-
1.
MiR-17-5p enhances pancreatic cancer proliferation by altering cell cycle profiles via disruption of RBL2/E2F4-repressing complexes.
Zhu, Y, Gu, J, Li, Y, Peng, C, Shi, M, Wang, X, Wei, G, Ge, O, Wang, D, Zhang, B, et al
Cancer letters. 2018;:59-68
Abstract
The members of the miR-17-92 cluster are upregulated in various cancers and function as a cluster of oncogenic miRNA. Our study characterized a new function of miR-17-5p, a member of the miR-17-92 cluster, in regulating cell proliferation in pancreatic cancer. Our results indicate that miR-17-5p was up-regulated in pancreatic adenocarcinoma and directly targeted the retinoblastoma-like protein 2 (RBL2), a tumor suppressor belonging to the Rb family. High levels of miR-17-5p and low levels of RBL2 were associated with poor prognosis. RBL2 interacted with the transcription factor E2F4 and bound to the promoter regions of the E2F target genes. Disruption of the RBL2/E2F4 complex by miR-17-5p overexpression shifted the activity of E2F from gene repressing to gene activating, which induced cell cycle entry and proliferation. These results suggest that miR-17-5p promoted proliferation in pancreatic ductal adenocarcinoma cells (PDAC), and altered cell cycle profiles in vivo and in vitro, by disrupting the RBL2/E2F4-associated gene repressing complexes via direct targeting of RBL2. The new regulatory network, involving miR-17-5p and RBL2, emerges as a new target of PDAC treatment.
-
2.
[Effect of microRNA-34a/SIRT1/p53 signal pathway on notoginsenoside R₁ delaying vascular endothelial cell senescence].
Lai, XH, Lei, Y, Yang, J, Xiu, CK
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica. 2018;(3):577-584
Abstract
This study aimed to investigate the effect of notoginsenoside R₁ in delaying H₂O₂-induced vascular endothelial cell senescence through microRNA-34a/SIRT1/p53 signal pathway. In this study, human umbilical vein endothelial cells(HUVECs) were selected as the study object; the aging model induced by hydrogen peroxide(H₂O₂) was established, with resveratrol as the positive drug. HUVECs were randomly divided into four groups, youth group, senescence model group, notoginsenoside R₁ group and resveratrol group. Notoginsenoside R₁ group and resveratrol group were modeled with 100 μmoL·L⁻¹ H₂O₂ for 4 h after 24 h treatment with notoginsenoside R₁(30 μmoL·L⁻¹) and resveratrol(10 μmoL·L⁻¹) respectively. At the end, each group was cultured with complete medium for 24 h. The degree of cellular senescence was detected by senescence-associated β-galactosidase(SA-β-Gal) staining kit, the cell viability was detected by cell counting kit-8, the cell cycle distribution was analyzed by flow cytometry, and the cellular SOD activity was detected by WST-1 method in each group. The expressions of SIRT1, p53, p21 and p16 proteins in HUVECs were detected by Western blot. In addition, the mRNA expressions of miRNA-34a, SIRT1 and p53 in HUVECs were assayed by Real-time PCR. These results indicated that notoginsenoside R₁ significantly reduced the positive staining rate of senescent cells, enhanced the cell proliferation capacity and intracellular SOD activity, decreased the proportion of cells in G₀/G₁ phase, and increased the percentage of cells in S phase simultaneously compared with the senescence model group. Moreover, notoginsenoside R₁ decreased the mRNA expressions of miRNA-34a and p53 and the protein expression of p53, p21 and p16.At the same time, notoginsenoside R₁ increased the protein and mRNA expressions of SIRT1. The differences in these results between the senescence model group and the notoginsenoside R₁ group were statistically significant(P<0.05). However, there was not statistically significant difference in these results between the notoginsenoside R₁ group and the resveratrol group. In conclusion, the senescence of endothelial cells induced by H₂O₂ can be used as a model for studying aging. Notoginsenoside R₁ has an obvious anti-aging effect on vascular endothelial cells in this study. The possible mechanism is that notoginsenoside R₁ can delay the senescence process of vascular endothelial cells induced by H₂O₂ by regulating microRNA-34a/SIRT1/p53 signal pathway.
