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1.
Cancer Med ; 12(13): 14130-14137, 2023 07.
Article in English | MEDLINE | ID: mdl-37183837

ABSTRACT

BACKGROUND: Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) can be used in pediatric patients. This study assessed the safety and efficacy of PEG-rhG-CSF as a primary prophylactic drug against neutropenia after chemotherapy in pediatric patients with solid tumors or non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: This phase II study (between October 2020 and March 2022) enrolled pediatric patients with solid tumors or NHL treated with high-intensity chemotherapy and with grade ≥3 myelosuppression for at least 14 days during chemotherapy. Prophylactic PEG-rhG-CSF was given at 100 µg/kg body weight (maximum total dosage of 6 mg) once 24-48 h following chemotherapy for two cycles. The primary endpoint was the incidence of PEG-rhG-CSF-related adverse events (AEs). The key secondary endpoints were the rates of grade 3/4 neutropenia and febrile neutropenia (FN). RESULTS: This study included 160 pediatric patients with a median age of 6.22 (0.29, 18.00) years. Fifty-eight patients (36.25%) were diagnosed with sarcoma. AEs potentially related to PEG-rhG-CSF included bone pain (n = 32), fatigue (n = 21), pain at the injection site (n = 21), and myalgia (n = 20). The rates of grade 3/4 neutropenia and FN during treatment were 57.28% and 29.45%, respectively. CONCLUSION: PEG-rhG-CSF is well tolerated and effective in pediatric patients with solid tumors or NHL. These findings should be substantiated with further trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04547829.


Subject(s)
Lung Neoplasms , Lymphoma, Non-Hodgkin , Neutropenia , Humans , Child , Lung Neoplasms/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/etiology , Granulocyte Colony-Stimulating Factor/adverse effects , Polyethylene Glycols/adverse effects , Recombinant Proteins/adverse effects , Neutropenia/chemically induced , Neutropenia/prevention & control , Neutropenia/drug therapy , Pain/chemically induced , Antineoplastic Combined Chemotherapy Protocols/adverse effects
2.
Liver Int ; 43(6): 1307-1319, 2023 06.
Article in English | MEDLINE | ID: mdl-36892418

ABSTRACT

BACKGROUND AND AIMS: Liver diseases present a wide range of fibrosis, from fatty liver with no inflammation to steatohepatitis with varying degrees of fibrosis, to established cirrhosis leading to HCC. In a multivariate analysis, serum levels of spermidine were chosen as the top metabolite from 237 metabolites and its levels were drastically reduced along with progression to advanced steatohepatitis. Our previous studies that showed spermidine supplementation helps mice prevent liver fibrosis through MAP1S have prompted us to explore the possibility that spermidine can alleviate or cure already developed liver fibrosis. METHODS: We collected tissue samples from patients with liver fibrosis to measure the levels of MAP1S. We treated wild-type and MAP1S knockout mice with CCl4 -induced liver fibrosis with spermidine and isolated HSCs in culture to test the effects of spermidine on HSC activation and liver fibrosis. RESULTS: Patients with increasing degrees of liver fibrosis had reduced levels of MAP1S. Supplementing spermidine in mice that had already developed liver fibrosis after 1 month of CCl4 induction for an additional 3 months resulted in significant reductions in levels of ECM proteins and a remarkable improvement in liver fibrosis through MAP1S. Spermidine also suppressed HSC activation by reducing ECM proteins at both the mRNA and protein levels, and increasing the number of lipid droplets in stellate cells. CONCLUSIONS: Spermidine supplementation is a potentially clinically meaningful approach to treating and curing liver fibrosis, preventing cirrhosis and HCC in patients.


Subject(s)
Carcinoma, Hepatocellular , Fatty Liver , Liver Cirrhosis , Liver Neoplasms , Animals , Mice , Autophagy/physiology , Carcinoma, Hepatocellular/pathology , Fatty Liver/pathology , Fibrosis , Hepatic Stellate Cells/metabolism , Liver/pathology , Liver Cirrhosis/chemically induced , Liver Cirrhosis/drug therapy , Liver Cirrhosis/genetics , Liver Neoplasms/pathology , Microtubule-Associated Proteins/metabolism , Spermidine/pharmacology , Spermidine/therapeutic use , Spermidine/metabolism , Humans
4.
Dis Markers ; 2022: 4752184, 2022.
Article in English | MEDLINE | ID: mdl-35756490

