CircRNA-104718 acts as competing endogenous RNA and promotes hepatocellular carcinoma progression through microRNA-218-5p/TXNDC5 signaling pathway

2019 ◽  
Vol 133 (13) ◽  
pp. 1487-1503 ◽  
Author(s):  
Jiaze Yu ◽  
Minjie Yang ◽  
Bo Zhou ◽  
Jianjun Luo ◽  
Zihan Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Tumor Size ◽  
Cancer Biology ◽  
Underlying Mechanism ◽  
Vital Role ◽  
In Vivo Studies ◽  
Circular Rnas ◽  
Mice Model

AbstractAccumulating evidences indicate that circular RNAs (circRNAs) play a vital role in diverse cancer biology. However, the contributions of circRNAs to hepatocellular carcinoma (HCC) and their underlying mechanism remain largely unknown. The present study aims at investigating the role of circRNA-104718 in HCC progression, which has been observed to be significantly up-regulated in HCC tissues. We found that, higher expression of circRNA-104718 also leds to a poor prognosis in HCC patients. Using luciferase binding assays and RNA immunoprecipitation studies, we identified circRNA-104718 is physically associated and co-expressed with microRNA (miR)-218-5p in HCC. Mechanistically, we demonstrated that circRNA-104718 functions as a competing endogenous RNAs (ceRNAs) and competes with thioredoxin domain-containing protein 5 (TXNDC5) mRNA and directly binds to miR-218-5p. Functionally, we found that ectopically expressed circRNA-104718 accelerated cell proliferation, migration, invasion, and inhibited apoptosis. In vivo studies on a nude mice model showed that circRNA-104718 overexpression could increase the tumor size and the rate of metastasis. Silencing of circRNA-104718 could decrease both the tumor size and metastasis significantly. Conversely, we also observed overexpression of miR-218-5p could in turn decrease the proliferation, migration, invasion, and increase apoptosis. Furthermore, circRNA-104718 could relieve the suppression of miR-218-5p target TXNDC5 and thereby cause an inhibition of miR’s functions. In summary, our results indicate that circRNA-104718 acts as a ceRNA and promotes HCC progression through the targeting of miR-218-5p/TXNDC5 signaling pathway. Thus, we propose that circRNA-104718 would be a promising target for HCC diagnosis and therapy.

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

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.

scholarly journals Dickkopf-1 contributes to hepatocellular carcinoma tumorigenesis by activating the Wnt/β-catenin signaling pathway

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Rui Zhang ◽  
Hao-Ming Lin ◽  
Ruth Broering ◽  
Xiang-de Shi ◽  
Xian-huan Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Tumor Formation ◽  
In Vivo Studies ◽  
Qrt Pcr ◽  
Subsequent Investigation ◽  
Dkk1 Expression ◽  
Tumor Number

AbstractDysregulation of dickkopf-related protein 1 (DKK1) expression has been reported in a variety of human cancers. We previously reported that DKK1 was upregulated in hepatocellular carcinoma (HCC). However, the role of DKK1 in HCC remains unclear. This study aimed to investigate the clinical significance and biological functions of DKK1 in HCC. The expression of DKK1 was examined in cirrhotic and HCC tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). DKK1 was silenced or overexpressed in HCC cell lines, and in vitro and in vivo studies were performed. Immunohistochemistry revealed that DKK1 was weakly expressed in cirrhotic tissues (8/22, 36.4%) but upregulated in HCC tissues (48/53, 90.6%, cohort 1). Significant upregulation of DKK1 was observed in 57.6% (19/33, cohort 2) of HCC tissues by qRT-PCR, and the expression of DKK1 was associated with tumor size (P = 0.024) and tumor number (P = 0.019). Genetic depletion of DKK1 impaired the proliferation, colony-forming ability, invasion, and tumor formation of HCC cells (HepG2 and HUH-7). Conversely, forced expression of DKK1 increased the proliferation, colony-forming ability, and invasion of HepG2 and HUH-7 cells in vitro and enhanced tumor formation in vivo. Subsequent investigation revealed that the DKK1-mediated proliferation and tumorigenicity of HepG2 and HUH-7 cells is dependent on the Wnt/β-catenin signaling pathway. These findings indicate that DKK1 plays an oncogenic role in HCC by activating the Wnt/β-catenin signaling pathway.

