circRNA hsa_circ_104566 Sponged miR-338-3p to Promote Hepatocellular Carcinoma Progression

Circular RNAs (circRNAs) could sponge micro-RNAs (miRNAs) to regulate tumor progression of hepatocellular carcinoma (HCC). Hsa_circ_104566 contributes to papillary thyroid carcinoma progression. However, the tumorigenic mechanism of hsa_circ_104566 on HCC remains enigmatic. The role of hsa_circ_104566 on HCC was therefore evaluated in this study. First, the high expression of hsa_circ_104566 was found in HCC tissues, which was significantly associated with poor prognosis in HCC patients. Second, Hsa_circ_104566 promoted HCC progression by decreasing apoptosis and E-cadherin, while increasing cell viability, proliferation, migration, invasion, and N-cadherin. On the other hand, HCC progression was suppressed by knockdown of hsa_circ_104566. Hsa_circ_104566 could target miR-338-3p, and its expression was negatively correlated with miR-338-3p in HCC patients. Moreover, miR-338-3p suppressed protein expression of Forkhead box protein 1 (FOXP1) and had a negative correlation with FOXP1 in HCC patients. Functional assay further indicated that the promotion of HCC progression by hsa_circ_104566 was reversed by miR-338-3p, and miR-338-3p inhibitor could counteract the effect of hsa_circ_104566 knockdown on the suppression of HCC progression. In vivo assay indicated that hsa_circ_104566 knockdown suppressed HCC tumor growth and metastasis. In conclusion, hsa_circ_104566 sponged miR-338-3p to promote HCC progression, providing a potential therapeutic target for cancer intervention.

Download Full-text

Hsa_circRNA_002144 promotes growth and metastasis of colorectal cancer through regulating miR-615-5p/LARP1/mTOR pathway

Carcinogenesis ◽

10.1093/carcin/bgaa140 ◽

2020 ◽

Author(s):

Mengqiong Wu ◽

Cancan Kong ◽

Manni Cai ◽

Weiwei Huang ◽

Yiming Chen ◽

...

Keyword(s):

Colorectal Cancer ◽

Therapeutic Target ◽

Poor Prognosis ◽

Migration And Invasion ◽

Circular Rnas ◽

Over Expression ◽

Functional Assays ◽

Cancer Intervention

Abstract CircRNAs (circular RNAs), recently identified as a critical regulator in tumorigenesis, participate in colorectal cancer (CRC) growth. However, role of hsa_circRNA_002144 in CRC was poorly understood. Firstly, hsa_circRNA_002144 showed significantly elevation in both of CRC tissues and cell lines, and suggested closely associated with poor prognosis in patients. Secondly, data from functional assays revealed that silence of hsa_circRNA_002144 inhibited CRC progression with reduced cell viability, proliferation, migration and invasion, while enhanced cell apoptosis. In addition, in vivo CRC growth and metastasis were also suppressed by knockdown of hsa_circRNA_002144. However, CRC progression was promoted with over-expression of hsa_circRNA_002144. Thirdly, hsa_circRNA_002144 colocalized with miR-615-5p in the cytoplasm of CRC cells, and decreased miR-615-5p expression. Moreover, miR-615-5p could target LARP1 (La ribonucleoprotein 1, translational regulator). Lastly, the suppressive effects of hsa_circRNA_002144 knockdown on CRC progression was reversed by LARP1 over-expression. In conclusion, hsa_circRNA_002144 could sponge miR-615-5p to promote CRC progression through regulation of LARP1, providing a therapeutic target for cancer intervention.