ABSTRACT

Background: Immune-related long noncoding RNAs (IrlncRNAs) are recognized as important prognostic factors in a variety of cancers, but thus far, their prognostic value in pediatric rhabdoid tumor of the kidney (pRTK) has not been reported. Here, we clarified the associations between IrlncRNAs and overall survival (OS) of pRTK patients and constructed a model to predict their prognosis. Methods: We accessed RNA sequencing data and corresponding clinical data of pRTK from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. An expression profile of immune-related genes (Irgenes) and lncRNAs of pRTK was extracted from the RNA sequencing data. IrlncRNAs were defined by co-expression analysis of lncRNAs and Irgenes. The limma R package was used to identify differential expression IrlncRNAs. Univariate and multivariate Cox regression analyses were conducted to build a prognostic IrlncRNAs model. The performance of this prognostic model was validated by multimethods, like ROC curve analysis. Results: A total of 1097 IrlncRNAs were defined. Univariate Cox regression analysis identified 7 IrlncRNAs (AC004791.2, AP003068.23, RP11-54O7.14, RP11-680F8.1, TBC1D3P1-DHX40P1, TUNAR, and XXbac-BPG308K3.5) and were significantly associated with OS. Multivariate regression analysis constructed the best prognostic model based on the expression of AC004791.2, AP003068.23, RP11-54O7.14, TBC1D3P1-DHX40P1, and TUNAR. According to the prognostic model, a risk score of each patient was calculated, and patients were divided into high-risk and low-risk groups accordingly. The survival time of low-risk patients was significantly better than high-risk patients (p < 0.001). Univariate (hazard ratio 1.098, 95% confidence interval 1.048-1.149, p value <0.001) and multivariate (hazard ratio 1.095, 95% confidence interval 1.043-1.150, p value <0.001) analyses confirmed that the prognostic model was reliable and independent in prediction of OS. Time-dependent ROC analysis showed that 1-year survival AUC of prognostic model, stage, age, and sex was 0.824, 0.673, 0.531, and 0.495, respectively, which suggested that the prognostic model was the best predictor of survival in pRTK patients. Conclusions: The prognostic model based on 5 IrlncRNAs was robust and could better predict the survival of pRTK than other clinical factors. Additionally, the mechanism of regulation and action of prognosis-associated lncRNAs could provide new avenues for basic research to explore the mechanism of tumor initiation and development in order to prevent and treat pRTK.


Subject(s)
Kidney Neoplasms , RNA, Long Noncoding , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Child , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/genetics , Prognosis , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism
5.
Cell Death Dis ; 12(7): 639, 2021 06 23.
Article in English | MEDLINE | ID: mdl-34162830

ABSTRACT

Increasing studies have found that circular RNAs (circRNAs) are aberrantly expressed and play important roles in the occurrence and development of human cancers. However, the function of circRNAs on environmental carcinogen-induced gastric cancer (GC) progression remains poorly elucidated. In the present study, hsa_circ_0110389 was identified as a novel upregulated circRNA in malignant-transformed GC cells through RNA-seq, and subsequent quantitative real-time PCR verified that hsa_circ_0110389 was significantly increased in GC tissues and cells. High hsa_circ_0110389 expression associates with advanced stages of GC and predicts poor prognosis. Knockdown and overexpression assays demonstrated that hsa_circ_0110389 regulates proliferation, migration, and invasion of GC cells in vitro. In addition, hsa_circ_0110389 was identified to sponge both miR-127-5p and miR-136-5p and SORT1 was validated as a direct target of miR-127-5p and miR-136-5p through multiple mechanism assays; moreover, hsa_circ_0110389 sponged miR-127-5p/miR-136-5p to upregulate SORT1 expression and hsa_circ_0110389 promoted GC progression through the miR-127-5p/miR-136-5p-SORT1 pathway. Finally, hsa_circ_0110389 knockdown suppressed GC growth in vivo. Taken together, our findings firstly identify the role of hsa_circ_0110389 in GC progression, which is through miR-127-5p/miR-136-5p-SORT1 pathway, and our study provides novel insight for the identification of diagnostic/prognostic biomarkers and therapeutic targets for GC.


