Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Center of Evidence-Based Medicine, Fudan University, China.
Biomed Pharmacother. 2018 Jan;97:1138-1146. doi: 10.1016/j.biopha.2017.11.031. Epub 2017 Nov 10.
Cetuximab is one of the most widely used epidermal growth factor receptor (EGFR) inhibitors to treat patients with metastatic colorectal cancer (mCRC) harboring wild-type of RAS/RAF status. However, primary and acquired resistance to cetuximab is often found during target therapy.
To gain insights into the functions of long non-coding RNA (lncRNA) in cetuximab resistance, we used a lncRNA-mining approach to distinguish lncRNA specific probes in Affymetrix HG-U133A 2.0 arrays. Then we performed lncRNA expression profiling in a cetuximab treated mCRC cohort from Gene Expression Ominus (GEO). The potential lncRNAs were further validated in acquired cetuximab resistant cell lines and clinical samples of our hospital. The functions and associated pathways of the prognostic lncRNA were predicted by GO and KEGG analyses.
249 lncRNA-specific probe sets (corresponding to 212 lncRNAs) were represented in Affymetrix HG-U133A 2.0 arrays. We found that 9 lncRNAs were differentially expressed between disease control group (DCG) and non-responders, and 5 of these 9 lncRNAs were significantly related with the progression-free survival (PFS) of the patients. Among those 5 lncRNAs, POU5F1P4 was also down-regulated in acquired cetuximab resistant cells, as well as in cetuximab resistant patients. Downregulation of POU5F1P4 decreased the sensitivity of colorectal cancer cells to cetuximab.
Our findings indicate the potential roles of lncRNAs in cetuximab resistance, and may provide the useful information for discovery of new biomarkers and therapeutic targets.
西妥昔单抗是一种最广泛使用的表皮生长因子受体（EGFR）抑制剂，用于治疗携带野生型 RAS/RAF 状态的转移性结直肠癌（mCRC）患者。然而，在靶向治疗过程中，经常会发现对西妥昔单抗的原发性和获得性耐药。
为了深入了解长链非编码 RNA（lncRNA）在西妥昔单抗耐药中的作用，我们使用 lncRNA 挖掘方法来区分 Affymetrix HG-U133A 2.0 阵列中 lncRNA 特异探针。然后，我们在 Gene Expression Ominus（GEO）的西妥昔单抗治疗 mCRC 队列中进行 lncRNA 表达谱分析。潜在的 lncRNA 进一步在获得性西妥昔单抗耐药细胞系和我们医院的临床样本中进行验证。通过 GO 和 KEGG 分析预测预后 lncRNA 的功能和相关途径。
Affymetrix HG-U133A 2.0 阵列中代表了 249 个 lncRNA 特异探针集（对应于 212 个 lncRNA）。我们发现，疾病对照组（DCG）和无应答者之间有 9 个 lncRNA 表达差异，其中 5 个与患者的无进展生存期（PFS）显著相关。在这 5 个 lncRNA 中，POU5F1P4 在获得性西妥昔单抗耐药细胞以及西妥昔单抗耐药患者中也下调。POU5F1P4 的下调降低了结直肠癌细胞对西妥昔单抗的敏感性。
我们的研究结果表明 lncRNA 在西妥昔单抗耐药中的潜在作用，并为发现新的生物标志物和治疗靶点提供了有用的信息。