-
3.
MiR-128-3p directly targets VEGFC/VEGFR3 to modulate the proliferation of lymphatic endothelial cells through Ca2+ signaling.
Zhou, J, He, Z, Guo, L, Zeng, J, Liang, P, Ren, L, Zhang, M, Zhang, P, Huang, X
The international journal of biochemistry & cell biology. 2018;:51-58
Abstract
Lymphangiogenesis has been regarded as a physiological response to pathologic stimuli. The abnormal proliferation of lymphatic endothelial cell (LECs) and lymphangiogenesis is involved in the development of lymphatic disorders. Reportedly, VEGFC/VEGFR3 plays a key role in lymphangiogenesis; moreover, VEGFC/VEGFR3 exerts their cellular effects through activation of Ca2+ signaling in several cell types. Herein, we demonstrated that VEGFC significantly up-regulated LEC proliferation through VEGFR3; moreover, VEGFC/VEGFR3 induced Ca2+ signaling activation. By using online tools, miR-128 and miR-3916 were predicted as candidate upstream miRNAs which might target VEGFC/VEGFR3. As verified using Immunoblotting assays, miR-128 significantly regulated the protein levels of VEGFC/VEGFR3, whereas miR-3916 only slightly modulated VEGFC and VEGFR3 proteins. Contrary to VEGFC, miR-128 overexpression remarkably suppressed LEC proliferation, Ca2+ release and ERK1/2-Akt signaling; moreover, the effect of VEGFC could be partially attenuated by miR-128. In summary, miR-128 interacts with the 3'-UTR of VEGFC and VEGFR3 to inhibit their expression, thus suppressing LEC proliferation through Ca2+ and ERK1/2-Akt signaling. Taken together, we provided novel experimental basis for miRNA-regulated LEC proliferation through Ca2+ signaling.
-
4.
Dairy Protein Supplementation Modulates the Human Skeletal Muscle microRNA Response to Lower Limb Immobilization.
D'Souza, RF, Zeng, N, Figueiredo, VC, Markworth, JF, Durainayagam, BR, Mitchell, SM, Fanning, AC, Poppitt, SD, Cameron-Smith, D, Mitchell, CJ
Molecular nutrition & food research. 2018;(7):e1701028
Abstract
Limb immobilization results in a rapid loss of muscle size and strength. The resultant alterations in signaling pathways governing myogenesis, catabolism, and mitochondrial biogenesis are likely to include posttranscriptional regulation mediated by altered microRNAs (miRNAs). Given that protein ingestion exerts an anabolic action and may act as a countermeasure to mitigate muscle loss with immobilization, it is important to examine miRNA in this context. The objective of the study is therefore to characterize the vastus lateralis miRNA response to 14 days of disuse in males (45-60 years) randomized to receive supplementation with 20 g d-1 of dairy protein (n = 12) or isocaloric carbohydrate placebo (n = 13). Biopsies are collected before and after a 2-week immobilization period. Of the 24 miRNAs previously identified in myogenic regulation, seven (miR-133a, -206, -15a, -451a, -126, -208b, and let-7e) are increased with immobilization irrespective of group; five (miR-16, -494, let-7a, -7c, and 7d) increased only in the carbohydrate group; and eight (miR-1, -486, -23a, -23b, -26a, -148b, let-7b, and -7g) are divergently expressed between groups (suppressed with protein). The ability of protein supplementation to differentially regulate miRNAs involved in key muscle regulatory pathways following short-term limb immobilization reflects potential protective function in mitigating muscle loss during limb immobilization.
-
5.
Central nervous system development-related microRNAs levels increase in the serum of gestational diabetic women during the first trimester of pregnancy.
