scholarly journals Curcumin Inhibits Hepatocellular Carcinoma via Regulating miR-21/TIMP3 Axis

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Jingtao Li ◽  
Hailiang Wei ◽  
Yonggang Liu ◽  
Qian Li ◽  
Hui Guo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Anticancer Activities ◽  
Anticancer Effects ◽  
Cell Proliferation Inhibition

Background/Aim. Curcumin exhibits anticancer effects against various types of cancer including hepatocellular carcinoma (HCC). miR-21 has been reported to be involved in the malignant biological properties of HCC. However, whether miR-21 plays a role in curcumin-mediated treatment of HCC is unknown. The purpose of this study was to identify the potential functions and mechanisms of miR-21 in curcumin-mediated treatment of HCC. Methods. The anticancer effects of curcumin were assessed in vivo and in vitro. The underlying mechanism of miR-21 in curcumin-mediated treatment of HCC was assessed by quantitative real-time PCR (RT-qPCR), western blot, and Dual-Luciferase Reporter assays. Results. The present study revealed that curcumin suppressed HCC growth in vivo and inhibited HCC cell proliferation and induced cell apoptosis in a dose-dependent manner in vitro. Meanwhile, the curcumin treatment can downregulate miR-21 expression, upregulate TIMP3 expression, and inhibit the TGF-β1/smad3 signaling pathway. miR-21 inhibition enhanced the effect of curcumin on cell proliferation inhibition, apoptosis, and TGF-β1/smad3 signaling pathway inhibition in HepG2 and HCCLM3 cells. It demonstrated that TIMP3 was a direct target gene of miR-21. Interestingly, the effect of miR-21 inhibition on cell proliferation, apoptosis, and TGF-β1/smad3 signaling pathway in HepG2 and HCCLM3 cells exposed to curcumin was attenuated by TIMP3 silencing. Conclusion. Taken together, the present study suggests that miR-21 is involved in the anticancer activities of curcumin through targeting TIMP3, and the mechanism possibly refers to the inhibition of TGF-β1/smad3 signaling pathway.

scholarly journals KLF7/VPS35 axis contributes to hepatocellular carcinoma progression through CCDC85C-activated β-catenin pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yarong Guo ◽  
Bao Chai ◽  
Junmei Jia ◽  
Mudan Yang ◽  
Yanjun Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Luciferase Reporter ◽  
Aberrant Expression ◽  
Proliferation And Invasion ◽  
Hcc Cells

Abstract Objective Dysregulation of KLF7 participates in the development of various cancers, but it is unclear whether there is a link between HCC and aberrant expression of KLF7. The aim of this study was to investigate the role of KLF7 in proliferation and migration of hepatocellular carcinoma (HCC) cells. Methods CCK8, colony growth, transwell, cell cycle analysis and apoptosis detection were performed to explore the effect of KLF7, VPS35 and Ccdc85c on cell function in vitro. Xenografted tumor growth was used to assess in vivo role of KLF7. Chip-qPCR and luciferase reporter assays were applied to check whether KLF7 regulated VPS35 at transcriptional manner. Co-IP assay was performed to detect the interaction between VPS35 and Ccdc85c. Immunohistochemical staining and qRT-PCR analysis were performed in human HCC sampels to study the clinical significance of KLF7, VPS35 and β-catenin. Results Firstly, KLF7 was highly expressed in human HCC samples and correlated with patients’ differentiation and metastasis status. KLF7 overexpression contributed to cell proliferation and invasion of HCC cells in vitro and in vivo. KLF7 transcriptional activation of VPS35 was necessary for HCC tumor growth and metastasis. Further, co-IP studies revealed that VPS35 could interact with Ccdc85c in HCC cells. Rescue assay confirmed that overexpression of VPS35 and knockdown of Ccdc85c abolished the VPS35-medicated promotion effect on cell proliferation and invasion. Finally, KLF7/VPS35 axis regulated Ccdc85c, which involved in activation of β-catenin signaling pathway, confirmed using β-catenin inhibitor, GK974. Functional studies suggested that downregulation of Ccdc85c partly reversed the capacity of cell proliferation and invasion in HCC cells, which was regulated by VPS35 upregulation. Lastly, there was a positive correlation among KLF7, VPS35 and active-β-catenin in human HCC patients. Conclusion We demonstrated that KLF7/VPS35 axis promoted HCC cell progression by activating Ccdc85c-medicated β-catenin pathway. Targeting this signal axis might be a potential treatment strategy for HCC.

