Eptaminitaki Giasemi C, Zaravinos Apostolos, Stellas Dimitris, Panagopoulou Maria, Karaliota Sevasti, Baltsavia Ismini, Iliopoulos Ioannis, Chatzaki Ekaterini, Iliopoulos Dimitrios, Baritaki Stavroula
Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71003 Heraklion, Greece.
Basic and Translational Cancer Research Center (BTCRC), Genomics and Systems Biology Laboratory, Cancer Genetics, Nicosia 1516, Cyprus.
Cancers (Basel). 2023 Feb 7;15(4):1053. doi: 10.3390/cancers15041053.
Pancreatic ductal adenocarcinoma (PDAC), the second most prevalent gastrointestinal malignancy and the most common type of pancreatic cancer is linked with poor prognosis and, eventually, with high mortality rates. Early detection is seldom, while tumor heterogeneity and microarchitectural alterations benefit PDAC resistance to conventional therapeutics. Although emerging evidence suggest the core role of cancer stem cells (CSCs) in PDAC aggressiveness, unique stem signatures are poorly available, thus limiting the efforts of anti-CSC-targeted therapy. Herein, we report the findings of the first genome-wide analyses of mRNA/lncRNA transcriptome profiling and co-expression networks in PDAC cell line-derived CD133+/CD44+ cells, which were shown to bear a CSC-like phenotype in vitro and in vivo. Compared to CD133-/CD44- cells, the CD133+/CD44+ population demonstrated significant expression differences in both transcript pools. Using emerging bioinformatic tools, we performed lncRNA target coding gene prediction analysis, which revealed significant Gene Ontology (GO), pathway, and network enrichments in many dyregulated lncRNA nearby ( or ) mRNAs, with reported involvement in the regulation of CSC phenotype and functions. In this context, the construction of lncRNA/mRNA networks by ingenuity platforms identified the lncRNAs ATF2, CHEK1, DCAF8, and PAX8 to interact with "hub" SC-associated mRNAs. In addition, the expressions of the above lncRNAs retrieved by TCGA-normalized RNAseq gene expression data of PAAD were significantly correlated with clinicopathological features of PDAC, including tumor grade and stage, nodal metastasis, and overall survival. Overall, our findings shed light on the identification of CSC-specific lncRNA signatures with potential prognostic and therapeutic significance in PDAC.
胰腺导管腺癌（PDAC）是第二常见的胃肠道恶性肿瘤，也是最常见的胰腺癌类型，其预后较差，最终死亡率很高。早期检测很少见，而肿瘤异质性和微结构改变使PDAC对传统疗法产生耐药性。尽管新出现的证据表明癌症干细胞（CSC）在PDAC侵袭性中起核心作用，但独特的干细胞特征却很少见，因此限制了抗CSC靶向治疗的努力。在此，我们报告了对PDAC细胞系来源的CD133+/CD44+细胞进行的首次全基因组mRNA/lncRNA转录组分析和共表达网络的研究结果，这些细胞在体外和体内均表现出类似CSC的表型。与CD133-/CD44-细胞相比，CD133+/CD44+群体在两个转录组中均表现出显著的表达差异。我们使用新兴的生物信息学工具进行了lncRNA靶标编码基因预测分析，结果显示在许多失调lncRNA附近（或）的mRNA中存在显著的基因本体论（GO）、通路和网络富集，这些mRNA参与了CSC表型和功能的调控。在此背景下，通过 Ingenuity 平台构建的lncRNA/mRNA网络确定lncRNAs ATF2、CHEK1、DCAF8和PAX8与“枢纽”SC相关mRNA相互作用。此外，通过PAAD的TCGA标准化RNAseq基因表达数据检索到的上述lncRNAs的表达与PDAC的临床病理特征显著相关，包括肿瘤分级和分期、淋巴结转移和总生存期。总体而言，我们的研究结果为识别在PDAC中具有潜在预后和治疗意义的CSC特异性lncRNA特征提供了线索。
