CircRNA UBAP2 Serves as a Sponge of miR-1294 to Increase Tumorigenesis in Hepatocellular Carcinoma through Regulating c-Myc Expression

Abstract Background: Circular RNAs (circRNAs) are a class of regulatory RNAs with complex roles in healthy and diseased tissues. However, the oncogenic role of circRNAs in hepatocellular carcinoma (HCC) remains poorly understood, including the mechanisms by which the circRNA UBAP2 contributes to tumorigenesis. Methods: We analyzed the expression of circUBAP2 in 20 paired samples of HCC and healthy tissue as well as in seven HCC cell lines via quantitative real-time polymerase chain reaction (qRT-PCR). Functional experiments, such as CCK8 viability assays, colony formation assays, wound healing, transwell assays, and flow cytometry, were conducted to assess the effects of circUBAP2 in vitro. To further elucidate the mechanisms by which circUBAP2 acts, we conducted dual-luciferase assays, western blots, RNA pull-down assays, and rescue experiments. Results: circUBAP2 was highly upregulated in most HCC tissues and was associated with poor prognosis. HCC patients with high circUBAP2 expression had greater vascular invasion and worse differentiation. Functionally, circUBAP2 overexpression enhanced HCC cell proliferation, migration, and invasion and inhibited apoptosis. Furthermore, we found that circUBAP2 upregulated c-Myc expression by sponging miR-1294, thus contributing to hepatocarcinogenesis. Inhibiting circUBAP2 expression in HCC attenuated the oncogenic effects of c-Myc. Conclusions: These findings suggest that circUBAP2 promotes HCC growth and metastasis. circUBAP2 may have value as an independent prognostic biomarker or as a new target for the treatment of HCC.

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The Circular RNA hsa_circ_0001445 Regulates the Proliferation and Migration of Hepatocellular Carcinoma and May Serve as a Diagnostic Biomarker

Disease Markers ◽

10.1155/2018/3073467 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 27

Author(s):

Xianwei Zhang ◽

Hu Zhou ◽

Wei Jing ◽

Ping Luo ◽

Shili Qiu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B ◽

Characteristic Curve ◽

Circular Rna ◽

Migration And Invasion ◽

Circular Rnas ◽

Healthy Controls ◽

Polymerase Chain ◽

And Migration

Circular RNAs (circRNA), a class of noncoding RNAs, have been found to be involved in various diseases. Here, the expression levels of the circRNA hsa_circ_0001445 in 73 pairs of hepatocellular carcinoma (HCC) and adjacent nontumor tissues were investigated by quantitative real-time polymerase chain reaction (qRT-PCR). Our data demonstrate that the hsa_circ_0001445 levels were significantly decreased in HCC tissues (P<0.001) and markedly associated with the number of tumor foci (P=0.014). Furthermore, in vitro approaches showed that overexpression of hsa_circ_0001445 promoted apoptosis and inhibited proliferation, migration, and invasion of HCC-derived cells, suggesting that hsa_circ_0001445 might be involved in the development of HCC. In addition, we found that the plasma hsa_circ_0001445 transcription levels in HCC patients were lower than those in cirrhosis (P<0.001) and hepatitis B (P<0.001) patients as well as in healthy controls (P<0.001). In fact, receiver operating characteristic curve analysis indicated that plasma hsa_circ_0001445 could be a fairly accurate marker to distinguish HCC cases from healthy controls as well as patients with cirrhosis or hepatitis B.

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miR-369-3p serves as prognostic factor and regulates cancer progression of hepatocellular carcinoma

Personalized Medicine ◽

10.2217/pme-2020-0012 ◽

2021 ◽

Author(s):

Can Chen ◽

Yi Zong ◽

Jiaojiao Tang ◽

Ruisheng Ke ◽

Lizhi Lv ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Cancer Progression ◽

Cell Counting ◽

Migration And Invasion ◽

Pcr Analysis ◽

Reverse Transcription Pcr ◽

Huh7 Cells

Background: The aim of this study was to investigate the role of miR-369-3p in hepatocellular carcinoma (HCC). Materials & methods: The expression levels of miR-369-3p were detected using the quantitative real-time reverse transcription-PCR analysis. The cell counting kit-8 and transwell assays were used to explore the effects of miR-369-3p on cell proliferation, migration and invasion of HCC cells. Results: The miR-369-3p expression was downregulated in HCC tissues and cell lines, in comparison to the normal controls, respectively. In vitro, overexpression of miR-369-3p in Hep 3B and Huh7 cells inhibited cell proliferation, migration and invasion. SOX4 was a direct target of miR-369-3p. Conclusion: Our results suggested that miR-369-3p may be a tumor suppressor in HCC by targeting SOX4.

