Sun X, Zhang J, Wang L, Tian ZGrowth inhibition of human hepatocellular carcinoma cells by blocking STAT3 activation with decoy-ODN. Cancer Lett 262(2): 201-213

Institute of Basic Medical Sciences, Shandong Academy of Medical Science, 89 Jingshi Road, Jinan 250062, China.
Cancer Letters (Impact Factor: 5.62). 05/2008; 262(2):201-13. DOI: 10.1016/j.canlet.2007.12.009
Source: PubMed


More and more studies show that signal transducer and activator of transcription 3 (STAT3) is frequently constitutively activated in a wide number of malignancies and named as an attractive molecular target for tumor treatment. Here, we employed STAT3-decoy ODN, which specifically block over-activated STAT3, to treat human hepatocellular carcinoma (HCC) cells, and evaluated the cellular proliferation ability and investigated the molecular mechanisms in vitro. The results demonstrated that the proliferation of HCC cells was suppressed significantly by STAT3-decoy ODN, being associated with the increased apoptosis and cell arrest at G0/G1 to S phase transition. Further investigates showed the expression of STAT3-regulated genes including bcl-x1, cyclin D1 and c-myc, which involved in cell apoptosis and cell cycle progression, were down-regulated significantly both at transcription and translation levels. These data suggested that STAT3 may be potentially used as a molecular target in HCC therapy.

10 Reads
  • Source
    • "In agreement with our findings, STAT3 is a transcriptional regulator that shows increased activity in solid tumors such as HCC and breast cancers, among others [10], [36]. Recent studies have shown that constitutively active gp130 mutants are responsible for increased STAT3 phosphorylation in HCC [37], and initial reports have demonstrated that inhibition of aberrantly activated STAT3 exerts an antitumor effect in HCC [38]. In addition to JAK-1 [9], IL-6/JAK-2/STAT3 activation and tumor progression in hepatocellular carcinoma has recently been reported [39]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There has been increased interest in the possible role of human cytomegalovirus (HCMV) in carcinogenesis during the last decade. HCMV seroprevalence was enhanced in patients with hepatocellular carcinoma (HCC) but a possible relationship between HCC and HCMV infection remained to be assessed. The aim of this work was to investigate the pro-tumor influence of HCMV on primary human hepatocytes (PHH) and HepG2 cells. Following infection of PHH and HepG2 cells by two different strains of HCMV, we measured the production of IL-6 in culture supernatants by ELISA and the protein levels of STAT3, pSTAT3, JAK, cyclin D1, survivin, p53, p21, and Mdm2 by western Blotting in infected and uninfected cells. Cell proliferation and transformation were investigated using Ki67Ag expression measurement and soft-agar colony formation assay respectively. Infection of HepG2 cells and PHH by HCMV resulted in the production of IL-6 and the subsequent activation of the IL-6R-JAK-STAT3 pathway. HCMV increased the expression of cyclin D1 and survivin. Cell proliferation was enhanced in HepG2 and PHH infected with HCMV, despite a paradoxical overexpression of p53 and p21. More importantly, we observed the formation of colonies in soft agar seeded with PHH infected with HCMV and when we challenged the HepG2 cultures to form tumorspheres, we found that the HCMV-infected cultures formed 2.5-fold more tumorspheres than uninfected cultures. HCMV activated the IL-6-JAK-STAT3 pathway in PHH and HepG2 cells, favored cellular proliferation, induced PHH transformation and enhanced HepG2 tumorsphere formation. Our observations raise the possibility that HCMV infection might be involved in the genesis of hepatocellular carcinoma.
    PLoS ONE 05/2013; 8(3):e59591. DOI:10.1371/journal.pone.0059591 · 3.23 Impact Factor
  • Source
    • "Thus, small molecule inhibitors of STAT3 activation have the potential for both prevention and treatment of cancer. Moreover, STAT3 has been implicated as a promising target for HCC therapy since inhibition of STAT3 using diverse strategies has been found to induce growth arrest and apoptosis of HCC cells (Li et al., 2006, 2010; Sun et al., 2008; Tan et al., 2010). Because of the pivotal role of STAT3 in tumor cell survival, proliferation, and angiogenesis, and its expression in various tumor cells, we investigated whether honokiol can mediate its anti-cancer effects in part through the modulation of the STAT3 activation pathway. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The activation of signal transducers and activators of transcription 3 (STAT3) has been closely linked with the proliferation, survival, invasion, and angiogenesis of hepatocellular carcinoma (HCC) and represents an attractive target for therapy. In the present report, we investigated whether honokiol mediates its effect through interference with the STAT3 activation pathway. The effect of honokiol on STAT3 activation, associated protein kinases, and phosphatase, STAT3-regulated gene products and apoptosis was investigated using both functional proteomics tumor pathway technology platform and different HCC cell lines. We found that honokiol inhibited both constitutive and inducible STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Vanadate treatment reversed honokiol-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that honokiol induced the expression of tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Moreover, deletion of SHP-1 gene by siRNA abolished the ability of honokiol to inhibit STAT3 activation. The inhibition of STAT3 activation by honokiol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Finally, honokiol inhibited proliferation and significantly potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, the results suggest that honokiol is a novel blocker of STAT3 activation and may have a great potential for the treatment of HCC and other cancers.
    Journal of Cellular Physiology 05/2012; 227(5):2184-95. DOI:10.1002/jcp.22954 · 3.84 Impact Factor
  • Source
    • "Vol. 39, No. 7, 2011 RAT HMTF IN HEPATOCARCINOGENESIS 1089 cyclin D1, Bcl-xL, and c-MYC (Cui et al. 2008; Sun et al. 2008; Yu et al. 2007). In this study, HMTF siRNA reduced both STAT3 and phospho-STAT3 expression, and this might suppress cyclin D1 and PCNA and cell proliferation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In a previous study, to identify genes of importance for hepatocellular carcinogenesis, and especially for processes involved in malignant transformation, the authors investigated differences in gene expression between adenomas and carcinomas by DNA microarray. In the present study, the authors investigated AW434047, one of the sequences that was upregulated in carcinomas. The investigation led to the identification of a novel gene, which the authors named hepatocyte malignant transforming factor (HMTF), of unknown function whose expression was increased in hepatocellular carcinomas. Northern blot and in situ hybridization also demonstrated high levels of HMTF in rat hepatocellular carcinoma (HCC) cell lines, lymphocytes in the spleen, colon mucosal epithelia, spermatocytes, and granule cells of the hippocampus. Reduction of HMTF by RNA interference (RNAi) in N1 cells, an HCC cell line, caused suppression of cell proliferation, invasion, and migration. Suppression of proliferation appeared to be due to cell cycle arrest without increased apoptosis. Decreased HMTF expression resulted in down-regulation of STAT3, PCNA, and cyclin D1 and upregulation of p27. These results suggest that HMTF is a new marker for rat HCC and is involved in HCC cell proliferation and may also be linked to cell proliferation in the spleen, colon, brain, and testis.
    Toxicologic Pathology 09/2011; 39(7):1084-90. DOI:10.1177/0192623311422077 · 2.14 Impact Factor
Show more