Download Full-text

MicroRNA-139-3p Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by Repressing ANXA2R

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504018x15178798885361 ◽

2018 ◽

Vol 26 (9) ◽

pp. 1391-1399 ◽

Cited By ~ 5

Author(s):

Zeng Cheng Zou ◽

Min Dai ◽

Zeng Yin Huang ◽

Yi Lu ◽

He Ping Xie ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Migration ◽

Cell Growth ◽

Mouse Model ◽

Migration And Invasion ◽

Tumor Growth And Metastasis ◽

Underlying Mechanisms ◽

Hcc Cells

The direct roles of miR-139-3p on hepatocellular carcinoma (HCC) cell growth and metastasis remain poorly understood. We attempted to demonstrate the regulatory role of miR-139-3p in HCC progression and its underlying mechanisms. Here we showed that miR-139-3p expression was significantly reduced in the HCC tissues compared to paratumor tissues. Exogenous overexpression of miR-139-3p inhibited the migration and invasion of HCC cells, whereas downregulation of miR-139-3p was able to induce HCC HepG2 and SNU-449 cell migration and invasion. In addition, miR-139-3p inhibited HCC growth and lung metastasis in an in vivo mouse model, which is mainly regulated by annexin A2 receptor (ANXA2R). Finally, we identified that the expression of miR-139-3p was inversely correlated with ANXA2R expression in human HCC tissue. All these results demonstrated that miR-139-3p inhibited the metastasis process in HCC by downregulating ANXA2R expression.

Download Full-text

Methyltransferase-Like 3-Mediated m6A Methylation of Hsa_circ_0058493 Accelerates Hepatocellular Carcinoma Progression by Binding to YTH Domain-Containing Protein 1

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.762588 ◽

2021 ◽

Vol 9 ◽

Author(s):

Anqi Wu ◽

Yuhao Hu ◽

Yao Xu ◽

Jing Xu ◽

Xinyue Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Intracellular Localization ◽

Rna Modification ◽

Circular Rnas ◽

Yth Domain ◽

Highly Correlated ◽

Hcc Cells

Circular RNAs (circRNAs) are highly correlated with the progression and prognosis of hepatocellular carcinoma (HCC). In addition, mounting evidence has revealed that N6-methyladenosine (m6A) methylation, a common RNA modification, is involved in the progression of malignancies. In this research, a novel circRNA, hsa_circ_0058493, was proven to be upregulated in HCC, which was correlated with the prognosis of HCC patients. Experimentally, hsa_circ_0058493 knockdown suppressed the growth and metastasis of HCC cells in vivo and in vitro. On the contrary, the overexpression of hsa_circ_0058493 in HCC cells had the opposite effect in vitro. Mechanistic experiments revealed that hsa_circ_0058493 contained m6A methylation sites and that methyltransferase-like 3 (METTL3) mediated the degree of methylation modification of hsa_circ_0058493. Furthermore, YTH domain-containing protein 1 (YTHDC1) could bind to hsa_circ_0058493 and promote its intracellular localization from the nucleus to the cytoplasm. In addition, both si-METTL3 and si-YTHDC1 suppressed HCC cell growth and metastasis, whereas rescue experiments confirmed that overexpression of hsa_circ_0058493 inverted the inhibitory effects of si-METTL3 and si-YTHDC1 on HCC cells. Taken together, this study explored the oncogenic role of m6A-modified hsa_circ_0058493 and found to accelerate HCC progression via the METTL3-hsa_circ_0058493-YTHDC1 axis, indicating a potential therapeutic target for this deadly disease.

Download Full-text

LINC01018 confers a novel tumor suppressor role in hepatocellular carcinoma through sponging microRNA-182-5p

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00005.2019 ◽

2019 ◽

Vol 317 (2) ◽

pp. G116-G126 ◽

Cited By ~ 4

Author(s):

