DNAJB4 suppresses breast cancer progression and promotes tumor immunity by regulating the Hippo signaling pathway,Hormones and Cancer

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DNAJB4 suppresses breast cancer progression and promotes tumor immunity by regulating the Hippo signaling pathway
Hormones and Cancer Pub Date : 2023-08-07 , DOI: 10.1007/s12672-023-00762-8
Yanru Chen _{1,

2} , Jingjia Li _{1,

2} , Lulan Pu _{1,

2} , Jinghua Hu _{1,

2} , Lingyu Fang _{1,

2} , Fangfang Zhou _{1,

2} , Hongying Zhang ₃ , Yi Yang _{1,

2} , Xinxin Rong _{1,

2} , Shishan Deng _{1,

2} , Lingmi Hou _{1,

2}

Affiliation

Purpose

Breast cancer is the most common cancer worldwide. Low DNAJB4 expression levels are strongly correlated with poor prognosis in breast cancer patients. However, the molecular mechanism by which DNAJB4 regulates breast cancer progression is unclear.

Methods

The expression of DNAJB4 was validated in human breast cancer tissues, normal human breast tissues, and breast cancer cell lines. CCK-8, colony-forming, and wound healing assays were used to assess the biological effect of DNAJB4 overexpression on cell proliferation and migration in MCF-7 cell lines. Bioinformatic analysis was used to identify the DNAJB4 related pathways in breast cancer. Epithelial-mesenchymal transition (EMT)-related biomarkers and Hippo pathway components were quantified by Western blots. Luciferase and Western blot assays were used to validate which miRNA regulates DNAJB4. In addition, the effects of DNAJB4 on in vivo tumor growth were assessed in xenograft models.

Results

DNAJB4 was expressed at low levels in human breast cancer tissues and breast cancer cell lines and correlated with poor prognosis. DNAJB4 overexpression significantly inhibited cell proliferation and migration in vitro by activating the Hippo pathway. The dual-luciferase assay showed that hsa-miR-183-5p targeted DNAJB4. Moreover, the effects of DNAJB4 could be reversed by miR-183-5p. In addition, the expression of DNAJB4 was strongly correlated with immune infiltration levels. Notably, DNAJB4 overexpression markedly enhanced CD4 + and CD8 + T cells and reduced PD-L1 levels in 4T1 tumors via the Hippo pathway, which retarded tumor growth in a subcutaneous xenograft tumor mouse model of 4T1 cells.

Conclusions

The present study demonstrated that DNAJB4 overexpression inhibited the malignant biological behavior of breast cancer by regulating the Hippo pathway and tumor immunosuppressive environment.

中文翻译：

DNAJB4通过调节Hippo信号通路抑制乳腺癌进展并促进肿瘤免疫

目的

乳腺癌是全世界最常见的癌症。DNAJB4 低表达水平与乳腺癌患者的不良预后密切相关。然而，DNAJB4 调节乳腺癌进展的分子机制尚不清楚。

方法

DNAJB4的表达在人乳腺癌组织、正常人乳腺组织和乳腺癌细胞系中得到验证。使用 CCK-8、集落形成和伤口愈合测定来评估 DNAJB4 过表达对 MCF-7 细胞系中细胞增殖和迁移的生物学效应。利用生物信息学分析来鉴定乳腺癌中 DNAJB4 相关通路。通过蛋白质印迹对上皮间质转化 (EMT) 相关生物标志物和 Hippo 通路成分进行定量。使用荧光素酶和蛋白质印迹测定来验证哪些 miRNA 调节 DNAJB4。此外，在异种移植模型中评估了 DNAJB4 对体内肿瘤生长的影响。

结果

DNAJB4 在人类乳腺癌组织和乳腺癌细胞系中低水平表达，与不良预后相关。DNAJB4过表达通过激活Hippo途径显着抑制体外细胞增殖和迁移。双荧光素酶测定显示 hsa-miR-183-5p 靶向 DNAJB4。此外，DNAJB4 的作用可以被 miR-183-5p 逆转。此外，DNAJB4的表达与免疫浸润水平密切相关。值得注意的是，DNAJB4 过表达通过 Hippo 途径显着增强了 4T1 肿瘤中的 CD4 + 和 CD8 + T 细胞并降低了 PD-L1 水平，从而延缓了 4T1 细胞皮下异种移植肿瘤小鼠模型中的肿瘤生长。