Lamadrid-Romero, M, Solís, KH, Cruz-Reséndiz, MS, Pérez, JE, Díaz, NF, Flores-Herrera, H, García-López, G, Perichart, O, Reyes-Muñoz, E, Arenas-Huertero, F, et al
Neuroscience research. 2018;:8-22
Abstract
MicroRNAs are heterochronic molecules important during brain development, which could be altered by gestational diabetes mellitus (GDM). To explore these molecules in maternal serum, we performed an RT-qPCR analysis. Our results revealed the heterochronic character of some neural development-related microRNA in serum samples of pregnant women. In relation to the first trimester, higher levels of miR-183-5p, -200b-3p, and -125-5p in the second trimester, and higher levels of miR-137 in the third trimester, were found. Furthermore, an insult such as GDM led to higher levels of miR-183-5p, -200b-3p, -125-5p, and -1290 relative to the control in the first trimester, which might be related to changes in neurogenesis and cell proliferation. An in silico analysis suggested that increased microRNAs in the second trimester in the control contributed to cell proliferation and neuron differentiation and that the rise in miR-137 in the third trimester led to neuron maturation. In the diabetic, higher levels of the microRNAs in the first trimester suggested alterations in cell proliferation and neuron differentiation. In conclusion, we showed that fetal-related microRNAs can be detected in the serum of pregnant woman and exhibit temporary regulation during pregnancy and that microRNAs involved in cell proliferation and neuron differentiation are upregulated under GDM.
-
6.
The effects of expression of different microRNAs on insulin secretion and diabetic nephropathy progression.
Mafi, A, Aghadavod, E, Mirhosseini, N, Mobini, M, Asemi, Z
Journal of cellular physiology. 2018;(1):42-50
Abstract
MicroRNAs (miRNAs) have recently become well-known efficacious biomarkers for the diagnosis of diabetic nephropathy (DN). MiRNAs, short noncoding RNAs, are posttranscriptional regulators of gene expression, which regulate several biological cell functions, including insulin production and secretion, as well as insulin resistance in tissues. Today, the focus of the medical world is centered on the role of miRNAs as mediators for different diseases, such as DN and end-stage renal diseases (ESRD). MiRNAs are stable and detectable in human biological fluids, so their detection for early diagnosis of different diseases is highly sensitive and specific. Previous reports have shown that the alteration of miRNA profiles significantly correlates with specific stages of DN, kidney fibrosis, and renal dysfunction. This review was aimed at assessing the pathway of different miRNA expressions responsible for insulin secretion disorder and DN progression.
-
7.
Modulation of Human Subcutaneous Adipose Tissue MicroRNA Profile Associated with Changes in Adiposity-Related Parameters.
Giardina, S, Hernández-Alonso, P, Salas-Salvadó, J, Rabassa-Soler, A, Bulló, M
Molecular nutrition & food research. 2018;(2)
Abstract
SCOPE To analyze the effect of three calorie-restricted diets with different amount and quality of carbohydrates on subcutaneous adipose tissue (SAT) microRNA (miRNA) profile. METHODS AND RESULTS 6-month parallel, randomized trial conducted on overweight and obese subjects randomized to: 1) low glycemic index diet (LGI), 2) high glycemic index diet (HGI), and 3) low-fat (LF). The genome-wide SAT miRNA profile was assessed in eight randomly selected participants and the most relevant changing miRNAs (n = 13) were validated in 48 subjects. None of the miRNAs showed significant changes between the intervention groups. However, changes in some of them correlated with changes in biochemical and anthropometric variables. Stratifying our population according to tertiles of percentage change in body weight (BW), we observed a significant down-regulation of miR-210 in those subjects in Tertile 1 as compared to Tertile 3. When our population was stratified by tertiles of waist circumference, miR-132, miR-29a, miR-34a, and miR-378 were found to be significantly down-regulated, in T2 compared to T3. Furthermore, when stratified by tertiles of fat mass, we also observed the significant down-regulation of miR-132 in T1. CONCLUSION The macronutrient composition of a calorie-restricted diet does not affect the expression of the miRNAs analyzed, while changes in adiposity play a primary regulatory role.
-
8.
MicroRNA: A novel target of curcumin in cancer therapy.
