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1.
Cell Signal ; 104: 110565, 2023 04.
Article in English | MEDLINE | ID: mdl-36539000

ABSTRACT

Metastasis is a landmark event for rapid postsurgical relapse and death of HCC patients. Although distinct genomic and transcriptomic profiling of HCC metastasis had been reported previously, the causal relationships of somatic mutants, mRNA levels and metastatic potentials were difficult to be established in clinic. Therefore, 11 human HCC cell lines and 7 monoclonal derivatives with definite metastatic potentials and tropisms were subjected to whole exome sequencing (WES) and whole transcriptome sequencing (WTS). TP53, MYO5A, ROS1 and ARID2 were the prominent mutants of metastatic drivers in HCC cells. During HCC clonal evaluation, TP53, MYO5A and ROS1 mutations occurred in the early stage, EXT2 and NIN in the late stage. NF1 mutant was unique in lung tropistic cell lines, RNF126 mutant in lymphatic tropistic ones. PER1, LMO2, GAS7, NR4A3 expression levels were positively associated with relapse-free survival (RFS) of HCC patients. The integrative analysis revealed 58 genes exhibited both somatic mutation and dysregulated mRNA levels in high metastatic cells. Altogether, metastatic drivers could accumulate gradually at different stages during HCC progression, some drivers might modulate HCC metastatic potentials and the others regulate metastatic tropisms.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Transcriptome/genetics , Protein-Tyrosine Kinases/metabolism , Mutation/genetics , Proto-Oncogene Proteins/metabolism , Genomics , RNA, Messenger/metabolism , Ubiquitin-Protein Ligases/metabolism
2.
Acta Clin Belg ; 77(1): 227-232, 2022 Feb.
Article in English | MEDLINE | ID: mdl-32703103

ABSTRACT

OBJECTIVES: To assess the diagnostic value of serum carcinoembryonic antigen (CEA) as a diagnostic biomarker that can be used to differentiate between benign and malignant lung nodules (LNs). METHODS: PubMed, Cochrane Library, and Embase were reviewed from January 2000 to April 2020 for eligible studies. Stata v12.0 was used to conduct this meta-analysis. RESULTS: Our initial literature search identified 511 potentially relevant studies, of which 11 were ultimately included in the present meta-analysis. Ten studies were retrospective and only 1 study was prospective. Overall these studies incorporated 2760 patients and 2760 total LNs (1733 malignant, 1027 benign). Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) values for these studies were 0.33 (95% CI: 0.20-0.49), 0.92 (95% CI: 0.85-0.96), 3.96 (95% CI: 2.84-5.54), 0.73 (95% CI: 0.62-0.87), and 5.42 (95% CI: 3.77-7.78), respectively. The area under curve (AUC) value was 0.77, consistent with moderate diagnostic accuracy. We detected significant heterogeneity when calculating pooled sensitivity (I2 = 95.9%, P = 0.00), specificity (I2 = 92.0%, P = 0.00), PLR (I2 = 61.7%, P = 0.00), NLR (I2 = 92.8%, P = 0.00), and DOR (I2 = 93.8%, P = 0.00). No significant evidence of publication bias was detected via Deeks' funnel plot asymmetry test (P = 0.371). Meta-regression analysis revealed different reference standards to be closely associated with both sensitivity and specificity. CONCLUSIONS: Serum CEA can achieve moderate diagnostic performance as a means of differentiating between malignant and benign LNs.


Subject(s)
Carcinoembryonic Antigen , Lung Neoplasms , Humans , Lung , Lung Neoplasms/diagnosis , Prospective Studies , Retrospective Studies
3.
Biochem Biophys Res Commun ; 447(1): 210-5, 2014 Apr 25.
Article in English | MEDLINE | ID: mdl-24704424

ABSTRACT

Previous research showed that microRNA-612 (miR-612) has inhibitory effects on cell proliferation, migration, invasion, and metastasis of hepatocellular carcinoma (HCC). AKT2 was confirmed to be a direct target of miR-612, through which the epithelial-mesenchymal transition (EMT) and metastasis of HCC were inhibited. Our present findings reveal that miR-612 is able to suppress the stemness of HCC by reducing the number and size of tumorspheres as well as clone formation in soft agar, and to relieve drug resistance to cisplatin and 5-fluorouracil. In addition, miR-612 hampered the capacity of tumorigenesis in NOD/SCID mice and redistributed the tumor invasive frontier of miR-612-modulating cells. Finally, our findings suggest that Wnt/ß-catenin signaling is required in the regulation of EMT-associated stem cell-like traits by miR-612.


