microRNA Let-7c Research Articles

Retraction: MicroRNA let-7c Inhibits Cell Proliferation and Induces Cell Cycle Arrest by Targeting CDC25A in Human Hepatocellular Carcinoma.

Retraction: MicroRNA let-7c Inhibits Cell Proliferation and Induces Cell Cycle Arrest by Targeting CDC25A in Human Hepatocellular Carcinoma.

Iron Oxide Nanoparticles Conjugated to Thiosemicarbazone Reduce the Survival of Cancer Cells by Increasing the Gene Expression of MicroRNA let-7c in Lung Cancer A549 Cells.

Cancer cells have a higher demand for iron to grow and proliferate. A new complex of iron nanoparticles and thiosemicarbazones was synthesized. Confirmation tests included UV-visible, scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), Fourier transform infrared (FTIR), X-ray diffraction (XRD) and zeta potential. MTT assay, flow cytometry and qRT-PCR were used to investigate anti-proliferative effect, amount of apoptosis and the effect of Fe3 O4 @Glu/BTSC on changes in gene expression of microRNA let-7c (let-7c), respectively. The specifications of Fe3 O4 @ Glu/BTSC were confirmed at 5 nm. Fe3O4@Glu/BTSC was more effective than BTSC and Fe3 O4 on A549 cells (IC50=166.77 µg/mL) but its effect on healthy cells was smaller (CC50=189.15 µg/mL). The drug selectivity index (SI) was calculated to be 1.13. The initial apoptosis rate was 46.33% for Fe3 O4 @Glu/BTSC, 28.27% for BTSC and 26.02% for Fe3 O4 . BTSC and BTSC@Fe3 O4 inhibited the cell cycle progression in the Sub-G1 and S phases. let-7c expression was 6.9 times higher in treated cells compared to the control group. The expression rate was 2.2 with BTSC compared to the control group and 1.6 times for Fe3 O4. Fe3 O4 @Glu/BTSC has proper anti-proliferative effects against lung cancer cells by increasing the expression of let-7c and inhibiting the cell cycle with the apoptosis activation pathway.

Endothelial Cell-Derived Let-7c-Induced TLR7 Activation on Smooth Muscle Cell Mediate Vascular Wall Remodeling in Moyamoya Disease.

Moyamoya disease (MMD) is characterized by frequent migration and phenotypic transformation of vascular smooth muscle cells (VSMCs) in the intima layer of blood vessels. However, the underlying mechanism is unclear. Toll-like receptor (TLR) 7 is abundantly expressed in smooth muscle cells (SMCs) in multiple vascular diseases, which might be linked to the disease-associated vascular remodeling. In the present study, the expression of TLR7 in MMD vessels was examined using the superficial temporal artery (STA) and middle cerebral artery (MCA) from MMD patients. Furthermore, the effect of TLR7 activation on the VSMC phenotype switch in vitro and vascular remodeling in vivo was assessed using a 9.4Tesla MRI. Our results demonstrated that the TLR7 and microRNA Let-7c expression are upregulated in VSMCs and the plasma of MMD patients, respectively. Additionally, TLR7 stimulation by Let-7c or Imiquimod induces a synthetic phenotype switch in VSMCs. Mechanistic studies revealed that Akt/mTOR signaling is responsible for this TLR-induced VSMC phenotypic switch. The Let-7c or Imiquimod treatment also resulted in reduced blood flow of internal carotid arteries (ICAs) in an in vivo model, while TLR7 inhibition attenuated the ICA stenosis. Besides, Let-7c was also found to be elevated in the hypoxic endothelial cells. Taken together, our study demonstrates that Let-7c released by endothelial cells under hypoxic conditions may activate TLR7 on VSMCs, ultimately leading to the phenotype switch and vascular wall remodeling. These findings thus elucidate the putative mechanisms underlying progressive stenosis of blood vessels in MMD and provide prospective therapeutic targets for further exploration.

