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

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.

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Activation of MAT2A-RIP1 signaling axis reprograms monocytes in gastric cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001364 ◽

2021 ◽

Vol 9 (2) ◽

pp. e001364

Author(s):

Yan Zhang ◽

Hui Yang ◽

Jun Zhao ◽

Ping Wan ◽

Ye Hu ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Metabolism ◽

Vital Role ◽

Methionine Metabolism ◽

Promoter Regions ◽

Normal Tissues ◽

Methionine Cycle

BackgroundThe activation of tumor-associated macrophages (TAMs) facilitates the progression of gastric cancer (GC). Cell metabolism reprogramming has been shown to play a vital role in the polarization of TAMs. However, the role of methionine metabolism in function of TAMs remains to be explored.MethodsMonocytes/macrophages were isolated from peripheral blood, tumor tissues or normal tissues from healthy donors or patients with GC. The role of methionine metabolism in the activation of TAMs was evaluated with both in vivo analyses and in vitro experiments. Pharmacological inhibition of the methionine cycle and modulation of key metabolic genes was employed, where molecular and biological analyses were performed.ResultsTAMs have increased methionine cycle activity that are mainly attributed to elevated methionine adenosyltransferase II alpha (MAT2A) levels. MAT2A modulates the activation and maintenance of the phenotype of TAMs and mediates the upregulation of RIP1 by increasing the histone H3K4 methylation (H3K4me3) at its promoter regions.ConclusionsOur data cast light on a novel mechanism by which methionine metabolism regulates the anti-inflammatory functions of monocytes in GC. MAT2A might be a potential therapeutic target for cancer cells as well as TAMs in GC.

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MicroRNA-361-5p Inhibits Cancer Cell Growth by Targeting CXCR6 in Hepatocellular Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000443033 ◽

2016 ◽

Vol 38 (2) ◽

pp. 777-785 ◽

Cited By ~ 24

Author(s):

Jian-Jun Sun ◽

Guo-Yong Chen ◽

Zhan-Tao Xie

Keyword(s):

Hepatocellular Carcinoma ◽

Nude Mice ◽

In Vivo Studies ◽

Luciferase Reporter ◽

Western Blots ◽

Normal Tissues ◽

Proliferation And Invasion ◽

Hcc Cells

Background/Aims: A growing body of evidence supports the notion that MicroRNAs (miRNAs) function as key regulators of tumorigenesis. In the present study, the expression and roles of miRNA-361-5p were explored in hepatocellular carcinoma (HCC). Methods: Quantitative real-time PCR was used to detect the expression miR-361-5p in HCC tissues and pair-matched adjacent normal tissues. MTT and BrdU assays were used to identify the role of miR-361-5p in the regulation of proliferation and invasion of HCC cells. Using bioinformatics analysis, luciferase reporter assays and Western blots were used to identify the molecular target of miR-361-5p. nude mice were used to detect the anti-tumor role of miR-361-5p in vivo. Results: miR-361-5p was down-regulated in HCC tissues in comparison to adjacent normal tissues, due to hypermethylation at its promoter region. Overexpression of miR-361-5p suppressed proliferation and invasion of HCC cells. Chemokine (C-X-C Motif) receptor 6 (CXCR6) was identified as a target of miR-361-5p. Indeed, knockdown of CXCR6 photocopied, while overexpression of CXCR6 largely attenuated the anti-proliferative effect of miR-361-5p. More importantly, in vivo studies demonstrated that forced expression of miR-361-5p significantly inhibited tumor growth in the nude mice. Conclusion: Our results indicate that miR-361-5p acts as a tumor suppressor and might serve as a novel therapeutic target for the treatment of HCC patients.

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MiR-423-3p Enhances Cell Growth Through Inhibition of p21Cip1/Waf1 in Colorectal Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000430230 ◽

2015 ◽

Vol 37 (3) ◽

pp. 1044-1054 ◽

Cited By ~ 18

Author(s):

Hong-tao Li ◽

Hui Zhang ◽

Yong Chen ◽

Xian-fu Liu ◽

Jun Qian

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Vital Role ◽

Luciferase Reporter ◽

Normal Tissues ◽

Non Coding Rnas ◽

And Migration

Background/Aims: Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths globally, with many oncogenes and tumor suppressors involved. The miRNAs are small non-coding RNAs known to play a vital role in the pathogenesis of CRC. The miR-423-3p was reported to act as an oncogene; however, its role in CRC growth remains unknown. Methods: qPCR assay was used to detect miR-423-3p expression in CRC specimens. Cell proliferation assay and transwell assay were conducted to evaluate CRC cell proliferation and migration. Luciferase reporter assay was to identify the target gene of miR-423-3p. And tumorigenesis model was established to test the role of miR-423-3p in CRC development in vivo. Results: Here, we showed that miR-423-3p was significantly up regulated in CRC tissues and cells compared with normal tissues and cells. Overexpression of miR-423-3p promoted CRC cell proliferation via enhancing the G1/S transition phase of the cell cycle, while inhibition of miR-423-3p repressed cell growth. Further studies showed that p21Cip1/Waf1 mediated the function of miR-423-3p, and overexpression of p21Cip1/Waf1 reversed the augmented effect of miR-423-3p on cell proliferation. Importantly, all these data were validated in the tumorigenesis assay in vivo. Conclusions: In conclusion, our findings demonstrated a critical impact of miR-423-3p on CRC growth.