Shuai Wang ◽

Mingfang Xu ◽

Zhengang Sun ◽

Xiao Yu ◽

Yan Deng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Formation ◽

Cell Cycle Distribution ◽

Tissue Samples ◽

In Vivo Experiments ◽

Forkhead Box ◽

Related Mortality ◽

Hcc Cells

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Emerging evidence has demonstrated that some long noncoding RNAs (lncRNAs) are involved in the development and progression of HCC. Herein, the current study aimed to explore the potential mechanism of LINC01018 in regulating the progression of HCC. Initially, the expression of LINC01018, microRNA-182-5p (miR-182-5p), and forkhead box protein O1 (FOXO1) was quantified in 72 paired HCC and adjacent normal tissue samples as well as HCC cells, followed by identification of the interaction among them. To define the contributory role of LINC01018 in the progression of HCC, the expression of LINC01018, miR-182-5p, or FOXO1 was altered in HCC cells, followed by evaluation of cell proliferation, cell cycle distribution, and cell apoptosis. Finally, in vivo tests were performed to further verify the role of LINC01018 in HCC. It was observed that LINC01018 and FOXO1 were poorly expressed but miR-182-5p was highly expressed in HCC tissues and cells. The upregulation of LINC01018 was shown to decrease proliferation while promoting apoptosis of HCC cells. LINC01018 acted as a sponge of miR-182-5p, which targeted FOXO1. Last, mice injected with Hep3B overexpressing FOXO1 displayed suppressed xenograft tumor formation. Collectively, overexpression of LINC01018 represses proliferation and promotes apoptosis of HCC cells via upregulation of FOXO1 by sponging miR-182-5p, which highlights overexpression of LINC01018 as a candidate suppressor of HCC. NEW & NOTEWORTHY This study provides evidence for understanding the molecular mechanism involved in the progression of hepatocellular carcinoma and identifies a novel network of LINC01018/miR-182-5p/FOXO1. We also conducted in vivo experiments in nude mice to validate the anti-tumor effect of LINC01018.

Download Full-text

Circular RNA hsa_Circ_101141 as a Competing Endogenous RNA Facilitates Tumorigenesis of Hepatocellular Carcinoma by Regulating miR-1297/ROCK1 Pathway

Cell Transplantation ◽

10.1177/0963689720948016 ◽

2020 ◽

Vol 29 ◽

pp. 096368972094801 ◽

Cited By ~ 1

Author(s):

Tao Zhang ◽

Lijuan Zhang ◽

Dan Han ◽

Kebinur Tursun ◽

Xiaobo Lu

Keyword(s):

Hepatocellular Carcinoma ◽

Coiled Coil ◽

Circular Rna ◽

Migration And Invasion ◽

Circular Rnas ◽

Competing Endogenous Rna ◽

Direct Target ◽

And Function

As a novel class of noncoding RNAs, circular RNAs (circRNAs) have been recently reported to be involved in cell development and function. However, the functional role of circRNAs in hepatocellular carcinoma (HCC) remains unclear. In the present study, we found that the expression of human circ_101141 was upregulated in HCC tissues and cells. In addition, downregulation of circ_101141 dramatically inhibited cell proliferation, migration, and invasion in HCC cells. In addition, by using the bioinformatics tools, the potential target of circ_101141 was predicted. Mechanistic investigations indicated that circ_101141 acted as a miR-1297 “sponge”; meanwhile, Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) was a direct target of miR-1297. Further experiments demonstrated that circ_101141 contributed to the progression of HCC by acting as competing endogenous RNA (ceRNA) of miR-1297 to regulate ROCK1 expression. Furthermore, knockdown of circ_101141 attenuated HCC tumorigenesis in vivo. Taken together, these findings indicated that circRNA circ_101141 acted as a ceRNA to facilitate tumorigenesis of HCC by regulating miR-1297/ROCK1 pathway.

Download Full-text

Circ_0001955 facilitates hepatocellular carcinoma (HCC) tumorigenesis by sponging miR-516a-5p to release TRAF6 and MAPK11

Cell Death and Disease ◽

10.1038/s41419-019-2176-y ◽

2019 ◽

Vol 10 (12) ◽

Cited By ~ 21

Author(s):

Zhicheng Yao ◽

Ruiyun Xu ◽

Lin Yuan ◽

Mingxing Xu ◽

Haiyun Zhuang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Opposite Effect ◽

Target Genes ◽

Circular Rnas ◽

Rna Molecules ◽

Normal Tissues ◽

Tumor Tissues

AbstractCircular RNAs (circRNAs) have been increasingly demonstrated to function as novel promising therapeutic RNA molecules for diverse human diseases, including cancer. Although the important role of circRNAs has been well documented in HCC, the complex mechanisms of circRNAs in HCC need to be elucidated. Here, a novel circRNA circ_0001955 was identified from three GSE datasets (GSE7852, GSE94508, and GSE97322) as a differentially expressed circRNA between HCC and normal samples. We revealed that circ_0001955, TRAF6 and MAPK11 levels were increased, while miR-516a-5p levels were decreased in HCC tumor tissues compared to adjacent normal tissues. Knockdown of circ_0001955 repressed HCC tumor growth in vitro and in vivo, while overexpression of circ_0001955 exhibited the opposite effect. Circ_0001955 was identified as a sponge for miR-145-5p and miR-516a-5p, and TRAF6 and MAPK11 were demonstrated to be two target genes of miR-516a-5p. In conclusion, circ_0001955 facilitated HCC tumorigenesis by sponging miR-516a-5p to release TRAF6 and MAPK11 expression.