Evaluation of Serum microRNA Let-7c and Let-7d as Predictive Biomarkers for Metastatic Pancreatic Cancer

Background:First-line treatments for metastatic pancreatic cancer are chemotherapy regimens consisting of 5-fluorouracil or gemcitabine; however, there are no biomarkers to help determine which patients might benefit from which treatment regimens. We aimed to show that microRNAs let-7c and 7d can be used as independent predictive biomarkers for metastatic pancreatic cancer.Methods:A total of 55 patients who had first-line chemotherapy with FOLFIRINOX or gemcitabine + capecitabine were included. Patients were divided into groups based on let-7c and let-7d levels and chemotherapy treatment as let-7c-7d high FOLFIRINOX, let-7c-7d high gemcitabine + capecitabine, let-7c-7d low FOLFIRINOX, and let-7c-7d low gemcitabine + capecitabine. Blood samples were taken from patients before chemotherapy for microRNA let-7c and 7d analysis. MicroRNA isolation was performed using a miRNeasy Serum/Plasma Kit and identified using spectrophotometric measurements. After isolation, microRNA was converted to cDNA using a microRNA cDNA Synthesis Kit with poly (A) polymerase tailing. The expression of microRNA was examined using quantitative real-time polymerase chain reaction.Results:The overall survival of patients who received FOLFIRINOX treatment with a high let-7c-7d level was statistically significantly longer than those who received gemcitabine + capecitabine with a high let-7c-7d level. In addition, patients with low let-7c expression receiving FOLFIRINOX progressed significantly 2.104 times earlier than patients with high let-7c expression receiving FOLFIRINOX.Conclusion:The serum MicroRNA let-7c level was found to be an independent predictive biomarker in the FOLFIRINOX treatment group.

Abstract 1151: Targeting castration-resistant prostate cancer using mesenchymal stem cell exosomes for therapeutic microRNA let-7c delivery

Abstract Introduction: Castration-resistant prostate cancer (CRPC) has poor response to androgen deprivation therapy, which is caused by a sustained androgen receptor (AR) signal and therefore is considered as an incurable disease. MicroRNA let-7c has been implied as a tumor suppressor in prostate cancer by antagonizing AR expression and activity. In addition to cancer cells, our group previously also demonstrated that downregulation of let-7c by cancer-associated mesenchymal stem cells (MSCs) triggering a reactive stromal response to facilitate prostate cancer growth and metastasis (PLoS ONE 8(8): e71637). Accordingly, treatment with exogenous let-7c would target both cancer cells and their associated MSCs and could be an attractive therapeutic approach to effectively inhibit CRPC recurrence and prevent metastasis. Exosomes are nanometer-sized membrane-bound vesicles with functions as mediators of cell-cell communication, which have the absolute predominance in biocompatibility for clinical applications in drug delivery and gene therapy. Objective: By taking the intrinsic tumor-targeting property of MSCs, this study aimed to investigate the feasibility of using MSC-derived exosomes as an exogenous let-7c delivery system to target CRPC. Methods: Relative miRNA-let-7c expression across various prostate cancer cell lines was examined using q-RT PCR. MSC-derived exosomes were collected from a 3A6 human bone marrow-derived MSC cell line after cell transfection with pre-miR negative control and pre-miR-let-7c, and further characterized through transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blot. The effects of either naked or MSC-exosome encapsulated let-7c on CRPC cells was determined by WST-1 cell proliferation assay and wound healing migration assay. Results: MiRNA-let-7c expression was confirmed to be downregulated in most of CRPC-like cell lines compared with androgen-sensitive LNCaP. Overexpression of pre-miR-let-7 inhibited the ability of cell proliferation and migration of prostate cancer cells. Exogenous microRNAs can be successfully packaged into MSC-exosomes by cell transfection, without a disruption of exosome integrity. Treatment of CRPC-like PC3 (AR-negative) and CWR22r-v1 (AR-positive) cells with MSC-exosome encapsulated let-7c effectively delivered let-7c into cells and resulted in a significant reduction in cancer cell growth and metastasis in vitro. Conclusion: Herein, we have provided in vitro evidences to prove the concept that microRNA let-7c is a potential therapeutic intervention for CRPC, as well as MSC-derived exosomes can serve as a therapeutic let-7c delivery system to target the CRPC. Further in vivo validation of distribution and therapeutic efficacy of MSC-exosome-delivered let-7c in CRPC xenograft mouse model is currently being explored. Citation Format: Ida Kurniawati, Chia-Yen Hsueh, Shian-Ying Sung, Chia-Ling Hsieh. Targeting castration-resistant prostate cancer using mesenchymal stem cell exosomes for therapeutic microRNA let-7c delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1151.