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circATP2A2 promotes osteosarcoma progression by upregulating MYH9

Open Medicine ◽

10.1515/med-2021-0370 ◽

2021 ◽

Vol 16 (1) ◽

pp. 1749-1761

Author(s):

Xin Cao ◽

Xianfeng Meng ◽

Peng Fu ◽

Lin Wu ◽

Zhen Yang ◽

...

Keyword(s):

Cell Proliferation ◽

Area Under Curve ◽

Prognostic Biomarker ◽

Migration And Invasion ◽

Promising Target ◽

Repressive Effect ◽

Cell Malignancy

Abstract Osteosarcoma (OS) is a highly metastatic primary malignant tumor. CircRNA hsa_circ_0028173 (circATP2A2) has been uncovered to be related to the advancement of OS. However, the biological role of circATP2A2 in OS has not been validated. circATP2A2 and MYH9 were upregulated while miR-335-5p was downregulated in OS. OS patients with high circATP2A2 expression displayed a shorter overall survival and the area under curve of circATP2A2 was 0.77, manifesting that circATP2A2 might be a diagnostic and prognostic biomarker. circATP2A2 silencing repressed OS cell proliferation and glycolysis in vivo and constrained OS cell proliferation, glycolysis, migration, and invasion in vitro. circATP2A2 regulated MYH9 expression through sponging miR-335-5p. MiR-335-5p inhibitor reversed the repressive effect of circATP2A2 knockdown on OS cell malignancy and glycolysis. MYH9 overexpression overturned miR-335-5p upregulation-mediated OS cell malignancy and glycolysis. circATP2A2 accelerated OS cell malignancy and glycolysis through upregulating MYH9 via sponging miR-335-5p, offering a promising target for OS treatment.

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Downregulation of CRABP2 Inhibit the Tumorigenesis of Hepatocellular Carcinoma In Vivo and In Vitro

BioMed Research International ◽

10.1155/2020/3098327 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Qingmin Chen ◽

Ludong Tan ◽

Zhe Jin ◽

Yahui Liu ◽

Ze Zhang

Keyword(s):

Hepatocellular Carcinoma ◽

Retinoic Acid ◽

Cell Lines ◽

Molecular Mechanisms ◽

Tumor Stage ◽

Migration And Invasion ◽

Hcc Cells

Cellular retinoic acid-binding protein 2 (CRABP2) binds retinoic acid (RA) in the cytoplasm and transports it into the nucleus, allowing for the regulation of specific downstream signal pathway. Abnormal expression of CRABP2 has been detected in the development of several tumors. However, the role of CRABP2 in hepatocellular carcinoma (HCC) has never been revealed. The current study aimed to investigate the role of CRABP2 in HCC and illuminate the potential molecular mechanisms. The expression of CRABP2 in HCC tissues and cell lines was detected by western blotting and immunohistochemistry assays. Our results demonstrated that the expression levels of CRABP2 in HCC tissues were elevated with the tumor stage development, and it was also elevated in HCC cell lines. To evaluate the function of CRABP2, shRNA-knockdown strategy was used in HCC cells. Cell proliferation, metastasis, and apoptosis were analyzed by CCK-8, EdU staining, transwell, and flow cytometry assays, respectively. Based on our results, knockdown of CRABP2 by shRNA resulted in the inhibition of tumor proliferation, migration, and invasion in vitro, followed by increased tumor apoptosis-related protein expression and decreased ERK/VEGF pathway-related proteins expression. CRABP2 silencing in HCC cells also resulted in the failure to develop tumors in vivo. These results provide important insights into the role of CRABP2 in the development and development of HCC. Based on our findings, CRABP2 may be used as a novel diagnostic biomarker, and regulation of CRABP2 in HCC may provide a potential molecular target for the therapy of HCC.