scholarly journals Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma

2022 ◽  
Vol 41 (1) ◽  
Author(s):  
Yuanjun Lu ◽  
Yau-Tuen Chan ◽  
Hor-Yue Tan ◽  
Cheng Zhang ◽  
Wei Guo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Bioinformatics Analyses ◽  
Sorafenib Treatment ◽  
Hcc Cells

Abstract Background Drug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified. Methods The clinical significance of miRNA-related epigenetic changes in sorafenib-resistant HCC was evaluated by analyzing publicly available databases and in-house human HCC tissues. The biological functions of miR-23a-3p were investigated both in vitro and in vivo. Proteomics and bioinformatics analyses were conducted to identify the mechanisms that regulating miR-23a-3p. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to validate the binding relationship of miR-23a-3p and its targets. Results We found that miR-23a-3p was the most prominent miRNA in HCC, which was overexpressed in sorafenib non-responders and indicated poor survival and HCC relapse. Sorafenib-resistant cells exhibited increased miR-23a-3p transcription in an ETS Proto-Oncogene 1 (ETS1)-dependent manner. CRISPR-Cas9 knockout of miR-23a-3p improved sorafenib response in HCC cells as well as orthotopic HCC tumours. Proteomics analysis suggested that sorafenib-induced ferroptosis was the key pathway suppressed by miR-23a-3p with reduced cellular iron accumulation and lipid peroxidation. MiR-23a-3p directly targeted the 3′-untranslated regions (UTR) of ACSL4, the key positive regulator of ferroptosis. The miR-23a-3p inhibitor rescued ACSL4 expression and induced ferrotoptic cell death in sorafenib-treated HCC cells. The co-delivery of ACSL4 siRNA and miR-23a-3p inhibitor abolished sorafenib response. Conclusion Our study demonstrates that ETS1/miR-23a-3p/ACSL4 axis contributes to sorafenib resistance in HCC through regulating ferroptosis. Our findings suggest that miR-23a-3p could be a potential target to improve sorafenib responsiveness in HCC patients.

scholarly journals Dysregulation of miR-23b-5p promotes cell proliferation via targeting FOXM1 in hepatocellular carcinoma

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Xinchen Yang ◽  
Shikun Yang ◽  
Jinhua Song ◽  
Wenjie Yang ◽  
Yang Ji ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Tumor Development ◽  
Loss Of Function ◽  
Cycle Arrest ◽  
Cell Proliferation Inhibition

AbstractGrowing evidence demonstrates that MicroRNAs (miRNAs) play an essential role in contributing to tumor development and progression. However, the underlying role and mechanisms of miR-23b-5p in hepatocellular carcinoma (HCC) formation remain unclear. Our study showed that miR-23b-5p was downregulated in the HCC tissues and cell lines, and lower expression of miR-23b-5p was associated with more severe tumor size and poorer survival. Gain- or loss-of-function assays demonstrated that miR-23b-5p induced G0/G1 cell cycle arrest and inhibited cell proliferation both in vitro and in vivo. qRT-PCR, western blot and luciferase assays verified that Mammalian transcription factor Forkhead Box M1 (FOXM1), upregulated in HCC specimens, was negatively correlated with miR-23b-5p expression and acted as a direct downstream target of miR-23b-5p. In addition, miR-23b-5p could regulate cyclin D1 and c-MYC expression by directly targeting FOXM1. Further study revealed that restoration of FOXM1 neutralized the cell cycle arrest and cell proliferation inhibition caused by miR-23b-5p. Taken together, our findings suggest that miR-23b-5p acted as a tumor suppressor role in HCC progression by targeting FOXM1 and may serve as a potential novel biomarker for HCC diagnosis and prognosis.

scholarly journals circRPS16 Promotes Proliferation and Invasion of Hepatocellular Carcinoma by Sponging miR-876-5p to Upregulate SPINK1

2021 ◽  
Vol 11 ◽  
Author(s):  
Shuwen Lin ◽  
Ye Lin ◽  
Zhongshi Wu ◽  
Wuzheng Xia ◽  
Chenglong Miao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Luciferase Reporter ◽  
Downstream Target ◽  
Proliferation And Invasion

