Ribosomal protein L23 drives the metastasis of hepatocellular carcinoma via upregulating MMP9

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally and tumor metastasis is one of the major causes of high mortality. To identify novel molecules contributing to HCC metastasis is critical to understanding the underlining mechanism of cancer metastasis. Here, combining the analyze based on published database and liver tissues from HCC patients, we identified that RNA binding protein L23 (RPL23) as a tumor metastasis driver in HCC. RPL23 was elevated in HCC and closely related to poor clinical outcomes. Furthermore, RPL23 depletion inhibited HCC cell proliferation, migration and invasion, while RPL23 overexpression promoted HCC cell metastasis. Mechanistically, RPL23 positively regulated MMP9 expression by stabilizing its mRNA. And increased MMP9 is involved in RPL23-mediated HCC metastasis. Importantly, RPL23 silencing reduced tumor growth and metastasis in vivo. In summary, we identified that RPL23 play an important role in HCC metastasis in an MMP9-dependent manner and may be a novel potential therapeutic target for HCC tumorigenesis and metastasis.

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Ribosomal Protein L23 Drives the Metastasis of Hepatocellular Carcinoma via Upregulating MMP9

Frontiers in Oncology ◽

10.3389/fonc.2021.779748 ◽

2021 ◽

Vol 11 ◽

Author(s):

Minli Yang ◽

Yujiao Zhou ◽

Haijun Deng ◽

Hongzhong Zhou ◽

Shengtao Cheng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Metastasis ◽

Molecular Mechanisms ◽

Rna Binding ◽

Migration And Invasion ◽

Dependent Manner ◽

Key Factors ◽

Potential Therapeutic Target ◽

Normal Tissues ◽

Mmp9 Expression

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. Tumor metastasis is one of the major causes of high mortality of HCC. Identifying underlying key factors contributing to invasion and metastasis is critical to understand the molecular mechanisms of HCC metastasis. Here, we identified RNA binding protein L23 (RPL23) as a tumor metastasis driver in HCC. RPL23 was significantly upregulated in HCC tissues compared to adjacent normal tissues, and closely related to poor clinical outcomes in HCC patients. RPL23 depletion inhibited HCC cell proliferation, migration and invasion, and distant metastasis. Mechanistically, RPL23 directly associated with 3’UTR of MMP9, therefore positively regulated MMP9 expression. In conclusion, we identified that RPL23 might play an important role in HCC metastasis in an MMP9-dependent manner and be a potential therapeutic target for HCC tumorigenesis and metastasis.

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LncRNA CASC11 Promotes Hepatocellular Carcinoma Progression via Upregulation of UBE2T in a m6A-Dependent Manner

Frontiers in Oncology ◽

10.3389/fonc.2021.772671 ◽

2021 ◽

Vol 11 ◽

Author(s):

Fei Chen ◽

Meijun Li ◽

Liang Wang

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Progression ◽

Cancer Susceptibility ◽

Underlying Mechanism ◽

Epigenetic Mechanism ◽

Migration And Invasion ◽

Dependent Manner ◽

Tumor Growth And Metastasis

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies and the third leading cause of cancer-related deaths worldwide. Besides, it has been revealed that long non-coding RNA (LncRNA) cancer susceptibility candidate 11 (CASC11) is involved in cancer progression. However, the functional role and underlying mechanism of CASC11 in HCC remains largely unknown. In this context, here, it was found that CASC11 was upregulated in HCC tissues and associated with tumor grades, metastasis, and prognosis of HCC patients. Functionally, CASC11 facilitated HCC cell proliferation, migration, and invasion in vitro, and enhanced tumor growth and metastasis in vivo. Mechanistically, CASC11 associated with and stabilized Ubiquitin-conjugating enzyme E2T (UBE2T) mRNA. To be specific, it decreased UBE2T N6-methyladenosine (m6A) level via recruiting ALKBH5. Moreover, CASC11 inhibited the association between UBE2T mRNA and m6A reader protein YTHDF2. Taken together, our findings demonstrate the epigenetic mechanism of CASC11 in the regulation of UBE2T expression and possibly provide a novel therapeutic target for HCC treatment.