Download Full-text

PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3

Cell Death and Disease ◽

10.1038/s41419-021-04013-y ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Dawei Chen ◽

Zhenguo Zhao ◽

Lu Chen ◽

Qinghua Li ◽

Jixue Zou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Alternative Splicing ◽

Protein Function ◽

Vital Role ◽

Normal Tissues ◽

Mechanistic Analysis ◽

Highly Correlated ◽

Splicing Patterns

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

Download Full-text

Knockout of Ajuba Attenuates the Growth and Migration of Hepatocellular Carcinoma Cells

Cytogenetic and Genome Research ◽

10.1159/000512264 ◽

2020 ◽

Vol 160 (11-12) ◽

pp. 650-658

Author(s):

Yichen Le ◽

Yi He ◽

Meirong Bai ◽

Ying Wang ◽

Jiaxue Wu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Growth ◽

Cancer Progression ◽

Normal Liver ◽

Cell Growth And Migration ◽

And Migration ◽

Hcc Cells

Ajuba has been found to be mutated or aberrantly regulated in several human cancers and plays important roles in cancer progression via different signaling pathways. However, little is known about the role of Ajuba in hepatocellular carcinoma (HCC). Here, we found an upregulation of Ajuba expression in HCC tissues compared with normal liver tissues, while a poor prognosis was observed in HCC patients with high Ajuba expression. Knockout of Ajuba in HCC cells inhibited cell growth in vitro and in vivo, suppressed cell migration, and enhanced the cell apoptosis under stress. Moreover, re-expression of Ajuba in Ajuba-deficient cells could restore the phenotype of Ajuba-deficient cells. In conclusion, these results indicate that Ajuba is upregulated in HCC and promotes cell growth and migration of HCC cells, suggesting that Ajuba could possibly be a new target for HCC diagnosis and treatment.

Download Full-text

CircFAM13B promotes the proliferation of hepatocellular carcinoma by sponging miR-212, upregulating E2F5 expression and activating the P53 pathway

Cancer Cell International ◽

10.1186/s12935-021-02120-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ying Xie ◽

Xiaofeng Hang ◽

Wensheng Xu ◽

Jing Gu ◽

Yuanjing Zhang ◽

...

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Gene Expression Omnibus ◽

Differentially Expressed ◽

In Vivo Studies ◽

Circular Rnas ◽

Novel Target ◽

Underlying Mechanisms

Abstract Background Most of the biological functions of circular RNAs (circRNAs) and the potential underlying mechanisms in hepatocellular carcinoma (HCC) have not yet been discovered. Methods In this study, using circRNA expression data from HCC tumor tissues and adjacent tissues from the Gene Expression Omnibus database, we identified out differentially expressed circRNAs and verified them by qRT-PCT. Functional experiments were performed to evaluate the effects of circFAM13B in HCC in vitro and in vivo. Results We found that circFAM13B was the most significantly differentially expressed circRNA in HCC tissue. Subsequently, in vitro and in vivo studies also demonstrated that circFAM13B promoted the proliferation of HCC. Further studies revealed that circFAM13B, a sponge of miR-212, is involved in the regulation of E2F5 gene expression by competitively binding to miR-212, inhibits the activation of the P53 signalling pathway, and promotes the proliferation of HCC cells. Conclusions Our findings revealed the mechanism underlying the regulatory role played by circFAM13B, miR-212 and E2F5 in HCC. This study provides a new theoretical basis and novel target for the clinical prevention and treatment of HCC.

Download Full-text

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

Cell & Bioscience ◽

10.1186/s13578-021-00585-6 ◽

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.

Download Full-text