Zhang Bo, Zhang Yao, Jiang Xizi, Su Hongbo, Wang Qiongzi, Wudu Muli, Jiang Jun, Ren Hongjiu, Xu Yitong, Liu Zongang, Qiu Xueshan
Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.
Department of Thoracic Surgical, Shengjing Hospital Affiliated with China Medical University, Shenyang, China.
J Cancer. 2021 Jan 1;12(4):976-987. doi: 10.7150/jca.50234. eCollection 2021.
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 . 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.
JMJD8是一种含JmjC结构域的蛋白质，尽管其在恶性肿瘤发展中具有潜在作用，但尚未得到广泛研究。JMJD8在非小细胞肺癌（NSCLC）中的潜在生物学功能和分子机制仍不清楚。在此，我们探讨了JMJD8与NSCLC中恶性肿瘤通路激活之间的关系。免疫组织化学分析显示，JMJD8高表达与NSCLC的细胞分化和晚期TNM分期显著相关。JMJD8的过表达促进细胞增殖和侵袭。在肺癌细胞系中敲低JMJD8后，细胞周期蛋白B1、RhoA、RhoC、基质金属蛋白酶9和N-钙黏蛋白下调，而p21和E-钙黏蛋白则相反地上调。PI3K/AKT信号通路中的关键因子，如磷酸化AKT（p-AKT），表达明显降低；此外，在PI3K上游起作用的表皮生长因子受体（EGFR）的表达也发生了改变。免疫共沉淀实验表明，JMJD8与EGFR相互作用，敲低JMJD8可加速EGFR降解。我们的结果表明，JMJD8在NSCLC中作为一种致癌调节因子发挥作用。我们发现，JMJD8通过促进EGFR稳定性来促进NSCLC细胞的致癌活性，从而激活下游的PI3K/AKT信号通路。JMJD8显示出作为肺癌患者预后标志物的潜力，为治疗策略提供了新的靶点。