Mirzaei, H, Masoudifar, A, Sahebkar, A, Zare, N, Sadri Nahand, J, Rashidi, B, Mehrabian, E, Mohammadi, M, Mirzaei, HR, Jaafari, MR
Journal of cellular physiology. 2018;(4):3004-3015
Abstract
Curcumin is known as a natural dietary polyphenol which is extracted from Curcuma longa L. It has been shown that curcumin has a variety of pharmacological effects such as antioxidant, anti-cancer, anti-inflammatory, and anti-microbial activities. Anti-cancer effects of curcumin are due to targeting of a wide range of cellular and molecular pathways involved in cancer pathogenesis including NF-kB, MAPK, PTEN, P53, and microRNAs (miRNA) network. Multiple lines of evidence have indicated that curcumin exerts its therapeutic effects via regulating miRNA expression (e.g., miR-1, miR-7, miR-9, miR-34a, miR-181, miR-21, and miR-19) which could lead to the regulation of underlying cellular and molecular pathways involved in cancer pathogenesis. Exosomes are one of the important classes of biological vehicles which could be released from various types of cells such as cancer cells and stem cells and could change the behavior of recipient cells. It has been shown that treatment of cancer cells with different dose of curcumin leads to the release of exosomes containing curcumin. These exosomes could induce anti-cancer properties in recipient cells and reduce tumor growth. Hence, exosomes containing curcumin could be applied as powerful tools for cancer treatment. Here, we highlighted various miRNAs which could be affected by curcumin in various types of cancer. Moreover, we highlight exosomes containing curcumin as suitable therapeutic tools in cancer therapy.
-
9.
Aberrant miRNAs Regulate the Biological Hallmarks of Glioblastoma.
Yu, W, Liang, S, Zhang, C
Neuromolecular medicine. 2018;(4):452-474
Abstract
GBM is the highest incidence in primary intracranial malignancy, and it remains poor prognosis even though the patient is gave standard treatment. Despite decades of intense research, the complex biology of GBM remains elusive. In view of eight hallmarks of cancer which were proposed in 2011, studies related to the eight biological capabilities in GBM have made great progress. From these studies, it can be inferred that miRs, as a mode of post-transcriptional regulation, are involved in regulating these malignant biological hallmarks of GBM. Herein, we discuss state-of-the-art research on how aberrant miRs modulate the eight hallmarks of GBM. The upregulation of 'oncomiRs' or the genetic loss of tumor suppressor miRs is associated with these eight biological capabilities acquired during GBM formation. Furthermore, we also discuss the applicable clinical potential of these research results. MiRs may aid in the diagnosis and prognosis of GBM. Moreover, miRs are also therapeutic targets of GBM. These studies will develop and improve precision medicine for GBM in the future.
-
10.
Serum miRNAs Predicting Sustained HBs Antigen Reduction 48 Weeks after Pegylated Interferon Therapy in HBe Antigen-Negative Patients.
Fujita, K, Mimura, S, Iwama, H, Nakahara, M, Oura, K, Tadokoro, T, Nomura, T, Tani, J, Yoneyama, H, Morishita, A, et al
International journal of molecular sciences. 2018;(7)
Abstract
The therapeutic goal for hepatitis B virus (HBV) infection is HBs antigen (HBsAg) seroclearance, which is achieved through 48-week pegylated interferon (Peg-IFN) therapy. This study aimed to identify predictive biomarkers for sustained HBsAg reduction by analyzing serum microRNAs. Twenty-two consecutive chronic HBV infection patients negative for HBe antigen (HBeAg) with HBV-DNA levels <5 log copies/mL, alanine aminotransferase (ALT) <100 U/L, and compensated liver functions, were enrolled. The patients were subcutaneously injected with Peg-IFNα-2a weekly for 48 weeks (treatment period), followed by the 48-week observation period. HBsAg 1-log drop relative to baseline levels recorded at the end of the observation period was considered effective. Sera were obtained at weeks 0 and 24 during the treatment period analyzed for microRNAs. The microRNA (miRNA) antiviral activity was evaluated in vitro using Huh7/sodium taurocholate cotransporting polypeptide (NTCP) cells. As a result, six patients achieved the HBsAg 1-log drop after the observation periods. Comparison of serum microRNA levels demonstrated that high miR-6126 levels at week 24 predicted HBsAg 1-log drop. Furthermore, miR-6126 reduced HBsAg in culture medium supernatants and intracellular HBV-DNA quantities in Huh7/NTCP cells. In conclusion, high serum miR-6126 levels during Peg-IFN therapy predicted the HBsAg 1-log drop 48 weeks after the completion of therapy. In vitro assays revealed that miR-6126 was able to suppress HBsAg production and HBV replication.