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Scorpion inhibits epithelial–mesenchymal transition and metastasis of hepatocellular carcinoma

Experimental Biology and Medicine ◽

10.1177/1535370218762514 ◽

2018 ◽

Vol 243 (7) ◽

pp. 645-654 ◽

Cited By ~ 3

Author(s):

Yi-Quan Yan ◽

Juan Xie ◽

Jing-Fu Wang ◽

Zhao-Feng Shi ◽

Xiang Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Poor Prognosis ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Unfavorable Clinical Outcome ◽

Metastasis Models ◽

Tumor Growth And Metastasis

Hepatocellular carcinoma (HCC) is one of the most malignant diseases worldwide. The unfavorable clinical outcome and poor prognosis are due to high rates of recurrence and metastasis after treatments. Some scholars of traditional Chinese medicine suggested that endogenous wind-evil had played an important role in metastasis of malignant tumor. Therefore, the drug of dispelling wind-evil could be used to prevent cancer metastasis and improve the poor prognosis. So we wondered whether Scorpion, one of the most important wind calming drugs, has antitumor effect especially in epithelial–mesenchymal transition (EMT) and metastasis of HCC in this research. We found that Scorpion-medicated serum could inhibit proliferation, induce apoptosis, and decrease migration and invasion capacity of Hepa1-6 cells in vitro. Meanwhile, we observed that water decoction of Scorpion restrained tumor growth and metastasis in nude mouse of HCC metastasis models. Further experiments showed that Scorpion could suppress EMT, which is characterized by increased epithelial marker E-cadherin expression and decreased mesenchymal markers N-cadherin and Snail expression following Scorpion treatment both in vitro and in vivo. These results suggested that the Scorpion could inhibit Hepa1-6 cells’ invasion and metastasis in part by reversing EMT and providing a possible potential approach for preventing HCC metastasis. Impact statement The unfavorable clinical outcome and poor prognosis of hepatocellular carcinoma (HCC) are due to high rates of recurrence and metastasis after treatments. Here we found Scorpion, one of the most important wind calming drugs, has antitumor effect. Scorpion-medicated serum inhibited the proliferation, induced apoptosis, and decreased migration and invasion capacity of Hepa1-6 cells in vitro. Water decoction of Scorpion restrained tumor growth and metastasis in nude mouse of HCC metastasis models. Further experiments showed that Scorpion could suppress EMT of HCC both in vitro and in vivo. Our results suggested that the Scorpion could inhibit Hepa1-6 cells’ invasion and metastasis in part by reversing EMT and providing a possible potential approach for preventing HCC metastasis.

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Secalonic Acid-F, a Novel Mycotoxin, Represses the Progression of Hepatocellular Carcinoma via MARCH1 Regulation of the PI3K/AKT/β-catenin Signaling Pathway

Molecules ◽

10.3390/molecules24030393 ◽

2019 ◽

Vol 24 (3) ◽

pp. 393 ◽

Cited By ~ 12

Author(s):

