FAM83D promotes epithelial-mesenchymal transition, invasion and cisplatin resistance through regulating the AKT/mTOR pathway in non-small-cell lung cancer
FAM83D promotes epithelial-mesenchymal transition, invasion and cisplatin resistance through regulating the AKT/mTOR pathway in non-small-cell lung cancer
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FAM83D 通过调节非小细胞肺癌中的 AKT/mTOR 通路促进上皮间质转化、侵袭和顺铂耐药。
DOI：
10.1007/s13402-020-00494-9
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发表时间：
2020-01
影响因子：
6.6
通讯作者：
Zhang Pengju
中科院分区：
文献类型：
--
作者：
Yin Chunli;Lin Xiaoyan;Wang Yige;Liu Xianqiang;Xiao Yi;Liu Jingchao;Snijders Antoine M.;Wei Guangwei;Mao Jian-Hua;Zhang Pengju
目的FAM 83 D被认为是多种人类肿瘤中的癌蛋白。然而，其在人类非小细胞肺癌（NSCLC）转移中的作用和作用方式及其对化疗的影响尚不清楚。方法采用qRT-PCR、Western blotting和免疫组织化学方法检测FAM 83 D在非小细胞肺癌（NSCLC）细胞和正常肺上皮细胞以及原发性非小细胞肺癌组织和相应的癌旁非癌组织中的表达。使用逆转录病毒或慢病毒载体，FAM 83 D在BEAS 2B细胞中稳定过表达或在A549和H1299细胞中沉默。采用MTT法和集落形成试验评价NSCLC细胞的生长能力。采用免疫印迹法和免疫荧光法评估上皮-间质转化（EMT）。使用划痕伤口愈合和Boyden室测定评估NSCLC细胞侵袭能力。NSCLC细胞生存能力顺铂治疗进行了评估，使用MTT法在体外和异种移植模型在vivo.ResultsWe发现，FAM 83 D表达水平显着升高，在NSCLC细胞和组织，与肿瘤进展和预后不良呈正相关。外源性FAM 83 D过表达促进NSCLC细胞增殖、EMT和侵袭，而FAM 83 D沉默抑制NSCLC细胞增殖、EMT和侵袭。FAM 83 D沉默也降低顺铂耐药性。一致地，我们发现具有低FAM 83 D表达的NSCLC患者从化疗中获益最多。在机制上，我们发现FAM 83 D激活蛋白激酶B（AKT）/哺乳动物雷帕霉素靶（mTOR）途径。无论是AKT或mTOR抑制剂的药物治疗逆转FAM 83 D诱导的肿瘤发生phenotypes.ConclusionsOur结果表明，FAM 83 D在非小细胞肺癌的发展中的作用。此外，我们的结果表明，表现出FAM 83 D过表达的NSCLC患者可能受益于AKT和/或mTOR抑制剂治疗。
PurposeFAM83D has been proposed to act as an oncoprotein in several types of human cancer. Its role and mode of action in human non-small cell lung cancer (NSCLC) metastasis and its impact on chemotherapy are as yet, however, poorly understood.MethodsFAM83D expression was measured in NSCLC cells and normal lung epithelial cells, as well as in primary NSCLC tissues and corresponding adjacent non-cancerous tissues, using qRT-PCR, Western blotting and immunohistochemistry. FAM83D was stably overexpressed in BEAS2B cells or silenced in A549 and H1299 cells using retroviral or lentiviral vectors. The growth capacity of NSCLC cells was evaluated using MTT and colony formation assays. Epithelial-mesenchymal transition (EMT) was assessed using Western blotting and immunofluorescence. NSCLC cell invasive capacities were assessed using scratch wound healing and Boyden chamber assays. NSCLC cell viability in response to cisplatin treatment was assessed using MTT assays in vitro and a xenograft model in vivo.ResultsWe found that FAM83D expression levels were significantly elevated in NSCLC cells and tissues, and positively correlated with tumor progression and a poor prognosis. Exogenous FAM83D overexpression promoted, while FAM83D silencing inhibited NSCLC cell proliferation, EMT and invasion. FAM83D silencing also reduced cisplatin resistance. Concordantly, we found that NSCLC patients with a low FAM83D expression benefited most from chemotherapy. Mechanistically, we found that FAM83D activated the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Pharmacological treatment with either AKT or mTOR inhibitors reverted FAM83D-induced tumorigenic phenotypes.ConclusionsOur results suggest a role of FAM83D in NSCLC development. In addition, our results indicate that NSCLC patients exhibiting FAM83D overexpression are likely to benefit from AKT and/or mTOR inhibitor treatment.
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