scholarly journals FAM21C Promotes Hepatocellular Carcinoma Invasion and Metastasis by Driving Actin Cytoskeleton Remodeling via Inhibiting Capping Ability of CAPZA1

2022 ◽  
Vol 11 ◽  
Author(s):  
Yao Lu ◽  
Deng Huang ◽  
Baolin Wang ◽  
Bowen Zheng ◽  
Jialong Liu ◽  
...  

Hepatocellular carcinoma (HCC) is characterized by a high incidence of metastasis. The dynamic remodeling of the actin cytoskeleton plays an important role in the invasion and migration of HCC cells. In previous studies, we found that CAPZA1, a capping protein, can promote EMT of HCC cells by regulating the remodeling of the actin filament (F-actin) cytoskeleton, thus promoting the invasion and migration of HCC cells. In this study, we found that FAM21C may have a regulatory effect on CAPZA1, and we conducted an in-depth study on its potential regulatory mechanism. First, we found that FAM21C is highly expressed in HCC tissues and its high expression could promote the malignant progression of HCC. Meanwhile, the high expression of FAM21C promoted the invasion and migration of HCC cells in vitro and in vivo. Further, FAM21C interacted with CAPZA1, and their binding inhibited the capping capacity of CAPZA1, thus promoting the invasion and migration of HCC cells. This effect of FAM21C was abolished by mutating the CP-interacting (CPI) domain, the CAPZA1 binding site on FAM21C. In conclusion, high expression of FAM21C in HCC tissues can promote malignant progression of HCC and its potential mechanism involves FAM21C inhibition of CAPZA1 capping capacity by binding to CAPZA1, which drives F-actin cytoskeleton remodeling, and thus promotes invasion and migration of HCC cells.

2020 ◽  
Vol 160 (11-12) ◽  
pp. 650-658
Author(s):  
Yichen Le ◽  
Yi He ◽  
Meirong Bai ◽  
Ying Wang ◽  
Jiaxue Wu ◽  
...  

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.


2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Qinchen Cao ◽  
Yonggang Shi ◽  
Xinxin Wang ◽  
Jing Yang ◽  
Yin Mi ◽  
...  

AbstractCircular RNAs (circRNAs) are a newly identifed non-coding RNA in many cellular processes and tumours. This study aimed to investigate the role of hsa_circ_0037251, one circRNA generated from several exons of the gene termed METRN, in glioma progression. Through in vitro experiments, we discovered that high expression of hsa_circ_0037251 was related to low expression of the microRNA miR-1229-3p and high expression of mTOR. The over-expressed hsa_circ_0037251 promoted cell proliferation, invasion and migration in glioma, while knockdown of hsa_circ_00037251 promoted cell apoptosis and induced G1 phase arrest. Then, hsa_circ_0037251 was observed to directly sponge miR-1229-3p, and mTOR was identified as a direct target of miR-1229-3p. In addition, knockdown of hsa_circ_0037251 up-regulated the expression of miR-1229-3p and inhibited the expression of mTOR. And overexpression of miR-1229-3p or low-expressed mTOR inhibited the glioma cell progression. Furthermore, transfection with mTOR overexpression vectors can restore the abilities of glioma cell progression even if hsa_circ_00037251 was knocked down using siRNAs. In vivo experiments revealed that hsa_circ_00037251 promoted the growth of xenografted tumours and shortened the survival period. These results indicated that hsa_circ_0037251 may act as a tumour promoter by a hsa_circ_0037251/miR-1229-3p/mTOR axis, and these potential biomarkers may be therapeutic targets for glioma.


2020 ◽  
Vol 168 (5) ◽  
pp. 535-546 ◽  
Author(s):  
Yuepei Zou ◽  
Zhonghua Sun ◽  
Shuangming Sun

Abstract Long non-coding RNA (lnc) HCG18 has been reported to contribute progression of a variety of tumours. However, its roles in hepatocellular carcinoma (HCC) remains unknown. In the current study, we intended to uncover the biological functions of HCG18 in HCC. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the expression of HCG18, microRNA-214-3p (miR-214-3p) and centromere protein M (CENPM) messenger RNA (mRNA). The role of HCG18 in the growth and migration were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, wound healing assay and flow cytometry in vitro and animal experiments in vivo. The results showed that HCG18 was highly expressed in HCC tissues. HCG18 silencing inhibited the proliferation and migration while induced the apoptosis of HCC cells. Besides, miR-214-3p was down-regulated in HCC cells. Further experiments revealed that miR-214-3p could directly bind to HCG18 and exerted an anti-tumour role to counteracted siHCG18-1-mediated influence in HCC cells. Moreover, miR-214-3p could directly interact with CENPM mRNA and down-regulating the expression of CENPM. While HCG18 could up-regulate the expression of CENPM through acting as a sponge of miR-214-3p. Therefore, those results suggested HCG18 functioned as an oncogene to promote the proliferation and migration of HCC cells via miR-214-3p/CENPM axis.


