TNFAIP8 promotes the proliferation and cisplatin chemoresistance of non-small cell lung cancer through MDM2/p53 pathway.
TNFAIP8 promotes the proliferation and cisplatin chemoresistance of non-small cell lung cancer through MDM2/p53 pathway.
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TNFAIP8通过MDM2/p53通路促进非小细胞肺癌的增殖和顺铂化疗耐药。
DOI：
10.1186/s12964-018-0254-x
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发表时间：
2018-07-31
期刊：
影响因子：
--
通讯作者：
Cai L
中科院分区：
文献类型：
--
作者：
Xing Y;Liu Y;Liu T;Meng Q;Lu H;Liu W;Hu J;Li C;Cao M;Yan S;Huang J;Wang T;Cai L
非小细胞肺癌（non-small cell lung cancer，NSCLC）对化疗药物的高度难治性是导致其预后不良的重要因素。最近的研究表明，肿瘤坏死因子α诱导蛋白8（TNFAIP 8）参与细胞的各种生物学和病理学过程，但其在从癌症发展到耐药性过程中的潜在机制尚未完全阐明。通过免疫组织化学（IHC）检查临床NSCLC样品中的TNFAIP 8表达。采用倾向评分匹配调整患者特征后，根据TNFAIP 8水平进行Kaplan-Meier分析和考克斯回归分析，比较患者的生存率。使用具有TNFAIP 8特异性shRNA的慢病毒转染来建立稳定的TNFAIP 8敲低（TNFAIP 8 KD）NCI-H460、A549和顺式二氨二氯铂II抗性A549（A549/cDDP）细胞系。CCK-8法检测细胞增殖活性。流式细胞仪检测细胞周期。基因芯片分析显示TNFAIP 8 KD调控的多种途径。我们发现TNFAIP 8高表达与NSCLC患者的晚期pT分期、晚期pTNM分期、淋巴结转移和不良生存率相关。TNFAIP 8 shRNA降低体外癌细胞增殖和体内肿瘤生长。此外，TNFAIP 8 KD在体外和体内增加NSCLC细胞对顺铂的敏感性。相反，TNFAIP 8的上调促进了NSCLC细胞的增殖和对顺铂的耐药性。 TNFAIP 8影响涉及MDM 2/p53途径的癌症进展途径。事实上，我们观察到TNFAIP 8 KD介导MDM 2下调和p53泛素化，从而减少p53蛋白的降解。shRNA p53逆转了TNFAIP 8 shRNA介导的对细胞增殖、细胞周期、顺铂敏感性和DNA修复基因RAD 51表达水平的调节。我们的工作揭示了TNFAIP 8在NSCLC增殖和顺铂耐药性中迄今未被认识到的作用，该作用是通过MDM 2/p53途径介导的。这些发现可能为逆转TNFAIP 8高表达的NSCLC患者的顺铂耐药性提供潜在的治疗靶点。本文的在线版本（10.1186/s12964-018-0254-x）包含补充材料，可供授权用户使用。
The highly refractory nature of non-small cell lung cancer (NSCLC) to chemotherapeutic drugs is an important factor resulting in its poor prognosis. Recent studies have revealed that tumour necrosis factor alpha-induced protein 8 (TNFAIP8) is involved in various biological and pathological processes of cells, but their underlying mechanisms in processes ranging from cancer development to drug resistance have not been fully elucidated. TNFAIP8 expression in clinical NSCLC samples was examined through immunohistochemistry (IHC). After adjusting for patients’ characteristics with propensity score matching, Kaplan-Meier analysis and Cox regression analysis were performed for comparison of patients’ survival according to the TNFAIP8 level. Lentiviral transfection with TNFAIP8-specific shRNAs was used to establish stable TNFAIP8 knockdown (TNFAIP8 KD) NCI-H460, A549 and cis-diamminedichloroplatinum II resistant A549 (A549/cDDP) cell lines. Cell proliferation and viability were assessed by CCK-8 assay. Cell cycle was examined by flow cytometry. Multiple pathways regulated by TNFAIP8 KD were revealed by microarray analysis. We found that high TNFAIP8 expression was associated with advanced pT stage, advanced pTNM stage, lymph node metastasis and unfavourable survival in NSCLC patients. TNFAIP8 shRNAs reduced in vitro cancer cell proliferation and in vivo tumor growth. Additionally, TNFAIP8 KD increased the sensitivity of NSCLC cells to cisplatin in vitro and in vivo. Conversely, up-regulation of TNFAIP8 promoted the proliferation and drug resistance to cisplatin of NSCLC cells. TNFAIP8 influences cancer progression pathways involving the MDM2/p53 pathway. Indeed, we observed that TNFAIP8 KD mediated the MDM2 downregulation and the p53 ubiquitination, thereby decreasing the degradation of p53 protein. shRNA p53 reversed TNFAIP8 shRNA-mediated regulation of cell proliferation, cell cycle, cisplatin sensitivity, and expression levels of RAD51, a DNA repair gene. Our work uncovers a hitherto unappreciated role of TNFAIP8 in NSCLC proliferation and cisplatin chemoresistance that is mediated through the MDM2/p53 pathway. These findings might offer potential therapeutic targets for reversing cisplatin resistance in NSCLC patients with high TNFAIP8 expression. The online version of this article (10.1186/s12964-018-0254-x) contains supplementary material, which is available to authorized users.
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影响因子：
--
作者：
Liu, Tianbo;Gao, Hongyu;Lou, Ge
通讯作者：
Lou, Ge
影响因子：
2.4
作者：
Eisele, L.;Klein-Hitpass, L.;Flasshove, M.
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影响因子：
3.3
作者：
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影响因子：
8.8
作者：
Liu, T.;Gao, H.;Chen, X.;Lou, G.;Gu, L.;Yang, M.;Xia, B.;Yin, H.
通讯作者：
Yin, H.
影响因子：
8
作者：
Kumar, D;Gokhale, P;Kasid, U
通讯作者：
Kasid, U