miR-145-3p Inhibits MuSCs Proliferation and Mitochondria Mass via Targeting MYBL1 in Jianzhou Big-Eared Goats.

Muscle growth and injury-induced regeneration are controlled by skeletal muscle satellite cells (MuSCs) through myogenesis in postnatal animals. Meanwhile, myogenesis is accompanied by mitochondrial function and enzyme activity. Nevertheless, the underlying molecular mechanisms involving non-coding RNAs including circular RNAs (circRNAs) and microRNAs (miRNAs) remain largely unsolved. Here, we explored the myogenic roles of miR-145-3p and MYBL1 on muscle development and mitochondrial mass. We noticed that overexpression of miR-145-3p inhibited MuSCs proliferation and reduced the number of viable cells. Meanwhile, deficiency of miR-145-3p caused by LNAantimiR-145-3p or an inhibitor retarded the differentiation of MuSCs. miR-145-3p altered the mitochondrial mass in MuSCs. Moreover, miR-145-3p targeted and negatively regulated the expression of CDR1as and MYBL1. The knockdown of the MYBL1 using ASO-2'MOE modification simulated the inhibitory function of miR-145-3p on cell proliferation. Additionally, MYBL1 mediated the regulation of miR-145-3p on Vexin, VCPIP1, COX1, COX2, and Pax7. These imply that CDR1as/miR-145-3p/MYBL1/COX1, COX2, VCPIP1/Vexin expression at least partly results in a reduction in mitochondrial mass and MuSCs proliferation. These novel findings confirm the importance of mitochondrial mass during myogenesis and the boosting of muscle/meat development in mammals.

LINC00958 promotes endometrial cancer cell proliferation and metastasis by regulating the miR-145-3p/TCF4 axis.

BACKGROUND: Long noncoding RNAs (lncRNAs) exert an essential regulatory role in cancer progression. This work focuses on the role of LINC00958 in endometrial cancer (EC). METHODS: LINC00958 expression in EC tissues was examined by GEPIA database and TCGA-UCEC dataset. LINC00958, miR-145-3p, and TCF4 mRNA expression levels in EC tissues and cells were examined by qRT-PCR. Western blot was employed to determine TCF4, E-cadherin, and N-cadherin protein expression levels. After LINC00958 was overexpressed or silenced, cell proliferation was determined using Cell Counting Kit 8 (CCK-8) and bromodeoxyuridine (BrdU) incorporation experiments. Cell migration and invasion were examined by Transwell experiment. Dual-luciferase reporter gene or RNA immunoprecipitation (RIP) experiments were executed to validate the targeting relationships among LINC00958 and miR-145-3p and TCF4. The effects of LINC00958 on EC cell proliferation and metastasis were investigated in vivo using a nude mouse subcutaneous graft model and a caudal vein injection model. RESULTS: LINC00958 was remarkably upmodulated in EC. Moreover, its overexpression was strongly linked to unfavorable overall survival of the patients. Functional experiments confirmed that in vitro knockdown of LINC00958 suppressed EC cell proliferation and metastasis. LINC00958 was validated to decoy miR-145-3p and repressed its expression, and TCF4 was uncovered to be a target gene of miR-145-3p and negatively modulated by miR-145-3p. Furthermore, the function of LINC00958 was dependent on its regulation of miR-145-3p and TCF4. CONCLUSIONS: LINC00958 acts as an oncogenic lncRNA to regulate EC progression by modulating the miR-145-3p/TCF4 axis. Knockdown of LINC00958 impedes tumor growth and metastasis in vitro and in vivo, opening a new avenue for therapeutic intervention.

Circ_KATNAL1 regulates prostate cancer cell growth and invasiveness through the miR-145-3p/WISP1 pathway.