Subject(s)
Adaptor Proteins, Vesicular Transport/metabolism , MicroRNAs/metabolism , RNA, Circular/metabolism , Stomach Neoplasms/metabolism , Adaptor Proteins, Vesicular Transport/genetics , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/genetics , Neoplasm Invasiveness , RNA, Circular/genetics , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Tumor Burden , Up-Regulation
6.
Oncogene ; 39(19): 3879-3892, 2020 05.
Article in English | MEDLINE | ID: mdl-32203162

ABSTRACT

Mutants in the gene encoding mitochondrion-associated protein LRPPRC were found to be associated with French Canadian Type Leigh syndrome, a human disorder characterized with neurodegeneration and cytochrome c oxidase deficiency. LRPPRC interacts with one of microtubule-associated protein family MAP1S that promotes autophagy initiation and maturation to suppress genomic instability and tumorigenesis. Previously, although various studies have attributed LRPPRC nuclear acid-associated functions, we characterized that LRPPRC acted as an inhibitor of autophagy in human cancer cells. Here we show that liver-specific deletion of LRPPRC causes liver-specific increases of YAP and P27 and decreases of P62, leading to an increase of cell polyploidy and an impairment of autophagy maturation. The blockade of autophagy maturation and promotion of polyploidy caused by LRPPRC depletion synergistically enhances diethylnitrosamine-induced DNA damage, genome instability, and further tumorigenesis so that LRPPRC knockout mice develop more and larger hepatocellular carcinomas and survive a shorter lifespan. Therefore, LRPPRC suppresses genome instability and hepatocellular carcinomas and promotes survivals in mice by sustaining Yap-P27-mediated cell ploidy and P62-HDAC6-controlled autophagy maturation.


Subject(s)
Carcinoma, Hepatocellular/genetics , Cytochrome-c Oxidase Deficiency/genetics , Histone Deacetylase 6/genetics , Leigh Disease/genetics , Liver Neoplasms/genetics , Neoplasm Proteins/genetics , Adaptor Proteins, Signal Transducing/genetics , Animals , Autophagy/genetics , Canada , Carcinogenesis/genetics , Carcinoma, Hepatocellular/pathology , Cytochrome-c Oxidase Deficiency/pathology , Genomic Instability/genetics , HeLa Cells , Humans , Leigh Disease/pathology , Liver/metabolism , Liver/pathology , Liver Neoplasms/pathology , Mice , Mice, Knockout , Ploidies , Proliferating Cell Nuclear Antigen/genetics , RNA-Binding Proteins/genetics , Transcription Factors/genetics , YAP-Signaling Proteins
7.
J Exp Clin Cancer Res ; 38(1): 500, 2019 12 20.
Article in English | MEDLINE | ID: mdl-31861994

ABSTRACT

In the original publication of this article [1], the author found an error in Fig. 2f. lncGPR107 should be changed to lncMAPK6, and the corrected Fig. 2 is shown below.

8.
Biosci Rep ; 39(6)2019 06 28.
Article in English | MEDLINE | ID: mdl-31189743

ABSTRACT

Background/Aim: Gastric cancer is one of the most common malignant tumors, and its complex pathogenesis has not been fully elucidated. Circular RNAs (circRNAs) are involved in various biological processes and human diseases. However, their exact functional roles and mechanisms of action remain largely unclear. We previously discovered the differential expression of non-coding RNAs (ncRNAs) during the malignant transformation of human gastric epithelial cells. In this study, we investigated the functional roles of a significantly up-regulated circRNA (hsa_circ_0000592) in gastric cancer. Methods:N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced malignant-transformed gastric epithelial cells (GES-1-T) and normal gastric epithelial cells (GES-1-N) were analyzed by high-throughput circRNA sequencing. The top 15 up-regulated circRNAs in high-throughput sequencing results were further confirmed by qRT-PCR in different gastric epithelial cell lines. The function of the most significant circRNA (hsa_circ_0000592) was investigated by using RNA interference (RNAi) assays, fluorescence in situ hybridization analysis (FISH), and bioinformatics prediction methods. Results: A total of 1509 genes were up-regulated and 3142 genes were down-regulated in GES-1-T cells when compared with GES-1-N cells. When compared with GES-1-N cells, hsa_circ_0000592 was obviously up-regulated in GES-1-T cells, as well as in other gastric cancer cell lines. The silencing of hsa_circ_0000592 mRNA led to a decrease in cell proliferation, cell cycle arrest at the G0/G1 phase, an increased rate of apoptosis, and a reduction in cell migration. Furthermore, FISH showed that hsa_circ_0000592 was mainly located in the cytoplasm, and a bioinformatics analysis suggested that hsa_circ_0000592 might function by sponging multiple miRNAs, and most notably four conserved miRNAs, including miR-139-3p, miR-200, miR-367-3p, and miR-33a-3p. Conclusion: This study is the first to identify hsa_circ_0000592 as a novel circRNA with a critical role in MNNG-induced gastric cancer. Due to the essential role of hsa_circ_0000592 in gastric carcinoma cells, it may be considered as a potential biomarker for use in diagnosing gastric carcinoma. Our findings provide a new insight into the function of circRNAs in environmental carcinogen-induced gastric cancer.