2021 ◽  
Vol 11 ◽  
Author(s):  
Hua Ren ◽  
Zhi-cheng Wei ◽  
Yan-xia Sun ◽  
Chun-yan Qiu ◽  
Wen-jue Zhang ◽  
...  

BackgroundLong intergenic non-protein coding RNA 882 (LINC00882) are abnormally expressed in several tumors. Our research aimed to uncover the functions and the potential mechanisms of LINC00882 in hepatocellular carcinoma (HCC) progression.MethodsRT-qPCR was applied to identify LINC00882 and miR-214-3p levels in HCC specimens and cells. Luciferase reporter was applied for the exploration of whether activating transcription factor 2 (ATF2) could bind to the promoter region of LINC00882. Cell proliferation, invasion, and migration were evaluated. In vivo tumor xenograft models were constructed to assess tumorigenicity. RT-PCR, Western blot and Luciferase reporter assays were conducted to examine the regulatory relationships among LINC00882, miR-214-3p and ATF2.ResultsLINC00882 was markedly upregulated in HCC cells and clinical specimens. Additionally, ATF2 could bind directly to the LINC00882 promoter region and activate its transcription. Loss-of-function studies further demonstrated that LINC00882 knockdown inhibited proliferation, invasion, and migration of HCC cells. Mechanistically, LINC00882 adsorbed miR-214-3p, thus promoting the expressions of CENPM. Rescue assays demonstrated that functions of LINC00882 deficiency in HCC cells were reversed through suppressing miR-214-3p.ConclusionOur group identified a novel regulatory axis of ATF2/LINC00882/miR-214-3p/CENPM, which may provide potential therapeutic targets for HCC.


2020 ◽  
Author(s):  
Han Hong ◽  
Chengjun Sui ◽  
Tao Qian ◽  
Xiaoyong Xu ◽  
Xiang Zhu ◽  
...  

Abstract Background: Long-chain non-coding RNA (LncRNA) plays a key role in the biological processes of tumors. LncRNA CASC15 has been shown to be involved in the development of a variety of tumors. The study aimed to elucidate the mechanism of lncRNA CASC15 in the progression of hepatocellular carcinomas (HCC).Methods: qRT-PCR was used to detect the expression levels of CASC15, miR-2355-5p and Six1 mRNA in HCC tissues and cells. Six1 protein expression levels were detected by Western Blot. CCK-8 experiment, colony formation experiment, Edu staining and Transwell experiment analysis were used to analyze the effects of CASC15, miR-2355-5p and Six1 on cell proliferation, cell invasion and migration. The relationship between CASC15, miR-2355-5p and Six1 was analyzed using bioinformatics analysis and Luciferase.Result: CASC15 was raised in HCC tissues and HCC cells. Down-regulation of CASC15 inhibited the growth, migration, invasion and tumor growth of HCC cells. The expression level of miR-2355-5p was reduced in HCC tissues. In addition, miR-2355-5p inhibitor induced the growth, migration and invasion of HCC cells. MiR-2355-5p was predicted to be a downstream target of CASC15. The expression level of miR-2355-5p was negatively correlated with CASC15 in HCC tumor tissues. Six1 was predicted to be a downstream target of miR-30a-5p. In vitro and in vivo results showed that CASC15/miR-2355-5p can regulate Six1.Conclusion: LncCASC15 regulated the proliferation and invasion of Six1 by binding with miR-2355-5p in HCC, suggesting that CASC15 may be a potential target for HCC.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shihai Liu ◽  
Jing Qiu ◽  
Guifang He ◽  
Weitai He ◽  
Changchang Liu ◽  
...  

AbstractTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce substantial cytotoxicity in tumor cells but rarely exert cytotoxic activity on non-transformed cells. In the present study, we therefore evaluated interactions between TRAIL and IER3 via co-immunoprecipitation and immunofluorescence analyses, leading us to determine that these two proteins were able to drive the apoptotic death of hepatocellular carcinoma (HCC) cells and to disrupt their proliferative and migratory abilities both in vitro and in vivo. From a mechanistic perspective, we determined that TRAIL and IER3 were capable of inhibiting Wnt/β-catenin signaling. Together, these results indicate that TRAIL can control the pathogenesis of HCC at least in part via interacting with IER3 to inhibit Wnt/β-catenin signaling, thus indicating that this TRAIL/IER3/β-catenin axis may be a viable therapeutic target in HCC patients.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Lei Zhang ◽  
Jing Zhang ◽  
Pengfei Li ◽  
Ting Li ◽  
Zhiqin Zhou ◽  
...  

AbstractMacrophage-derived exosomes (Mφ-Exo) have multidimensional involvement in tumor initiation, progression, and metastasis, but their regulation in hepatocellular carcinoma (HCC) is not fully understood. RBPJ has been implicated in macrophage activation and plasticity. In this study we assess the role of exosomes derived from RBPJ-overexpressed macrophages (RBPJ+/+ Mφ-Exo) in HCC. The circular RNA (circRNA) profiles in RBPJ+/+ Mφ-Exo and THP-1-like macrophages (WT Mφ)-Exo was evaluated using circRNA microarray. CCK-8, Transwell, and flow cytometry analyses were used to evaluate the function of Mφ-Exo-circRNA on HCC cells. Luciferase reporter assays, RNA immunoprecipitation, and Pearson’s correlation analysis were used to confirm interactions. A nude mouse xenograft model was used to further analyze the functional significance of Mφ-Exo-cirRNA in vivo. Our results shown that hsa_circ_0004658 is upregulated in RBPJ+/+ Mφ-Exo compared to WT Mφ-Exo. RBPJ+/+ Mφ-Exo and hsa_circ_0004658 inhibits proliferation and promotes apoptosis in HCC cells, whereas hsa_circ_0004658 knockdown stimulated cell proliferation and migration but restrained apoptosis in vitro and promotes tumor growth in vivo. The effects of RBPJ+/+ Mφ-Exo on HCC cells can be reversed by the hsa_circ_0004658 knockdown. Mechanistic investigations revealed that hsa_circ_0004658 acts as a ceRNA of miR-499b-5p, resulting in the de-repression of JAM3. These results indicate that exosome circRNAs secreted from RBPJ+/+ Mφ inhibits tumor progression through the hsa_circ_0004658/miR-499b-5p/JAM3 pathway and hsa_circ_0004658 may be a diagnostic biomarker and potential target for HCC therapy.


2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yanhe Zhang ◽  
Hui Wang ◽  
Chao Li ◽  
Linlin Gao ◽  
Yayun Zheng ◽  
...  

Abstract Background There is evidence that circSMYD4 is differentially expressed in hepatocellular carcinoma (HCC), but its mechanism of action remains unclear. Therefore, this study aimed to explore the role of circSMYD4 in the occurrence and development of HCC and its specific molecular mechanism. Methods The expressions of related genes and proteins in the development of HCC were detected by real-time quantitative-PCR and Western blot. HCC cells treated with RNase R and Actinomycin D were used to examine the stability of circSMYD4. Bioinformatics analysis, RNA pull-down assay, luciferase assay and Spearman correlation analysis were performed to evaluate the interaction between circSMYD4 and miRNA. Cell Counting Kit-8, clone formation assay, wound healing assay, Transwell, flow cytometry, nude tumor formation experiment, and immunohistochemistry were employed to analyze the function of circSMYD4 in HCC. A rescue experiment was conducted to analyze the effect of miR-584-5p on the physiological functions of cells. Results CircSMYD4 was down-regulated in HCC tissues and cells, and was not easily affected by RNase R and Actinomycin D. The abundances of circSMYD4 and SMYD4 in the cytoplasm were significantly higher than in the nucleus. Up-regulation of circSMYD4 inhibited the proliferation, invasion and migration and promoted the apoptosis of HCC cells in vitro, while it inhibited tumor growth, promoted apoptosis-related proteins, and suppressed alpha-fetoprotein (AFP) levels in vivo. CircSMYD4 could be used as a miRNA sponge to target miR-584-5p. In addition, miR-584-5p overexpression partially reversed the regulatory effect of circSMYD4 on HCC. Conclusion CircSMYD4 prevents the development of HCC through regulating multiple signaling pathways such as metastasis and apoptosis by sponging miR-584-5p.


