RESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Transcatheter arterial chemoembolization (TACE) has been performed as a palliative treatment for patients with HCC. However, HCC is easy to recur after TACE. Magnetic resonance imaging (MRI) has clinical potential in evaluating the TACE treatment effect for patients with liver cancer. However, traditional MRI has some limitations. AIM: To explore the clinical potential of diffusion kurtosis imaging (DKI) in predicting recurrence and cellular invasion of the peritumoral liver zone of HCC after TACE. METHODS: Seventy-six patients with 82 HCC nodules were recruited in this study and underwent DKI after TACE. According to pathological examinations or the overall modified response evaluation criteria in solid tumors (mRECIST) criterion, 48 and 34 nodules were divided into true progression and pseudo-progression groups, respectively. The TACE-treated area, peritumoral liver zone, and far-tumoral zone were evaluated on DKI-derived metric maps. Non-parametric U test and receiver operating characteristic curve (ROC) analysis were used to evaluate the prediction performance of each DKI metric between the two groups. The independent t-test was used to compare each DKI metric between the peritumoral and far-tumoral zones of the true progression group. RESULTS: DKI metrics, including mean diffusivity (MD), axial diffusivity (DA), radial diffusivity (DR), axial kurtosis (KA), and anisotropy fraction of kurtosis (Fak), showed statistically different values between the true progression and pseudo-progression groups (P < 0.05). Among these, MD, DA, and DR values were higher in pseudo-progression lesions than in true progression lesions, whereas KA and FAk values were higher in true progression lesions than in pseudo-progression lesions. Moreover, for the true progression group, the peritumoral zone showed significantly different DA, DR, KA, and FAk values from the far-tumoral zone. Furthermore, MD values of the liver parenchyma (peritumoral and far-tumoral zones) were significantly lower in the true progression group than in the pseudo-progression group (P < 0.05). CONCLUSION: DKI has been demonstrated with robust performance in predicting the therapeutic response of HCC to TACE. Moreover, DKI might reveal cellular invasion of the peritumoral zone by molecular diffusion-restricted change.
RESUMEN
OBJECTIVES: To systematically test the reproducibility of DKI technique in normal liver and report a complete set of DKI measurement data. MATERIALS AND METHODS: Thirty-two healthy volunteers were examined with liver DKI twice on the GE 3.0 T MRI scanner and reviewed by three professional experts. DKI-derived parameters fractional anisotropy of kurtosis (FAk), mean diffusivity (Md), axial diffusivity (Da), radial diffusivity (Dr), mean kurtosis (Mk), axial kurtosis (Ka), and radial kurtosis (Kr) in eight segments divided by Couinaud octagonal method were collected. Inter-class correlation coefficient (ICC) was used to assess the agreement between three experts. For each expert, the reproducibility of twice scans was evaluated by Bland-Altman method. Multivariate analysis of variance was to explore the regional distribution characteristics of DKI-derived parameters, and showed with box-plot graph. RESULTS: Using ICC analysis, except for FAk (ICC 0.312, 0.307), other DKI metric values showed high reproducibility (0.716 < ICC < 0.907) between three experts for each of two DKI measurements. With Bland-Altman method, liver segment 5 (S5) showed the best reproducibility between two DKI measurement, and the reproducibility of segment 4 (S4) was the worst. The reproducibility of the right lobe was significantly higher than the left lobe. The values of diffusion metrics (Md, Da, and Dr) and kurtosis metrics (Mk, Ka, and Kr) existed significantly difference between the right and left hepatic lobes. CONCLUSION: DKI has shown excellent reproducibility in liver imaging. The range of values for multiple DKI parameters, derived from the normal liver, was reported, and may provide data reference for further clinical DKI applications. Additionally, DKI technique is a non-invasive method to reflect the perfusion or structural differences between the left and right hepatic lobes from the molecular level.
Asunto(s)
Imagen de Difusión Tensora , Hígado , Anisotropía , Imagen de Difusión por Resonancia Magnética , Voluntarios Sanos , Humanos , Hígado/diagnóstico por imagen , Reproducibilidad de los ResultadosRESUMEN
The expression of lysine methyltransferase SET8, which is involved in carcinogenesis of many types of human cancers through monomethylation of histone H4 lysine 20 (H4K20), is associated with the prognosis of hepatocellular carcinoma (HCC). We performed a functional analysis for SET8 to assess its effect on HCC progression. SET8 knockdown inhibited proliferation, migration and invasion of HCC cells. SET8 knockdown also inhibited tumour growth in a human xenograft mouse model. Overexpression of SET8 displayed the reverse effect, while treatment with the SET8 inhibitor UNC0379 produced an effect similar to SET8 knockdown. In addition, drug sensitivity testing in SET8-siRNA transfected HCC cells indicated that docetaxel inhibited cell growth dramatically, as demonstrated by the Cell Counting Kit-8 (CCK-8) assay. Furthermore, gene expression microarray analysis showed that genes altered after SET8 knockdown were clustered in pathways related to tumorigenesis and metastasis. Our data suggests that targeting SET8 for HCC therapy can inhibit the proliferation and invasion of HCC cells as well as increase their sensitivity to chemotherapy.