scholarly journals Circ_0001367 inhibits glioma proliferation, migration and invasion by sponging miR-431 and thus regulating NRXN3

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Liang Liu ◽  
Peng Zhang ◽  
Xuchen Dong ◽  
Haoran Li ◽  
Suwen Li ◽  
...  
Keyword(s):  
Close Correlation ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Dependent Manner ◽  
Glioma Growth

AbstractMany studies have reported that circular RNAs play a vital role in the malignant progression of human cancers. However, the role and underlying mechanism of circRNAs in the development of gliomas have not been fully clarified. In this study, we found that circ_0001367 was downregulated in glioma tissues and showed a close correlation with glioma patient survival. Functional assays demonstrated that upregulation of circ_0001367 could suppress the proliferation, migration and invasion of glioma cells in vitro and inhibit glioma growth in vivo. Furthermore, bioinformatics analysis, luciferase reporter assay and RNA immunoprecipitation assay indicated that circ_0001367 can serve as a sponge for miR-431 and that miR-431 acts as an oncogene by regulating neurexin 3 (NRXN3). In addition, rescue experiments verified that circ_0001367 could regulate both the expression and function of NRXN3 in a miR-431-dependent manner. In conclusion, circ_0001367 functions as an suppressor in glioma by targeting the miR-431/NRXN3 axis and may be a promising therapeutic target against gliomas.

scholarly journals Naa20, the catalytic subunit of NatB complex, contributes to hepatocellular carcinoma by regulating the LKB1–AMPK–mTOR axis

2020 ◽  
Vol 52 (11) ◽  
pp. 1831-1844
Author(s):  
Taek-Yeol Jung ◽  
Jae-Eun Ryu ◽  
Mi-Mi Jang ◽  
Soh-Yeon Lee ◽  
Gyu-Rin Jin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Underlying Mechanism ◽  
Bioinformatic Analysis ◽  
Catalytic Subunit ◽  
The Cancer Genome Atlas ◽  
Ampk Activity

AbstractN-α-acetyltransferase 20 (Naa20), which is a catalytic subunit of the N-terminal acetyltransferase B (NatB) complex, has recently been reported to be implicated in hepatocellular carcinoma (HCC) progression and autophagy, but the underlying mechanism remains unclear. Here, we report that based on bioinformatic analysis of Gene Expression Omnibus and The Cancer Genome Atlas data sets, Naa20 expression is much higher in HCC tumors than in normal tissues, promoting oncogenic properties in HCC cells. Mechanistically, Naa20 inhibits the activity of AMP-activated protein kinase (AMPK) to promote the mammalian target of rapamycin signaling pathway, which contributes to cell proliferation, as well as autophagy, through its N-terminal acetyltransferase (NAT) activity. We further show that liver kinase B1 (LKB1), a major regulator of AMPK activity, can be N-terminally acetylated by NatB in vitro, but also probably by NatB and/or other members of the NAT family in vivo, which may have a negative effect on AMPK activity through downregulation of LKB1 phosphorylation at S428. Indeed, p-LKB1 (S428) and p-AMPK levels are enhanced in Naa20-deficient cells, as well as in cells expressing the nonacetylated LKB1-MPE mutant; moreover, importantly, LKB1 deficiency reverses the molecular and cellular events driven by Naa20 knockdown. Taken together, our findings suggest that N-terminal acetylation of LKB1 by Naa20 may inhibit the LKB1–AMPK signaling pathway, which contributes to tumorigenesis and autophagy in HCC.

scholarly journals Gundelia Tournefortii Extracts Inhibit Progressions of Hepatocellular Carcinoma in Mice Model Through Decrease in p53/Akt/PI3K Signaling Pathway