2020 ◽  
Author(s):  
Han Hong ◽  
Chengjun Sui ◽  
Tao Qian ◽  
Xiaoyong Xu ◽  
Xiang Zhu ◽  
...  

Abstract Background: Long-chain non-coding RNA (LncRNA) plays a key role in the biological processes of tumors. LncRNA CASC15 has been shown to be involved in the development of a variety of tumors. The study aimed to elucidate the mechanism of lncRNA CASC15 in the progression of hepatocellular carcinomas (HCC). Methods: qRT-PCR was used to detect the expression levels of CASC15, miR-2355-5p and Six1 mRNA in HCC tissues and cells. Six1 protein expression levels were detected by Western Blot. CCK-8 experiment, colony formation experiment, Edu staining and Transwell experiment analysis were used to analyze the effects of CASC15, miR-2355-5p and Six1 on cell proliferation, cell invasion and migration. The relationship between CASC15, miR-2355-5p and Six1 was analyzed using bioinformatics analysis and Luciferase. Result: CASC15 was raised in HCC tissues and HCC cells. Down-regulation of CASC15 inhibited the growth, migration, invasion and tumor growth of HCC cells. The expression level of miR-2355-5p was reduced in HCC tissues. In addition, miR-2355-5p inhibitor induced the growth, migration and invasion of HCC cells. MiR-2355-5p was predicted to be a downstream target of CASC15. The expression level of miR-2355-5p was negatively correlated with CASC15 in HCC tumor tissues. Six1 was predicted to be a downstream target of miR-30a-5p. In vitro and in vivo results showed that CASC15/miR-2355-5p can regulate Six1.Conclusion: LncCASC15 regulated the proliferation and invasion of Six1 by binding with miR-2355-5p in HCC, suggesting that CASC15 may be a potential target for HCC.


Author(s):  
Jun-Jie Hu ◽  
Cui Zhou ◽  
Xin Luo ◽  
Sheng-Zheng Luo ◽  
Zheng-Hong Li ◽  
...  

Abstract Background Increasing evidence has demonstrated that long noncoding RNAs (lncRNAs) have regulatory functions in hepatocellular carcinoma (HCC). The link between lincSCRG1 and HCC remains unclear. Methods To explore the lincSCRG1 regulation axis, bioinformatics, RIP and luciferase reporter assay were performed. The expressions of lincSCRG1-miR26a-SKP2 were detected in HCC tissues and cell lines through qPCR and western blot. The functions of HCC cells were investigated through in vitro assays (MTT, colony formation, transwell and flow cytometry) and the inner effect of lincSCRG1-miR26a in vivo was evaluated by xenografts and liver metatstatic nude mice models. Results LincSCRG1 was found to be strongly elevated in human HCC tissues and cell lines. MiR26a and S phase kinase-related protein 2 (SKP2) were predicted as the target miRNA for lincSCRG1 and the target gene for miR26a with direct binding sites, respectively. LincSCRG1 was verified as a competing endogenous RNA (ceRNA) via negative regulation of miR26a and derepression of SKP2 in HCC cells. Both overexpression of lincSCRG1 (ov-lincSCRG1) and inhibition of miR26a (in-miR26a) obviously stimulated cellular viability, colony formation, migration and proliferation of S phase cells and also significantly increased the protein levels of cyclinD1, CDK4, MMP2/3/9, Vimentin, and N-cadherin or inhibited the protein level of E-cadherin of HCC cells, while knockdown of lincSCRG1 (sh-lincSCRG1) and upregulation of miR26a (mi-miR26a) had the opposite effects on HCC cells. Cotransfection of in-miR26a or overexpression of SKP2 (ov-SKP2) with sh-lincSCRG1 could rescue the anticancer functions of sh-lincSCRG1, including suppressing proliferation and migration of HCC cells. Additionally, sh-lincSCRG1 could effectively inhibit the growth of subcutaneous xenograft tumours and lung metastasis, while the anticancer effect of sh-lincSCRG1 could be reversed by cotransfection of in-miR26a. Conclusions LincSCRG1 acts as a ceRNA of miR26a to restrict its ability to derepress SKP2, thereby inducing the proliferation and migration of HCC cells in vitro and in vivo. Depletion of lincSCRG1 could be used as a potential therapeutic approach in HCC.


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