The regulation of tumor‐suppressive microRNA, miR‐126, in chronic lymphocytic leukemia

Abstract

The introduction of miR profiling of chronic lymphocytic leukemia (CLL) patients with different cytogenetic profiles and responses to therapy has allowed incorporation of important miR‐mRNA interactions into the understanding of disease biology. In this study, we performed miR expression analysis using NanoString nCounter to discover differentially regulated miRs after therapy with the Bruton tyrosine kinase inhibitor ibrutinib. Of the differentially regulated miRs in the discovery set, miR‐29c and miR‐126 were confirmed using real‐time PCR to be upregulated in CLL patient cells with ibrutinib therapy. In the validation set, an inverse correlation was observed between miR‐126 levels and expression of its putative target p85β, an isoform of the phosphoinositide 3‐kinase p85 regulatory subunit. We found that mRNA for the host gene EGFL7, primary unprocessed miR‐126, and mature miR‐126 are all downregulated in CLL cells compared to normal B cells. Patients in later stages of disease have a greater decrease in miR‐126 expression compared to treatment‐naive patients, indicating that lower miR‐126 levels may associate with disease progression. Overexpression of miR‐126 in leukemia cell lines significantly downregulates p85β expression and decreases activation of prosurvival mitogen‐activated protein kinase (MAPK) signaling. These results implicate miR‐126 in the pathology of CLL.

ATF-3/miR-590/GOLPH3 signaling pathway regulates proliferation of breast cancer

“…miRNAs have been reported to be the biomarkers of cancer detection and have directly or indirectly relation with tumorigenesis and further development [38]. Previous study showed that miR-126, a tumor suppressor, promotes apoptosis or induced proliferation repression in many kinds of caners [39–41] and also was reported to target GOLPH3 to suppress proliferation, migration and invasion in esophageal squamous cell carcinoma [20]. In gastric cancer cells miR-134 suppresses cell proliferation via targeting of GOLPH3 [42].…”

Involvement of miR-126 in autoimmune disorders

“…Through these processes, miR-126 plays a role in cancer and autoimmune biology. The microRNA 126 was shown to have important roles in cancers of the gastrointestinal and genital tracts, in the cancers of the breast, the thyroid, the lung and in some other ones [ 8 – 14 ]. Usually, miR-126 is down-regulated in tumours, most likely due to its ability to inhibit malignant cell growth, adhesion, migration, and invasion through suppressing a range of important target genes.…”

MicroRNAs: Tiny Regulators of Gene Expression with Pivotal Roles in Normal B-Cell Development and B-Cell Chronic Lymphocytic Leukemia

“…Therefore, high expression of miR-21-5p leads to an upregulation of MAPK/ERK signaling and a relative result to survival and proliferation of the leukemic B cells [ 63 ]. However, tumor-suppressive miRNAs which contribute negatively to the MAPK/ERK signaling pathway have also been identified in B-CLL [ 64 , 65 ]. As described previously, miRNAs are also involved in the regulation of the PI3K/AKT pathway, either by directly influencing the pathway or by downregulating the expression of PTEN, a tumor suppressor of this pathway [ 66 , 67 ].…”