Subject(s)
Carcinoma, Hepatocellular/pathology , Epithelial-Mesenchymal Transition/drug effects , Liver Neoplasms/pathology , MicroRNAs/physiology , Neoplastic Stem Cells/drug effects , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/pharmacology , Drug Resistance, Neoplasm/drug effects , Fluorouracil/pharmacology , Hep G2 Cells , Humans , Male , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Invasiveness/prevention & control , Neoplasm Transplantation , Neoplastic Stem Cells/physiology , Wnt Signaling Pathway/physiology , beta Catenin/drug effects , beta Catenin/physiology
4.
Carcinogenesis ; 34(9): 2071-9, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23671131

ABSTRACT

Endothelial cells (ECs) are critical for angiogenesis, and microRNAs play important roles in this process. We investigated the regulatory role of microRNAs in ECs of hepatocellular carcinoma (HCC) by examining the microRNA expression profile of human umbilical vein endothelial cells (HUVECs) in the absence or presence of human HCC cells, and identified miR-146a as the most highly upregulated microRNA. Furthermore, we revealed that miR-146a promoted the expression of platelet-derived growth factor receptor α (PDGFRA) in HUVECs, and this process was mediated by BRCA1. Overexpression of PDGFRA in the ECs of HCC tissues was associated with microvascular invasion and predicted a poorer prognosis. These results suggest that miR-146a plays a key role in regulating the angiogenic activity of ECs in HCC through miR-146a-BRCA1-PDGFRA pathway. MiR-146a and PDGFRA may emerge as potential anti-angiogenic targets on ECs for HCC therapy.


Subject(s)
Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , MicroRNAs/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , BRCA1 Protein/metabolism , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Gene Expression Regulation, Neoplastic/genetics , Human Umbilical Vein Endothelial Cells , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , MicroRNAs/metabolism , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Signal Transduction/genetics , Up-Regulation
5.
J Exp Med ; 210(4): 789-803, 2013 Apr 08.
Article in English | MEDLINE | ID: mdl-23478189

ABSTRACT

MicroRNAs (miRNAs) play a critical role in tumor metastasis. In this study, we identified a set of 32 miRNAs involved in hepatocellular carcinoma (HCC) metastasis. Among them, miR-612 was shown for the first time to have inhibitory effects on HCC proliferation, migration, invasion, and metastasis. AKT2 was verified to be one of the direct targets of miR-612, through which the epithelial-mesenchymal transition (EMT) and metastasis were inhibited. The level of miR-612 in HCC patients was inversely associated with tumor size, stage, EMT, and metastasis. Of particular importance, miR-612 is involved in both the initial and final steps of the metastatic cascade, by suppressing local invasion and distant colonization. The pleiotropic roles of miR-612 in the HCC metastatic cascade suggest that it could be an effective target for both early and advanced HCC.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Cell Proliferation , Epithelial-Mesenchymal Transition , Liver Neoplasms/metabolism , MicroRNAs/metabolism , RNA, Neoplasm/metabolism , Animals , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Female , Follow-Up Studies , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/genetics , Neoplasm Invasiveness , Neoplasm Metastasis , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA, Neoplasm/genetics
6.
Zhonghua Gan Zang Bing Za Zhi ; 19(2): 110-3, 2011 Feb.
Article in Chinese | MEDLINE | ID: mdl-21492513