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Inhibition of hypoxia-inducible factor-1α by PX-478 as a potential targeted therapy in ESCC.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14083 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14083-e14083

Author(s):

Yingming Zhu ◽

Yuanwei Zang ◽

Minghuan Li ◽

Jinming Yu

Keyword(s):

Targeted Therapy ◽

Hypoxia Inducible Factor ◽

Radical Resection ◽

Carcinoma Cells ◽

Migration And Invasion ◽

Hypoxia Inducible Factor 1Α ◽

Polymerase Chain ◽

Cox 2

e14083 Background: Hypoxia is a unique microenvironment in solid tumors, including ESCC. We aim to investigate the interaction between hypoxia-inducible factor-1α (HIF-1α), COX-2 and programmed cell death ligand-1 (PD-L1) and uncover the role of HIF-1α inhibitor PX-478 as a potential targeted therapy in ESCC. Methods: Immunohistochemical staining was performed to investigate the levels of HIF-1α, COX-2 and PD-L1 from 133 pT3N0M0 ESCC patients after radical resection. The prognostic value of the expression of HIF-1α, COX-2 and PD-L1 and the correlation with clinicopathologic features was evaluated. Knockdown assay, CCK-8 assay, Western blot, real-time polymerase chain reaction (RT-PCR), flow cytometry and Transwell migration assays were used in cells experiment. Results: HIF-1α and PD-L1 are independent prognostic factors in pT3N0M0 ESCC. Further data showed that HIF-1α plays an important role in regulation of COX-2 and PD-L1 expression. Our in vitro studies demonstrated that HIF-1α inhibitor, PX-478, induced G2 phase arrest, increased apoptosis, and inhibited migration and invasion of esophageal carcinoma cells, and thus significantly inhibit ESCC cells proliferation. Conclusions: Our results provide new insight into the potential role of HIF-1α inhibitors, PX-478 and open up the possibility of PX-478 for targeted therapy of ESCC.

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Elevated FOXC2 Expression Promotes Invasion of HCC Cell Lines and is Associated with Poor Prognosis in Hepatocellular Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000484586 ◽

2017 ◽

Vol 44 (1) ◽

pp. 99-109 ◽

Cited By ~ 7

Author(s):

Fang Yang ◽

Lizhi Lv ◽

Kun Zhang ◽

Qiucheng Cai ◽

Jianyong Liu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Flow Cytometric Analysis ◽

Vital Role ◽

Migration And Invasion ◽

Flow Cytometric ◽

Kaplan Meier ◽

Proliferation Assays ◽

The Relationship

Background/Aims: Increasing evidence has indicated that Forkhead box protein C2 (FOXC2) plays an important role in carcinogenesis. However, the expression and the role of FOXC2 in hepatocellular carcinoma (HCC) have not been extensively studied. Methods: FOXC2 expression was analyzed by quantitative real-time polymerase chain reaction, Western blot analysis and immunohistochemistry in HCC tissue and cells. The relationship between FOXC2 expression and patient clinical significance and survival were assessed by Pearson’s correlation and Kaplan-Meier analysis, respectively. Cell proliferation assays, colony formation assays, flow cytometric analysis and Transwell assays were employed to measure the effects of FOXC2 on HCC cells in vitro. Results: The expression of FOXC2 was increased in HCC tissue, and high FOXC2 expression was associated with worse patient survival. Knockdown of FOXC2 inhibited HCC cell growth, migration, and invasion in vitro, as well as tumor growth. Furthermore, we found that activation of AKT-mediated MMP-2 and MMP-9 was involved in FOXC2 promoting an aggressive phenotype. Conclusions: Taken together, these findings demonstrate that FOXC2 is upregulated in HCC tissue and is associated with tumor size, vascular invasion and advanced TNM stage. Further investigation suggested that FOXC2 may play a vital role in promoting proliferation and invasion in HCC and serves as a novel therapeutic target in HCC.