Prostate cancer (PCa) is the second leading cause of death in men, and current studies have shown that circular RNAs (circRNAs) play important roles in its occurrence and development. Detection of circRNAs in PCa cells showed that circ_KATNAL1 is down-regulated, mainly located in the cytoplasm, and contains multiple binding sites of miR-145-3p, which is an anticancer miRNA. RNA immunoprecipitation with anti-AGO2 antibody, RNA pull-down assays with biotin-labeled circ_KATNAL1 probe or an miR-145-3p mimic, and dual luciferase reporter gene assays confirmed that circ_KATNAL1 binds directly to miR-145-3p in cells, and that WISP1, which is highly expressed in many types of tumors, is an important target gene of miR-145-3p. Circ_KATNAL1 and miR-145-3p promote each other's expression, and down-regulate the expression of the target gene WISP1. Both circ_KATNAL1 and miR-145-3p inhibit cell proliferation, invasiveness, and migration, down-regulate the expression of MMP-2 and MMP-9, promote cell apoptosis and the activation of caspase-3, caspase-8, caspase-9, and PARP, whereas WISP1 has the opposite effect, and the above-mentioned functions of circ_KATNAL1 were achieved through the miR-145-3p/WISP1 pathway. Therefore, circ_KATNAL1 plays an anticancer role in PCa cells through the miR-145-3p/WISP1 pathway, which could be an important target for the diagnosis and treatment of PCa.

Genomic and functional characterization of the lect2 gene from Siniperca chuatsi.

Mandarin fish (Siniperca chuatsi) is an important economic fish in China. Viral and bacterial diseases seriously affect the artificial culture of S. chuatsi. As a carnivorous fish, artificial feed domestication is also an important means to improve the scale of S. chuatsi culture. Therefore, the study of immunology and digestive physiology is very important to the industrial development of S. chuatsi. In this work, we analyzed the expression and function of the S. chuatsi leukocyte cell-derived chemotaxin 2 (Sc-lect2) gene on a basis of next generation, single-molecule long-read sequencing. Sc-lect2 was mainly expressed in the liver but barely expressed in the gill, skin, muscle, kidney, head kidney, brain, stomach, and intestine. When the fish were infected with infectious spleen and kidney necrosis virus and challenged with lipopolysaccharide and polyinosinic-polycytidylic acid, Sc-lect2 expression significantly increased by about 40, 17, and 7-fold, respectively, compared with unstimulated samples. We also found that Sc-lect2 increases by approximately 8-fold after the fish are fed an artificial diet. These results show that mandarin fish liver can not only digest food but also express specific immune genes. Changes in the diet can cause the differential expression of Sc-lect2 genes. Four Sc-lect2 interaction genes were differentially expressed in the skin or blood. Interestingly, miR-145-3p could inhibit Sc-lect2 gene expression by targeting its coding sequence region. One CpG island in the promoter region showed a high level of methylation, suggesting that high methylation does not affect Sc-lect2 gene expression in the liver.

Small extracellular vesicles derived from tendon stem cells promote the healing of injured Achilles tendons by regulating miR-145-3p.

The therapeutic role of tendon stem cells (TSCs) in tendon-related injuries has been well documented. Small extracellular vesicles (sEVs) are being increasingly used as new biotherapeutic agents for various diseases. Therefore, the potential function of TSC-sEVs in tendon injury repair warrants further investigation. In this study, we explored the effects of TSC-sEVs on TSC proliferation, migration, and differentiation in vitro in an autocrine manner. We further used a novel exosomal topical treatment with TSC-sEVs loaded with gelatin methacryloyl (GelMA) hydrogel in vivo; we mixed sufficient amounts of TSC-sEVs with GelMA hydrogel to cover the damaged molded Achilles tendon tissue and then exposed them to UV irradiation for coagulation. GelMA loading ensured that TSC-sEVs were slowly released at the injury site over a long period, thereby achieving their full local therapeutic effects. Treatment with TSC-sEVs loaded with GelMA significantly improved the histological score of the regenerated tendon by increasing the tendon expression while inhibiting the formation of excessive ossification and improving the mechanical properties of the tissue. Moreover, miRNA sequencing in TSC-sEVs, TSCs, and TSCs receiving sEVs revealed that TSC-sEVs altered the miRNA expression profile of TSCs, with increased expression of miR-145-3p. In conclusion, our study demonstrates that TSC-sEVs can play a key role in treating tendon injuries and that loading them with GelMA can enhance their effect in vivo. Moreover, miR-145-3p has a major functional role in the effect of TSC-sEVs. This study offers new therapeutic ideas for the local treatment of Achilles tendon injuries using sEVs. STATEMENT OF SIGNIFICANCE: In this study, we demonstrated that TSC-sEVs play a key role in treating tendon injuries and that loading them with GelMA hydrogel can act as a fixation and slow release in vivo. Moreover, it identifies the major functional role of miR-145-3p in the effect of TSCs that were identified and validated by miRNA sequencing. Our study provides a basis for further research on GelMA slow-release assays that have potential clinical applications. It offers new therapeutic ideas for the local treatment of Achilles tendon injuries using TSC-sEVs.