Mesenchymal Stem Cell-Derived Exosomes Induced by IL-1β Attenuate Urethral Stricture Through Let-7c/PAK1/NF-κB-Regulated Macrophage M2 Polarization.

BackgroundUrethral stricture is a clinical challenge for both patients and clinicians. Post-traumatic urethral stricture is associated with formation of scar tissue caused by excessive inflammation. The aim of this study is exploring potential therapeutic strategies for this condition.MethodsIn vivo experiments on New Zealand rabbits and in vitro experiments on THP-1 monocytes and urethral fibroblasts were performed to investigate the effects on post-traumatic urethral stricture of exosomes isolated from IL-1β-treated mesenchymal stem cells (Exo-MSCsIL−1β) and the role of macrophage M2 polarization in this process. Additionally, related signaling and mechanism behind were explored.ResultsIn a New Zealand rabbit model of post-traumatic urethral stricture, injection of Exo-MSCsIL−1β significantly reduced urethral stricture and collagen fiber accumulation compared with Exo-MSCs. Addition of Exo-MSCsIL−1β to THP-1 monocytes in vitro induced M2 macrophage polarization, which, in turn, inhibited activation of urethral fibroblasts and synthesis of collagen. Mechanistically, Exo-MSCsIL−1β were found to contain high levels of the microRNA let-7c, and luciferase reporter assays showed that let-7c interacted with the 3′UTR of PAK1 mRNA. Transfection of THP-1 cells with a let-7c mimic downregulated PAK1 expression and inhibited activation of the NF-κB signaling pathway.ConclusionThese results support a role for let-7c-containing Exo-MSCsIL−1β in reducing urethral stricture via inhibition of PAK1–NF-κB signaling, M2 macrophage polarization, and differentiation of urethral myofibroblasts.

Lin28A promotes the proliferation and stemness of lung cancer cells via the activation of mitogen-activated protein kinase pathway dependent on microRNA let-7c.

BackgroundAmong patients with lung cancer, metastatic and relapsed cases account for the largest proportion of disease-associated deaths. Tumor metastasis and relapse are believed to originate from cancer stem cells (CSCs), which have the capacity to be highly proliferative and invasive. In our previous studies, we established a conditional basement membrane extract-based (BME-based) 3-dimensional (3D) culture system to mimic the tumor growth environment in vivo and further amplified lung cancer stem cells (LCSCs) in our system. However, the molecular mechanisms of LCSC amplification and development in our 3D culture system have not been fully uncovered.MethodWe established the conditional 3D culture system to amplify LCSCs in other lung cancer cell lines, followed by examining the expression of Lin28A and let-7 microRNAs in them. We also explored the expression of Lin28A and let-7 microRNAs in LCSCs from clinical lung cancer tissue samples and even analyzed the correlation of Lin28A/let-7c and patients’ survival outcomes. We further constructed A549 cells either knockdown of Lin28A or overexpression of let-7c, followed by investigating stemness marker gene expression, and stemness phenotypes including mammosphere culture, cell migration and invasion in vitro, as well as tumorigenicity in vivo.ResultsHere, we observed that Lin28A/let-7c was dysregulated in LCSCs in both the 3D culture system and lung cancer tissues. Further, the abnormal expression of Lin28A/let-7c was correlated with poor survival outcomes. Via the construction of A549 cells with let-7c over-expression, we found that let-7c inhibited the maintenance of LCSC properties, while the results of Lin28A knockdown showed that Lin28A played a critical role in the enrichment and proliferation of LCSCs via mitogen-activated protein kinase (MAPK) signaling pathway. Importantly, we found that LCSCs with knockdown of Lin28A or over-expression of let-7c exhibited inhibited carcinogenesis and disrupted expansion in vivo.ConclusionsOur study uncovered the functions and mechanisms of the Lin28A/let-7c/MAPK signaling pathway in promoting the proliferation and cancer stemness of LCSCs, which might be a potential therapeutic target for reducing and even eliminating LCSCs in the future.

