Candidate tumor suppressor gene IRF6 is involved in human breast cancer pathogenesis via modulating PI3K-regulatory subunit PIK3R2 expression
Candidate tumor suppressor gene IRF6 is involved in human breast cancer pathogenesis via modulating PI3K-regulatory subunit PIK3R2 expression
复制标题
候选抑癌基因IRF6通过调节PI3K调节亚基PIK3R2表达参与人类乳腺癌发病机制
DOI：
10.2147/cmar.s203060
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发表时间：
2019
影响因子：
3.3
通讯作者：
Huang Bi-Jun
中科院分区：
文献类型：
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作者：
Xu Hong-Fa;Huang Tie-Jun;Yang Qin;Xu Liang;Lin Fen;Lang Yan-Hong;Hu Hao;Peng Li-Xia;Meng Dong-Fang;Xie Yu-Jie;Tan Li;Qian Chao-Nan;Huang Bi-Jun
背景/目标：干扰素调节因子6（interferon regulatory factor 6，IRF 6）在某些肿瘤中的抑瘤作用已初步确立，但其在女性最常见的恶性肿瘤乳腺癌中的发病机制和潜在的分子机制仍知之甚少。研究方法：除了27例乳腺癌组织样本和31例非癌乳腺组织样本外，还使用成对的典型乳腺癌细胞系（高侵袭性和低侵袭性）来研究IRF 6的表达水平，并使用慢病毒介导的功能获得研究、短发夹RNA介导的功能丧失研究在体内和体外验证IRF 6在乳腺癌中的作用。接下来，我们进行了RNA-Seq分析，以确定IRF 6参与乳腺癌进展的分子机制。结果：我们的研究结果表明，IRF 6在高侵袭性乳腺癌细胞系中下调，但在低侵袭性乳腺癌细胞系中上调。功能分析显示，IRF 6表达升高可抑制细胞增殖和致瘤性，并增强细胞化疗敏感性。为了确定所涉及的分子机制，我们在乳腺癌细胞中进行了全基因组和京都基因和基因组百科全书（KEGG）分析，使用IRF 6过表达后基因表达谱的RNA测序。全基因组和KEGG分析表明，IRF 6可能介导PI 3 K调节亚基PIK 3R 2，进而调节PI 3 K/AKT通路以控制乳腺癌发病机制。结论：我们提供了IRF 6参与乳腺癌发病机制的第一个证据，发现IRF 6通过介导PIK 3R 2调节PI 3 K/AKT通路;表明IRF 6可以作为乳腺癌的潜在治疗方法。
Background/Aims: The tumor-suppressive functions of interferon regulatory factor 6 (IRF6) in some tumors have been preliminarily established, but its pathogenesis and underlying molecular mechanisms in breast cancer, the most common malignancy in women, remains poorly understood. Methods: Pairs of typical breast cancer cell lines (high- and low-aggressive) in addition to 27 breast cancer tissue samples and 31 non-cancerous breast tissues were used to investigate the expression level of IRF6 and Lentivirus-mediated gain-of-function studies, short hairpin RNA-mediated loss-of-function studies in vivo and in vitro were used to validate the role of IRF6 in breast cancer. Next, we performed RNA-Seq analysis to identify the molecular mechanisms of IRF6 involved in breast cancer progression. Results: Our findings showed that IRF6 was downregulated in highly invasive breast cancer cell lines but upregulated in poorly aggressive ones. Functional assays revealed that elevated IRF6 expression could suppress cell proliferation and tumorigenicity, and enhanced cellular chemotherapeutic sensitivity. To identify the molecular mechanisms involved, we performed a genome-wide and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis in breast cancer cells using RNA sequencing of gene expression profiles following the overexpression of IRF6. Genome-wide and KEGG analyses showed that IRF6 might mediate the PI3K-regulatory subunit PIK3R2, which in turn modulated the PI3K/AKT pathway to control breast cancer pathogenesis. Conclusion: We provide the first evidence of the involvement of IRF6 in breast cancer pathogenesis, which was found to modulate the PI3K/AKT pathway via mediating PIK3R2; indicating that IRF6 can be targeted as a potential therapeutic treatment of breast cancer.