[Corrigendum] The targeting of MTDH by miR­145­5p or miR­145­3p is associated with prognosis and regulates the growth and metastasis of prostate cancer cells.

Following the publication of the above article, an interested reader drew to the authors' attention that the Transwell invasion assay images in Fig. 3B on p. 1961 representing the Con/PWR­1E and the PC­3/siMTDH experiments contained overlapping sections, such that they appeared to have been derived from the same original source, even though they were intending to have shown the results from differently performed experiments. Similarly, in Fig. 8A on p. 1965, the representative images selected for the PC­3/miR­145­3p and LNCaP/miR­145­3p data panels were also found to contain overlapping sections. After having consulted their original data, the authors realized that these errors had occurred while compiling the affected figure parts. The revised versions of Figs. 3 and 8, containing the data from one of the repeated experiments in Fig. 3B and 8A, are shown on the next two pages. Concerns about the western blots featured in Figs. 4C and D and 9F were also raised by the interested reader; upon querying these with the authors, however, they were able to provide the full blots in these cases, thereby confirming their authenticity. The authors regret that these errors went unnoticed prior to publication, and thank the Editor of International Journal of Oncology for allowing them the opportunity to publish this corrigendum. All the authors agree with the publication of this corrigendum; furthermore, they also apologize to the readership of the journal for any inconvenience caused. [International Journal of Oncology 54: 1955­1968, 2019; DOI: 10.3892/ijo.2019.4782].

LINC00958 Targets miR-145-3p/CDK1 Axis to Aggravate the Malignancy of Colon Cancer.

OBJECTIVE: Studies summarize that LINC00958 manifests considerable oncogenic potential in diverse cancers. However, its role in colon cancer (CC) is rarely studied. Herein, we attempted to disclose LINC00958's mechanism of action and function in the development of CC. METHODS: The relative expressions of LINC00958, CDK1 mRNA, and miR-145-3p were quantified by means of RT-qPCR. CDK1 protein levels were determined via western blotting. CCK-8, wound healing, and transwell experiments were conducted to assess the abilities of cells to proliferate, migrate, and invade. To ascertain the role of LINC00958, in vivo xenograft assays were performed. The predicted binding relationships of miR-145-3p with LINC00958 and CDK1 were confirmed by means of dual-luciferase reporter and RIP studies. RESULTS: A reinforced expression of LINC00958 was observed among CC cells and tumor samples. The deficiency in LINC00958 not only restrained the invasion, migration, and proliferation of the cancer cells but also impeded the development of tumors in vivo. LINC00958 directly bound to miR-145-3p, which was downregulated in CC. Consequently, the depletion in miR-145-3p attenuated the anti-cancer effects induced by the shortage of LINC00958. MiR-145-3p directly interacted with downstream functional molecule CDK1. CDK1 expression was enhanced in CC. It exerted oncogenic properties by stimulating CC cell proliferation, invasion, and survival. Meanwhile, miR-145-3p negatively modulated the expression of CDK1, thus attenuating the oncogenic effects produced by CDK1 in CC. CONCLUSIONS: LINC00958 interacts with miR-145-3p and modulates the miR-145-3p/CDK1 axis. Hence, LINC00958 contributes to CC's malignant progression.