Subject(s)
Carcinogenesis/genetics , Gene Expression Regulation, Neoplastic , RNA, Circular/genetics , Stomach Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation , High-Throughput Nucleotide Sequencing , Humans
9.
Hepatology ; 70(1): 372-388, 2019 07.
Article in English | MEDLINE | ID: mdl-30873635

ABSTRACT

Spermidine (SPD), a naturally occurring polyamine, has been recognized as a caloric restriction mimetic that confers health benefits, presumably by inducing autophagy. Recent studies have reported that oral administration of SPD protects against liver fibrosis and hepatocarcinogenesis through activation of microtubule associated protein 1S (MAP1S)-mediated autophagy. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a transcription factor that mediates cellular protection by maintaining the cell's redox, metabolic, and proteostatic balance. In this study, we demonstrate that SPD is a noncanonical NRF2 inducer, and that MAP1S is a component of this noncanonical pathway of NRF2 activation. Mechanistically, MAP1S induces NRF2 signaling through two parallel mechanisms, both resulting in NRF2 stabilization: (1) MAP1S competes with Kelch-like ECH-associated protein 1 (KEAP1) for NRF2 binding through an ETGE motif, and (2) MAP1S accelerates p62-dependent degradation of KEAP1 by the autophagy pathway. We further demonstrate that SPD confers liver protection by enhancing NRF2 signaling. The importance of both NRF2 and p62-dependent autophagy in SPD-mediated liver protection was confirmed using a carbon tetrachloride-induced liver fibrosis model in wild-type, Nrf2-/- , p62-/- and Nrf2-/- ;p62-/- mice, as the protective effect of SPD was significantly reduced in NRF2 or p62 single knockout mice, and completely abolished in the double knockout mice. Conclusion: Our results demonstrate the pivotal role of NRF2 in mediating the health benefit of SPD, particularly in the context of liver pathologies.


Subject(s)
Liver Cirrhosis/drug therapy , Liver/drug effects , Microtubule-Associated Proteins/metabolism , NF-E2-Related Factor 2/metabolism , Spermidine/pharmacology , Animals , Autophagy , Drug Evaluation, Preclinical , HEK293 Cells , Hepatic Stellate Cells/drug effects , Humans , Kelch-Like ECH-Associated Protein 1/metabolism , Mice , Proto-Oncogene Proteins c-myc/metabolism , Spermidine/therapeutic use
10.
Cell Death Differ ; 26(8): 1379-1395, 2019 08.
Article in English | MEDLINE | ID: mdl-30315205

ABSTRACT

RASSF1A (Ras association domain family 1 isoform A) is a tumor suppressor and frequently inactivated by promoter hypermethylation in hepatocellular carcinoma (HCC). Autophagy is to degrade misfolded or aggregated proteins and dysfunctional organelles. Autophagy defects enhance oxidative stress and genome instability to promote tumorigenesis. Activating autophagy flux by increasing levels of the RASSF1A-interacting microtubule-associated protein 1 S (MAP1S) leads to suppression of HCC in addition to extending lifespans. Here we tested whether RASSF1A itself functions as a HCC suppressor and activates autophagy similarly as MAP1S does. We show that RASSF1A deletion leads to an acceleration of diethylnitrosamine-induced HCC and a 31% reduction of median survival times in mice. RASSF1A enhances autophagy initiation by suppressing PI3K-AKT-mTOR through the Hippo pathway-regulatory component MST1 and promotes autophagy maturation by recruiting autophagosomes on RASSF1A-stabilized acetylated microtubules through MAP1S. RASSF1A deletion causes a blockade of autophagy flux. Therefore, RASSF1A may suppress HCC and improve survival by activating autophagy flux.