MicroRNA Let-7c Contributes to Paclitaxel Resistance via Aurora-B in Endometrial Serous Carcinoma.

The incidence of endometrial cancer has rapidly risen over recent years. Paclitaxel, a key drug for endometrial cancer treatment, inhibits microtubule depolymerization and induces apoptosis in cancer cells. Endometrial serous carcinoma (ESC) accounts for < 10% of all endometrial carcinomas, but its aggressive nature makes it responsible for close to 40% of cancer deaths. Thus, novel therapeutic targets are required for ESC. To identify microRNAs that promote paclitaxel resistance, we established two paclitaxel-resistant cell lines from USPC1 human ESC cells by exposing paclitaxel to parental cells for 12 weeks. Paclitaxel concentrations were increased every 2 weeks, and after 12 weeks of paclitaxel exposure, two replicate paclitaxel-resistant cell lines were established (USPC1-PTSR1 and USPC1-PTXR2). The microarray analysis was performed using USPC1 cells and USPC1-PTXR1 cells, and eight candidate microRNAs were thus selected as potential mediators of paclitaxel sensitivity. Among these candidate microRNAs, let-7c precursor treatment of paclitaxel-resistant USPC1-PTXR1 cells caused the greatest increase in paclitaxel-mediated cytotoxicity. Let-7c inhibition conversely decreased paclitaxel-induced apoptosis. It is known that let-7a microRNA, a member of the let-7 family, inhibits growth of endometrial carcinoma cells targeting Aurora-B that controls progression through each phase of mitosis. We thus studied whether let-7c mediates Aurora-B expression in ESC cells. The expression levels of Aurora-B mRNA and protein were higher in USPC-PTXR1 cells compared with USPC1 cells. Let-7c inhibition increased Aurora-B expression in USPC1 cells but decreased Aurora-B expression in USPC1-PTXR1 cells. These results indicate that let-7c mediates paclitaxel resistance via inhibition of Aurora-B expression in ESC cells.

MicroRNA let-7c Improves LPS-Induced Outcomes of Endometritis by Suppressing NF-κB Signaling.

Endometritis is a common inflammatory disease which endangers human and animal reproductive health. MicroRNA (miRNA) let-7c plays an important role in the inflammatory process; however, the regulatory underlying mechanism of let-7c in endometritis is unclear. In this study, we confirmed that let-7c was significantly reduced in LPS-induced mouse endometritis model, and overexpression of let-7c was able to effectively reduce uterine tissue damage caused by lipopolysaccharide (LPS), and then, a LPS-induced bovine endometrial epithelial cell (BEND) line was used to mimic the inflammatory model in vitro. Our data showed that overexpression of let-7c significantly reduced the expression of pro-inflammatory cytokines in BEND cells induced by LPS. Meanwhile, immunofluorescence and western blotting results showed that let-7c significantly inhibited LPS-induced phosphorylation of NF-κB, thereby inhibiting downstream pro-inflammatory cytokine expression. Taken together, our results suggested that let-7c ameliorates LPS-induced endometritis by attenuating the expression of pro-inflammatory cytokines via inhibition of the activation of NF-κB.

GW29-e0252 MicroRNA let-7c inhibits Bcl-xl expression and regulates ox-LDL-induced endothelial apoptosis

GW29-e0252 MicroRNA let-7c inhibits Bcl-xl expression and regulates ox-LDL-induced endothelial apoptosis

Hsa-let-7c controls the committed differentiation of IGF-1-treated mesenchymal stem cells derived from dental pulps by targeting IGF-1R via the MAPK pathways

