Ma Hong-Yu, Li Yang, Yin Hui-Zi, Yin Hang, Qu Yuan-Yuan, Xu Qing-Yong
Department of Breast Radiotherapy, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, P.R. China.
Mol Ther Nucleic Acids. 2020 Sep 26;22:640-656. doi: 10.1016/j.omtn.2020.09.025. eCollection 2020 Dec 4.
Tumor necrosis factor alpha-induced protein 8 (TNFAIP8) is implicated in the tumor progression and prognosis of triple-negative breast cancer (TNBC), but the detailed regulatory mechanism of TNFAIP8 in cisplatin tolerance in TNBC has not yet been investigated. TNFAIP8 was evidently upregulated in TNBC tumor tissues and cell lines. Knocking down TNFAIP8 led to impaired proliferation and elevated apoptosis of TNBC cells upon cisplatin (DDP) treatment. Mechanistic studies revealed that TNFAIP8 repressed the expression of p53 and p53-promoted microRNA (miR)-205-5p; moreover, miR-205-5p targeted multiple genes required for the cell cycle and repressed Akt phosphorylation, which thus inhibited the proliferation of TNBC cells. In addition, silencing of TNFAIP8 led to the upregulation of miR-205-5p and the restraint of the TRAF2-NF-κB pathway, which thus enhanced the suppressive effects of DDP on tumor growth in nude mice. This study revealed that TNFAIP8 was essential in the DDP tolerance formation of TNBC cells by reducing p53-promoted miR-205-5p expression. Thus, targeting TNFAIP8 might become a promising strategy to suppress TNBC progression.
肿瘤坏死因子α诱导蛋白8（TNFAIP8）与三阴性乳腺癌（TNBC）的肿瘤进展和预后有关，但TNFAIP8在TNBC顺铂耐受性中的详细调控机制尚未得到研究。TNFAIP8在TNBC肿瘤组织和细胞系中明显上调。敲低TNFAIP8会导致顺铂（DDP）处理后TNBC细胞的增殖受损和凋亡增加。机制研究表明，TNFAIP8抑制p53和p53促进的微小RNA（miR）-205-5p的表达；此外，miR-205-5p靶向细胞周期所需的多个基因并抑制Akt磷酸化，从而抑制TNBC细胞的增殖。此外，沉默TNFAIP8会导致miR-205-5p上调并抑制TRAF2-NF-κB途径，从而增强DDP对裸鼠肿瘤生长的抑制作用。这项研究表明，TNFAIP8通过降低p53促进的miR-205-5p表达在TNBC细胞的DDP耐受性形成中至关重要。因此，靶向TNFAIP8可能成为抑制TNBC进展的一种有前景的策略。