The roles of serine protease inhibitor Kazal type 1 (SPINK1) in multiple types of cancers have been significantly documented. However, its specific roles in hepatocellular carcinoma (HCC) remain to be investigated. This study found that SPINK1 is upregulated in HCC and its upregulation correlates with poor prognosis. Besides, functional assays revealed that SPINK1 promotes cell proliferation, cell cycle, and invasion in vitro. Through bioinformatics analysis, we speculate that circRPS16 regulates SPINK1 expression by sponging miR-876-5p. This was further verified by the dual-luciferase reporter and fluorescent in situ hybridization (FISH) assays. Subsequently, rescue assays verified that circRPS16 promotes cell proliferation, cell cycle, and invasion through miR-876-5p. Importantly, silencing circRPS16 inhibited tumor growth by downregulating SPINK1 expression in vivo. Collectively, our results confirm that SPINK1 is a downstream target of circRPS16. Besides, circRPS16 and SPINK1 are oncogenic factors in HCC progression; they provide novel diagnostic and therapeutic targets for HCC patients.

scholarly journals Artemisia argyi Essential Oil Inhibits Hepatocellular Carcinoma Metastasis via Suppression of DEPDC1 Dependent Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Yanli Li ◽  
Yang Tian ◽  
Wei Zhong ◽  
Ning Wang ◽  
Yafeng Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Essential Oil ◽  
Signaling Pathway ◽  
Nude Mice ◽  
Migration And Invasion ◽  
Advanced Hepatocellular Carcinoma ◽  
Dependent Manner ◽  
Artemisia Argyi

The tumor metastasis is the major hurdle for the treatment of advanced hepatocellular carcinoma (HCC), due in part to the lack of effective systemic treatments. DEPDC1, a novel oncoantigen upregulated in HCC, is thought to be a molecular-target for novel therapeutic drugs. Artemisia argyi is a traditional Chinese medicine with anti-inflammatory and anti-tumor activities. This study investigated the potential therapeutic benefits of Artemisia argyi essential oil (AAEO) in suppressing metastasis of HCC by targeting DEPDC1. Assessment of AAEO cytotoxicity was performed by MTT assay. Anti-metastatic effects of AAEO were investigated in vitro using wound healing and transwell assays. The HepG2 cells were transduced with lentiviral vector containing luciferase (Luc). A metastasis model of nude mice was established by tail vein injection of HepG2-Luc cells. The nude mice were treated with AAEO (57.5, 115, and 230 mg/kg) or sorafenib (40 mg/kg). Metastasis of HCC cells was monitored via in vivo bioluminescence imaging. After treatment for 21 days, tissues were collected for histological examination and immunohistochemistry analysis. Gene and protein levels were determined by real-time quantitative PCR and western blotting. The results revealed that AAEO significantly inhibits the migration and invasion in vitro in a concentration-dependent manner. In vivo assays further confirmed that AAEO markedly inhibits HCC metastasis into lung, brain, and femur tissues and exhibits low toxicity. Our results suggested that AAEO significantly downregulates the mRNA and protein expression of DEPDC1. Also, AAEO attenuated Wnt/β-catenin signaling through reduction of Wnt1 and β-catenin production. Moreover, AAEO prevented epithelial-mesenchymal transition (EMT) by downregulation of vimentin and upregulation of E-cadherin. Furthermore, we found that DEPDC1 promoted HCC migration and invasion via Wnt/β-catenin signaling pathway and EMT. These results demonstrate that AAEO effectively inhibits HCC metastasis via attenuating Wnt/β-catenin signaling and inhibiting EMT by suppressing DEPDC1 expression. Thus, AAEO likely acts as a novel inhibitor of the DEPDC1 dependent Wnt/β-catenin signaling pathway.

scholarly journals Hsa_circ_0011385 knockdown represses cell proliferation in hepatocellular carcinoma

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Chuangye Ni ◽  
Shikun Yang ◽  
Yang Ji ◽  
Yunfei Duan ◽  
Wenjie Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Reporter Gene ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Luciferase Reporter Gene ◽  
Reporter Gene Assays

AbstractCircular RNAs (circRNAs), continuous loops of single-stranded RNA, regulate gene expression during the development of various cancers. However, the function of circRNAs in hepatocellular carcinoma (HCC) is rarely discussed. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the mRNA levels of circ_0011385, miR-361-3p, and STC2 in 96 pairs of HCC tissues (tumor tissues and adjacent normal tissues), HCC cell lines, and L02 (human normal liver cell line) cells. The relationships between circ_0011385 expression and clinical features of HCC were evaluated. Functional experiments in vitro or in vivo were used to evaluate the biological function of circ_0011385. Bioinformatics analysis was performed to predict miRNAs and mRNAs sponged by circ_0011385. RNA immunoprecipitation (RIP) and dual-luciferase reporter gene assays were used to elucidate the interactions among circ_0011385, miR-361-3p, and STC2 (stanniocalcin 2). ChIP and dual-luciferase reporter gene assays were used to identify the upstream regulator of circ_0011385. High expression of circ_0011385 was observed in HCC tissues and cell lines and was significantly associated with tumor size, TNM stage, and prognosis. In addition, inhibition of circ_0011385 expression prevented the proliferation of HCC cells in vitro and in vivo. Circ_0011385 sponged miR-361-3p, thereby regulating the mRNA expression of STC2. In addition, the transcription of circ_0011385 was regulated by SP3. Circ_0011385 knockdown suppressed cell proliferation and tumor activity in HCC. Circ_0011385 may therefore serve as a new biomarker in the diagnosis and treatment of HCC.

