Acute myeloblastic leukemia (AML) is characterized by the accumulation of abnormal myeloblasts (mainly granulocyte or monocyte precursors) in the bone marrow and blood. Though great progress has been made for improvement in clinical treatment during the past decades, only minority with AML achieve long-term survival. Therefore, further understanding mechanisms of leukemogenesis and exploring novel therapeutic strategies are still crucial for improving disease outcome. MicroRNA-100 (miR-100), a small non-coding RNA molecule, has been reported as a frequent event aberrantly expressed in patients with AML; however, the molecular basis for this phenotype and the statuses of its downstream targets have not yet been elucidated. In the present study, we found that the expression level of miR-100 in vivo was related to the stage of the maturation block underlying the subtypes of myeloid leukemia. In vitro experiments further demonstrated that miR-100 was required to promote the cell proliferation of promyelocytic blasts and arrest them differentiated to granulocyte/monocyte lineages. Significantly, we identified RBSP3, a phosphatase-like tumor suppressor, as a bona fide target of miR-100 and validated that RBSP3 was involved in cell differentiation and survival in AML. Moreover, we revealed a new pathway that miR-100 regulates G1/S transition and S-phase entry and blocks the terminal differentiation by targeting RBSP3, which partly in turn modulates the cell cycle effectors pRB/E2F1 in AML. These events promoted cell proliferation and blocked granulocyte/monocyte differentiation. Our data highlight an important role of miR-100 in the molecular etiology of AML, and implicate the potential application of miR-100 in cancer therapy.
Cholangiocarcinoma (CCA), which is a poor prognosis malignancy that arises from the malignant transformation of cholangiocytes, is associated with chronic inflammation of the biliary epithelium. Thus far, the molecular mechanisms of the origin and neoplastic processes of CCA that are promoted by inflammation are still unclear and need to be fully elucidated. Here using small RNA sequencing to determine the microRNA (miRNA) expression profiles in CCA, we found that let-7c, miR-99a and miR-125b, which are three miRNAs of the same cluster, were downregulated in CCA and targeted interleukin 6 (IL-6), IL-6R and type 1 insulin-like growth factor, which are important cytokines and receptors of the IL-6/signal transducer and activator 3 (STAT3) pathway and have key roles in inflammation and CCA initiation. We also found that enforced expression of let-7c, miR-99a or miR-125b could reduce the activity of STAT3 and further suppress CCA tumorigenicity in vivo and inhibit the migration and invasion of CCA cells in vitro. Surprisingly, let-7c/miR-99a/miR-125b cluster also significantly decreased the ability of CCA cells for cancer stem cell-like mammosphere generation by downregulating CD133 and CD44, which suggests the pivotal roles of let-7c, miR-99a and miR-125b in CCA by regulating both inflammation and stem-like properties. Our findings showed potential links between miRNAs and inflammation, and provide a potential treatment strategy for developing an miRNA-based therapy via IL-6/STAT3 targeting for CCA.
The study of the characteristics of non-eosinophilic and eosinophilic chronic polyposis rhinosinusitis (CRSwNP) is necessary to improve understanding of the pathophysiological mechanisms of this disease and determine the optimal treatment strategy. We studied the specific features of eosinophilic and noneosinophilic CRSwNP in Vietnamese patients. Patients (48 male and 35 female) with a diagnosis of CRSwNP took part in the work. Patients were operated on at the National ENT Hospital from 9/2017 to 8/2018. Based on a study of the pathology of nasal polyps, CRSwNPs were classified as eosinophilic or non-eosinophilic. In men, 35% had eosinophilic CRSwNP and 65% had non-eosinophilic CRSwNP. In the subgroup of women, eosinophilic CRSwNP was observed in 31% and non-eosinophilic CRSwNP in 69%. In total, 34% of 83 people had eosinophilic CRSwNP. The average duration of eosinophilic CRSwNP disease was 45.0 ± 43.1 months; noneosinophilic CRSwNP was 25.5 ± 20.5 months. In this cohort of patients, 8.4% suffered from bronchial asthma, and a high probability ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 20 (1): gmr18733 L.M. Ky et al. 2of this pathology was found in combination with the eosinophilic CRSwNP (OR = 5.76; 1.04-31.89 CI 95%; P = 0.045). The proportion of allergic rhinitis with eosinophilic CRSwNP was 39.3%, and with non-eosinophilic CRSwNP was 12.7%. The share of uni-and bilateral eosinophilic CRSwNPs was 10.7 and 89.3%, while noneosinophilic CRSwNPs were 41.8 and 58.2%, respectively. Thus, CRSwNP is a complex heterogeneous inflammatory disease.Eosinophilia plays an important role in the pathogenesis of this disease and significantly worsens the clinical picture. There are significant differences in the duration of the pathological manifestations, the presence of allergic rhinitis, bronchial asthma and the severity of polyps in patients with eosinophilic and noneosinophilic CRSwNP.
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