Apigenin suppresses TGF-β1-induced cardiac fibroblast differentiation and collagen synthesis through the downregulation of HIF-1α expression by miR-122-5p

BackgroundApigenin can reduce cardiomyocyte hypertrophy by downregulating hypoxia inducible factor-1 alpha (HIF-1α) expression. However, its effects on cardiac fibroblasts (CFs) and its exact inhibitory molecular mechanisms on HIF-1α remain unclear.PurposeThis study aims to examine the effects of apigenin on cell proliferation and differentiation, microRNA-122-5p (miR-122-5p) expression, and HIF-1α-mediated Smad signaling pathway in transforming growth factor beta 1 (TGF-β1)-stimulated CFs and cardiac fibrosis and to investigate the relationship between miR-122-5p and HIF-1α.MethodsThe TGF-β1-stimulated CFs, the combination of TGF-β1-stimulated and miR-122-5p mimic-transfected CFs, the combination of TGF-β1-stimulated and miR-122-5p inhibitor-transfected CFs, and the isoproterenol-induced cardiac fibrotic mice were used and treated with or without apigenin. The recombinant lentiviruses overexpressing HIF-1α vector and miR-122-5p mimic were co-transfected to observe their interaction. Related mRNA and protein expressions and myocardial collagen were determined. The luciferase reporter gene that contains HIF-1α wild type or mutant type 3’-UTR was used, and the luciferase activity was determined to verify the direct link between miR-122-5p and HIF-1α.ResultsIn the TGF-β1-stimulated CFs, apigenin treatment increased the miR-122-5p and Smad7 expressions and decreased the HIF-1α, α-smooth muscle actin, collagen Ⅰ/Ⅲ, Smad2/3, and p-Smad2/3 expressions. Similar and inverse results were observed in the miR-122-5p mimic- and inhibitor-transfected CFs, respectively. Moreover, the miR-122-5p mimic could antagonize the effects of TGF-β1 in the TGF-β1 and miR-122-5p mimic-combined CFs, and the miR-122-5p inhibitor could enhance the effects of TGF-β1 in the TGF-β1 and miR-122-5p inhibitor-combined CFs. In the two aforementioned cell models, the addition of apigenin could further enhance the effects of miR-122-5p mimic and partially reverse the effects of miR-122-5p inhibitor. After treatment of HIF-1α-transfected CFs with miR-122-5p mimic, the HIF-1α expression decreased. Further study confirmed that HIF-1α was a direct target of miR-122-5p. Apigenin also decreased the myocardial collagen accumulation in cardiac fibrotic mice.ConclusionApigenin could suppress the differentiation and collagen synthesis of TGF-β1-stimulated CFs and mouse cardiac fibrosis, and its mechanisms were related to the increment of miR-122-5p expression and subsequent downregulation of HIF-1α expression via direct interaction, which might finally result in the decrements of Smad2/3 and p-Smad2/3 expressions and increment of Smad7 expression.     

Diallyl disulfide suppresses FOXM1-mediated proliferation and invasion in osteosarcoma by upregulating miR-134

Diallyl disulfide (DADS), a volatile component of garlic oil, exerts anticancer activity in various types of cancers, while its anticancer effects against osteosarcoma (OS) have not been previously explored. This study aimed to investigate the anticancer potential of DADS in OS and to explore the underlying mechanisms. DADS reduced the cell viability and increased the expression of miR-134 in OS cell lines, and this effect was in a time- and concentration-dependent manner. Furthermore, in vitro functional assays revealed that DADS significantly inhibited the proliferation and invasion of human OS U2OS and MG-63 cells, which was partially reversed by miR-134 inhibitor transfection. DADS exhibited in vivo antitumor activity and upregulated miR-134 expression in xenograft tumors. Downregulation of miR-134 attenuated DADS-induced antitumor capacity. Further bioinformatics prediction analysis revealed that the 3′-untranslated region (3′-UTR) of Forkhead Box M1 (FOXM1) harbored miR-134-binding sites, and overexpression of miR-134 repressed the luciferase activity of the reporting vector containing FOXM1 3′-UTR. Both miR-134 overexpression and DADS inhibited FOXM1 expression in U2OS cells, while enforced expression of FOXM1 suppressed DADS-induced antiproliferation and anti-invasion capacity in U2OS cells. Furthermore, DADS treatment led to significant downregulation of cyclin D1, c-myc, and lymphoid enhancer-binding factor 1 expression, but the remarkably upregulated p21 level in U2OS cells. Collectively, DADS could be a promising anticancer agent for OS, and the underlying mechanisms might be associated with the antiproliferation and anti-invasion properties through upregulating miR-134 expression.     