Knockdown of rno_circRNA_009194 Improves Outcomes in Traumatic Brain Injury Rats through Inhibiting Voltage-Gated Sodium Channel Nav1.3.

Excessive activation of voltage-gated sodium channel Nav1.3 has been recently reported in secondary traumatic brain injury (TBI). However, the molecular mechanisms underlying regulating voltage-gated sodium channel (Nav1.3) have not been well understood. The present study used a TBI rat model induced by a fluid percussion device and performed a circular RNA (circRNA) microarray (n = 3) to profile the altered circRNAs in the hippocampus after TBI. After polymerase chain reaction (PCR) validation, certain circRNAs were selected to investigate the function and mechanism in regulating Nav1.3 in the TBI rat model by intracerebroventricular injection with lentivirus. The neurological outcome was evaluated by Morris water maze test, modified Neurological Severity Score (mNSS), brain water content measurement, and hematoxylin and eosin staining. The related molecular mechanisms were explored with PCR, Western blotting, luciferase reporter, chromatin immunoprecipitation assay, and electrophoretic mobility shift assay (EMSA). A total of 347 circRNAs were observed to be differentially expressed (fold change [FC] ≥ 1.2 and p < 0.05) after TBI, including 234 up-regulated and 113 down-regulated circRNAs. Among 10 validated circRNAs, we selected circRNA_009194 with the maximized up-regulated fold change (n = 5, FC = 4.45, p < 0.001) for the in vivo functional experiments. Down-regulation of circRNA_009194 resulted in a 27.5% reduced mNSS in rat brain (n = 6, p < 0.01) after TBI and regulated the expression levels of miR-145-3p, Sp1, and Nav1.3, which was reversed by sh-miR-145-3p or Sp1/Nav1.3 overexpression (n = 5, p < 0.05). Mechanistically, circRNA_009194 might act as a sponge for miR-145-3p to regulate Sp1-mediated Nav1.3. This study demonstrated that circRNA_009194 knockdown could improve neurological outcomes in TBI in vivo by inhibiting Nav1.3, directly or indirectly.

Long noncoding RNA H19 suppresses cardiac hypertrophy through the MicroRNA-145-3p/SMAD4 axis.

Sustained cardiac hypertrophy (CH) contributes to many heart diseases. Long noncoding RNAs (lncRNAs) collectively play critical roles in cardiovascular diseases (CVDs). However, the roles of lncRNA H19 in CH are still unclear. A CH model was constructed utilizing isoproterenol (ISO). We demonstrated H19 could participate in regulating ISO-induced CH development both in vivo and in vitro. The online databases DIANA and TargetScan were used to predict the targets of H19 and MicroRNA-145-3p (miR-145-3p), respectively. Luciferase reporter assay was used to verify the downstream targets. The results showed that H19 was decreased under ISO stimulation. The H19 overexpression resulted in significant decrease in mouse heart size and weight, left ventricular systolic dysfunction, left ventricular posterior wall thickness and cardiac hypertrophic growth, while promoted the increase of left ventricular ejection fraction and left ventricle fraction shortening. H19 also inhibited protein expression levels of CH markers, such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and MYH7. Luciferase assays results showed that miR-145-3p was a target of H19 and SMAD4 was a target of miR-145-3p. We found that H19 regulated SMAD4 by sponging miR-145-3p. Knockout of miR-145-3p or overexpression of SMAD4 facilitated H19-induced decreases in ANP, BNP, and MYH7. Collectively, our findings have indicated that the H19/miR-145-3p/SMAD4 axis should be a negative regulator involved in CH progression.

PCDHB17P/miR-145-3p/MELK/NF-κB Feedback Loop Promotes Metastasis and Angiogenesis of Breast Cancer.

