Ryu Kyung Ju, Lee Ji Young, Choi Myung Eun, Yoon Sang Eun, Cho Junhun, Ko Young Hyeh, Shim Joon-Ho, Kim Won Seog, Park Chaehwa, Kim Seok Jin
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Korea.
Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
Cancers (Basel). 2020 Nov 27;12(12):3548. doi: 10.3390/cancers12123548.
Exosomes containing microRNAs (miRNAs) might have utility as biomarkers to predict the risk of treatment failure in extranodal NK/T-cell lymphoma (ENKTL) because exosomal cargo miRNAs could reflect tumor aggressiveness. We analyzed the exosomal miRNAs of patients in favorable ( = 22) and poor outcome ( = 23) groups in a training cohort. Then, using the Nanostring nCounter microRNA array, we compared them with miRNAs identified in human NK/T lymphoma (NKTL) cell line-derived exosomes to develop exosomal miRNA profiles. We validated the prognostic value of serum exosomal miRNA profiles with an independent cohort ( = 85) and analyzed their association with treatment resistance using etoposide-resistant cell lines. A comparison of the top 20 upregulated miRNAs in the training cohort with poor outcomes with 16 miRNAs that were upregulated in both NKTL cell lines, identified five candidate miRNAs (miR-320e, miR-4454, miR-222-3p, miR-21-5p, and miR-25-3p). Among these, increased levels of exosomal miR-4454, miR-21-5p, and miR-320e were associated with poor overall survival in the validation cohort. Increased levels were also found in relapsed patients post-treatment. These three miRNAs were overexpressed in NKTL cell lines that were resistant to etoposide. Furthermore, transfection of NKTL cell lines with miR-21-5p and miR-320e induced an increase in expression of the proinflammatory cytokines such as macrophage inflammatory protein 1 alpha. These studies show that serum levels of exosomal miR-21-5p, miR-320e, and miR-4454 are increased in ENKTL patients with poor prognosis. Upregulation of these exosomal miRNAs in treatment-resistant cell lines suggests they have a role as biomarkers for the identification of ENKTL patients at high risk of treatment failure.
含有微小RNA（miRNA）的外泌体可能具有作为生物标志物的作用，以预测结外NK/T细胞淋巴瘤（ENKTL）治疗失败的风险，因为外泌体携带的miRNA可以反映肿瘤的侵袭性。我们在一个训练队列中分析了预后良好（n = 22）和预后不良（n = 23）组患者的外泌体miRNA。然后，使用纳米串nCounter miRNA阵列，我们将它们与在人NK/T淋巴瘤（NKTL）细胞系衍生的外泌体中鉴定出的miRNA进行比较，以建立外泌体miRNA谱。我们用一个独立队列（n = 85）验证了血清外泌体miRNA谱的预后价值，并使用依托泊苷耐药细胞系分析了它们与治疗耐药性的关联。将训练队列中预后不良的前20个上调miRNA与NKTL细胞系中上调的16个miRNA进行比较，确定了5个候选miRNA（miR-320e、miR-4454、miR-222-3p、miR-21-5p和miR-25-3p）。其中，外泌体miR-4454、miR-21-5p和miR-320e水平升高与验证队列中较差的总生存期相关。在治疗后复发的患者中也发现水平升高。这三个miRNA在对依托泊苷耐药的NKTL细胞系中过表达。此外，用miR-21-5p和miR-320e转染NKTL细胞系会诱导促炎细胞因子如巨噬细胞炎性蛋白1α的表达增加。这些研究表明，预后不良的ENKTL患者血清中外泌体miR-21-5p、miR-320e和miR-4454水平升高。这些外泌体miRNA在治疗耐药细胞系中的上调表明它们可作为生物标志物，用于识别有治疗失败高风险的ENKTL患者。