miR-134-5p inhibits osteoclastogenesis through a novel miR-134-5p/Itgb1/MAPK pathway

Osteoporosis affects approximately 200 million people and severely affects quality of life, but the exact pathological mechanisms behind this disease remain unclear. Various miRNAs have been shown to play a predominant role in the regulation of osteoclast formation. In this study, we explored the role of miR-134-5p in osteoclastogenesis both in vivo and in vitro. We constructed an ovariectomized (OVX) mouse model and performed microarray analysis using bone tissue from OVX mice and their control counterparts. Quantitative RT-PCR data from bone tissue and bone marrow macrophages (BMMs) confirmed the decreased expression of miR-134-5p in OVX mice observed in microarray analysis. In addition, a decrease in miR-134-5p was also observed during induced osteoclastogenesis of BMMs collected from C57BL/6N mice. Through transfection with miR-134-5p agomirs and antagomirs, we found that miR-134-5p knockdown significantly accelerated osteoclast formation and cell proliferation and inhibited apoptosis. Furthermore, a luciferase reporter assay showed that miR-134-5p directly targets the integrin surface receptor gene Itgb1. Cotransfection with Itgb1 siRNA reversed the effect of the miR-134-5p antagomir in promoting osteoclastogenesis. Moreover, the abundance levels of MAPK pathway proteins phosphorylated-p38 (p-p38) and phosphorylated-ERK (p-ERK) were significantly increased after transfection with the miR-134-5p antagomir but decreased after transfection with the miR-134-5p agomir or Itgb1 siRNA, which indicated a potential relationship between the miR-134-5p/Itgb1 axis and the MAPK pathway. Collectively, these results revealed that miR-134-5p inhibits osteoclast differentiation of BMMs both in vivo and in vitro and that the miR-134-5p/Itgb1/MAPK pathway might be a potential target for osteoporosis therapy.     

Highly upregulated in liver cancer (HULC): An update on its role in carcinogenesis

Highly upregulated in liver cancer (HULC) was initially recognized during the screening of a hepatocellular carcinoma (HCC)-specific gene library. Further studies demonstrated its aberrant upregulation in several other tumor types. The oncogenic roles of this long noncoding RNA (lncRNA) have been verified through expression studies as well as functional studies. Moreover, the results of knockdown experiments have indicated diminished carcinogenic effects of cancer cell line in nude mice following HULC silencing. More recent studies have shown that expression levels of this lncRNA might be used as diagnostic biomarkers in cancer patients. Moreover, mechanistical studies have revealed associations between HULC and two HCC-related viruses namely hepatitis B and C viruses. Taken together, HULC can be regarded as a therapeutic target not only for HCC but also for a variety of human malignancies. In the current review, we summarized the recent literature about the role of HULC in the carcinogenesis and its potential application in cancer diagnosis and prognosis.     