Subject(s)
Autophagy , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Tumor Suppressor Proteins/metabolism , Animals , Carcinoma, Hepatocellular/pathology , Humans , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Tumor Suppressor Proteins/deficiency , Tumor Suppressor Proteins/genetics
11.
Cancer Manag Res ; 10: 5027-5041, 2018.
Article in English | MEDLINE | ID: mdl-30464603

ABSTRACT

BACKGROUND: Elevated plasma fibrinogen levels have been associated with tumor progression in several malignancies. Our study aims to characterize the clinical significance of elevated plasma fibrinogen levels in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Relevant published articles were systematically searched in electronic databases including PubMed, Embase, and Web of Science. The pooled differences in plasma fibrinogen levels among HCC, cirrhotic, and control groups were expressed as weighted mean differences (WMDs) and their corresponding 95% CIs. The associations between elevated fibrinogen and overall survival (OS) and disease-free survival (DFS)/recurrence-free survival (RFS) were expressed as HRs and their 95% CIs, whereas the associations between elevated fibrinogen and various types of clinical characteristic of patients with HCC were expressed as ORs and their corresponding 95% CIs. RESULTS: Results showed that the plasma fibrinogen levels in patients with HCC were not significantly different than that in healthy controls (WMD = 0.50, 95% CI = [-0.82, 1.82], P = 0.457) or patients with cirrhosis (WMD = -0.62, 95% CI = [-1.56, 0.33], P = 0.200). However, our results showed that compared to those with normal levels, patients with HCC and elevated plasma fibrinogen levels showed poorer OS (HR = 2.08, 95% CI = [1.67, 2.59], P < 0.0001) and DFS/RFS (HR = 1.90, 95% CI = [1.52, 2.37], P < 0.0001). Results of trial sequential analysis of the OS indicated that currently available studies were sufficient to validate the negative prognostic value of elevated plasma fibrinogen in patients with HCC. Clinicopathological analyses showed that high plasma fibrinogen levels were associated with tumor progression as indicated by advanced tumor stage, larger tumor size, increased tumor number, and the presence of vascular invasion. CONCLUSION: Elevated plasma fibrinogen levels are associated with poor prognosis and advanced tumor progression. Plasma fibrinogen may serve as a negative prognostic biomarker in patients with HCC.

12.
J Exp Clin Cancer Res ; 37(1): 105, 2018 May 15.
Article in English | MEDLINE | ID: mdl-29764463

ABSTRACT

BACKGROUND: Liver tumor initiating cells (TICs) have self-renewal and differentiate capacities, and largely contribute to tumor initiation, metastasis and drug resistance. MAPK signaling is a critical pathway in many biological processes, while its role in liver TICs hasn't been explored. METHODS: Online-available dataset was used for unbiased screening. Liver TICs were examined CD133 FACS or oncosphere formation. TIC self-renewal was detected by oncosphere formation and tumor initiation assay. LncRNA function was detected by loss of function or gain of function assays. The molecular mechanism of lncRNA was explored by RNA pulldown, RNA immunoprecipitation, ChIP, western blot and double FISH. RESULTS: Here, we examined the expression profiles of MAPK components (MAPKs, MAP2Ks, MAP3Ks, MAP4Ks), and found MAPK6 is most highly expressed in liver cancer samples. Moreover, a divergent lncRNA (long noncoding RNA) of MAPK6, termed lncMAPK6 here, is also overexpressed along with liver tumorigenesis. LncMAPK6 promotes liver tumor propagation and TIC self-renewal through MAPK6. LncMAPK6 interacts with and recruits RNA polymerase II to MAPK6 promoter, and finally activates the transcription of MAPK6. Through MAPK6 transcriptional regulation, lncMAPK6 drives MARK signaling activation. LncMAPK6-MAPK6 pathway can be used for liver TIC targeting. Altogether, lncMAPK6 promotes MARK signaling and the self-renewal of liver TICs through MAPK6 expression. CONCLUSION: MAPK6 was the most highly expressed MAPK component in liver cancer and liver TICs and lncMAPK6 participated in the transcriptional regulation of MAPK6in cis. This work revealed the importance role of MAPK signaling in liver TIC self-renewal and added a new layer for liver TIC and MAPK6 expression regulation.


