弥漫性大B细胞淋巴瘤中血管生成微小RNA的表达谱分析

Angiomirs expression profiling in diffuse large B-Cell lymphoma.

作者信息

Borges Natália M, do Vale Elias Marcela, Fook-Alves Veruska L, Andrade Tathiana A, de Conti Marina Lourenço, Macedo Mariana Petaccia, Begnami Maria Dirlei, Campos Antônio Hugo J F M, Etto Leina Yukari, Bortoluzzo Adriana Bruscato, Alves Antonio C, Young Ken H, Colleoni Gisele W B

机构信息

Departamento de Oncologia Clínica e Experimental, Universidade Federal de São Paulo, São Paulo, Brazil.

A.C. Camargo Cancer Center, São Paulo, Brazil.

出版信息

Oncotarget. 2016 Jan 26;7(4):4806-16. doi: 10.18632/oncotarget.6624.

Despite advances in treatment, 30% of diffuse large B-cell lymphoma (DLBCL) cases are refractory or relapse after chemoimmunotherapy. Currently, the relationship between angiogenesis and angiomiRs in DLBCL is unknown. We classified 84 DLBCL cases according to stromal signatures and evaluated the expression of pro- and antiangiomiRs in paraffin embedded tissues of DLBCL and correlated them with microvascular density (MVD). 40% of cases were classified as stromal-1, 50% as stromal-2 and 10% were not classified. We observed increased expression of proangiomiRs Let-7f, miR-17, miR-18a, miR-19b, miR-126, miR-130a, miR-210, miR-296 and miR-378 in 14%, 57%, 30%, 45%, 12%, 12%, 56%, 58% and 48% of the cases, respectively. Among antiangiomiRs we found decreased expression of miR-16, miR-20b, miR-92a, miR-221 and miR-328 in, respectively, 27%, 71%, 2%, 44% and 11%. We found association between increased expression of proangiomiRs miR-126 and miR-130a and antiangiomiR miR-328 and the subtype non-GCB. We found higher levels of the antiangiomiRs miR-16, miR-221 and miR-328 in patients with low MVD and stromal-1 signature. IPI and CD34 confirmed independent impact on survival of the study group. None of the above angiomiRs showed significance as biomarker in an independent serum samples cohort of patients and controls. In conclusion, we confirmed association between antiangiomiRs miR-16, miR-221 and miR-328 and stromal-1 signature. Four angiomiRs emerged as potential therapeutic targets: proangiomiRs miR-17, miR-210 and miR-296 and antiangiomiR miR-20b. Although the four microRNAs seem to be important in DLBCL pathogenesis, they were not predictive of DLBCL onset or relapse in the serum independent cohort.

尽管治疗取得了进展，但30%的弥漫性大B细胞淋巴瘤（DLBCL）病例在接受化疗免疫治疗后仍难治或复发。目前，DLBCL中血管生成与血管生成相关微小RNA（angiomiRs）之间的关系尚不清楚。我们根据基质特征对84例DLBCL病例进行分类，并评估DLBCL石蜡包埋组织中促血管生成和抗血管生成微小RNA的表达，并将它们与微血管密度（MVD）相关联。40%的病例被分类为基质-1型，50%为基质-2型，10%未分类。我们观察到促血管生成微小RNA Let-7f、miR-17、miR-18a、miR-19b、miR-126、miR-130a、miR-210、miR-296和miR-378的表达分别在14%、57%、30%、45%、12%、12%、56%、58%和48%的病例中增加。在抗血管生成微小RNA中，我们发现miR-16、miR-20b、miR-92a、miR-221和miR-328的表达分别在27%、71%、2%、44%和11%的病例中降低。我们发现促血管生成微小RNA miR-126和miR-130a以及抗血管生成微小RNA miR-328的表达增加与非生发中心B细胞（non-GCB）亚型相关。我们发现抗血管生成微小RNA miR-16、miR-221和miR-328在MVD低和基质-1型特征的患者中水平较高。国际预后指数（IPI）和CD34证实对研究组的生存有独立影响。在患者和对照的独立血清样本队列中，上述任何一种血管生成相关微小RNA均未显示出作为生物标志物的意义。总之，我们证实了抗血管生成微小RNA miR-16、miR-221和miR-328与基质-1型特征之间的关联。四种血管生成相关微小RNA成为潜在的治疗靶点：促血管生成微小RNA miR-17、miR-210和miR-296以及抗血管生成微小RNA miR-20b。尽管这四种微小RNA似乎在DLBCL发病机制中很重要，但在独立的血清队列中它们并不能预测DLBCL的发病或复发。