Hepatitis B core protein promotes liver cancer metastasis through miR-382-5p/DLC-1 axis

The hepatitis B virus core protein (HBc), also named core antigen, is well-known for its key role in viral capsid formation and virus replication. Recently, studies showed that HBc has the potential to control cell biology activity by regulating host gene expression. Here, we utilized miRNA microarray to identify 24 upregulated miRNAs and 21 downregulated miRNAs in HBc-expressed HCC cells, which were involved in multiple biological processes, including cell motility. Consistently, the in vitro transwell assay and the in vivo tail-vein injection model showed HBc promotion on HCC metastasis. Further, the miRNA-target gene network analysis displayed that the deleted in liver cancer (DLC-1) gene, an important negative regulator for cell motility, was potentially targeted by several differentially expressed miRNAs in HBc-introduced cells. Introduction of miRNAs mimics or inhibitors and 3′UTR luciferase activity assay proved that miR-382-5p efficiently suppressed DLC-1 expression and its 3′-UTR luciferase reporter activity. Importantly, cotransfection of miR-382-5p mimics/inhibitors and the DLC-1 expression vector almost abrogated HBc promotion on cell motility, indicating that the miR-382-5p/DLC-1 axis is important for mediating HBc-enhanced HCC motility. Clinical HCC samples also showed a negative correlation between miR-382-5p and DLC-1 expression level. Furthermore, HBc-positive HCC tissues showed high miR-382-5p level and reduced DLC-1 expression. In conclusion, our findings revealed that HBc promoted HCC motility by regulating the miR-382-5p/DLC-1 axis, which might provide a novel target for clinical diagnosis and treatment.     

miR-342-3p suppresses proliferation,migration and invasion by targeting FOXM1 in human cervical cancer

FOXM1 is a well-established oncogenic factor that has been reported to be involved in multiple biological processes including cell proliferation, growth, angiogenesis, migration and invasion. It can also be regulated by miRNAs. In this study, we reported that FOXM1 is directly targeted by miR-342-3p, which is down-regulated along with its host gene, EVL, in human cervical cancer tissues compared to the adjacent normal tissues. Functional studies suggested that the overexpression of miR-342-3p inhibits cell proliferation, migration and invasion in cervical cell lines. FOXM1 is upregulated and negatively correlates with miR-342-3p in cervical cancer tissues, and the overexpression of FOXM1 rescues the phenotype changes induced by the overexpression of miR-342-3p.     

CircMTO1 suppresses hepatocellular carcinoma progression via the miR-541-5p/ZIC1 axis by regulating Wnt/β-catenin signaling pathway and epithelial-to-mesenchymal transition

CircRNA mitochondrial tRNA translation optimization 1 (circMTO1) functions as a tumor suppressor usually and is related to the progression of many tumors, including hepatocellular carcinoma (HCC). CircMTO1 is downregulated in HCC as compared to adjacent nontumor tissue, which may suppress the HCC progression by certain signal pathways. However, the underlying signal pathway remains largely unknown. The interactions between circMTO1 and miR-541-5p were predicted through bioinformatics analysis and verified using pull-down and dual-luciferase reporter assays. CCK-8, transwell, and apoptosis assays were performed to determine the effect of miR-541-5p on HCC progression. Using bioinformatic analysis, dual-luciferase reporter assay, RT-qPCR, and western blot, ZIC1 was found to be the downstream target gene of miR-541-5p. The regulatory mechanisms of circMTO1, miR-541-5p, and ZIC1 were investigated using in vitro and in vivo rescue experiments. The results depicted that silencing circMTO1 or upregulating miR-541-5p expression facilitated HCC cell proliferation, migration, and invasion and inhibited apoptosis. CircMTO1 silencing upregulated the expression of downstream ZIC1 regulators of the Wnt/β-catenin pathway markers, β-catenin, cyclin D1, c-myc, and the mesenchymal markers N-cadherin, Vimentin, and MMP2, while the epithelial marker E-cadherin was downregulated. MiR-541-5p knockdown had the opposite effect and reversed the effect of circMTO1 silencing on the regulation of downstream ZIC1 regulators. Intratumoral injection of miR-541-5p inhibitor suppressed tumor growth and reversed the effect of circMTO1 silencing on the promotion of tumor growth in HCC. These findings indicated that circMTO1 suppressed HCC progression via the circMTO1/ miR-541-5p/ZIC1 axis by regulating Wnt/β-catenin signaling and epithelial-to-mesenchymal transition, making it a novel therapeutic target. Subject terms: Cancer therapy, Liver cancer, Tumour-suppressor proteins     