Subject(s)
Cell Self Renewal/genetics , Gene Expression Regulation, Neoplastic , Liver Neoplasms/genetics , Mitogen-Activated Protein Kinase 6/genetics , Neoplastic Stem Cells/metabolism , RNA Interference , RNA, Long Noncoding/genetics , Aged , Cell Line, Tumor , Computational Biology/methods , Female , Gene Expression Profiling , Humans , Immunohistochemistry , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Middle Aged , Mitogen-Activated Protein Kinase 6/metabolism , Promoter Regions, Genetic , Protein Binding , RNA Polymerase II/metabolism , Signal Transduction , Transcriptome , Tumor Burden
13.
Cell Death Dis ; 9(5): 487, 2018 05 01.
Article in English | MEDLINE | ID: mdl-29706630

ABSTRACT

Hepatocellular carcinoma is the sixth most common cancer and gives rise to numerous deaths around the world every year. However, the molecular mechanism that controls hepatocarcinogenesis remains largely unknown. Here we found out an uncharacterized long noncoding RNA named lncAKHE. We found that lncAKHE was highly expressed in hepatocellular carcinoma tissues. lncAKHE depletion remarkably impaired the abilities of cell proliferation, migration, and invasion in hepatocellular carcinoma while promgoogoting cell apoptosis. Moreover, higher expression level of lncAKHE in hepatocellular carcinoma tissues was associated with more clinical severity and lower survival rates. Mechanistically, lncAKHE cooperated with YEATS4 to enhance the activation of NOTCH2 signaling which is usually abnormally upregulated in hepatocellular carcinoma. In conclusions, our study showed that lncAKHE may promote tumor progression in HCC and serve as a novel target for HCC treatment.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Cell Movement , Cell Proliferation , Liver Neoplasms/metabolism , RNA, Long Noncoding/metabolism , Receptor, Notch2/metabolism , Animals , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Gene Expression Regulation, Neoplastic , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness , RNA, Long Noncoding/genetics , Receptor, Notch2/genetics , Signal Transduction , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Cells, Cultured
14.
Life Sci ; 193: 93-103, 2018 Jan 15.
Article in English | MEDLINE | ID: mdl-29223541

ABSTRACT

AIMS: Evidence shows that aberrant expression of long non-coding RNA (lncRNA) is closely associated with tumor development and progression. However, the role of lncRNA in environmental carcinogen induced gastric tumorigenesis remains largely unknown. This study aimed at investigating the function role of lncRNA in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induce malignantly transformed human gastric epithelial cells. MAIN METHODS: In this study, high-throughput sequencing and qRT-PCR assay revealed marked downregulation of lncRNA LOC101927497 in the malignant transformed gastric epithelial cells induced by MNNG (GES-1-T cells), gain-of-function and loss-of-function assays showed that LOC101927497 can suppress the proliferation and migration of GES-1-T cells in vitro. RNA antisense purification experiment showed that LOC101927497 interacted with miR-574-5p in GES-1-T cells the most obvious. Further studies suggested that LOC101927497 may function as a tumor suppressor by interacting with miR-574-5p. KEY FINDINGS: LncRNA LOC101927497 functions as a suppressor by interacting with miR-574-5p, thus inhibiting the malignant phenotype of GES-1-T cells. SIGNIFICANCE: To the best of our knowledge, this is the first study to demonstrate the role of lncRNA in MNNG-induced gastric tumorigenesis, and it will provide new insights into the role of lncRNA in environmental carcinogen-induced gastric cancer.


Subject(s)
RNA, Long Noncoding/metabolism , Stomach Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Cell Proliferation/physiology , Cell Transformation, Neoplastic/metabolism , Epithelial Cells/metabolism , Gastric Mucosa/metabolism , Humans , Methylnitronitrosoguanidine , RNA, Long Noncoding/genetics , Stomach Neoplasms/pathology
15.
Sci Rep ; 7(1): 17176, 2017 12 07.
Article in English | MEDLINE | ID: mdl-29214989

