miR-125b induces cellular senescence in malignant melanoma

Abstract

BackgroundMicro RNAs (miRs) have emerged as key regulators during oncogenesis. They have been found to regulate cell proliferation, differentiation, and apoptosis. Mir-125b has been identified as an oncomir in various forms of tumours, but we have previously proposed that miR-125b is a suppressor of lymph node metastasis in cutaneous malignant melanoma. Our goal was therefore to further examine this theory.MethodsWe used in-situ-hybridization to visualise miR-125b expression in primary tumours and in lymph node metastasis. Then using a miRVector plasmid containing a miR-125b-1 insert we transfected melanoma cell line Mel-Juso and then investigated the effect of the presence of a stable overexpression of miR-125b on growth by western blotting, flow cytometry and β-galactosidase staining. The tumourogenicity of the transfected cells was tested using a murine model and the tumours were further examined with in-situ-hybridization.ResultsIn primary human tumours and in lymph node metastases increased expression of miR-125b was found in single, large tumour cells with abundant cytoplasm. A stable overexpression of miR-125b in human melanoma cell line Mel-Juso resulted in a G0/G1 cell cycle block and emergence of large cells expressing senescence markers: senescence-associated beta-galactosidase, p21, p27 and p53. Mel-Juso cells overexpressing miR-125b were tumourigenic in mice, but the tumours exhibited higher level of cell senescence and decreased expression of proliferation markers, cyclin D1 and Ki67 than the control tumours.ConclusionsOur results confirm the theory that miR-125b functions as a tumour supressor in cutaneous malignant melanoma by regulating cellular senescence, which is one of the central mechanisms protecting against the development and progression of malignant melanoma.

Long noncoding RNA LINC00152 promotes cell proliferation through competitively binding endogenous miR‐125b with MCL‐1 by regulating mitochondrial apoptosis pathways in ovarian cancer

“…We first predicted that LINC00152 was a potential target of miR‐125b, as the same binding site was also found in MCL‐1 and miR‐125b, which had a verified targeting relationship . LINC00152 was located in the cytoplasm, just as observed with miR‐125b and MCL‐1, which provides the necessary conditions for endogenous competition . Second, we proved that miR‐125b was negatively correlated with LINC00152 in ovarian cancer tissues, while MCL‐1 was positively correlated.…”

cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation

“…We did not observe this phenomenon in normal HMEC cells. While it has been previously reported that miR-125b targets and reduces JUN expression during granulocyte differentiation 33,42 and promotes cellular senescence in melanoma 57 , this is the first report identifying these two genes interacting within the same regulatory network to confer γ-irradiation sensitivity in breast cancer. We also identified miR-125b regulated genes involved in stress-response MAPK signaling, which are induced in cancer cells after γ-irradiation, presumably to promote cell survival.…”

“…The role of miR-125b in modulating irradiation-sensitivity in breast cancer is most likely a cell-context specific phenotype, given miR-125b itself has been described as a tumor suppressor in breast cancer 37,54–56 , melanoma 57 , and bladder cancer 58 , but also as an oncogene in prostate cancer 59 and leukemia 60,61 . miR-125b has also been shown to promote stem cell-like properties in cholangiocarcinoma 62 and expand progenitor cell populations in acute megakaryoblastic leukemia 63 .…”

Non-coding RNAs: An emerging player in DNA damage response

“…4, miRNAs can control cell cycle progression after DNA damage by targeting CHK1 [70][71][72][73][74], p53 [75,76], retinoblastoma 1 serine phosphates from human chromosome 3 (RBSP3) [77], cyclin D [73,78,79], CDC25a [80][81][82], p21, CDK2 [83][84][85], WEE1, PLK1, and so on. One study showed that RBSP3 is a target gene of miR-100.…”