Breast cancer is one of the most common life-threatening cancers, mainly because of its aggressiveness and metastasis. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) participate in the development and progression of breast cancer. Nevertheless, the function and expression level of lncRNAs in breast cancer are still not fully understood. Here, we demonstrated that lncRNA PCDHB17P was up-expressed in human breast cancer tissues and cell lines. Knockdown of PCDHB17P remarkably suppressed migration and invasion, as well as tube formation ability of breast cancer cells. MiR-145-3p was significantly decreased in breast cancer samples, which was negatively correlated to the expression of PCDHB17P. In addition, we identified that MELK was a direct target gene of miR-145-3p, which was higher expressed in breast cancer tissues than that in adjacent normal tissues. Mechanistic investigation indicated that PCDHB17P acted as a cancer-promoting competing endogenous RNA (ceRNA) by binding miR-145-3p and upregulating MELK. Interestingly, MELK could in turn increase the promoter activity and expression of PCDHB17P via NF-κB, thus forming a positive feedback loop that drives the metastasis and angiogenesis of breast cancer. Overall, the results demonstrated that the constitutive activation of PCDHB17P/miR-145-3p/MELK/NF-κB feedback loop promotes the metastasis and angiogenesis of breast cancer, suggesting that this lncRNA might be a promising prognostic biomarker and therapeutic target for breast cancer.

Increased Salivary microRNAs That Regulate DJ-1 Gene Expression as Potential Markers for Parkinson's Disease.

Small molecule RNAs (microRNAs) are a kind of endogenous, stable, and noncoding RNA molecule that can regulate the expression of target genes such as DJ-1 at the posttranscriptional level. This study aimed to detect the expression of salivary microRNAs and to discover their value as a salivary potential biomarker for Parkinson's disease (PD). Through a case-control study, RT-qPCR technology was used to detect the expression of miR-874 and miR-145-3p in the saliva of 30 PD patients and 30 healthy volunteers. Then we compared the differences in the expression levels of salivary miR-874 and miR-145-3p between the PD group and the control group and analyzed the correlation between the expression of salivary miR-874 and miR-145-3p in terms of age, gender, disease condition, and disease course. We found that salivary miR-874 and miR-145-3p were both positively expressed in the PD group and control group, and their expression in the PD group was higher than that in the control group. The expression of salivary miRNA-874 and miR-145-3p had no clear correlation to age, gender, total RNA concentrations in saliva, the score of UPDRSII, UPDRSIII, olfactory test scale, MMSE, MoCA, Hohn-Yahr stage and disease course. In conclusion, in the PD group and the control group with positive expression, the expression levels of miR-874 and miR-145-3p in the PD group were higher than those in the control group. The detection of miR-874 and miR-145-3p expression in saliva can be used as an auxiliary biomarker for PD.

MIR145-3p promotes autophagy and enhances bortezomib sensitivity in multiple myeloma by targeting HDAC4.

Multiple myeloma (MM) is an incurable plasma cell malignancy with poor survival. Autophagy, a stress-responsive catabolic process mediated by lysosomal activity, plays a crucial role in the pathophysiology of MM. Growing evidence has indicated that dysregulated microRNAs (miRNAs) are associated with the aberrant autophagy in various human cancers. However, to date, few miRNAs have been reported to directly modulate autophagy in the pathobiology of MM. In this study, we investigated the role of MIR145-3p (microRNA 145-3p) in MM, with focus on cellular processes autophagy and cell death. Our results provided evidence that downregulation of MIR145-3p expression was associated with disease progression in human MM. MIR145-3p triggered autophagic flux through direct targeting of HDAC4 (histone deacetylase 4) in MM cells, leading to enhanced apoptosis. Silencing HDAC4 recapitulated the effects of MIR145-3p, whereas enforced expression of HDAC4 abrogated the effects of MIR145-3p. Furthermore, we showed that suppression of HDAC4 by MIR145-3p resulted in upregulation of the pro-apoptotic protein BCL2L11 and caused MTORC1 inactivation, which in turn led to enhanced autophagy and cell death. Importantly, we demonstrated that MIR145-3p mimic could potentiate the anti-MM activity of bortezomib in both in vitro and in vivo experiments. Overall, our findings indicate that MIR145-3p exerted a tumor suppression function in MM by inducing autophagic cell death and suggest that MIR145-3p-based targeted therapy would represent a novel strategy for MM treatment.Abbreviations: 3-MA: 3-methyladenine; 3'-UTR: 3'-untranslated region; 7-AAD: 7-aminoactinomycin D; ACTB: actin beta; ANXA5: annexin A5; ATG5: autophagy related 5; ATG7: autophagy related 7; B2M: beta-2-microglobulin; BAF: bafilomycin A1; BCL2L11: BCL2 like 11; Bort: bortezomib; CASP3: caspase 3; CCK-8: Cell Counting Kit-8; CQ: chloroquine; Ct: threshold cycle; ctrl: control; DAPI: 4',6-diamidino-2-phenylindole; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HDAC4: histone deacetylase 4; ISS: International Staging System; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; miRNAs: microRNAs; MIR145-3p: microRNA 145-3p; MM: multiple myeloma; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; PCs: plasma cells; PFS: progression-free survival; qRT-PCR: quantitative reverse transcription PCR; RPS6KB1: ribosomal protein S6 kinase B1; SD: standard deviation; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STV: starvation; TUBB: tubulin beta class I.