scholarly journals KLF7/VPS35 Axis Contributes to Hepatocellular Carcinoma Progression through CCDC85C-activated β Catenin Pathway

2020 ◽  
Author(s):  
Yarong Guo ◽  
Bao Chai ◽  
Junmei Jia ◽  
Mudan Yang ◽  
Yanjun Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Luciferase Reporter ◽  
Aberrant Expression ◽  
Proliferation And Invasion ◽  
Hcc Cells

Abstract Objective: Dysregulation of KLF7 participates in the development of various cancers, but it is unclear whether there is a link between HCC and aberrant expression of KLF7. The aim of this study was to investigate the role of KLF7 in proliferation and migration of hepatocellular carcinoma (HCC) cells. Methods: CCK8, colony growth, transwell, cell cycle analysis and apoptosis detection were performed to explore the effect of KLF7, VPS35 and Ccdc85c on cell function in vitro. Xenografted tumor growth was used to assess in vivo role of KLF7. Chip-qPCR and luciferase reporter assays were applied to check whether KLF7 regulated VPS35 at transcriptional manner. Co-IP assay was performed to detect the interaction between VPS35 and Ccdc85c. Human HCC tissues were collected to study the clinical significance VPS35 and β-catenin. Results: Firstly, KLF7 overexpression contributed to cell proliferation and invasion of HCC cells in vitro and in vivo. KLF7 transcriptional activation of VPS35 was necessary for HCC tumor growth and metastasis. Further, co-IP studies revealed that VPS35 could interact with Ccdc85c in HCC cells. Rescue assay confirmed that overexpression of VPS35 and knockdown of Ccdc85c abolished the VPS35-medicated promotion effect on cell proliferation and invasion. Finally, KLF7/VPS35 axis regulated Ccdc85c, which involved in activation of β-catenin signaling pathway, confirmed using β-catenin inhibitor, GK974. Functional studies suggested that downregulation of Ccdc85c partly reversed the capacity of cell proliferation and invasion in HCC cells, which was regulated by VPS35 upregulation. Conclusion: We demonstrated that KLF7/VPS35 axis promoted HCC cell progression by activating Ccdc85c-medicated β-catenin pathway. Targeting this signal axis might be a potential treatment strategy for HCC.

scholarly journals miR-142-5p regulates the progression of diabetic retinopathy by targeting IGF1

2020 ◽  
Vol 34 ◽  
pp. 205873842090904 ◽  
Author(s):  
Xiuming Liu ◽  
Jianchang Li ◽  
Xiaofeng Li
Keyword(s):  
Cell Proliferation ◽  
Diabetic Retinopathy ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Igf1r Signaling

As one of leading causes of blindness, diabetic retinopathy (DR) is a progressive microvascular complication of diabetes mellitus (DM). Despite significant efforts have been devoted to investigate DR over the years, the molecular mechanisms still remained unclear. Emerging evidences demonstrated that microRNAs (miRNAs) were tightly associated with pathophysiological development of DR. Hence, this study was aimed to illustrate the role and molecular mechanisms of miR-412-5p in progression of DR. Streptozotocin (STZ) treatment in rats and human retinal endothelial cell (HREC) models were used to simulate DR conditions in vivo and in vitro. Hematoxylin-eosin (HE) staining was used to demonstrate the morphology of retinal tissues of rats. Qualitative real-time polymerase chain reaction (qRT-PCR) detected miR-142-5p and vascular endothelial growth factor (VEGF) expression levels. Cell counting kit-8 (CCK8) assay and immunofluorescence (IF) measured the cell proliferation rates. Western blot tested the expression status of IGF1/IGF1R-mediated signaling pathway. Dual-luciferase reporter assays demonstrated the molecular mechanism of miR-142-5p. miR-142-5p level was down-regulated in retinal tissues of DR rats and high glucose (HG)-treated HRECs. Insulin-like growth factor 1 (IGF1) was identified as a direct target of miR-142-5p. The reduced miR-142-5p level enhanced HRECs proliferation via activating IGF/IGF1R-mediated signaling pathway including p-PI3K, p-ERK, p-AKT, and VEGF activation, ultimately giving rise to cell proliferation. Either miR-142-5p overexpression or IGF1 knockdown alleviated the pathological effects on retinal tissues in DR rats. Collectively, miR-142-5p participated in DR development by targeting IGF1/p-IGF1R signaling pathway and VEGF generation. This miR-142-5p/IGF1/VEGF axis provided a novel therapeutic target for DR clinical treatment.