Lulu Xie ◽

Minjing Li ◽

Desheng Liu ◽

Xia Wang ◽

Peiyuan Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Mouse Model ◽

Colony Formation ◽

Migration And Invasion ◽

Dependent Manner ◽

Small Interfering Rnas ◽

Nude Mouse Model ◽

Hep3b Cells

Liver cancer is a very common and significant health problem. Therefore, powerful molecular targeting agents are urgently needed. Previously, we demonstrated that secalonic acid-F (SAF) suppresses the growth of hepatocellular carcinoma (HCC) cells (HepG2), but the other anticancer biological functions and the underlying mechanism of SAF on HCC are unknown. In this study, we found that SAF, which was isolated from a fungal strain in our lab identified as Aspergillus aculeatus, could inhibit the progression of hepatocellular carcinoma by targeting MARCH1, which regulates the PI3K/AKT/β-catenin and antiapoptotic Mcl-1/Bcl-2 signaling cascades. First, we confirmed that SAF reduced the proliferation and colony formation of HCC cell lines (HepG2 and Hep3B), promoted cell apoptosis, and inhibited the cell cycle in HepG2 and Hep3B cells in a dose-dependent manner. In addition, the migration and invasion of HepG2 and Hep3B cells treated with SAF were significantly suppressed. Western blot analysis showed that the level of MARCH1 was downregulated by pretreatment with SAF through the regulation of the PI3K/AKT/β-catenin signaling pathways. Moreover, knockdown of MARCH1 by small interfering RNAs (siRNAs) targeting MARCH1 also suppressed the proliferation, colony formation, migration, and invasion as well as increased the apoptotic rate of HepG2 and Hep3B cells. These data confirmed that the downregulation of MARCH1 could inhibit the progression of hepatocellular carcinoma and that the mechanism may be via PI3K/AKT/β-catenin inactivation as well as the downregulation of the antiapoptotic Mcl-1/Bcl-2. In vivo, the downregulation of MARCH1 by treatment with SAF markedly inhibited tumor growth, suggesting that SAF partly blocks MARCH1 and further regulates the PI3K/AKT/β-catenin and antiapoptosis Mcl-1/Bcl-2 signaling cascade in the HCC nude mouse model. Additionally, the apparent diffusion coefficient (ADC) values, derived from magnetic resonance imaging (MRI), were increased in tumors after SAF treatment in a mouse model. Taken together, our findings suggest that MARCH1 is a potential molecular target for HCC treatment and that SAF is a promising agent targeting MARCH1 to treat liver cancer patients.

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Gelsolin Promotes Cancer Progression by Regulating Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma and Correlates with a Poor Prognosis

Journal of Oncology ◽

10.1155/2020/1980368 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Yixi Zhang ◽

Xiaojing Luo ◽

Jianwei Lin ◽

Shunjun Fu ◽

Pei Feng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Progression ◽

Poor Prognosis ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Disease Free Survival ◽

Tumour Cells ◽

Migration And Invasion ◽

Mesenchymal Transition

Gelsolin (GSN), a cytoskeletal protein, is frequently overexpressed in different cancers and promotes cell motility. The biological function of GSN in hepatocellular carcinoma (HCC) and its mechanism remain unclear. The expression of GSN was assessed in a cohort of 188 HCC patients. The effects of GSN on the migration and invasion of tumour cells were examined. Then, the role of GSN in tumour growth in vivo was determined by using a cancer metastasis assay. The possible mechanism by which GSN promotes HCC progression was explored. As a result, GSN was overexpressed in HCC tissues. High GSN expression was significantly correlated with late Edmondson grade, encapsulation, and multiple tumours. Patients with high GSN expression had worse overall survival (OS) and disease-free survival (DFS) than those with low GSN expression. GSN expression was identified as an independent risk factor in both OS (hazard risk (HR) = 1.620, 95% confidence interval (CI) = 1.105–2.373, P<0.001) and DFS (HR = 1.744, 95% CI = 1.205–2.523, P=0.003). Moreover, GSN knockdown significantly inhibited the migration and invasion of HCC tumour cells, while GSN overexpression attenuated these effects by regulating epithelial-mesenchymal transition (EMT) In conclusion, GSN promotes cancer progression and is associated with a poor prognosis in HCC patients. GSN promotes HCC progression by regulating EMT.

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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.

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miR-186-5p Prevents Hepatocellular Carcinoma Progression Through Targeting METTL3 to Regulate m6A-Mediated Stabilization of FSTL5

10.21203/rs.3.rs-598803/v1 ◽

2021 ◽

Author(s):

DengYong Zhang ◽

FangFang Chen ◽

ShuoShuo Ma ◽

YongChun Zhou ◽

Wanliang Sun ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Rna Stability ◽

