Abstract
Background Aberrant STAT1 signaling is observed in human hepatocellular carcinoma (HCC) and has been associated with the modulation of cell proliferation and survival. However, the role of STAT1 signaling in HCC and its underlying mechanism remain elusive.MethodsWe transiently transfected pcDNA3.1-STAT1 and STAT1 siRNA into SMMC7721 and HepG2 cells. Western blot and qRT-PCR examined the expression of protein and RNA of target genes. Cell viability was assessed using MTT assay, and cell cycle and apoptosis were analyzed by flow cytometry.ResultsWe found that STAT1 overexpression increased protein expression of p53 and Fbxw7, and downregulated the expression of cyclin A, cyclin D1, cyclin E, CDK2, Hes-1 and NF-κB p65. These changes led to growth inhibition and induced G0/G1 cell cycle arrest and apoptosis in SMMC7721 and HepG2 cells. Conversely, ablation of STAT1 had the opposite effect on p53, Fbxw7, Hes-1, NF-κB p65, cyclin A, cyclin D1, cyclin E and CDK2, and improved the viability of SMMC7721 and HepG2 cells.ConclusionsOur data indicate that STAT1 exerts tumor-suppressive effects in hepatocarcinogenesis through induction of G0/G1 cell cycle arrest and apoptosis, and may provide a basis for the design of new therapies for the intervention of HCC in the clinic.
Highlights
Aberrant STAT1 signaling is observed in human hepatocellular carcinoma (HCC) and has been associated with the modulation of cell proliferation and survival
We found that apoptosis was more prevalent in pcDNA3.1-STAT1transfected cells than in empty vector (EV) (P < 0.05) (Fig. 1d, f )
Flow cytometry analysis was used to measure the cell cycle distribution, as predicted, pcDNA3.1STAT1-transfected SMMC7721 and HepG2 cells showed a higher proportion of cells in G0/G1 phase (88.17 and 90.87 %) compared with control EV cells (76.80 and 77.27 %) (P < 0.05), indicating that STAT1 significantly inhibited cell cycle progression (Fig. 1e, g), suggesting that STAT1 induces G0/G1 cell cycle arrest and apoptosis in SMMC7721 and HepG2 cells
Summary
Aberrant STAT1 signaling is observed in human hepatocellular carcinoma (HCC) and has been associated with the modulation of cell proliferation and survival. The role of STAT1 signaling in HCC and its underlying mechanism remain elusive. Emerging lines of evidence indicate that aberrant activation of several signaling cascades, including the activator of transcription (Jak/STAT), epidermal growth factor receptor (EGFR), Ras/extracellular signal-regulated kinase (ERK), CDKN1C/P57, phosphoinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) [3], Cyclooxygenase-2/Snail/E-cadherin, NF-κB [4,5,6,7] and HGF/cMET pathways [8, 9] contributes to the pathogenesis of HCC. There is compelling evidence that STAT1 play an important role in promoting apoptotic cell death, and has been supported by the findings that growth inhibiting and pro-apoptotic activities of interferon-gamma (IFN-γ) are largely mediated by STAT1 signaling [11].
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