IL-16 regulates macrophage polarization as a target gene of mir-145-3p.

BACKGROUND: Interleukin 16 is an immunomodulatory chemokine that signals through CD4 + T cells, monocytes, macrophages and dendritic cells. Its expression in immune-related cells enhances the antimicrobial effect and inhibits HIV replication in macrophages. However, the role of IL-16 in macrophage polarization is uncertain. Mir-145 was reported to regulate IL-10 expression by targeting histone deacetylase 11 and promotes alternatively activated macrophage (M2) polarization. Mir-145 was also predicted to target IL-16 mRNA. We aimed to explore the roles of IL-16 and mir-145 in macrophage polarization and antimicrobial functions. METHODS: THP1 monocytes were employed in this study, and their cell activity when incubated with different concentrations of IL-16 was evaluated using the CCK-8 cell counting kit. To obtain polarized macrophages, THP-1 cells were induced by IL-4 and IL-13 following PMA incubation (M2 polarized macrophages) or induced by IFN-gamma and LPS (M1 classical macrophage activation). The influence of IL-16 on macrophage phagocytosis was quantified by the amount of chicken red blood cell phagocytized. IL-16, IL-10 and miR-145 expression in THP1 monocytes and induced macrophages was quantified by quantitative PCR. The miR-145 and IL-16 targeting relationship was verified by the dual luciferase reporter assay. The influence of IL-16 and mir-145 on macrophage polarization was evaluated by M1 and M2 macrophage characterized marker gene expression. RESULTS: The M0 macrophage subtype was induced by PMA. The M1 and M2 subtypes of macrophage were successfully induced by M1- and M2-specific induction. M1 macrophages express higher levels of IL-16 than M2 macrophages but express lower levels of IL-10 and mir-145 than M2 cells. IL-16 with a concentration up to 150 ng/mL has no influence on THP-1 cell proliferation but improves macrophage phagocytosis ability with the down-expression of IL-10 and up-expression of pro-inflammatory cytokines such as IL-1a and IL-6. Knockdown with its target siRNA is beneficial for macrophage maintenance but reduces phagocytosis ability. Mir-145 specifically targets the IL-16 3'UTR verified by the dual luciferase reporter assay. Mir-145 downregulates IL-16 expression and upregulates IL-10 expression, thereby promoting M2 macrophage polarization. CONCLUSION: IL-16 modulates macrophage polarization through regulating IL-10, IL-1a and IL-6 expression. Mir-145 is involved in M2 macrophage polarization by targeting IL-16 and enhancing IL-10 expression.

The biomarker features of miR-145-3p determined via meta-analysis validated by qRT-PCR in metastatic cancer cell lines.

