, Liu Z, Qiu X. JMJD8 Promotes Malignant Progression of Lung Cancer by Maintaining EGFR Stability and EGFR/PI3K/AKT Pathway Activation. J Cancer 2021; 12(4):976-987. doi:10.7150/jca.50234. Available from https://www.jcancer.org/v12p0976.htm

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Abstract

JMJD8 is a JmjC domain-containing protein that has not been widely examined, despite its potential role in malignant tumor development. The underlying biological functions and molecular mechanisms of JMJD8 in non-small-cell lung cancer (NSCLC) remain unclear. Herein, we explored the relationship between JMJD8 and the activation of malignancy pathways in NSCLC. Immunohistochemical analyses revealed that high JMJD8 expression significantly correlated with cell differentiation and advanced TNM stages of NSCLC. The overexpression of JMJD8 promoted cell proliferation and invasion in vitro. Upon JMJD8 knockdown in lung cancer cell lines, cyclin B1, RhoA, RhoC, MMP9, and N-cadherin were down-regulated, and p21 and E-cadherin were conversely up-regulated. Key factors in the PI3K/AKT signaling pathway, such as p‑AKT, showed clear decreases in expression; additionally, the expression of epidermal growth factor receptor (EGFR), which functions upstream of PI3K, was altered. Co-immunoprecipitation experiments indicated that JMJD8 interacts with EGFR, and JMJD8 knockdown accelerated EGFR degradation. Our results suggested that JMJD8 functions as an oncogenic regulator in NSCLC. We found that JMJD8 promotes carcinogenic activity in NSCLC cells by facilitating EGFR stability, thereby activating the downstream PI3K/AKT signaling pathway. JMJD8 shows potential as a prognostic marker for lung cancer patients, providing a new target for therapeutic strategies.

Keywords: cell invasion, cell proliferation, epidermal growth factor receptor, JMJD8, PI3K/AKT