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PLOD1 Is a Prognostic Biomarker and Mediator of Proliferation and Invasion in Osteosarcoma

BioMed Research International ◽

10.1155/2020/3418398 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Haoli Jiang ◽

Wei Guo ◽

Shanyou Yuan ◽

Lixia Song

Keyword(s):

Survival Analysis ◽

Expression Pattern ◽

Migration And Invasion ◽

Western Blots ◽

Primary Bone Tumor ◽

Kaplan Meier ◽

The Status ◽

Public Datasets

Objective. Osteosarcoma is the most common primary bone tumor and most frequently develops during adolescence. PLOD family was mainly involved in lysyl hydroxylation and rarely investigated in cancers, especially in osteosarcoma. The aim of this study was to investigate the expression pattern and oncogenic role of PLODs in osteosarcoma. Methods. GEO datasets (GSE16088, GSE33382, and GSE16091) and validation cohort were used to analyze the expression pattern of PLODs in osteosarcoma. Kaplan-Meier survival analysis was used to explore the prognostic role of PLODs in patients with osteosarcoma. RNA interference of KRT19 was performed using small interfering RNA (siRNA) in MG-63 and U-2OS cells. The proliferation was detected using CCK8, clone formation assay, and EdU staining. Migration and invasion were determined using the transwell assay. Western blots and luciferase assays for β-catenin-T-cell factor protein/β-catenin-lymphoid enhancer factor- (β-catenin-TCF/LEF-) driven transcriptional activity. Results. PLOD1 was upregulated in osteosarcoma tissues compared with control tissues both in public datasets and in in-house cohort. The expression of PLOD1 in osteosarcoma tissues was significantly associated with the status of distance metastasis and Enneking stage, while PLOD2 and PLOD3 expressed no difference between osteosarcoma and benign tissues and showed no correlation with tumor malignancy. Furthermore, Kaplan-Meier survival analysis revealed that patients with a higher level of PLOD1 had worse prognosis than those with a lower level of PLOD1. Downregulation of PLOD1 dramatically inhibited proliferation, migration, and invasion of MG-63 cells and U-2OS cells in vitro. Mechanistically, PLOD1 regulated β-catenin signaling pathway in osteosarcoma. Conclusion. Our results indicated that PLOD1 promoted proliferation, migration, and invasion of osteosarcoma cells. PLOD1 was a novel prognostic marker, as well as a therapeutic target in osteosarcoma.

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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.

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Circular RNA hsa_circ_0013958 Functions as an Oncogenic Gene Through Modulating miR-532-3p/WEE1 Axis in Hepatocellular Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.585172 ◽

2021 ◽

Vol 11 ◽

Author(s):

Tao Ma ◽

Yue Ma ◽

Yongjun Du ◽

Zhongheng Wei ◽

Jianchu Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Circular Rna ◽

Luciferase Reporter ◽

Western Blot Assay ◽

Polymerase Chain ◽

Oncogenic Gene ◽

Proliferation And Invasion

Backgroundcirc0013958 was identified as a biomarker, which can be used for the diagnosis and screening of lung cancer. However, the role of circ0013958 in hepatocellular carcinoma (HCC) remains unclear.MethodsIn our study, quantitative real-time polymerase chain reaction was performed to determine the levels of circ0013958 in HCC tissues and cell lines. EdU, CCK-8, transwell, flow cytometry and tumorigenesis assays were applied to assess the functions of circ0013958 in HCC in vitro and in vivo. Western blot assay was to detect the expression of WEE1. Luciferase reporter assay, bioinformatics analysis and rescue experiments were used to examine the interaction among circ0013958, miR-532-3p and WEE1.ResultsIt revealed that circ0013958 was significantly up-regulated in HCC, which was positively correlated with poor prognosis of HCC patients. Circ0013958 promoted HCC cell proliferation and invasion, inhibited cell apoptosis in vitro, and promoted tumorigenesis in vivo. Circ0013958 acted as a miR-532-3p sponge to regulate WEE1 expression, thus promoting the progression of HCC.ConclusionsCirc0013958 promotes HCC progression through miR-532-3p/WEE1 axis. Circ0013958 may serve as a potential diagnostic biomarker and therapeutic target of HCC.

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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.

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