The Cancer Genome Atlas ◽

Cell Counting ◽

Migration And Invasion ◽

Dependent Manner ◽

Report Analysis ◽

Hcc Cells

Abstract Background: Hepatocellular carcinoma (HCC) processes in multi-steps which involves the sophisticated interactions of genetics, epigenetics, and transcriptional changes. According to before investigations, methyltransferase-like 3 (METTL3)-mediated m6A modification regulates the development of various cancers by regulating gene stability. However, the studies focusing on miRNA’s regulatory effect of N6-methyladenosine (m6A) modification on HCC progression are still limited. Methods: Immunochemistry (IHC) staining detected the histopathological changes in the tumor tissues. Cell Counting Kit-8 (CCK-8), clone formation, and transwell assay investigated the changes in cancer cell proliferation, invasion, and migration. The RNA m6A level was confirmed by methylated RNA immunoprecipitation. The RNA stability assay indicated the half-life (t1/2) of RNA in HCC cells. The prognosis of the indicated patients’ cohort was analyzed using the cancer genome atlas (TCGA) datasets. Luciferase report analysis was used to study the potential binding between microRNA (miRNA) and mRNA. A mice tumor transplant model was further established to study the changes in tumor progression. Results: Follistatin-like 5 (FSTL5) was found to be significantly downregulated in HCC, and it inhibited the further progression of HCC. The RNA stability analysis indicated that the mRNA t1/2 gene of HCC cells was shortened. Besides, METTL3 reduced the stability of FSTL5 mRNA in a m6A-YTH domain family 2(YTHDF2)-dependent manner. Functional experiments revealed that the downregulated METTL3 inhibited the HCC progression by up-regulating FSTL5 in vitro and in vivo. Luciferase report analysis confirmed that miR-186-5p directly targeted the METTL3. Additionally, miR-186-5p inhibited the proliferation, migration, and invasion of HCC cells by downregulating METTL3. We identified that miR-186-5p prevented the HCC progression by targeting METTL3 to regulate m6A-mediated FSTL5 stabilization. Conclusions: The miR-186-5p/METTL3/YTHDF2/FSTL5 axis perhaps point out a new direction for the targeted therapy of HCC.

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SYT8 promotes pancreatic cancer progression via the TNNI2/ERRα/SIRT1 signaling pathway

Cell Death Discovery ◽

10.1038/s41420-021-00779-4 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Zhiping Fu ◽

Xing Liang ◽

Ligang Shi ◽

Liang Tang ◽

Danlei Chen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Tumor Metastasis ◽

Molecular Mechanisms ◽

Hormone Secretion ◽

Migration And Invasion ◽

Dependent Manner ◽

Orphan Nuclear Receptor

AbstractPancreatic cancer is a highly lethal malignancy due to failures of early detection and high metastasis in patients. While certain genetic mutations in tumors are associated with severity, the molecular mechanisms responsible for cancer progression are still poorly understood. Synaptotagmin-8 (SYT8) is a membrane protein that regulates hormone secretion and neurotransmission, and its expression is positively regulated by the promoter of the insulin gene in pancreatic islet cells. In this study, we identified a previously unknown role of SYT8 in altering tumor characteristics in pancreatic cancer. SYT8 levels were upregulated in patient tumors and contributed towards increased cell proliferation, migration, and invasion in vitro and in vivo. Increased SYT8 expression also promoted tumor metastasis in an in vivo tumor metastasis model. Furthermore, we showed that SYT8-mediated increase in tumorigenicity was regulated by SIRT1, a protein deacetylase previously known to alter cell metabolism in pancreatic lesions. SIRT1 expression was altered by orphan nuclear receptor ERRα and troponin-1 (TNNI2), resulting in cell proliferation and migration in an SYT8-dependent manner. Together, we identified SYT8 to be a central regulator of tumor progression involving signaling via the SIRT1, ERRα, and TNNI2 axis. This knowledge may provide the basis for the development of therapeutic strategies to restrict tumor metastasis in pancreatic cancer.