Downregulation of circDYNC1H1 exhibits inhibitor effect on cell proliferation and migration in hepatocellular carcinoma through miR-140-5p

Circular RNAs have been found to be aberrantly expressed in tumors and their significance in tumorigenesis has been focused on. The role of circDYNC1H1 in hepatocellular carcinoma (HCC) pathogenesis and its relationship with miR-140-5p were explored. The expression of circDYNC1H1, miR-140-5p, and SULT2B1 in HCC tissues and cells was measured, and Pearson's analysis was used to analyze their expression correlation. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assays were performed to determine cell proliferation and migration. Binding between circDYNC1H1 and miR-140-5p was evaluated with RNA pull-down assay. A luciferase reporter assay was conducted to assess the interaction between circDYNC1H1 and miR-140-5p and between miR-140-5p and SULT2B1. circDYNC1H1 was highly expressed in HCC tissues (n = 20), and it was negatively associated with the expression of miR-140-5p but positively correlated with SULT2B1 messenger RNA expression. circDYNC1H1 was upregulated in cell lines of HCC. Interference of circDYNC1H1 suppressed cell proliferation and migration of HCC. circDYNC1H1 acted as a sponge of miR-140-5p. miR-140-5p controlled SULT2B1 expression by targeting its 3′-untranslated region. circDYNC1H1 enhanced SULT2B1 expression via sponging miR-140-5p. Downregulation of circDYNC1H1 disturbed cell proliferation and migration of HCC through miR-140-5p/SULT2B1 pathway. Silencing of circDYNC1H1 delayed tumor growth in HCC mouse model. Acting like a sponge of miR-140-5p, silenced circDYNC1H1 downregulated SULT2B1 to restrain HCC cell proliferation and migration, which is adverse to HCC growth and progression.     

Knockdown of terminal differentiation induced ncRNA (TINCR) suppresses proliferation and invasion in hepatocellular carcinoma by targeting the miR-218-5p/DEAD-box helicase 5 (DDX5) axis

Terminal differentiation induced ncRNA (TINCR), a newly identified lncRNA, has been found to be associated with different human cancers including hepatocellular carcinoma (HCC). However, little is known regarding the pathological mechanisms of TINCR in HCC progression. In this study, we confirmed that TINCR expression was upregulated in HCC tumors and cell lines, and high TINCR expression was associated with larger tumor size, advanced tumor node metastasis stage, and poor prognosis. Functionally, knockdown of TINCR facilitated apoptosis and suppressed viability, colony formation and invasion in Huh7 and Hep3B cells. Mechanically, TINCR functioned as competing endogenous RNA (ceRNA) to regulate DEAD-box helicase 5 (DDX5) expression through sponging miR-218-5p. Moreover, the miR-218-5p expression was downregulated and DDX5 expression was upregulated in HCC tumors. The silencing of miR-218-5p or ectopic expression of DDX5 abated the tumor-suppressive effect of TINCR knockdown in vitro. Furthermore, si-TINCR-induced inactivation of AKT signaling was rescued by suppression of miR-218-5p or overexpression of DDX5. Also, the silencing of TINCR resulted in tumor growth inhibition in vivo. In summary, knockdown of TINCR suppressed HCC progression presumably by inactivation of AKT signaling through targeting the miR-218-5p/DDX5 axis, suggesting a novel TINCR/miR-218-5p/DDX5 pathway and therapy target for HCC.     

