Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma.
Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma.
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DOI：
10.1158/1078-0432.ccr-21-0573
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发表时间：
2021-11-01
期刊：
影响因子：
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通讯作者：
Iqbal J
中科院分区：
文献类型：
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作者：
Lone W;Bouska A;Sharma S;Amador C;Saumyaranjan M;Herek TA;Heavican TB;Yu J;Lim ST;Ong CK;Slack GW;Savage KJ;Rosenwald A;Ott G;Cook JR;Feldman AL;Rimsza LM;McKeithan TW;Greiner TC;Weisenburger DD;Melle F;Motta G;Pileri S;Vose JM;Chan WC;Iqbal J
外周 T 细胞淋巴瘤 (PTCL) 是一组具有侵袭性临床行为的异质性非霍奇金淋巴瘤。我们对 PTCL 和相应的正常 CD4+ T 辅助细胞 1/2 和 TFH 样极化子集进行了全面的 miRNA 分析，以阐明 miRNA 在 T 细胞淋巴瘤发生中的作用。我们使用 nCounter (NanoString Inc) 进行 miRNA 分析，并使用 Taqman™ qRT-PCR (Applied Biosystem, Inc) 进行验证。使用特征细胞因子将正常 CD4+ T 细胞极化为效应 TH 子集，并通过功能实验揭示 miRNA 的意义。效应器 TH 子集显示出与相应转录因子表达不同的 miRNA 表达（例如 IL21 极化细胞中的 BCL6/miR-19b、-106、-30d、-26b；TH2 极化细胞中的 GATA3/miR-155、miR-337 和 TH1 极化细胞中的 TBX21/miR-181a,331-3p）。 miRNA 特征的整合表明 IL21 极化细胞中 TCR 和 PI3K 信号传导、TH1 极化细胞中 ERK 信号传导以及 TH2 极化细胞中 AKT-mTOR 信号传导在蛋白质水平上得到验证。在肿瘤对应物中，独特的 miRNA 在一个独立队列中被鉴定和证实。综合 miRNA-mRNA 分析发现，靶转录本丰度降低导致 AITL 中鞘脂和 Wnt 信号传导失调以及表观遗传失调，而 PTCL 子集中发现了 ERK、MAPK 和细胞周期，并且在独立队列中验证了靶转录本丰度降低。 AITL 中 miRNA（miR-126-3p、miR-145-5p）表达升高与不良临床结果相关。计算机模拟和实验验证表明有两个靶点（miR126→SIPR2 和 miR145→ROCK1）导致 RhoA-GTPase 活性和 T-B 细胞相互作用降低。独特的 microRNA 和失调的致癌途径与 PTCL 亚型相关。上调的 miRNA-126-3p 和 miR-145-5p 表达可调节 RhoA-GTPase 并抑制 T 细胞迁移，这对 AITL 病理学至关重要。
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4+ T-helper 1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis. We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman™ qRT-PCR (Applied Biosystem, Inc). Normal CD4+ T-cells were polarized into effector TH-subsets using signature cytokines, and miRNA significance was revealed using functional experiments. Effector TH-subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g. BCL6/miR-19b, −106, −30d,−26b, in IL21-polarized; GATA3/miR-155, miR-337 in TH2-polarized and TBX21/miR-181a,331-3p in TH1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in TH1-polarized and AKT-mTOR signaling in TH2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA-mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in AITL, while ERK, MAPK and cell cycle were identified in PTCL-subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL were associated with poor clinical-outcome. In-silico and experimental validation suggest two targets (miR126→ SIPR2 and miR145 → ROCK1) resulting in reduced RhoA-GTPase activity and T-B cell interaction. Unique microRNAs and deregulated oncogenic pathways are associated with PTCL-subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.