Asunto(s)
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Animales , Apoptosis/genética , Biomarcadores de Tumor , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Ratones , Interferencia de ARN , ARN Interferente Pequeño/genética , TranscriptomaRESUMEN
Human immediate early response 2 (IER2) has been characterized as a putative nuclear protein that functions as a transcription factor or transcriptional coactivator in the regulation of cellular responses, and may be involved in the regulation of tumor progression and metastasis. Data from our previous gene expression profile of the human microvascular endothelial cells during capillary morphogenesis showed a significant alteration of IER2 expression, suggesting that IER2 may participate in the regulation of the endothelial cell morphogenesis and angiogenesis. The aim of the present study was to investigate the role of IER2 in cell motility, cellmatrix adhesion and in vitro capillarylike structures formation of the human umbilical vein endothelium cells (HUVECs). IER2 was constitutively expressed in HUVECs, and lentiviralmediated depletion of IER2 significantly reduced the cell motility, cellmatrix adhesion and capillarylike structures formation of HUVECs. Results also showed that depletion and overexpression of IER2 altered the actin cytoskeleton rearrangement in HUVECs. Furthermore, results from western blot analysis showed that the activity of the focal adhesion kinase (FAK) can be regulated by IER2. These results indicated that IER2 regulates endothelial cell motility, adhesion on collagen type I matrix and the capillary tube formation, as the result of the regulation of the actin cytoskeleton rearrangement presumably via a FAKdependent mechanism.
Asunto(s)
Movimiento Celular/fisiología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Proteínas Inmediatas-Precoces/metabolismo , Neovascularización Fisiológica/fisiología , Transactivadores/metabolismo , Adhesión Celular/fisiología , Citoesqueleto/genética , Citoesqueleto/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Proteínas Inmediatas-Precoces/genética , Transactivadores/genéticaRESUMEN
miR-30c has been reported to act as a tumor suppressor and negatively regulate cancer metastasis by directly targeting metastasis associated genes; however, miR-30c has also been shown to promote the invasion of metastatic breast cancer cells, suggesting that miR-30c might be involved in cancer cell metastasis in different ways via targeting different genes. In this study, we demonstrated that over-expression and knockdown of immediate early response protein 2 (IER2) modulated the general capacity of the migration and invasion in hepatocellular carcinoma cell line SMMC-7721 and HepG2, whereas overexpression and knockdown of miR-30c decreased and promoted cell motility, respectively. Further studies revealed that miR-30c overexpression down-regulated the expression of IER2 protein but not its mRNA level, and miR-30c can directly target the 3' untranslated region (3'UTR) of IER2, and subsequently reducing its expression. Moreover, we also showed that suppression of cell motility by miR-30c was partially rescued by IER2 re-expression. Our results indicated that miR-30c may function as a negative regulator in cell motility, with IER2 as a direct and functional target in SMMC-7721 and HepG2 cells.
RESUMEN
Human monopolar spindle-one-binder 2 (hMOB2) is a member of the hMOB family of proteins, and it has been reported to regulate the nuclear-Dbf2-related kinase (NDR) activation. However, the function of hMOB2 expression in tumor cell adhesion and motility has not been addressed. Herein, the lentiviral-mediated overexpression and the knockdown of hMOB2 in HepG2 and SMMC-7721 cells was established. It was demonstrated that overexpression of hMOB2 significantly reduced the cell motility and enhanced the cell-matrix adhesion, while the hMOB2 knockdown decreased not only the cell motility, but also the cell-matrix adhesion. Immunofluorescence results showed that both hMOB2 overexpression and knockdown altered assembly of the focal adhesions and the actin cytoskeleton rearrangement. Furthermore, the focal adhesion kinase (FAK)-Src-paxillin signal pathway activated by hMOB2 was confirmed to be involved in controlling the cell motility and the cell-matrix adhesion. These results demonstrated that the altered cell-matrix adhesion and cell motility induced by hMOB2 expression was caused by the assembly of focal adhesions as well as the actin cytoskeleton rearrangement through the activation of the FAK-Src-paxillin signal pathway, unveiling a novel mechanism of cell motility and cell-matrix adhesion regulation induced by hMOB2 expression.