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Zhang N.,Institute of Hepatobiliary Surgery | Zhang N.,PLA Fourth Military Medical University | Duan W.-D.,Institute of Hepatobiliary Surgery | Leng J.-J.,Institute of Hepatobiliary Surgery | And 6 more authors.
Oncology Reports

Despite advances in the detection and treatment of hepatocellular carcinoma (HCC), the prognosis remains poor partly due to recurrence or extra/intrahepatic metastasis. Stem-like cancer cells are considered the source of malignant phenotypes including metastasis in various types of cancer. HCC side population (SP), considered as stem-like cancer cells, plays an important role in the migration and invasion in HCC, while the mechanisms involved remain unknown. In the present study, high levels of STAT3 and phospho-STAT3 were observed in MHCC97H SP cells compared with the main population (MP) cells. Inhibition of phospho-STAT3 led to a reduction of miR-21 expression, an increase of PTEN, RECK, and programmed cell death 4 (PDCD4) expression as well as the migration and invasion of SP cells. A set of rescue experiments was performed using different combinations of STAT3 inhibitor, miR-21 mimics and siRNAs to observe the expression of miR-21 targets, cell migration and invasion alterations. Data indicated that the alterations induced by STAT3 inhibition were partly reversed by the upregulation of miR-21. Additionally, the cells migration and invasion when silencing the targets of miR-21 were also reversed by STAT3 inhibition. In conclusion, the present study revealed the aberrant expression of STAT3 and miR-21 in HCC SP cells. Targeting STAT3 may limit HCC migration and invasion, which is likely to involve the regulation of miR-21 and its targets PTEN, RECK and PDCD4. Strategies directed towards STAT3 may therefore be a novel approach for the treatment of HCC. Source

Zhou L.,155 Central Hospital of PLA | Zhou L.,PLA Fourth Military Medical University | Wang D.E.-S.,PLA Fourth Military Medical University | Li Q.-J.,PLA Fourth Military Medical University | And 3 more authors.
Oncology Reports

Hepatocellular carcinoma (HCC) is one of the most common malignancies. The main cause of death in HCC patients is tumor progression with invasion and metastasis. However, the underlying mechanisms of HCC invasion and metastasis are still not fully understood. Some studies show that the Notch signaling pathway may participate in tumor invasion and metastasis. However, the mechanisms by which the Notch signaling pathway mediates tumor cell invasion, especially in hepatocellular carcinoma, are not yet known. In the current study, we investigated the anti-invasion effect of the downregulation of the Notch signaling pathway by DAPT in HCC cells. The Notch signaling pathway inhibitor could suppress invasion of HCC cells via the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathways, resulting in the downregulation of matrix metalloproteinase-2 and -9 (MMP-2 and -9) and vascular endothelial growth factor (VEGF). These observations suggested that inhibition of the Notch signaling pathway by DAPT would be useful for devising novel preventive and therapeutic strategies targeting invasion of HCC. Source

Lu C.-Y.,PLA Fourth Military Medical University | Yang Z.-X.,PLA Fourth Military Medical University | Zhou L.,155 Central Hospital of PLA | Huang Z.-Z.,PLA Fourth Military Medical University | And 4 more authors.
Oncology Reports

Although EphA3 expression has been associated with progression or prognosis in several types of tumors, the role of EphA3 in hepatocellular carcinoma (HCC) remains unknown. This study sought to investigate the clinicopathological and prognostic relevance of EphA3 expression in HCC as well as the underlying mechanisms responsible. EphA3 protein was mainly localized within the cytoplasm and at the cell membrane. High EphA3 expression was correlated with tumor size, tumor grade, metastasis, venous invasion and AJCC TNM stage (P<0.05), and patients with high levels of EphA3 expression were at a significantly increased risk for shortened survival time (P<0.05). In vitro, the downregulation of EphA3 expression decreased the invasive capacity of HCC cells via the regulation of VEGF. EphA3 may represent a novel candidate marker for patient prognosis as well a molecular target for HCC therapy. Source

Wang X.,PLA Fourth Military Medical University | Zhang J.,44 Hospital of PLA | Zhou L.,155 Central Hospital of PLA | Lu P.,PLA Fourth Military Medical University | And 8 more authors.
International Journal of Clinical and Experimental Pathology

MicroRNAs (miRNAs) are associated with human carcinogenesis and tumor development. Moreover, serum miRNAs can reflect the level of tissue miRNAs and be potential tumor markers. Serum microRNA-21 (miR-21) is overexpressed in many human cancers including hepatocellular carcinoma (HCC). However, how serum miR-21 changes during the HCC formation and whether miR-21 plays a regulatory role in this whole process are unknown. The current study evaluated the prognostic and diagnostic potential of serum miR-21 in HCC patients. Next, we established a HCC rat model and collected the blood and liver tissues at regular time points. AFP from the serum, RNA from the serum and liver tissues were collected and quantified separately. The results revealed that tissue and serum miR-21 was upregulated significantly in the groups of cirrhosis, early and advanced HCC compared with normal and fibrosis groups. The AFP levels were increased in early and advanced HCC compared with other groups. Then, the changes of miR-21 downstream proteins (i.e., programmed cell death 4 [PDCD4] and phosphatase and tensin homolog [PTEN]) in the liver tissues were measured. PDCD4 and PTEN expression was decreased gradually after tumor induction and negatively correlated with miR-21 expression. All these results suggested that serum miR-21 was associated with the prognosis of HCC; the changes in serum miR-21 were earlier and more accurately reflected the pathogenesis of HCC than AFP; therefore, it could be used as an early diagnostic marker for HCC. Our in vivo experiments further confirmed that miR-21 plays an important role in promoting the occurrence and development of HCC by regulating PDCD4 and PTEN. Source

Zhou L.,155 Central Hospital of PLA | Yang Z.-X.,PLA Fourth Military Medical University | Song W.-J.,PLA Fourth Military Medical University | Li Q.-J.,PLA Fourth Military Medical University | And 4 more authors.
International Journal of Oncology

Due to invasion and intrahepatic metastasis, the prognosis for patients with hepatocellular carcinoma (HCC) is poor. However, the mechanisms underlying these processes of HCC remain unclear. Cancer stem cells may be involved in early systemic dissemination and metastasis formation and side population (SP) cells isolated from diverse cancer cells possess stem cell-like properties. However, the mechanisms involved in migration and invasion of cancer stem cells are not well understood. In this study, we identified and isolated populations of SP cells from HCC cell lines using flow cytometry. SP cells showed higher levels of migration and invasion capability. Higher expression of miR-21 was observed in SP cells. Silencing of miR-21 led to a reduction in the migration and invasion of these cells and overexpression of miR-21 can increase in cell migration and invasion. Overexpression of miR-21 did not cause degradation of PTEN or RECK or PDCD4 mRNA but drastically inhibited its protein expression. Consistent with these results, silencing miR-21 increased the levels of PTEN, RECK and PDCD4 protein, respectively. The role of silencing miR-21 was partially attenuated by silencing of PTEN or RECK or PDCD4 mRNA. The results of this study revealed the aberrant expression of miR-21 in SP cells and showed that miR-21 regulates the expression of multiple target proteins that are associated with tumor dissemination. MiR-21 is a pro-metastatic miRNA in SP cells and raises the possibility that therapy of HCC may be improved by pharmaceutical strategies directed towards miR-21. Source

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