Wang Xin, Jia Yuming, Xu Xiaowu, Hu Yuheng, Fan Guixiong, Jing Desheng, Zhang Zhilei, Wang Chao, Song Changfeng, Qin Yi, Peng Li
Department of Emergency, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Cancer Med. 2023 Sep;12(17):18425-18439. doi: 10.1002/cam4.6427. Epub 2023 Aug 8.
Nuclear receptor coactivator 6 (NCoA6) is overexpressed in various cancers and considered a multifunctional coactivator of various transcription factors and nuclear receptors. However, the role of NCoA6 in pancreatic ductal adenocarcinoma (PDAC) remains unclear.
NCoA6 expression data in PDAC were extracted from TCGA and GTEx databases, and their correlation with survival outcomes were analyzed using the Kaplan-Meier plotter database. NCoA6 protein expression in PDAC tissues was evaluated using immunohistochemistry. RNA-sequencing technology was used to sequence the transcriptome of NCoA6-silenced PANC-1 cells, followed by differential expression, GO/KEGG and GSEA analyses. The effects of NCoA6 on cell proliferation, migration, invasion, cell cycle, and apoptosis were determined in two representative cell lines (PANC-1 and SW1990). Western blotting, qPCR, and co-immunoprecipitation were performed to explore the mechanism of action of NCoA6 in PDAC cells.
NCoA6 expression was markedly increased in PDAC tissues, and high NCoA6 expression was associated with poor survival prognosis. However, there was no significant relationship between NCoA6 expression and metastasis in PDAC patients. Our RNA-sequencing data analysis found 1194 significant differentially expressed genes between the control and NCoA6-silenced PANC-1 cells. GO/KEGG analysis results mainly focused on cytokine production, cytokine activity, and cytokine-cytokine receptor interactions. GSEA results showed that the knockdown of NCoA6 affected the expression of histone deacetylase 1 (HDAC1) targeted genes. NCoA6 knockdown suppressed proliferation, migration, and invasion of PDAC cells. Finally, western blotting, qPCR, and co-immunoprecipitation results showed that NCoA6 interacted with HDAC1 and that NCoA6 expression was negatively correlated with F-box and WD repeat domain-containing 7 (FBW7) and caudal-related homeobox transcription factor 2 (CDX2) expression in pancreatic cancer.
NCoA6 has a profound effect on cell proliferation, migration, invasion, and prognosis of PDAC and is potentially related to the expression of HDAC1, FBW7, and CDX2. Our results may provide novel therapeutic strategies for PDAC patients.
核受体辅激活因子6（NCoA6）在多种癌症中过表达，被认为是多种转录因子和核受体的多功能辅激活因子。然而，NCoA6在胰腺导管腺癌（PDAC）中的作用仍不清楚。
从TCGA和GTEx数据库中提取PDAC中NCoA6的表达数据，并使用Kaplan-Meier绘图仪数据库分析其与生存结果的相关性。采用免疫组织化学法评估PDAC组织中NCoA6蛋白的表达。利用RNA测序技术对NCoA6沉默的PANC-1细胞转录组进行测序，随后进行差异表达分析、GO/KEGG分析和基因集富集分析（GSEA）。在两种代表性细胞系（PANC-1和SW1990）中确定NCoA6对细胞增殖、迁移、侵袭、细胞周期和凋亡的影响。进行蛋白质免疫印迹、定量聚合酶链反应（qPCR）和免疫共沉淀实验，以探讨NCoA6在PDAC细胞中的作用机制。
PDAC组织中NCoA6表达明显增加，NCoA6高表达与生存预后不良相关。然而，PDAC患者中NCoA6表达与转移之间无显著相关性。我们的RNA测序数据分析发现，对照细胞和NCoA6沉默的PANC-1细胞之间有1194个显著差异表达基因。GO/KEGG分析结果主要集中在细胞因子产生、细胞因子活性和细胞因子-细胞因子受体相互作用。GSEA结果表明，NCoA6的敲低影响组蛋白去乙酰化酶1（HDAC1）靶向基因的表达。NCoA6敲低抑制了PDAC细胞的增殖、迁移和侵袭。最后，蛋白质免疫印迹、qPCR和免疫共沉淀结果表明，NCoA6与HDAC1相互作用，且在胰腺癌中NCoA6表达与含F盒和WD重复结构域7（FBW7）及尾相关同源框转录因子2（CDX2）表达呈负相关。
NCoA6对PDAC细胞的增殖、迁移和侵袭及预后有深远影响，且可能与HDAC1、FBW7和CDX2的表达有关。我们的研究结果可能为PDAC患者提供新的治疗策略。