2020 ◽  
Author(s):  
Johnny Amer ◽  
Nidal Jaradat ◽  
Hanood Aburas ◽  
Suhaib Hattab ◽  
Samer Abdallah
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Ex Vivo ◽  
Annexin V ◽  
Pi3k Signaling ◽  
Mice Model ◽  
Primary Hepatocytes ◽  
Phosphorylated Akt ◽  
Pi3k Signaling Pathway

Abstract Background: Gundelia (G.) tournefortii is one of the most famous plants used in Palestine for its traditional curative and nutritive properties. We evaluated effects of Gundelia (G.) tournefortii aqueous-extract in an ex-vivo and in in-vivo animal model of hepatocellular carcinoma (HCC).Methods: HCC cell-line (Hep3B) were injected in the back of male mice on NOD.CB17-Prkdc-scid/NCrHsD background. Tumor size, serum a-fetoprotein (αFP) and Glypican-3 (GPC3) were assessed at day 2 following HCC injections till day-12. G. tournifortii extracts were injected i.p at day 10 in HCC mice. Liver histology, hepatic-p53, p-Akt and p-PI3K expressions were evaluated. Primary-hepatocytes from HCC mice were ex-vivo treated with G. tournifortii and investigated for perturbation of the DNA cell cycle using propidium iodide (PI) staining assay, while apoptosis was estimated by staining with Annexin-V and PI by the flow cytometry.Results: Tumor mass increase in animals with HCC and was associated with elevated aFP and GPC3 (P<0.05). Mice receiving G. tournefortii extracts showed a significant decrease in tumor at days 12 with decreased hepatic-p53 and phosphorylated Akt/PI3K signaling pathway (p=0.001). Histology H&E staining showed remarkable reduction in inflammatory lesions in HCC livers receiving G. tournifortii extracts in line with delay in G2-M phase of HCC-primary-hepatocytes to 1.39-folds. Moreover, apoptotic activity was mostly enhanced by the 200mg/ml G. tournifortii extracts while a reduction of HCC necrosis to 2.4 fold (P<0.01).Conclusions: Our results explored an anti-cancer, anti-proliferative and apoptotic effects of G. tournifortii in an HCC mice model and in an ex-vivo setting. G. tournifortii could be a promising future cancer remedy.

scholarly journals Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Lu-Yu Yang ◽  
Qin Luo ◽  
Lu Lu ◽  
Wen-Wei Zhu ◽  
Hao-Ting Sun ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Inflammatory Response ◽  
Metastatic Potential ◽  
Underlying Mechanism ◽  
Mice Model ◽  
Extracellular Traps ◽  
Inflammatory Conditions ◽  
Hcc Cells

Abstract Background The propensity of the activated neutrophils to form extracellular traps (NETs) is demonstrated in multiple inflammatory conditions. In this study, we investigated the roles of NETs in metastasis of hepatocellular carcinoma (HCC) and further explored the underlying mechanism of how NETs affect metastasis as well as the therapeutic value. Methods The neutrophils were isolated from the blood of human HCC patients and used to evaluate the formation of NETs. The expression of NET markers was detected in tumor specimens. A LPS-induced NET model was used to investigate the role of NETs on HCC metastasis. RNA-seq was performed to identify the key molecular event triggered by NETs, and their underlying mechanism and therapeutic significance were explored using both in vitro and in vivo assays. Results NET formation was enhanced in neutrophils derived from HCC patients, especially those with metastatic HCCs. NETs trapped HCC cells and subsequently induced cell-death resistance and enhanced invasiveness to trigger their metastatic potential, which was mediated by internalization of NETs into trapped HCC cells and activation of Toll-like receptors TLR4/9-COX2 signaling. Inhibition of TLR4/9-COX2 signaling abrogated the NET-aroused metastatic potential. A combination of DNase 1 directly wrecking NETs with anti-inflammation drugs aspirin/hydroxychloroquine effectively reduced HCC metastasis in mice model. Conclusions NETs trigger tumorous inflammatory response and fuel HCC metastasis. Targeting NETs rather than neutrophils themselves can be a practice strategy against HCC metastasis.