MicroRNAs (miRNAs) play important roles in the cancer biology such as proliferation, differentiation, and apoptosis. The pivotal roles that miRNA expression plays, make them ideal candidates for detection of cancer progression as well as cancer metastasis. Especially for breast, lung and prostate cancer which are originated from soft tissues and prone to metastasis. Thus, the aim of this study is to evaluate the expression level of miR-145-3p which is a shared potential biomarker identified by meta-analysis of breast, prostate and lung cancer data sets. Six different data sets representative of three different cancer types were analyzed. These data sets are pooled together to have a master metamiRNA list while getting rid of the platform differentiations between them. As a result, 24 common differentially expressed miRNAs are determined in which miR-145-3p has the topmost rank. To mimic in vivo cancer microenvironment, hypoxia and serum deprivation were used to induce metastasis in breast (MCF-7, MDA-MB-231, MDA-MB-453), prostate (PC3, LNCaP, DU145), lung (A549, NCIH82,) cancer cell lines and noncancerous cell lines of the coresponding tissues (MCF10A, RWPE-1, MRC-5). miR-145-3p expression levels were determined by qRT-PCR. It has been shown that it is down regulated by the induction of metastasis in cancer cell lines while it is up regulated in normal cell lines to suppress the tumor formation. As a conclusion, as representing the same results in three different cancer cell types, miR-145-3p will be a promising biomarker to follow up its expression to detect cancer metastasis.

MicroRNA-145-3p suppresses proliferation and promotes apotosis and autophagy of osteosarcoma cell by targeting HDAC4.

Studies have shown that miR-145-3p functions as a tumor suppressor and is associated with tumor growth and metastasis. This study intends to uncover the mechanism of a tumor suppressor of miR-145-3p. The expressions of miR-194 in osteosarcoma cell lines and tissues were monitored by real-time PCR. The proliferation ability was examined by MTT assay. The apoptosis and autophagy of cells were monitored by flow cytometry and microcopy, respectively. The regulation of miR-145-3p on HDAC4 was determined by luciferase assays and western blot assay. The results showed that miR-145-3p was significantly reduced in the osteosarcoma compared with the normal bone tissue. Overexpression of miR-145-3p significantly attenuated the proliferation and induced the apoptosis and autophagy of osteosarcoma cells. Furthermore, we demonstrated that miR-145-3p has inhibited the malignant behavior of osteosarcoma by down-regulating HDAC4 expression. These findings suggested that miR-145-3p may act as a tumor suppressor in osteosarcoma. MiR-145-3p/HDAC4 may be a novel therapeutic target in treatment of osteosarcoma.

Regulation of UHRF1 by dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p): Inhibition of bladder cancer cell aggressiveness.

In microRNA (miRNA) biogenesis, the guide-strand of miRNA integrates into the RNA induced silencing complex (RISC), whereas the passenger-strand is inactivated through degradation. Analysis of our miRNA expression signature of bladder cancer (BC) by deep-sequencing revealed that microRNA (miR)-145-5p (guide-strand) and miR-145-3p (passenger-strand) were significantly downregulated in BC tissues. It is well known that miR-145-5p functions as a tumor suppressor in several types of cancer. However, the impact of miR-145-3p on cancer cells is still ambiguous. The aim of the present study was to investigate the functional significance of miR-145-3p and BC oncogenic pathways and targets regulated by miR-145-5p/miR-145-3p. Ectopic expression of either miR-145-5p or miR-145-3p in BC cells significantly suppressed cancer cell growth, migration and invasion and it also induced apoptosis. The gene encoding ubiquitin-like with PHD and ring finger domains 1 (UHRF1) was a direct target of these miRNAs. Silencing of UHRF1 induced apoptosis and inhibited cancer cell proliferation, migration, and invasion in BC cells. In addition, overexpressed UHRF1 was confirmed in BC clinical specimens, and the high UHRF1 expression group showed a significantly poorer cause specific survival rate in comparison with the low expression group. Taken together, our present data demonstrated that both strands of miR-145 (miR-145-5p: guide-strand and miR-145-3p: passenger-strand) play pivotal roles in BC cells by regulating UHRF1. The identification of the molecular target of a tumor suppressive miRNAs provides novel insights into the potential mechanisms of BC oncogenesis and suggests novel therapeutic strategies.