Zhou Ji, Peng Yang, Gao Ying-Chun, Chen Tai-Yu, Li Peng-Cheng, Xu Ke, Liu Tao, Ren Tao
Health Management Centre, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, 278 Baoguang St, Xindu Distr, Chengdu, 610500, Sichuan, China.
Hematology Department, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China.
Cancer Cell Int. 2021 Jul 3;21(1):338. doi: 10.1186/s12935-021-02054-z.
Some driver oncogenes are still unknown in non-small-cell lung cancer (NSCLC). DNAJC19, a major component of the translocation machinery of mitochondrial membranes, is a disease-associated protein. Herein, we report the role of DNAJC19 in NSCLC cell growth and metastasis.
Immunohistochemistry (IHC) was performed to investigate DNAJC19 expression in NSCLC clinical samples. For knockdown or overexpression assays in A549 or NCI-H1299 lung cancer cells, lentiviral vectors were used. After assessment of cell functions, DNAJC19-knockdown A549 cells were further applied to establish mouse xenograft and metastasis tumor models. Assessments based on the RNA-seq data, western blotting, PCR and IHC were performed for the mechanistic study.
Expression of DNAJC19 was higher in tumors than in noncancerous adjacent tissues. Survival analysis indicated that low DNAJC19 levels were correlated with an increased progression-free survival rate. ShRNA-mediated knockdown of DNAJC19 markedly inhibited cell growth, viability, migration and invasion. Moreover, RNA-seq analysis revealed that the PI3K/AKT signaling pathway was involved in molecular events when A549 cells were treated with shDNAJC19. In addition, DNAJC19 knockdown decreased PI3Kp85a, AKT and p-AKT expression in A549 cells, and cellular functions were greatly rescued in DNAJC19-knockdown A549 cells by ectopic overexpression of AKT. Furthermore, tumor xenograft growth and lung metastasis were markedly repressed in the shDNAJC19 group compared to the control group. As expected, the expression levels of DNAJC19, PI3K and AKT in xenograft mouse samples were also lower in the shDNAJC19 group than in the shCtrl group.
DNAJC19 greatly promotes NSCLC cell growth and lung metastasis by regulating PI3K/AKT signaling, providing a novel therapeutic target for treating NSCLC patients.
在非小细胞肺癌（NSCLC）中，一些驱动癌基因仍不明确。DNAJC19是线粒体膜转运机制的主要组成部分，是一种与疾病相关的蛋白质。在此，我们报告DNAJC19在NSCLC细胞生长和转移中的作用。
采用免疫组织化学（IHC）检测NSCLC临床样本中DNAJC19的表达。在A549或NCI-H1299肺癌细胞中进行敲低或过表达实验时，使用了慢病毒载体。在评估细胞功能后，将DNAJC19敲低的A549细胞进一步用于建立小鼠异种移植和转移瘤模型。基于RNA测序数据、蛋白质免疫印迹、聚合酶链反应和免疫组织化学进行机制研究评估。
DNAJC19在肿瘤中的表达高于癌旁非肿瘤组织。生存分析表明，低水平的DNAJC19与无进展生存率增加相关。短发夹RNA（shRNA）介导的DNAJC19敲低显著抑制细胞生长、活力、迁移和侵袭。此外，RNA测序分析显示，当用shDNAJC19处理A549细胞时，PI3K/AKT信号通路参与了分子事件。此外，DNAJC19敲低降低了A549细胞中PI3Kp85a、AKT和磷酸化AKT的表达，通过异位过表达AKT，DNAJC19敲低的A549细胞的细胞功能得到了极大挽救。此外，与对照组相比，shDNAJC19组的肿瘤异种移植生长和肺转移明显受到抑制。正如预期的那样，shDNAJC19组异种移植小鼠样本中DNAJC19、PI3K和AKT的表达水平也低于shCtrl组。
DNAJC19通过调节PI3K/AKT信号通路极大地促进NSCLC细胞生长和肺转移，为治疗NSCLC患者提供了一个新的治疗靶点。