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Mechanism and Molecular Network of RBM8A-Mediated Regulation of Oxaliplatin Resistance in Hepatocellular Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2020.585452 ◽

2021 ◽

Vol 10 ◽

Author(s):

Rong Liang ◽

Jinyan Zhang ◽

Zhihui Liu ◽

Ziyu Liu ◽

Qian Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Rna Binding ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Binding Motif ◽

Mesenchymal Transition ◽

Regulatory Pathways ◽

Wide Range

RNA-binding motif protein 8A (RBM8A) is abnormally overexpressed in hepatocellular carcinoma (HCC) and involved in the epithelial-mesenchymal transition (EMT). The EMT plays an important role in the development of drug resistance, suggesting that RBM8A may be involved in the regulation of oxaliplatin (OXA) resistance in HCC. Here we examined the potential involvement of RBM8A and its downstream pathways in OXA resistance using in vitro and in vivo models. RBM8A overexpression induced the EMT in OXA-resistant HCC cells, altering cell proliferation, apoptosis, migration, and invasion. Moreover, whole-genome microarrays combined with bioinformatics analysis revealed that RBM8A has a wide range of transcriptional regulatory capabilities in OXA-resistant HCC, including the ability to regulate several important tumor-related signaling pathways. In particular, histone deacetylase 9 (HDAC9) emerged as an important mediator of RBM8A activity related to OXA resistance. These data suggest that RBM8A and its related regulatory pathways represent potential markers of OXA resistance and therapeutic targets in HCC.

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Artemisia argyi Essential Oil Inhibits Hepatocellular Carcinoma Metastasis via Suppression of DEPDC1 Dependent Wnt/β-Catenin Signaling Pathway

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.664791 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yanli Li ◽

Yang Tian ◽

Wei Zhong ◽

Ning Wang ◽

Yafeng Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Essential Oil ◽

Signaling Pathway ◽

Nude Mice ◽

Migration And Invasion ◽

Advanced Hepatocellular Carcinoma ◽

Dependent Manner ◽

Artemisia Argyi

The tumor metastasis is the major hurdle for the treatment of advanced hepatocellular carcinoma (HCC), due in part to the lack of effective systemic treatments. DEPDC1, a novel oncoantigen upregulated in HCC, is thought to be a molecular-target for novel therapeutic drugs. Artemisia argyi is a traditional Chinese medicine with anti-inflammatory and anti-tumor activities. This study investigated the potential therapeutic benefits of Artemisia argyi essential oil (AAEO) in suppressing metastasis of HCC by targeting DEPDC1. Assessment of AAEO cytotoxicity was performed by MTT assay. Anti-metastatic effects of AAEO were investigated in vitro using wound healing and transwell assays. The HepG2 cells were transduced with lentiviral vector containing luciferase (Luc). A metastasis model of nude mice was established by tail vein injection of HepG2-Luc cells. The nude mice were treated with AAEO (57.5, 115, and 230 mg/kg) or sorafenib (40 mg/kg). Metastasis of HCC cells was monitored via in vivo bioluminescence imaging. After treatment for 21 days, tissues were collected for histological examination and immunohistochemistry analysis. Gene and protein levels were determined by real-time quantitative PCR and western blotting. The results revealed that AAEO significantly inhibits the migration and invasion in vitro in a concentration-dependent manner. In vivo assays further confirmed that AAEO markedly inhibits HCC metastasis into lung, brain, and femur tissues and exhibits low toxicity. Our results suggested that AAEO significantly downregulates the mRNA and protein expression of DEPDC1. Also, AAEO attenuated Wnt/β-catenin signaling through reduction of Wnt1 and β-catenin production. Moreover, AAEO prevented epithelial-mesenchymal transition (EMT) by downregulation of vimentin and upregulation of E-cadherin. Furthermore, we found that DEPDC1 promoted HCC migration and invasion via Wnt/β-catenin signaling pathway and EMT. These results demonstrate that AAEO effectively inhibits HCC metastasis via attenuating Wnt/β-catenin signaling and inhibiting EMT by suppressing DEPDC1 expression. Thus, AAEO likely acts as a novel inhibitor of the DEPDC1 dependent Wnt/β-catenin signaling pathway.

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