Summerer Isolde, Hess Julia, Pitea Adriana, Unger Kristian, Hieber Ludwig, Selmansberger Martin, Lauber Kirsten, Zitzelsberger Horst
Research Unit Radiation Cytogenetics, Helmholtz Center Munich, Ingolstaedter Landstr.1, 85764, Neuherberg, Germany.
Clinical Cooperation Group 'Personalized Radiotherapy of Head and Neck Cancer', Helmholtz Center Munich, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
BMC Genomics. 2015 Sep 2;16(1):654. doi: 10.1186/s12864-015-1865-x.
Head and neck squamous cell carcinoma (HNSCC) is a very heterogeneous disease resulting in huge differences in the treatment response. New individualized therapy strategies including molecular targeting might help to improve treatment success. In order to identify potential targets, we developed a HNSCC radiochemotherapy cell culture model of primary HNSCC cells derived from two different patients (HN1957 and HN2092) and applied an integrative microRNA (miRNA) and mRNA analysis in order to gain information on the biological networks and processes of the cellular therapy response. We further identified potential target genes of four therapy-responsive miRNAs detected previously in the circulation of HNSCC patients by pathway enrichment analysis.
The two primary cell cultures differ in global copy number alterations and P53 mutational status, thus reflecting heterogeneity of HNSCC. However, they also share many copy number alterations and chromosomal rearrangements as well as deregulated therapy-responsive miRNAs and mRNAs. Accordingly, six common therapy-responsive pathways (direct P53 effectors, apoptotic execution phase, DNA damage/telomere stress induced senescence, cholesterol biosynthesis, unfolded protein response, dissolution of fibrin clot) were identified in both cell cultures based on deregulated mRNAs. However, inflammatory pathways represented an important part of the treatment response only in HN1957, pointing to differences in the treatment responses of the two primary cultures. Focused analysis of target genes of four therapy-responsive circulating miRNAs, identified in a previous study on HNSCC patients, revealed a major impact on the pathways direct P53 effectors, the E2F transcription factor network and pathways in cancer (mainly represented by the PTEN/AKT signaling pathway).
The integrative analysis combining miRNA expression, mRNA expression and the related cellular pathways revealed that the majority of radiochemotherapy-responsive pathways in primary HNSCC cells are related to cell cycle, proliferation, cell death and stress response (including inflammation). Despite the heterogeneity of HNSCC, the two primary cell cultures exhibited strong similarities in the treatment response. The findings of our study suggest potential therapeutic targets in the E2F transcription factor network and the PTEN/AKT signaling pathway.
头颈部鳞状细胞癌（HNSCC）是一种异质性很强的疾病，导致治疗反应存在巨大差异。包括分子靶向治疗在内的新的个体化治疗策略可能有助于提高治疗成功率。为了确定潜在靶点，我们构建了一种由两名不同患者（HN1957和HN2092）的原发性HNSCC细胞组成的HNSCC放化疗细胞培养模型，并进行了整合的微小RNA（miRNA）和信使核糖核酸（mRNA）分析，以获取有关细胞治疗反应的生物网络和过程的信息。我们还通过通路富集分析确定了先前在HNSCC患者循环中检测到的四种治疗反应性miRNA的潜在靶基因。
两种原代细胞培养物在全基因组拷贝数改变和P53突变状态方面存在差异，从而反映了HNSCC的异质性。然而，它们也有许多共同的拷贝数改变和染色体重排，以及失调的治疗反应性miRNA和mRNA。因此，基于失调的mRNA，在两种细胞培养物中均鉴定出六种共同的治疗反应性通路（直接P53效应器、凋亡执行阶段、DNA损伤/端粒应激诱导的衰老、胆固醇生物合成、未折叠蛋白反应、纤维蛋白凝块溶解）。然而，炎症通路仅在HN1957中是治疗反应的重要组成部分，这表明两种原代培养物在治疗反应上存在差异。对先前在HNSCC患者研究中鉴定出的四种治疗反应性循环miRNA的靶基因进行的重点分析，揭示了其对直接P53效应器通路、E2F转录因子网络和癌症通路（主要由PTEN/AKT信号通路代表）的重大影响。
整合miRNA表达、mRNA表达及相关细胞通路的分析表明，原发性HNSCC细胞中大多数放化疗反应性通路与细胞周期、增殖、细胞死亡和应激反应（包括炎症）相关。尽管HNSCC具有异质性，但两种原代细胞培养物在治疗反应上表现出很强的相似性。我们的研究结果提示了E2F转录因子网络和PTEN/AKT信号通路中的潜在治疗靶点。