scholarly journals MiR-137's Tumor Suppression on Prolactinomas by Targeting MITF and Modulating Wnt Signaling Pathway

2019 ◽  
Vol 104 (12) ◽  
pp. 6391-6402 ◽  
Author(s):  
Cao Lei ◽  
Guo Jing ◽  
Wang Jichao ◽  
Lou Xiaohui ◽  
Qiuyue Fang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Tumor Suppression ◽  
Inhibitory Factor ◽  
Luciferase Reporter ◽  
Wnt Inhibitory Factor 1 ◽  
Mitf Expression ◽  
Inhibitory Factor 1

Abstract Context Prolactinomas are the most common functional pituitary adenomas; the aggressive tumors still present challenge to clinicians. Aberrant expression of miRNAs has been functionally associated with prolactinomas. Objective Here we explored the role of miR-137 on the proliferation, invasion, and apoptosis of prolactinomas and its possible mechanism. Results Low expression of miR-137 was correlated with the invasive behavior of human prolactinomas and predicted high recurrence. MiR-137 inhibited cell proliferation, invasion, and survivals of MMQ and GH3 cells and reduced tumor volume in F344 rat prolactinomas. The luciferase reporter assay confirmed that microphthalmia-associated transcription factor (MITF) was the direct target of miR-137. In addition, miR-137 mimics could inhibit MITF expression in vivo and in vitro. Upregulation of MITF expression promoted cell proliferation, invasion, and survivals and reversed the antitumor effect of miR-137 in vivo and in vitro. Furthermore, miR-137 could also upregulate wnt-inhibitory factor-1 and inhibit nuclear translocation of β-catenin. Upregulation of wnt-inhibitory factor-1 with decitabine can enhance the inhibition on cell proliferation of miR-137. A glycogen synthase kinase-3 inhibitor, SB 216763, promoted cell proliferation by upregulation of total/cytoplasmic/nuclear β-catenin and reversed tumor suppression of miR-137 mimics. Conclusions Our data suggest that miR-137 possesses a tumor invasive suppressor function with a prognostic value in prolactinomas by targeting MITF and modulating Wnt-β-catenin signaling pathway.

scholarly journals Anticancer Properties of Carnosol: A Summary of In Vitro and In Vivo Evidence

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 961
Author(s):  
Eric J. O’Neill ◽  
Danja J. Den Hartogh ◽  
Karim Azizi ◽  
Evangelia Tsiani
Keyword(s):  
Cell Proliferation ◽  
Nuclear Translocation ◽  
B Cell Lymphoma ◽  
Migration And Invasion ◽  
Anticancer Properties ◽  
Anticancer Effects ◽  
Cell Proliferation Inhibition ◽  
Apoptotic Marker

Cancer is characterized by unrestricted cell proliferation, inhibition of apoptosis, enhanced invasion and migration, and deregulation of signalling cascades. These properties lead to uncontrolled growth, enhanced survival, and the formation of tumours. Carnosol, a naturally occurring phyto-polyphenol (diterpene) found in rosemary, has been studied for its extensive antioxidant, anti-inflammatory, and anticancer effects. In cancer cells, carnosol has been demonstrated to inhibit cell proliferation and survival, reduce migration and invasion, and significantly enhance apoptosis. These anticancer effects of carnosol are mediated by the inhibition of several signalling molecules including extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK), Akt, mechanistic target of rapamycin (mTOR) and cyclooxygenase-2 (COX-2). Additionally, carnosol prevents the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and promotes apoptosis, as indicated by increased levels of cleaved caspase-3, -8, -9, increased levels of the pro-apoptotic marker Bcl-2-associated X (BAX), and reduced levels of the anti-apoptotic marker B-cell lymphoma 2 (Bcl-2). The current review summarizes the existing in vitro and in vivo evidence examining the anticancer effects of carnosol across various tissues.

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