The putative tumor suppressor microRNA let-7c is extensively associated with the biological properties of cancer cells. However, the potential involvement of let-7c in the differentiation of mesenchymal stem cells has not been fully explored. In this study, we investigated the influence of hsa-let-7c (let-7c) on the proliferation and differentiation of human dental pulp-derived mesenchymal stem cells (DPMSCs) treated with insulin-like growth factor 1 (IGF-1) via flow cytometry, CCK-8 assays, alizarin red staining, real-time RT-PCR, and western blotting. In general, the proliferative capabilities and cell viability of DPMSCs were not significantly affected by the overexpression or deletion of let-7c. However, overexpression of let-7c significantly inhibited the expression of IGF-1 receptor (IGF-1R) and downregulated the osteo/odontogenic differentiation of DPMSCs, as indicated by decreased levels of several osteo/odontogenic markers (osteocalcin, osterix, runt-related transcription factor 2, dentin sialophosphoprotein, dentin sialoprotein, alkaline phosphatase, type 1 collagen, and dentin matrix protein 1) in IGF-1-treated DPMSCs. Inversely, deletion of let-7c resulted in increased IGF-1R levels and enhanced osteo/odontogenic differentiation. Furthermore, the ERK, JNK, and P38 MAPK pathways were significantly inhibited following the overexpression of let-7c in DPMSCs. Deletion of let-7c promoted the activation of the JNK and P38 MAPK pathways. Our cumulative findings indicate that Let-7c can inhibit the osteo/odontogenic differentiation of IGF-1-treated DPMSCs by targeting IGF-1R via the JNK/P38 MAPK signaling pathways.

Let-7c inhibits cholangiocarcinoma growth but promotes tumor cell invasion and growth at extrahepatic sites

Cholangiocarcinoma (CCA) is a cancer type with high postoperative relapse rates and poor long-term survival largely due to tumor invasion, distant metastasis, and multidrug resistance. Deregulated microRNAs (miRNAs) are implicated in several cancer types including CCA. The specific roles of the miRNA let-7c in cholangiocarcinoma are not known and need to be further elucidated. In our translational study we show that microRNA let-7c expression was significantly downregulated in human cholangiocarcinoma tissues when compared to adjacent tissues of the same patient. Let-7c inhibited the tumorigenic properties of cholangiocarcinoma cells including their self-renewal capacity and sphere formation in vitro and subcutaneous cancer cell growth in vivo. Ectopic let-7c overexpression suppressed migration and invasion capacities of cholangiocarcinoma cell lines in vitro, however, promoted distant invasiveness in vivo. Furthermore, we found that let-7c regulated the aforementioned malignant biological properties, at least in part, through regulation of EZH2 protein expression and through the DVL3/β-catenin axis. The miRNA let-7c thus plays an important dual role in regulating tumorigenic and metastatic abilities of human cholangiocarcinoma through mechanisms involving EZH2 protein and the DVL3/β-catenin axis.

Up-regulation of microRNA let-7c by quercetin inhibits pancreatic cancer progression by activation of Numbl.

Pancreatic Ductal Adenocarcinoma (PDA) is a highly malignant tumor with poor prognosis. MicroRNAs (miRs) may offer novel therapeutic approaches to treatment. The polyphenol quercetin, present in many fruits and vegetables, possesses anti-carcinogenic properties. To unravel the effect of quercetin to miR signaling we performed miR profiling in PDA cells before and after quercetin treatment, followed by biostatistical analysis. miR let-7c was among the top up-regulated candidates after quercetin treatment, as measured by qRT-PCR and confirmed in two established and one primary PDA cell lines. By computational analysis we identified the Notch-inhibitor Numbl as let-7c target gene. This was strengthened by luciferase assays, where lipofected let-7c mimics induced a Numbl 3-UTR wild type construct, but not the mutated counterpart. Let-7c induced Numbl mRNA and protein expression but inhibited Notch just like quercetin. It also inhibited colony formation, wound healing, and protein expression of progression markers. In vivo xenotransplantation of PDA cells and subsequent intravenous injection of let-7c resulted in a significant decrease in tumor mass without obvious toxic effects in the fertilized chick egg model. The delivery rate of the miR mimics to the tumor mass was 80%, whereas minor amounts were present in host tissue. By immunohistochemistry we demonstrated that let-7c inhibited Notch and progression markers but up-regulated Numbl. These findings show that quercetin-induced let-7c decreases tumor growth by posttranscriptional activation of Numbl and indirect inhibition of Notch.

MicroRNA let-7c is essential for the anisomycin-elicited apoptosis in Jurkat T cells by linking JNK1/2 to AP-1/STAT1/STAT3 signaling.