microRNA-485-5p inhibits the progression of hepatocellular carcinoma through blocking the WBP2/Wnt signaling pathway

microRNA-485-5p (miR-485-5p) has been shown to act as a tumor-suppressor gene in some cancers, such as ovarian epithelial tumors and oral tongue squamous cell carcinoma. However, with regard to the anti-tumor role of miR-485-5p in hepatocellular carcinoma (HCC), evidence is unexpectedly limited. In the present study, we investigated the expression and the role of miR-485-5p in the progression of HCC. Microarray analysis revealed that miR-485-5p was downregulated and WBP2 was upregulated in HCC, which was consistent with RT-qPCR and immunohistochemistry assays in the HCC tissues we collected. A negative correlation between the expression of miR-485-5p and WBP2 was also found in HCC tissues. It was predicted and confirmed that miR-485-5p could bind to WW domain binding protein 2 (WBP2) through in silico analysis of genetic sequences and an in vitro dual-luciferase reporter gene assay. Next, gain- or loss-of-function studies were applied in the HCC cell line (Huh7) to examine the effects of miR-485-5p and WBP2 on HCC cell behavior. The effects of miR-485-5p and WBP2 on the Wnt/β-catenin signaling pathway were determined by TOP/FOP flash luciferase assays. miR-485-5p was shown to downregulate WBP2 and block the Wnt/β-catenin signaling pathway. As expected, elevated miR-485-5p levels and inhibition of WBP2 protein expression exerted inhibitory effects on HCC cell proliferation, migration and invasion and, induced apoptosis. In vivo experiments were finally conducted, which confirmed that upregulation of miR-485-5p or depletion of WBP2 attenuated tumor growth. Collectively, our results suggest miR-485-5p can downregulate WBP2 to inhibit the development of HCC by the blockade of the Wnt/β-catenin signaling, providing a novel molecular target for HCC treatment.     

Long non-coding RNA PAARH promotes hepatocellular carcinoma progression and angiogenesis via upregulating HOTTIP and activating HIF-1α/VEGF signaling

Hepatocellular carcinoma (HCC) is one of the leading lethal malignancies and a hypervascular tumor. Although some long non-coding RNAs (lncRNAs) have been revealed to be involved in HCC. The contributions of lncRNAs to HCC progression and angiogenesis are still largely unknown. In this study, we identified a HCC-related lncRNA, CMB9-22P13.1, which was highly expressed and correlated with advanced stage, vascular invasion, and poor survival in HCC. We named this lncRNA Progression and Angiogenesis Associated RNA in HCC (PAARH). Gain- and loss-of function assays revealed that PAARH facilitated HCC cellular growth, migration, and invasion, repressed HCC cellular apoptosis, and promoted HCC tumor growth and angiogenesis in vivo. PAARH functioned as a competing endogenous RNA to upregulate HOTTIP via sponging miR-6760-5p, miR-6512-3p, miR-1298-5p, miR-6720-5p, miR-4516, and miR-6782-5p. The expression of PAARH was significantly positively associated with HOTTIP in HCC tissues. Functional rescue assays verified that HOTTIP was a critical mediator of the roles of PAARH in modulating HCC cellular growth, apoptosis, migration, and invasion. Furthermore, PAARH was found to physically bind hypoxia inducible factor-1 subunit alpha (HIF-1α), facilitate the recruitment of HIF-1α to VEGF promoter, and activate VEGF expression under hypoxia, which was responsible for the roles of PAARH in promoting angiogenesis. The expression of PAARH was positively associated with VEGF expression and microvessel density in HCC tissues. In conclusion, these findings demonstrated that PAARH promoted HCC progression and angiogenesis via upregulating HOTTIP and activating HIF-1α/VEGF signaling. PAARH represents a potential prognostic biomarker and therapeutic target for HCC.Subject terms: Cancer microenvironment, Oncogenes, Translational research     

