MicroRNA-497/195 is tumor suppressive and cooperates with CDKN2A/B in pediatric acute lymphoblastic leukemia

Abstract

We previously identified an association of rapid engraftment of patient-derived leukemia cells transplanted into NOD/SCID mice with early relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In search for the cellular and molecular profiles associated with this phenotype, we investigated the expression of microRNAs (miRNAs) in different engraftment phenotypes and patient outcomes and found high miR-497/195 expression in patient-derived xenograft samples with slow engraftment, derived from patients with favorable outcome. In contrast, epigenetic repression and low expression of these miRNAs was observed in rapidly engrafting samples associated with early relapse. Overexpression of miR-497/195 in patient-derived leukemia cells suppressed in vivo growth of leukemia and prolonged recipient survival. Conversely, inhibition of miR-497/195 led to increased leukemia cell growth. Key cell cycle regulators were downregulated upon miR-497/195 overexpression and we identified CDK4/CCND3-mediated control of G1/S transition as a principal mechanism for the suppression of BCP-ALL progression by miR-497/195. The critical role for miR-497/195-mediated cell cycle regulation was underscored by the finding in an additional independent series of patient samples, showing that high miR-497/195 expression together with a full sequence of CDKN2A/B was associated with excellent outcome, while deletion of CDKN2A/B together with low expression of miR-497/195 was associated with clearly inferior relapse-free survival. These findings point to the cooperative loss of cell cycle regulators as new prognostic factor indicating possible therapeutic targets for pediatric BCP-ALL.

d-Limonene inhibits the occurrence and progression of LUAD through suppressing lipid droplet accumulation induced by PM2.5 exposure in vivo and in vitro

“…Furthermore, we found that the expression of miR-195 was increased significantly when the A549 and H1975 cell lines were treated with d -limonene. This miRNA reported by us and others before can suppress the growth of lung cancer and other cancers, including acute lymphoblastic leukaemia, triple-negative breast, liver, glioblastoma, prostate, stomach and colorectal cancers [ 54 – 59 ]. We also found that miR-195 could directly bind to the mRNAs of SREBF1 , FASN and ACACA in lung cancer cells resulting in decreases in lipid droplet formation induced by PM 2.5 exposure.…”

MiR-195-5p suppresses the proliferation, migration, and invasion of gallbladder cancer cells by targeting FOSL1 and regulating the Wnt/β-catenin pathway

“…MiR-195-5p is a multitarget regulator involved in various aspects of cancer cell behavior (31). It can regulate the cell cycle and inhibit the growth of leukemia cells; its expression is increased and is an important prognostic factor (32). Furthermore, stable expression of miR-195-5p in a mouse xenograft model of ovarian cancer significantly reduced tumor growth, increased tumor doubling time, and improved overall survival (33).…”

Sniping Cancer Stem Cells with Nanomaterials

“…Therefore, miRNAs stand out as prospective therapeutic targets against CSCs, necessitating an attentive consideration of the multifaceted spectrum of miRNA functionalities. Illustratively, miR-760, miR-205, miR-497, miR-136, let-7 family, among several others, have demonstrated the capability to suppress certain cancer types and exert negative modulation over CSCs. Conversely, miR-146, miR-221/222, etc.…”