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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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Upregulation of lncRNA DQ679794 contributes to preventing the progression of hepatocellular carcinoma both in vitro and in vivo

10.21203/rs.2.22787/v1 ◽

2020 ◽

Author(s):

Ze-wei Lin ◽

Qing-qi Ren ◽

Zhi-feng Huang ◽

Ji-kui Liu

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Development ◽

Quantitative Real Time Pcr ◽

Transplanted Tumors ◽

Normal Tissues ◽

Transplanted Tumor ◽

Aggressive Tumor

Abstract Background Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis. Long noncoding RNAs (lncRNAs) are key regulators of tumor development. However, lncRNA profiles in HCC remain largely unknown. In previous studies, we found that lncRNA DQ786243 plays an important role in the pathogenesis of HCC and promotes the development of HCC. In this study, we investigated the role of lncRNA DQ679794 in the pathogenesis of HCC. Methods and Results We first used quantitative real-time PCR among 64 paired HCC tissues, and the level of lncRNA DQ679794 was found to be significantly lower in tumors than in normal tissues. In addition, the effects of lncRNA DQ679794 were assessed by overexpression in vitro and in vivo . We found that the level of apoptosis was increased and that cell proliferation was weakened in HepG2 cells overexpressing DQ679794. Finally, the transplanted tumor experiment confirmed that after the overexpression of lncRNA DQ679794, the growth of transplanted tumors formed by liver cancer cells was inhibited. Conclusion This study suggests that lncRNA DQ679794 is an oncogene that inhibits tumor progression, and we believe that lncRNAs may be a key regulatory center in HCC progression.

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Downregulation of long noncoding RNA T1NCR inhibits cell proliferation, invasion, and epithelial-mesenchymal transition of hepatocellular carcinoma

Tobacco Regulatory Science ◽

10.18001/trs.7.6.125 ◽

2021 ◽

Vol 7 (6) ◽

pp. 6499-6510

Author(s):

Hongjuan Li ◽

Yaqin Chen ◽

Chunyan Wu ◽

Haiyan Zhao ◽

Xuesong Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Noncoding Rna ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Normal Tissues ◽

Proliferation Ability ◽

Non Coding Rnas

Accumulating reports have identified that long non-coding RNAs (IncRNAs) function as key regulators of tumor initiation and progression. The aim of the current study was to determine the clinical significance and functional role of TINCR in hepatocellular carcinoma (HCC). In the present study, the level of IncRNA TINCR expression was significantly upregulated in HCC tissues compared to adjacent normal tissues. Higher levels of IncRNA TINCR expression were significantly correlated with tumor size and vascular invasion of HCC patients. LncRNA TINCR knockdown inhibited cell proliferation ability, increased the proportion of G1 phase cells, reduced the proportion of S phase cells, and suppressed cell invasion of HCC in vitro. Additionally, IncRNA TINCR knockdown inhibited the HCC cell epithelial-mesenchymal transition (EMT) phenomenon by upregulating E-cadherin and reducing N-cadherin expression. We demonstrated that knockdown of IncRNA reduced tumor growth in vivo. Thus, these results indicated that IncRNA TINCR exhibits a tumor oncogenic role in HCC and inhibition of IncRNA TINCR might serve as a therapeutic target for HCC.

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Elafin promotes tumour metastasis and attenuates the anti-metastatic effects of erlotinib via binding to EGFR in hepatocellular carcinoma

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01904-y ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Chenwei Wang ◽