scholarly journals Long non-coding RNA LINC00473 acts as a microRNA-29a-3p sponge to promote hepatocellular carcinoma development by activating Robo1-dependent PI3K/AKT/mTOR signaling pathway

2020 ◽  
Vol 12 ◽  
pp. 175883592093789
Author(s):  
Qiqin Song ◽  
Hongyue Zhang ◽  
Jinan He ◽  
Hongyan Kong ◽  
Ran Tao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Progression ◽  
Signaling Pathway ◽  
Underlying Mechanism ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Regulatory Effects

Background: Long non-coding RNAs have suppressive or oncogenic effects in various types of cancers by serving as competing endogenous RNAs for specific microRNAs. In the present study, we aim to delineate the underlying mechanism by which the LINC00473/miR-29a-3p/Robo1 axis affects cell proliferation, migration, invasion, and metastasis in hepatocellular carcinoma (HCC). Methods: The level of Robo1 was examined in HCC tissues and cells, along with its regulatory effects on proliferation, migration, and invasion of HCC cells. Afterwards, the possible involvement of the PI3K/AKT/mTOR signaling pathway was determined. Next, miR-29a-3p expression was overexpressed or inhibited to investigate its regulatory role on HCC cell activities. The interaction among miR-29a-3p, Robo1, and LINC00473 was further characterized. Finally, a xenograft tumor in nude mice was conducted to measure tumorigenesis and metastasis in vivo. Results: miR-29a-3p was downregulated while Robo1 was upregulated in HCC tissues and cells. miR-29a-3p targeted Robo1 and negatively regulated its expression. In response to miR-29a-3p overexpression, Robo1 silencing or LINC00473 silencing, HCC cell proliferation, migration, invasion, tumor progression, and metastasis were impeded, which was involved with the inactivation of the PI3K/AKT/mTOR signaling pathway. Notably, LINC00473 could competitively bind to miR-29a-3p to upregulate Robo1 expression. Conclusion: LINC00473 might be involved in HCC progression by acting as a miR-29a-3p sponge to upregulate the expression of Robo1 that activates the PI3K/AKT/mTOR signaling pathway, which leads to enhanced cell proliferation, migration, invasion, tumor progression, and metastasis in HCC.

scholarly journals Long non-coding RNA MALAT1 promotes angiogenesis and immunosuppressive properties of HCC cells by sponging miR-140

2020 ◽  
Vol 318 (3) ◽  
pp. C649-C663 ◽  
Author(s):  
Zhou-Hua Hou ◽  
Xu-Wen Xu ◽  
Xiao-Yu Fu ◽  
Le-Du Zhou ◽  
Shui-Ping Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Regulatory Network ◽  
Primary Liver Cancer ◽  
Underlying Mechanism ◽  
In Vivo Studies ◽  
Non Coding Rna ◽  
Long Non Coding Rna ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer in adults. Previous studies in our laboratory found that long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was upregulated in HCC cells, which could affect the metastasis and invasion of HCC. However, the underlying mechanism remains unknown. Herein, we studied the interaction between MALAT1 and miR-140 on the regulation of angiogenesis and immunosuppressive properties. We revealed that the expression of MALAT1 and VEGF-A was significantly increased in HCC cells. Knockdown of MALAT1 in HCC cells suppressed the production of VEGF-A, impaired the angiogenesis of HUVECs, and facilitated the polarization of macrophage toward the M1 subset. Mechanistically, the interaction between MALAT1 and miR-140 or between miR-140 and VEGF-A was confirmed by multiple assays. Besides, a negative correlation between MALAT1 and miR-140 was found in HCC tissues. Furthermore, miR-140 inhibition significantly increased VEGF-A expression, promoted angiogenesis of HUVECs, and redirected the polarization of macrophages toward the M2 subset. In addition, in vivo studies also verified the regulatory network of the MALAT1/miR-140 axis on VEGF-A in HCC progression. In summary, this study revealed the mechanism that MALAT1 worked as a putative HCC promotor via inhibiting miR-140. Therefore, targeting MALAT1 or miR-140 might alleviate the progression of HCC in the future.

