MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B- cell lymphoma

作者：Leivonen Suvi Katri; Icay Katherine; Jantti Kirsi; Siren Ilari; Liu Chengyu; Alkodsi Amjad; Cervera Alejandra; Ludvigsen Maja; Hamilton Dutoit Stephen Jacques; d'Amore Francesco; Karjalainen Lind**erg Marja Liisa; Delabie Jan; Holte Harald; Lehtonen Rainer; Hautaniemi Sampsa; Leppa Sirpa

来源：Blood Cancer Journal, 2017, 7(12): 654.

DOI：10.1038/s41408-017-0033-8

<jats:title>Abstract</jats:title><jats:p>Despite better therapeutic options and improved survival of diffuse large B-cell lymphoma (DLBCL), 30–40% of the patients experience relapse or have primary refractory disease with a dismal prognosis. To identify biological correlates for treatment resistance, we profiled microRNAs (miRNAs) of matched primary and relapsed DLBCL by next-generation sequencing. Altogether 492 miRNAs were expressed in the DLBCL samples. Thirteen miRNAs showed significant differential expression between primary and relapse specimen pairs. Integration of the differentially expressed miRNAs with matched mRNA expression profiles identified highly anti-correlated, putative targets, which were significantly enriched in cancer-associated pathways, including phosphatidylinositol (PI)), mitogen-activated protein kinase (MAPK), and B-cell receptor (BCR) signaling. Expression data suggested activation of these pathways during disease progression, and functional analyses validated that miR-370-3p, miR-381-3p, and miR-409-3p downregulate genes on the PI, MAPK, and BCR signaling pathways, and enhance chemosensitivity of DLBCL cells in vitro. High expression of selected target genes, that is, <jats:italic>PIP5K1</jats:italic> and <jats:italic>IMPA1</jats:italic>, was found to be associated with poor survival in two independent cohorts of chemoimmunotherapy-treated patients (<jats:italic>n</jats:italic> = 92 and <jats:italic>n</jats:italic> = 233). Taken together, our results demonstrate that differentially expressed miRNAs contribute to disease progression by regulating key cell survival pathways and by mediating chemosensitivity, thus representing potential novel therapeutic targets.</jats:p>

• 出版日期2017-12-15