Anisomycin, an antibiotic produced by Streptomyces griseolus, strongly induces apoptosis in various tumor cells in vitro, superior dramatically to adriamycin. The present study aims to elucidate its detailed mechanistic process. The results showed that anisomycin sufficiently promoted the apoptosis in human leukemic Jurkat T cells at a quite low dose. microRNA let-7c (let-7c) contributed to the anisomycin-induced apoptosis, which could be abrogated by the inactivation of JNK signaling. The let-7c over-expression and the addition of its mimics facilitated the activation of AP-1, STAT1 and Bim by linking JNK1/2 to AP-1/STAT1, but rather inhibited the activation of STAT3 and Bcl-xL by connecting JNK1/2 to STAT3, followed by the augmented apoptosis in the cells. The let-7c deficiency reduced the AP-1, STAT1 and Bim activities, and enhanced the STAT3 and Bcl-xL, alleviating the anisomycin-induced apoptosis. The knockdown of the bim gene repressed the anisomycin-boosted apoptosis through the attenuation of the active Bak and Bax. The findings indicate for the first time that miR let-7c is essential for the anisomycin-triggered apoptosis by linking JNK1/2 to AP-1/STAT1/STAT3/Bim/Bcl-xL/Bax/Bak signaling. This provides a novel insight into the mechanism by which anisomycin leads to the tumor cell apoptosis, potentially laying the foundations for its development and clinical application.

JMJD1A promotes tumorigenesis and forms a feedback loop with EZH2/let-7c in NSCLC cells.

Lung cancer is the most common cause of cancer-related deaths worldwide, and non-small cell lung cancer (NSCLC) accounts for 80 to 85% of all lung cancer. Although the standard treatment regimen has been established, long-term survival for NSCLC patients is still generally poor. The histone demethylase Jumonji domain containing 1A (JMJD1A) has been proposed as an oncogene in several types of human cancer, but its clinical significance and functional roles in NSCLC remain largely unclear. In the present study, JMJD1A was frequently upregulated in NSCLC compared with para-carcinoma tissues. JMJD1A knockdown significantly inhibited NSCLC cell growth, migration, and invasion in vitro and tumorigenesis in vivo. Further experiments demonstrated that JMJD1A knockdown could decrease the expression of EZH2, which has been shown to play a crucial role in the carcinogenesis of NSCLC and, in turn, increase the expression of anti-tumor microRNA let-7c. Also, let-7c directly targeted the 3'-untranslated regions of JMJD1A and EZH2. Taken together, JMJD1A could promote NSCLC tumorigenesis. JMJD1A/EZH2/let-7c constituted a feedback loop and might represent a promising therapeutic target for NSCLC.

Anti-inflammatory role of microRNA let-7c in LPS treated alveolar macrophages by targeting STAT3.

To explore the expression of microRNA (miRNA) let-7c and its function in chronic obstructive pulmonary disease (COPD) and alveolar macrophage cells. Real time PCR was performed to detect the expression of miRNA let-7c in the lung tissue of COPD patients and COPD model in mice. MiRNA let-7c was overexpressed in alveolar macrophages isolated from mice and its effect was measured by the production of pro-inflammation cytokines and the protein level of signal transducer and activator of transcription 3 (STAT3) as well as phosphorylation level of STAT3 after LPS stimulation. Luciferase assay was used to detect the binding of miRNA let-7c and 3'UTR of STAT3. MiRNA let-7c expression was significantly lower in patients with COPD compared with control group, and the similar result was found in COPD mice and LPS stimulated alveolar macrophages. Overexpression of miRNA let-7c in alveolar macrophages inhibited LPS-induced increasing of tumor necrosis factor alpha, interleukin-6 and interleukin-1β. Luciferase assay showed STAT3 was a targeting of miRNA let-7c in alveolar macrophages. MiRNA let-7c low expression in COPD can regulate inflammatory responses by targeting STAT3 in alveolar macrophage, which may provide a new target for COPD treatment strategies.