ABSTRACT

Hepatocellular carcinoma (HCC) has become one of the most common leading causes of cancer-related deaths worldwide. This study investigates the role of lncRNA, SPRY4-IT1 in the development of HCC. Quantitative real-time PCR (qRT-PCR) was performed and the results showed that SPRY4-IT1 expression was up-regulated in HCC tissues and high expression of SPRY4-IT1 was associated with poor 5-year overall survival in the HCC patient cohort. Clinicopathological analysis showed that the expression of SPRY4-IT1 was significantly correlated with TNM stage in HCC patients. In vitro CCK-8 assay, colony formation assay, cell invasion and migration assays demonstrated that knock-down of SPRY4-IT1 suppressed cell proliferation, colony formation, cell invasion and migration in HCC cells. Flow cytometric analysis showed that knock-down of SPRY4-IT1 induced cell cycle arrest at G0/G1 phase and induced apoptosis. In addition, knock-down of SPRY4-IT1 also suppressed the mRNA and protein expression of estrogen-related receptor α (ERRα). Similarly, knock-down of ERRα inhibited cell proliferation, colony formation, cell invasion and migration in HCC cells. More importantly, ERRα overexpression antagonized the effects of SPRY4-IT1 knock-down on cell proliferation, colony formation, cell invasion and migration in HCC cells. Taken together, our data highlights the pivotal role of SPRY4-IT1 in the tumorigenesis of HCC.


Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , RNA, Long Noncoding/metabolism , Receptors, Estrogen/genetics , Apoptosis , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cell Cycle Checkpoints , Cell Movement , Cell Proliferation , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Male , Middle Aged , Neoplasm Invasiveness , Prognosis , RNA, Long Noncoding/genetics , ERRalpha Estrogen-Related Receptor
16.
Cancer Lett ; 411: 1-11, 2017 12 28.
Article in English | MEDLINE | ID: mdl-28964787

ABSTRACT

Increasing evidence suggests that therapy-induced senescence (TIS), a novel therapeutic approach in which low doses of therapeutic drugs or radiation are used to induce senescence, suppresses tumor development. Our previous in vitro studies have demonstrated that a low dose of metformin promoted hepatoma cell senescence instead of apoptosis via activation of AMP-activated protein kinase (AMPK) and inactivation of Sirtuin 1 (SIRT1) deacetylase activity. However, the intricate relationship between AMPK and SIRT1, and how they cooperate to induce senescence remains elusive. We showed here that persistent exposure to a low concentration of metformin led to AMPK activation in a mouse xenograft model of human hepatocellular carcinoma (HCC), resulting in senescence. Intriguingly, AMPK counter-regulated SIRT1 via direct phosphorylation in metformin-mediated senescence in hepatoma cells. Taken together, these findings suggest that a low dose of metformin could potentially be used as a TIS-inducing therapeutic drug for HCC, and that this occurs by inducing senescence of HCC cells via the AMPK-SIRT1 pathway.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Metformin/pharmacology , Sirtuin 1/metabolism , Animals , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Proliferation/drug effects , Cellular Senescence/drug effects , Humans , Hypoglycemic Agents/pharmacology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Random Allocation , Xenograft Model Antitumor Assays
17.
BMC Cancer ; 17(1): 414, 2017 Jun 14.
Article in English | MEDLINE | ID: mdl-28615075

ABSTRACT

BACKGROUND: As an end-proteolytic enzyme that cleaves the last three residues of proteins with a terminal CAAX, Ras-converting enzyme 1 (RCE1) has an essential role in multiple signaling pathways and take part in the process of differentiation, proliferation and carcinogenesis. The aim of the study is to investigate expression pattern of RCE1 and its prognosis in colorectal carcinoma (CRC). METHODS: The expression of RCE1 and phospho-MAPK family members was confirmed by immunohistochemical staining of CRC tissues. miR-RCE1 lentiviral vectors were transduced into HCT116 and SW489 cells. Reverse transcription PCR (RT-PCR) and western blot were conducted to measure the transfection efficiency. Transwell assays were used to detect the invasiveness of CRC cells. RESULTS: In the present study, we assessed RCE1 expression in 244 CRC specimens and matching adjacent, non-tumorous tissues by immunohistochemistry (IHC). Compared with the matched adjacent non-tumor tissue samples, the RCE1 reduced in the tumor tissue samples (p < 0.001). RCE1 expression was significantly decreased in 106 of 244 (43.4%) CRC cases. In univariate and multivariate analyses, Decreasing expression of RCE1 independently predicts poor prognosis for patients in both overall survival and disease-free survival. Further study indicated that RCE1 influenced tumor invasion through the p38 pathway. Knockdown of RCE1 reduced phosphorylation and significantly increased the invasive capacity of CRC cells. CONCLUSION: Taken together, the outcomes of this study indicate that RCE1 acts as a tumor suppressor in CRC, as its reduced expression may increase CRC cell invasion and independently predict an unsatisfactory prognosis in CRC patients.


