Let-7b overexpression leads to increased radiosensitivity of uveal melanoma cells

Abstract

Uveal melanoma (UM) is an intraocular malignant tumor in adults that is characterized by rapid progression and recurrence. Irradiation has become the primary therapy for UM patients who are not candidates for surgery. However, after large-dose fraction irradiation treatment, some patients undergo subsequent enucleation because of radiotherapy-related complications. This situation has raised concerns on how to optimize the effectiveness of radiation treatment. Recent investigations of microRNAs are changing our understanding of UM tumor biology and are helping to identify novel targets for radiotherapy. The radioresistant UM cell lines OM431 and OCM1 were selected and exposed to irradiation, and let-7b was found to be downregulated after exposure. We then confirmed that let-7b mimics could inhibit UM growth both in vitro and in vivo. More specifically, transfection with let-7b mimics markedly resensitized OCM1 and OM431 cells to irradiation by reducing the population of S-phase cells. Cyclin D1 plays a vital role in cell cycle arrest, which is induced by let-7b overexpression. Cyclin D1 is also a target of let-7b and its expression is suppressed by upregulation of let-7b. Collectively, our results indicate that let-7b overexpression can in turn downregulate cyclin D1 expression and enhance the radiosensitivity of UM through cell cycle arrest. Let-7b could serve as a marker for radiosensitivity and could enhance the therapeutic benefit of UM cell irradiation.

Role of Epigenetics in Uveal Melanoma

“…Let-7 has also been demonstrated as a strong discriminator in primary UM, and has been reported at low levels in OCM1 cells 11, 20. Research indicates that let-7b over-expression down-regulates cyclin D1 expression, which plays a critical role in cell cycle arrest, and enhances the radio-sensitivity of UM through cell cycle arrest 21.…”

“…Zhou et al . found that let-7b could potentially be used as a radio-sensitivity enhancer in UM radiotherapy 21. miR-34b/c expression, which is dramatically reduced in UM cells and clinical samples, can be up-regulated by doxorubicin and epigenetic drugs.…”

Extracellular microvesicle microRNAs as predictive biomarkers for targeted therapy in metastastic cutaneous malignant melanoma

“…Other data indicate an association of the let-7 family with outcome of chemo and radiotherapy. In uveal melanoma, high expression of let-7g has been associated with better outcome of chemo- or radiotherapy [ 27 ]. The up-regulation of let-7g-5p has also been correlated with improved PFS and OS in patients with ovarian cancer receiving neoadjuvant chemotherapy [ 28 ] and similar data is reported in rectal cancer for high expression of let-7g [ 26 ].…”

miR-185 enhances the inhibition of proliferation and migration induced by ionizing radiation in melanoma

“…It was identified that the miRNA profiles are significantly different in pre-and post-irradiated cells at 5 days in multiple melanoma cell lines and suggested that miRNAs with differential expression may be associated with resistance to IR. The study led to the development of research on sensitizing melanoma to IR via miRNAs, and miR-21 and let-7b were identified as important factors in response to IR in melanoma (7,8). Therefore, it is conceivable that more miRNAs may be involved in regulating the cellular sensitivity to IR in melanoma.…”

“…A previous study suggested an important role for miRNAs in the mediation of tumor cell sensitivity to ionizing radiation (IR) by efficiently influencing DNA damage repair, cell cycle checkpoints, apoptosis, radio-related signal transduction pathways and the tumor microenvironment (6). In melanoma, miRNA 21 (miR-21) and miR-let-7b have been demonstrated to be related to the cellular radioresistance (7,8). However, the underlying molecular mechanisms by which miRNAs regulate cellular sensitivity to IR remain unclear.…”