NCALD affects drug resistance and prognosis by acting as a ceRNA of CX3CL1 in ovarian cancer
NCALD affects drug resistance and prognosis by acting as a ceRNA of CX3CL1 in ovarian cancer
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NCALD 通过作为卵巢癌 CX3CL1 的 ceRNA 影响耐药性和预后。
DOI：
10.1002/jcb.29670
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发表时间：
2020-02-07
影响因子：
4
通讯作者：
Liu, Xia
中科院分区：
文献类型：
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作者：
Dong, Caihua;Yin, Fuqiang;Liu, Xia
耐药性是卵巢癌（OC）治疗中不可逾越的障碍，通常与不良结局相关。因此，迫切需要发现控制耐药性和生存的新因素。神经钙蛋白δ（NCALD）和癌症耐药性之间的关系知之甚少。在这里，我们揭示了NCALD信使RNA的表达，可能是由DNA甲基化和microRNA调控，在至少三个独立的微阵列中显著下调，涵盖633例卵巢癌和16例正常对照，其中包括癌症基因组图谱（TCGA）卵巢队列。在TCGA队列的亚组中，NCALD在90个铂耐药组织中受到抑制，而在197个敏感组织中受到抑制。这与定量逆转录聚合酶链反应结果相一致，该结果揭示了与对照相比，卡铂耐药的SKOV 3和HeyA 8 OC细胞中的基因下调。根据涵盖1815例OC患者的Kaplan-Meier检验，NCALD低表达预测1656例患者亚组的总生存期（OS）较差，1435例患者的无进展生存期（PFS）较差，782例患者的进展后生存期（PPS）较差。全面的生物信息学分析强烈暗示NCALD可能通过与CX 3CL 1和肿瘤免疫微环境竞争内源性RNA（ceRNA）相互作用来调节耐药性。NCALD在包括OC在内的21种不同癌症中充当CX 3CL 1的ceRNA。这两个基因与肿瘤纯度呈负相关，与OC中中性粒细胞和树突状细胞的浸润水平呈正相关。在1815例OC患者中，NCALD和CX 3CL 1的联合低表达显示出比任何单独检测的基因更好的OS、PFS和PPS预后潜力。总之，NCALD作为CX 3CL 1的ceRNA，其下调可能影响OC的耐药性和预后。因此，NCALD可能成为一个新的抗肿瘤治疗靶点和一个新的预测OC生存的生物标志物。
Drug resistance, an impenetrable barrier in the treatment of ovarian cancer (OC), is often associated with poor outcomes. Hence, it is urgent to discover new factors controlling drug resistance and survival. The association between neurocalcin delta (NCALD) and cancer drug resistance is poorly understood. Here, we reveal that NCALD messenger RNA expression, probably regulated by DNA methylation and microRNAs, was significantly downregulated in at least three independent microarrays covering 633 ovarian carcinomas and 16 normal controls, which includes the Cancer Genome Atlas (TCGA) ovarian cohort. In the sub-groups of the TCGA cohort, NCALD was suppressed in 90 platinum-resistant tissues vs in 197 sensitive tissues. It is consistent with the quantitative reverse transcription polymerase chain reaction results revealing gene downregulation in carboplatin-resistant SKOV3 and HeyA8 OC cells as compared with that in controls. Low expression of NCALD predicted poor overall survival (OS) in sub-groups of 1656 patients, progression-free survival (PFS) in 1435 patients, and post-progression survival (PPS) in 782 patients according to Kaplan-Meier plotter covering 1815 OC patients. Comprehensive bioinformatic analyses strongly implicated NCALD in the regulation of drug resistance, probably via competing for endogenous RNA (ceRNA) interactions with CX3CL1 and tumor immune-microenvironment. NCALD acted as a ceRNA for CX3CL1 in 21 different cancers includes OC according to Starbase. These two genes negatively correlated with tumor purity and positively correlated with infiltration levels of neutrophils and dendritic cells in OC. The combined low expression of NCALD and CX3CL1 showed better prognosis potential for OS, PFS, and PPS in the 1815 OC patients than any of the individually tested genes. In summary, NCALD acts as a ceRNA for CX3CL1, and its downregulation may affect drug resistance and prognosis in OC. Thus, NCALD could be a new therapeutic target for anticancer therapy and a new biomarker for survival prediction in OC.