ABSTRACT

To establish a systematic site-specific metastatsis model of human hepatocellular carcinoma (HCC) in nude mouse. HCCLM3-R cells were seeded into mice liver to establish xenograft mouse models. With the help of RFP, metastasis foci in lungs and lymph nodes in mice were detected using fluorescent stereomicroscopy and were removed. Cells derived from the metastasis foci were named HCCLM3-R-LM1 and HCCLM3-R-LnM1 respectively. HCCLM3-R-LM1 and HCCLM3-R-LnM1 cells were seeded into mice livers to analyze the lung and lymph node metastasis. Lungs of all tested mice were collected, examined by pathological evaluation and counted lung metastasis. Both lung and lymph node metastasis were found in HCCLM3-R-LM1, HCCLM3-R and HCCLM3-R-LnM1 cells and a significant difference was found between the lung and the lymph node metastasis levels in the three cells. The fluorescent areas (pixels) of lung and lymph node metastasis were 8687.00+/-1844.63 versus 2570.00+/-318.20 (P = 0.0031) in HCCLM3-R-LM1 cells, 6457.67+/-832.62 versus 10 994.33+/-2 212.31 (P = 0.0036) in HCCLM3-R cells, and 2968.67+/-2571.00 versus 24 416.00+/-7 186.13 (P = 0.0094) in HCCLM3-R-LnM1 cells, respectively. The middle numbers of microscopic lung metastatic foci were 775, 430 and 310 in HCCLM3-R-LM1, HCCLM3-R and HCCLM3-R-LnM1 cells (P less than 0.001), respectively, consist with the results quantified by RFP. We established the systematic site-specific metastasis models which demonstrates lung- and lymph node-specific metastasis potential in nude mice and can be used as a model for researches on site-specific metastasis of HCC.

7.
BMC Cancer ; 11: 150, 2011 Apr 22.
Article in English | MEDLINE | ID: mdl-21513518

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) usually has a dismal prognosis because of its limited response to current pharmacotherapy and high metastatic rate. Sulfated oligosaccharide has been confirmed as having potent antitumor activities against solid tumors. Here, we explored the preclinical effects and molecular mechanisms of isomalto oligosaccharide sulfate (IMOS), another novel sulfated oligosaccharide, in HCC cell lines and a xenograft model. METHODS: The effects of IMOS on HCC proliferation, apoptosis, adhesion, migration, and invasiveness in vitro were assessed by cell counting, flow cytometry, adhesion, wound healing, and transwell assays, respectively. The roles of IMOS on HCC growth and metastasis in xenograft models were evaluated by tumor volumes and fluorescent signals. Total and phosphorylated protein levels of AKT, ERK, and JNK as well as total levels of c-MET were detected by Western blotting. IMOS-regulated genes were screened by quantitative reverse-transcription PCR (qRT-PCR) array in HCCLM3-red fluorescent protein (RFP) xenograft tissues and then confirmed by qRT-PCR in HepG2 and Hep3B cells. RESULTS: IMOS markedly inhibited cell proliferation and induced cell apoptosis of HCCLM3, HepG2, and Bel-7402 cells and also significantly suppressed cell adhesion, migration, and invasion of HCCLM3 in vitro. At doses of 60 and 90 mg/kg/d, IMOS displayed robust inhibitory effects on HCC growth and metastasis without obvious side effects in vivo. The levels of pERK, tERK, and pJNK as well as c-MET were significantly down-regulated after treatment with 16 mg/mL IMOS. No obvious changes were found in the levels of pAkt, tAkt, and tJNK. Ten differentially expressed genes were screened from HCCLM3-RFP xenograft tissues after treatment with IMOS at a dose of 90 mg/kg/d. Similar gene expression profiles were confirmed in HepG2 and Hep3B cells after treatment with 16 mg/mL IMOS. CONCLUSIONS: IMOS is a potential anti-HCC candidate through inhibition of ERK and JNK signaling independent of p53 and worth studying further in patients with HCC, especially at advanced stages.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Oligosaccharides/pharmacology , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Carcinoma, Hepatocellular/genetics , Cell Adhesion/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Male , Maximum Tolerated Dose , Mice , Mice, Inbred BALB C , Mice, Nude , Oligosaccharides/chemistry , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
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