Elevated Serum MicroRNA Let-7c in Moyamoya Disease

Few studies have examined the relationship between mircroRNAs and moyamoya disease (MMD). We performed a study of the significance of let-7c expression in the serum of MMD patients. The experimental group includes 49 MMD patients, and the control group consists of 30 normal people, 20 cerebral hemorrhage patients, 20 massive cerebral infarction patients, 20 nonmassive cerebral infarction patients, and 20 neurological autoimmune disease patients. Let-7 family levels were determined by polymerase chain reaction. A dual luciferase assay was used to test whether let-7c recognized the 3'UTR of RNF213. The expression level of let-7c in MMD patients is higher than that observed in the control groups (P < .001). The luciferase assay results indicated that hsa-let-7c could diminish luciferase activity from a reporter vector containing the 3'-UTR of RNF213 (P < .05). The suppression of luciferase activity is not found in mutRNF213 (P > .05). Increased expression of let-7c in MMD patients may contribute to MMD pathogenesis by targeting RNF213. Thus, let-7c may be a potential biomarker for the diagnosis of MMD.

MicroRNA let-7c Inhibits Cell Proliferation and Induces Cell Cycle Arrest by Targeting CDC25A in Human Hepatocellular Carcinoma.

Down-regulation of the microRNA let-7c plays an important role in the pathogenesis of human hepatocellular carcinoma (HCC). The aim of the present study was to determine whether the cell cycle regulator CDC25A is involved in the antitumor effect of let-7c in HCC. The expression levels of let-7c in HCC cell lines were examined by quantitative real-time PCR, and a let-7c agomir was transfected into HCC cells to overexpress let-7c. The effects of let-7c on HCC proliferation, apoptosis and cell cycle were analyzed. The in vivo tumor-inhibitory efficacy of let-7c was evaluated in a xenograft mouse model of HCC. Luciferase reporter assays and western blotting were conducted to identify the targets of let-7c and to determine the effects of let-7c on CDC25A, CyclinD1, CDK6, pRb and E2F2 expression. The results showed that the expression levels of let-7c were significantly decreased in HCC cell lines. Overexpression of let-7c repressed cell growth, induced cell apoptosis, led to G1 cell cycle arrest in vitro, and suppressed tumor growth in a HepG2 xenograft model in vivo. The luciferase reporter assay showed that CDC25A was a direct target of let-7c, and that let-7c inhibited the expression of CDC25A protein by directly targeting its 3ʹ UTR. Restoration of CDC25A induced a let-7c-mediated G1-to-S phase transition. Western blot analysis demonstrated that overexpression of let-7c decreased CyclinD1, CDK6, pRb and E2F2 protein levels. In conclusion, this study indicates that let-7c suppresses HCC progression, possibly by directly targeting the cell cycle regulator CDC25A and indirectly affecting its downstream target molecules. Let-7c may therefore be an effective therapeutic target for HCC.

Insulin-like Growth Factor 1 Differentially Affects Lithium Sensitivity of Lymphoblastoid Cell Lines from Lithium Responder and Non-responder Bipolar Disorder Patients.

Bipolar disorder (BD) is a chronic psychiatric illness with an unknown etiology. Lithium is considered the cornerstone in the management of BD, though about 50-60 % of patients do not respond sufficiently to chronic treatment. Insulin-like growth factor 1 (IGF1) has been identified as a candidate gene for BD susceptibility, and its low expression has been suggested as a putative biomarker for lithium unresponsiveness. In this study, we examined the in vitro effects of insulin-like growth factor 1 (IGF-1) on lithium sensitivity in lymphoblastoid cell lines (LCLs) from lithium responder (R) and non-responder (NR) bipolar patients. Moreover, we evaluated levels of microRNA let-7c, a small RNA predicted to target IGF1. We found that exogenous IGF-1 added to serum-free media increased lithium sensitivity selectively in LCLs from NR BD patients. However, no significant differences were observed when comparing let-7c expression in LCLs from R vs. NR BD patients. Our data support a key role for IGF-1 in lithium resistance/response in the treatment of bipolar disorder.

MicroRNA let-7c (MIRLET7C; let-7c), miR-99a and miR-125b as prognostic markers of luminal breast cancer

MicroRNA let-7c (MIRLET7C; let-7c), miR-99a and miR-125b as prognostic markers of luminal breast cancer