Circular RNA hsa_circRNA_103809 promoted hepatocellular carcinoma development by regulating miR-377-3p/FGFR1/ERK axis

In the last decade, circular RNAs (circRNAs) emerge as important regulators in multiple biological processes. Lately, it is reported hsa_circRNA_103809 could play vital parts in several types of cancers. Based on the analysis of GEO data (GSE97332), hsa_circRNA_103809 was found to be dysregulated in hepatocellular carcinoma (HCC). However, the biological function and underlying regulatory mechanisms of hsa_circRNA_103809 in HCC remain unclear. Our results suggested that hsa_circRNA_103809 was overexpressed in HCC patients, and hsa_circRNA_103809 knockdown remarkably inhibited the proliferation, cycle progression, and migration of HCC cells. The investigations of molecular showed that hsa_circRNA_103809 could elevate the protein expression of a miR-377-3p target, fibroblast growth factor receptor 1 (FGFR1), through interacting with miR-377-3p and decreasing its expression level. Additionally, in vivo assays revealed hsa_circRNA_103809 short hairpin RNA served as a tumor suppressor through downregulating FGFR1 in HCC. This study systematically investigated novel regulatory signaling of hsa_circRNA_103809/miR-377-3p/FGFR1 axis, providing insights into hepatocellular carcinoma treatment from bench to clinic.     

Propofol-induced miR-219-5p inhibits growth and invasion of hepatocellular carcinoma through suppression of GPC3-mediated Wnt/β-catenin signalling activation

Propofol is one of the most extensively used intravenous anaesthetic agents, which has been found to improve the surgical intervention outcome of several types of cancer, including hepatocellular carcinoma (HCC). Additionally, in vitro and in vivo experiments have also indicated that propofol affects the biological behaviour of HCC. However, the underlying mechanisms of the surgical resection of HCC with propofol have not been fully understood. In the present study, we aimed to investigate the underlying mechanism of propofol inhibition of the growth and invasion of HCC cells. Our results showed that treatment with propofol suppressed the proliferation, invasion and migration of HCC in vitro. The subcutaneous xenograft tumour and orthotopic xenograft tumour experiments in nude mice showed that propofol significantly decreased tumour volumes, growth rates and the liver orthotopic xenograft tumour in vivo. Furthermore, the underlying mechanism investigations of the suppressive effects of propofol on HCC cells revealed that propofol treatment upregulated the expression levels of the candidate tumour suppressor miR-219-5p. Silencing of propofol-induced miR-219-5p using anti-miR-219-5p abrogated the inhibitory effects on the proliferation, migration and invasion of HCC cells exerted by propofol treatment. Additionally, we demonstrated that propofol reversed the epithelial-mesenchymal transition of Huh7 and SMMC7721 cells via miR-219-5p induction. The molecular mechanism behind these findings is that propofol-induced miR-219-5p inhibits HCC cell progression by targeting glypican-3 and subsequently results in the inhibition of Wnt/β-catenin signalling. Taken together, our study provides new insights into the advantages of the surgical intervention of HCC with propofol anaesthetization.     

In vitro and in vivo anti-metastatic effect of the alkaliod matrine from Sophora flavecens on hepatocellular carcinoma and its mechanisms

BackgroundsHepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancer with high metastasis and recurrence rates. Hypoxia-induced miRNAs and HIF-1α are demonstrated to play essential roles in tumor metastasis. Matrine (C₁₅H₂₄N₂O), an alkaloid extracted from Sophora flavescens Aiton, has been used as adjuvant therapy for liver cancer in China. The anti-metastasis effects of matrine on HCC and the underlying mechanisms remain poorly understood.PurposeWe aimed to investigate the effects of matrine on metastasis of HCC both in vitro and in vivo, and explored whether miR-199a-5p and HIF-1α are involved in the action of matrine.MethodsMTT method, colony formation, wound healing and matrigel transwell assays were performed to evaluate the effects of matrine on cell proliferation, migration and invasion. Nude mice xenograft model and immunohistochemistry (IHC) assay were employed to investigate the anti-metastatic action of matrine in vivo. Quantitative real-time PCR, western blot and dual luciferase reporter assay were conducted to determine the underlying mechanisms of matrine.ResultsMatrine exerted stronger anti-proliferative action on Bel7402 and SMMC-7721 cells under hypoxia than that in normoxia. Both matrine and miR-199a-5p exhibited significant inhibitory effects on migration, invasion and EMT in Bel7402 and SMMC-7721 cells under hypoxia. Further study showed that miR-199a-5p was downregulated in HCC cell lines, and this microRNA was identified to directly target HIF-1α, resulting in decreased HIF-1α expression. Matrine induced miR-199a-5p expression, decreased HIF-1α expression and inhibited metastasis of Bel7402 and SMMC-7721 cells, while miR-199a-5p knockdown reversed the inhibitory effects of matrine on cell migration, invasion, EMT and HIF-1α expression. In vivo, matrine showed significant anti-metastatic activity in the nude mouse xenograft model. H&E and IHC analysis indicated that lung and liver metastasis nodules were reduced, and the protein expression of HIF-1α and Vimentin were significantly decreased by i.p injection of matrine.ConclusionsMatrine exhibits significant anti-metastatic effect on HCC, which is attributed to enhanced miR-199a-5p expression and subsequently impaired HIF-1α signaling and EMT. These findings suggest that miR-199a-5p is a potential therapeutic target of HCC, and matrine may represent a promising anti-metastatic medication for HCC therapy.     

Long noncoding RNA linc00467 plays an oncogenic role in hepatocellular carcinoma by regulating the miR-18a-5p/NEDD9 axis

Increasing evidence has shown that numerous long noncoding RNAs (lncRNAs) play critical roles in tumorigenesis. Herein, we investigated the biological role of lncRNA linc00467 in the cancer biology of hepatocellular carcinoma (HCC). We observed that linc00467 was upregulated in HCC tissues and cells. Silencing of linc00467 using small interfering RNA interference significantly inhibited the growth and motility of HCC cells, and increased cell apoptosis through regulating the Bcl-2/Bax axis and the caspase cascade, suggesting that linc00467 exerted oncogenic functions in the progression of HCC. Moreover, we found that linc00467 could target miR-18a-5p, and NEDD9 was a target for miR-18a-5p in HCC cells. Furthermore, either the miR-18a-5p inhibitor or upregulation of NEDD9 could recover the inhibitory effects caused by silencing of linc00467. In conclusion, our data highlighted the oncogenic role of linc00467 in HCC progression by regulating the miR-18a-5p/NEDD9 axis.     

VCP/p97, down-regulated by microRNA-129-5p, could regulate the progression of hepatocellular carcinoma

Valosin containing protein (VCP)/p97 plays various important roles in cells. Moreover, elevated expression of VCP in hepatocellular carcinoma (HCC) is correlated with increased incidence of recurrence. But the role of VCP in HCC progression in vitro and in vivo is unclear. And there are few reports about the regulation mechanism on the expression of VCP in HCC. In this study, it was identified that the level of VCP was frequently increased in human HCC tissues. In addition, down-regulation of VCP with siRNAs could dramatically suppress the genesis and progression of tumor in vivo. It was found that miR-129-5p directly inhibited the expression of VCP in several HCC cell lines. Meanwhile, the level of VCP in HCC tissues was negatively associated with the level of miR-129-5p. Our further investigation showed that the enhanced expression of miR-129-5p also suppressed tumor growth in vivo. Moreover, it was revealed that miR-129-5p could inhibit the degradation of IκBα and increase the apoptosis and reduce the migration of HCC cells by suppressing the expression of VCP. Our results revealed that the expression of VCP was directly regulated by miR-129-5p and this regulation played an important role in the progression of HCC.