Down and reassembly and the DNA damage response. VRK1 acts through phosphorylation of several substrates, including CRE binding protein, histone H3, barrier-to-autointegration factor and p53. VRK1 Oncotarget mediates p53 accumulation by increasing its stability through phosphorylation of Thr-18 within its mdm-2 binding site. At the same time, VRK1 levels are downregulated by p53, forming autoregulatory loop. This p53-induced downregulation of VRK1 is dependent on an autophagic pathway and protein degradation by MedChemExpress AIC316 lysosomes. Emerging evidence suggests VRK1 plays an essential role in cancer progression. For example, high levels of VRK1 mRNA have been detected in actively proliferating cells within fetal tissues and in several cancer cell lines. In addition, VRK1 expression correlates positively with several proliferation markers in head-andneck squamous cell cancers and lung carcinomas, and VRK1 levels tend to be elevated in lung cancer tissues in which p53 is mutated. In breast cancer, VRK1 depletion inhibits tumor growth and metastasis and confers resistance to DNA-damaging agents, and it has been suggested that VRK1 is a potential therapeutic target and a get Cobicistat prognostic marker for breast cancer. On the other hand, there have been few studies examining the precise role of VRK1 in the progression of HCC or its clinical association with HCC. In the present study, therefore, our aim was to determine the function of VRK1 within HCC tissues and cell lines. Our findings suggest that VRK1 enhances HCC cell proliferation by modulating the levels of regulators associated with G1/S transition and that VRK1 levels are much higher in HCC tissues than non-tumor tissues, and are associated with shorter overall and disease-free survival and a higher recurrence rate. Based on these findings, we propose that VRK1 could potentially serve as a therapeutic target and/ or a prognostic marker in HCC. RESULTS VRK1 is overexpressed in HCC cells and its depletion suppresses HCC cell proliferation in vitro To identify the role of VRK1 in liver cancer, VRK1 levels were examined in an immortalized hepatocyte cell line, THLE-2, and in six HCC cell lines, including SH-J1, SK-Hep1, Huh-7, Hep3B, HepG2 and SNU449. With the exception of Hep3B cells, which grow slower the other HCC cells, VRK1 levels were higher in HCC cells than THLE-2 cells. VRK1 expression is known to be enhanced in lung cancers expressing a mutant p53 and to be down-regulated by ectopic expression of wild-type p53 in lung cancer cells. Therefore, to investigate why VRK1 levels are higher in HCC cells, we checked the levels and status of p53. p53 expression was relatively high in THLE-2, Huh-7 and SNU449 cells, but low in SH-J1, SK-Hep1, HepG2 and Hep3B cells. We found that there was not a detectable inverse correlation between p53 and VRK1 levels in the seven cell lines. We then examined VRK1 levels after transfecting SK-Hep1, SH-J1 and Hep3B cells with increasing amounts of pcDNA_p53 and the same amount of pCMV_VRK1-flag. As the level of p53 increased, the level PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19860992 of VRK1 expression declined in these cells. Thus an inverse relation was detected between the levels of VRK1 and ectopically expressed p53. The status of p53 in the tested HCC cell lines was examined previously and those findings are summarized in VRK1 depletion inhibits tumor growth in a xenograft mouse model To investigate the contribution of VRK1 to tumor growth in vivo, we established SK-Hep1 cells expressing shRNA targeting VRK1 through tran.Down and reassembly and the DNA damage response. VRK1 acts through phosphorylation of several substrates, including CRE binding protein, histone H3, barrier-to-autointegration factor and p53. VRK1 Oncotarget mediates p53 accumulation by increasing its stability through phosphorylation of Thr-18 within its mdm-2 binding site. At the same time, VRK1 levels are downregulated by p53, forming autoregulatory loop. This p53-induced downregulation of VRK1 is dependent on an autophagic pathway and protein degradation by lysosomes. Emerging evidence suggests VRK1 plays an essential role in cancer progression. For example, high levels of VRK1 mRNA have been detected in actively proliferating cells within fetal tissues and in several cancer cell lines. In addition, VRK1 expression correlates positively with several proliferation markers in head-andneck squamous cell cancers and lung carcinomas, and VRK1 levels tend to be elevated in lung cancer tissues in which p53 is mutated. In breast cancer, VRK1 depletion inhibits tumor growth and metastasis and confers resistance to DNA-damaging agents, and it has been suggested that VRK1 is a potential therapeutic target and a prognostic marker for breast cancer. On the other hand, there have been few studies examining the precise role of VRK1 in the progression of HCC or its clinical association with HCC. In the present study, therefore, our aim was to determine the function of VRK1 within HCC tissues and cell lines. Our findings suggest that VRK1 enhances HCC cell proliferation by modulating the levels of regulators associated with G1/S transition and that VRK1 levels are much higher in HCC tissues than non-tumor tissues, and are associated with shorter overall and disease-free survival and a higher recurrence rate. Based on these findings, we propose that VRK1 could potentially serve as a therapeutic target and/ or a prognostic marker in HCC. RESULTS VRK1 is overexpressed in HCC cells and its depletion suppresses HCC cell proliferation in vitro To identify the role of VRK1 in liver cancer, VRK1 levels were examined in an immortalized hepatocyte cell line, THLE-2, and in six HCC cell lines, including SH-J1, SK-Hep1, Huh-7, Hep3B, HepG2 and SNU449. With the exception of Hep3B cells, which grow slower the other HCC cells, VRK1 levels were higher in HCC cells than THLE-2 cells. VRK1 expression is known to be enhanced in lung cancers expressing a mutant p53 and to be down-regulated by ectopic expression of wild-type p53 in lung cancer cells. Therefore, to investigate why VRK1 levels are higher in HCC cells, we checked the levels and status of p53. p53 expression was relatively high in THLE-2, Huh-7 and SNU449 cells, but low in SH-J1, SK-Hep1, HepG2 and Hep3B cells. We found that there was not a detectable inverse correlation between p53 and VRK1 levels in the seven cell lines. We then examined VRK1 levels after transfecting SK-Hep1, SH-J1 and Hep3B cells with increasing amounts of pcDNA_p53 and the same amount of pCMV_VRK1-flag. As the level of p53 increased, the level PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19860992 of VRK1 expression declined in these cells. Thus an inverse relation was detected between the levels of VRK1 and ectopically expressed p53. The status of p53 in the tested HCC cell lines was examined previously and those findings are summarized in VRK1 depletion inhibits tumor growth in a xenograft mouse model To investigate the contribution of VRK1 to tumor growth in vivo, we established SK-Hep1 cells expressing shRNA targeting VRK1 through tran.

Down and reassembly and the DNA damage response. VRK1 acts through

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