miR-497 suppresses cycle progression through an axis involving CDK6 in ALK-positive cells

Abstract

Anaplastic large-cell lymphoma, a T-cell neoplasm, is primarily a pediatric disease. Seventy-five percent of pediatric anaplastic large-cell lymphoma cases harbor the chromosomal translocation t(2;5)(p23;q35) leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. NPM-ALK consists of an N-terminal nucleophosmin (NPM) domain fused to an anaplastic lymphoma kinase (ALK) cytoplasmic domain. Pediatric NPM-ALK+ anaplastic large-cell lymphoma is often a disseminated disease and young patients are prone to chemoresistance or relapse shortly after chemotherapeutic treatment. Furthermore, there is no gold standard protocol for the treatment of relapses. To the best of our knowledge, this is the first study on the potential role of the microRNA, miR-497, in NPM-ALK+ anaplastic large-cell lymphoma tumorigenesis. Our results show that miR-497 expression is repressed in NPM-ALK+ cell lines and patient samples through the hypermethylation of its promoter and the activity of NPM-ALK is responsible for this epigenetic repression. We demonstrate that overexpression of miR-497 in human NPM-ALK+ anaplastic large-cell lymphoma cells inhibits cellular growth and causes cell cycle arrest by targeting CDK6, E2F3 and CCNE1, the three regulators of the G1 phase of the cell cycle. Interestingly, we show that a scoring system based on CDK6, E2F3 and CCNE1 expression could help to identify relapsing pediatric patients. In addition, we demonstrate the sensitivity of NPM-ALK+ cells to CDK4/6 inhibition using for the first time a selective inhibitor, palbociclib. Together, our findings suggest that CDK6 could be a therapeutic target for the development of future treatments for NPM-ALK+ anaplastic large-cell lymphoma.

<p>MicroRNA-497-5p Induces Cell Cycle Arrest Of Cervical Cancer Cells In S Phase By Targeting CBX4</p>

“…When treating cervical cancer cells with miR-497-5p inhibitor, we found that CBX4 gene expression was increased, cell proliferation rate of cervical cancer cells was elevated, and cell cycle was arrested at S-phase, which is consistent with the regulatory effect of miR-497-5p on the cell cycle of ALK-positive cells, melanoma cells and 293T cells. [34][35][36] However, inhibition of miR-497-5p together with down-regulation of CBX4 resulted in decreased proliferation of cervical cancer cells. The number of S-phase cells in this group was lower than that of cells with inhibition of miR-497-5p, and higher than that of control group, suggesting that CBX4 is a key molecule in the regulation of the growth of cervical cancer cells by miR-497-5p, and changes in CBX4 expression directly affect the proliferation of cervical cancer cells.…”

Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma

“…In an NHL case–control population, Alan Fu et al demonstrated that reduced levels of mature miR-618 may lead to the deregulation of the targeted genes HAT1/HDAC3. The inactivation of miR-497 in human NPM-ALK ( +) anaplastic large-cell lymphoma cells promotes cell growth by dysregulating targeted CDK6, E2F3, and CCNE1, the three regulators of the G1 phase of the cell cycle [ 151 ]. These findings suggest that some miRNA genes are controlled by epigenetic alterations in their promoter regions and can be activated by inhibitors of DNA methylation and HDAC.…”

Regulation of microRNA‑497 expression in human cancer (Review)

“…cancer (44,45), thyroid cancer (46,47), cutaneous squamous cell carcinoma (48,49), melanoma (50), glioma (51), clear cell renal cell carcinoma (52), anaplastic large cell lymphoma (53), esophageal carcinoma (54) and bladder cancer (9), among others. These results suggest that miR-497 acts as a tumor suppressor.…”