scholarly journals Oxidative Medicine and Cellular Longevity Hsa_circ_0013731 mediated by E2F1 inhibits ferroptosis in hepatocellular carcinoma cells by sponging miR-877-3p and targeting SLC7A11

2021 ◽  
Author(s):  
Shiji Fang ◽  
Weiqian Chen ◽  
Jiayi Ding ◽  
Dengke Zhang ◽  
Liyun Zheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Cell Growth ◽  
Vital Role ◽  
Expression Level ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Regulatory Loop

Abstract Background: The regulatory loop between circular RNAs and microRNAs has a vital role in cell death. Ferroptosis is the form of iron-dependent cell death, which is distinct from necroptosis and apoptosis. Increasing evidences showed that ferroptosis is an important form of cell death in hepatocellular carcinoma.Methods: Real-time PCR were used to examine the expression level of circ_0013731 in hepatocellular carcinoma tissues. Edu and colony formation were performed to detect the cell proliferation. A luciferase reporter assay was used to determine the relationship between circ_0013731, miR-877-3p and SLC7A11. ChIP-qPCR assays were performed to examine the potential binding of E2F1 to the circ_0013731 promoter. Iron Assay Kit (Sigma Aldrich) was used to detect total iron or Fe2+. C11 BODIPY 581/591 staining and flow cytometer were used to examine the Lipid ROS. The role of circ_0013731 was examined in xenograft tumors model. Results: We revealed that the expression level of circ_0013731 was elevated in hepatocellular carcinoma. Moreover, E2F1 promote the transcription of circ_0013731. Overexpression of circ_0013731 promoted cell growth and inhibited ferroptosis in SMMC-7721 and QGY-7703 in vitro. miR-877-3p was proved as the direct target of circ_0013731. Then, inhibition of miR-877-3p enhanced cell growth and inhibited ferroptosis. Further mechanism research demonstrated that circ_0013731 upregulated the expression level of SLC7A11 by sponging miR-877-3p. Finally, circ_0013731 promoted HCC growth via miR-877-3p/ SLC7A11 axis in vivo.Conclusions: Our data reveal that circ_0013731 mediated by E2F1 facilitates cell growth and suppressed the ferroptosis via miR-877-3p/ SLC7A11 axis in hepatocellular carcinoma. Therefore, circ_0013731 could be acted as potential therapeutical target for hepatocellular carcinoma.

scholarly journals Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells

2021 ◽  
Vol 22 (23) ◽  
pp. 13071
Author(s):  
Tingting Shi ◽  
Hisakazu Iwama ◽  
Koji Fujita ◽  
Hideki Kobara ◽  
Noriko Nishiyama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Systemic Treatment ◽  
Underlying Mechanism ◽  
Erk Signaling ◽  
In Vivo Studies ◽  
Cross Resistance ◽  
First Line ◽  
Patient Response

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths worldwide. Sorafenib has been used as a first-line systemic treatment for over a decade. However, resistance to sorafenib limits patient response and presents a major hurdle during HCC treatment. Lenvatinib has been approved as a first-line systemic treatment for advanced HCC and is the first agent to achieve non-inferiority against sorafenib. Therefore, in the present study, we evaluated the inhibition efficacy of lenvatinib in sorafenib-resistant HCC cells. Only a few studies have been conducted on this topic. Two human HCC cell lines, Huh-7 and Hep-3B, were used to establish sorafenib resistance, and in vitro and in vivo studies were employed. Lenvatinib suppressed sorafenib-resistant HCC cell proliferation mainly by inducing G1 cell cycle arrest through ERK signaling. Hep-3B sorafenib-resistant cells showed partial cross-resistance to lenvatinib, possibly due to the contribution of poor autophagic responsiveness. Overall, the findings suggest that the underlying mechanism of lenvatinib in overcoming sorafenib resistance in HCC involves FGFR4-ERK signaling. Lenvatinib may be a suitable second-line therapy for unresectable HCC patients who have developed sorafenib resistance and express FGFR4.

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