Subject(s)
Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Endopeptidases/genetics , Gene Expression Regulation, Neoplastic , Adult , Aged , Biomarkers, Tumor , Cell Line, Tumor , Colorectal Neoplasms/pathology , Female , Gene Knockdown Techniques , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Phosphorylation , Prognosis , p38 Mitogen-Activated Protein Kinases/metabolism
18.
Oncotarget ; 7(1): 873-84, 2016 Jan 05.
Article in English | MEDLINE | ID: mdl-26621849

ABSTRACT

Overexpression of hypoxia-induced factor 1α (HIF-1α) has been shown to be involved in the development and progression of hepatocellular carcinoma (HCC). HIF-1α should therefore be a promising molecular target for the development of anti-HCC agents. Metformin, an established antidiabetic drug, has proved to also be effective in treating cancer although the precise underlying mechanisms of this activity are not fully elucidated. The aim of this study was to investigate the effects of metformin on the expression of HIF-1α and oxygen metabolism in HCC. The results showed that metformin inhibited hypoxia-induced HIF-1α accumulation and activation independent of AMP-activated protein kinase (AMPK). Moreover, this decrease in HIF-1α accumulation was accompanied by promotion of HIF-1α protein degradation. In addition, metformin significantly decreased oxygen consumption, ultimately leading to increased intracellular oxygen tension and decreased staining with the hypoxia marker pimonidazole. In vivo studies demonstrated that metformin delayed tumor growth and attenuated the expression of HIF-1α in HCC tumor xenografts. Together, these findings suggest that metformin decreases hypoxia-induced HIF-1α accumulation by actively suppressing mitochondrial oxygen consumption and enhancing cellular oxygenation ability, providing a fundamental mechanism of metformin activity against HCC.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Liver Neoplasms/metabolism , Metformin/pharmacology , Oxygen/metabolism , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Animals , Blotting, Western , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Hypoxia , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Hep G2 Cells , Humans , Hypoglycemic Agents/pharmacology , Hypoxia , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Immunohistochemistry , Ki-67 Antigen/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice, Inbred BALB C , Mice, Nude , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Transplantation, Heterologous
19.
Drug Des Devel Ther ; 9: 3607-16, 2015.
Article in English | MEDLINE | ID: mdl-26213461

ABSTRACT

BACKGROUND: Despite advances in clinical therapies and technologies, the prognosis for patients with gastric cancer is still poor. The aim of this study is to investigate new predictive markers for prognosis of gastric cancer. METHODS: In this study, we evaluated the expression pattern of PIK3CA in 107 gastric cancer specimens and their adjacent nontumorous tissues. PIK3CA siRNA was synthesized and transfected into gastric cancer cell lines. Colony formation and MTT assays were employed to analyze the cell proliferation. PIK3CA expression was examined by using immunohistochemical analysis and Western blot assay. Transwell invasion assay was used to detect the invasion capability of the cells. Luciferase activity was examined by using 3'-untranslated region luciferase reporter assays. RESULTS: We observed that PIK3CA was significantly upregulated in gastric cancer tissues. High expression level of PIK3CA was detectable in 48 (44.86%) of the gastric cancer specimens, and correlated with poor prognosis. In addition, our study indicated that miR203 inhibits cell proliferation and invasion via directly targeting and suppressing the PIK3CA expression. MiR203 expression is downregulated in gastric cancer tissues. Moreover, low expression level of miR203 predicted poor prognosis of gastric patients and induced overexpression of PIK3CA. Our further study also reported that overexpression of miR203 inhibited phosphorylation of AKT, while cotransfection of PIK3CA reversed the effect of miR203. CONCLUSION: Our study suggested a miR203-PIK3CA-AKT signaling pathway in gastric cancer cells. This signaling pathway might play an important role in gastric cancer genesis and development.


Subject(s)
MicroRNAs/genetics , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/metabolism , Stomach Neoplasms/pathology , Biomarkers, Tumor/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Class I Phosphatidylinositol 3-Kinases , Down-Regulation/genetics , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Invasiveness/genetics , Prognosis , RNA, Small Interfering/administration & dosage , Signal Transduction , Stomach Neoplasms/genetics , Transfection , Up-Regulation
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