Yadi Liao ◽

Wei He ◽

Hong Zhang ◽

Dinglan Zuo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Early Stage ◽

Tissue Microarrays ◽

Luciferase Reporter ◽

Normal Tissues ◽

Tumour Metastasis ◽

Hcc Cells

Abstract Background Elafin is a serine protease inhibitor critical for host defence. We previously reported that Elafin was associated with the recurrence of early-stage hepatocellular carcinoma (HCC) after surgery. However, the exact role of Elafin in HCC remains obscure. Methods HCC tissue microarrays were used to investigate the correlation between Elafin expression and the prognosis of HCC patients. In vitro migration, invasion and wound healing assays and in vivo lung metastasis models were used to determine the role of Elafin in HCC metastasis. Mass spectrometry, co-immunoprecipitation, western blotting, and immunofluorescence staining assays were performed to uncover the mechanism of Elafin in HCC. Dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the transcriptional regulation of Elafin. Results Elafin expression was frequently increased in HCC tissues compared to normal tissues, and high Elafin expression in HCC tissues was correlated with aggressive tumour phenotypes and a poor prognosis in HCC patients. Elafin dramatically enhanced the metastasis of HCC cells both in vitro and in vivo by interacting with EGFR and activating EGFR/AKT signalling. Moreover, Elafin attenuated the suppressive effects of erlotinib on HCC metastasis. Besides, Elafin was transcriptionally regulated by Sp1 in HCC cells. Clinically, Elafin expression was positively correlated with Sp1, Vimentin, and EGFR signalling in both our HCC tissue microarrays and TCGA database analysis. Conclusions Upregulation of Elafin by Sp1 enhanced HCC metastasis via EGFR/AKT pathway, and overexpression of Elafin attenuated the anti-metastatic effects of erlotinib, suggesting a valuable prognostic biomarker and therapeutic target for HCC.

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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.

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FAM172A suppresses polymerization of tubulin and development of HCC (Hepatocellular Carcinoma)

10.21203/rs.3.rs-29258/v1 ◽

2020 ◽

Author(s):

Jin-qian Zhang ◽

Zheng-lin Xia ◽

Li Li ◽

Dao-wei Li ◽

Yu Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Vital Role ◽

Tubulin Polymerization ◽

Xenograft Mice ◽

Proliferation Ability ◽

Two Hybrid ◽

Β Tubulin

Abstract BackgroundThe polymerization of tubulin play the vital role in development and pathogenesis of cancer. Our study will explain the role of FAM172A in tubulin polymerization of HCC cell line.MethodsFAM172A-interacting proteins were screened from cDNA library of human liver with the system of yeast two-hybrid, the combined protein of FAM172A was further identified with system of mammalian two-hybrid, CO-IP experiment, and assay of GST-pull down. Then cell line HepG2 of human hepatocellular carcinoma was transfected with AAV-FAM172A or FAM172A-shRNA, and then proliferation ability and cell cycle were assessed. The expression of FAM172A and β-tubulin polymerization were determined. The effect of FAM172A on development of hepatocellular carcinoma associated with polymerization of tubulin was studied, and we used xenograft mice in vivo experiment.ResultsSeveral clones were positively screened from library, which included β-tubulin cDNA. Further studies confirmed FAM172A could combine with β-tubulin. FAM172A suppressed polymerization of tubulin, meanwhile the proliferation and cell cycle of HepG2. Besides, AAV-FAM172A could inhibit the development of HCC in xenogarft mice. ConclusionsOur results indicated FAM172A might be the crucial mediator of polymerization tubulin and HCC development. It suggested that aim at FAM172A through suppressing the polymerizaton of tubulin maybe the viable strategy for treatment of HCC.

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Novel copper complex CTB regulates methionine cycle induced TERT hypomethylation to promote HCC cells senescence via mitochondrial SLC25A26

Cell Death and Disease ◽

10.1038/s41419-020-03048-x ◽

2020 ◽

Vol 11 (10) ◽

Author(s):

Chun Jin ◽

Yujia Li ◽

Ying Su ◽

Zijian Guo ◽

Xiaoyong Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Copper Complex ◽

Inhibitory Effect ◽

Vital Role ◽

Mitochondrial Carrier ◽

Tumor Tissues ◽

Methionine Cycle ◽

Hcc Cells

Abstract Related research has recognized the vital role of methionine cycle metabolism in cancers. However, the role and mechanism of methionine cycle metabolism in hepatocellular carcinoma are still unknown. In this study, we found that [Cu(ttpy-tpp)Br2]Br (Referred to as CTB) could induce hepatocellular carcinoma cells senescence, which is a new copper complex synthesized by our research group. Interestingly, CTB induces senescence by inhibiting the methionine cycle metabolism of HCC cells. Furthermore, the inhibitory effect of CTB on the methionine cycle depends on mitochondrial carrier protein SLC25A26, which was also required for CTB-induced HCC cells senescence. Importantly, we found that CTB-induced upregulation of SLC25A26 could cause abnormal methylation of TERT and inhibited TERT expression, which is considered to be an essential cause of cell senescence. The same results were also obtained in vivo, CTB inhibits the growth of subcutaneously implanted tumors in nude mice and promoted the expression of senescence markers in tumor tissues, and interference with SLC25A26 partially offset the antitumor effect of CTB.

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