Oncogenic activation of the Wnt/b-catenin signaling pathway is common in hepatocellular carcinoma (HCC). Our recent studies have demonstrated that SRY (sex determining region Y)-box 1 (SOX1) and secreted frizzled-related proteins are concomitantly promoter-hypermethylated, and this might lead to abnormal activation of the Wnt signaling pathway in HCC. SOX1 encodes a transcription factor involved in the regulation of embryonic development and cell fate determination. However, the expression and functional role of SOX1 in HCC remains unclear. In this study, we confirmed via quantitative methylation-specific polymerase chain reaction that SOX1 was frequently downregulated through promoter hypermethylation in HCC cells and tissues. Overexpression of SOX1 by a constitutive or inducible approach could suppress cell proliferation, colony formation, and invasion ability in HCC cell lines, as well as tumor growth in nonobese diabetic/severe combined immunodeficiency mice. Conversely, knockdown of SOX1 by withdrawal of doxycycline could partially restore cell proliferation and colony formation in HCC cells. We used a T cell factor (TCF)-responsive luciferase reporter assay and western blot analysis to prove that SOX1 could regulate TCF-responsive transcriptional activity and inhibit the expression of Wnt downstream genes. Furthermore, we used glutathione S-transferase pull-down, co-immunoprecipitation, and confocal microscopy to demonstrate that SOX1 could interact with b-catenin but not with the b-catenin/TCF complex. Moreover, restoration of the expression of SOX1 induces significant cellular senescence in Hep3B cells. Conclusion: Our data show that a developmental gene, SOX1, may function as a tumor suppressor by interfering with Wnt/b-catenin signaling in the development of HCC. (HEPATOLOGY 2012;56:2277-2287 T he incidence and mortality of hepatocellular carcinoma (HCC) have been increasing rapidly worldwide in recent decades.1 The risk factors associated with hepatocarcinogenesis are numerous and include chronic hepatitis B or C viral infection, alcohol, aflatoxin B1, and others. However, the molecular mechanisms involved in the development of HCC remain unclear. Recent studies have demonstrated that inactivation of tumor suppressor genes (TSGs) through promoter hypermethylation plays an essential role in carcinogenesis.2,3 Furthermore, methylation profiles have been used as potential biomarkers for early diagnosis, prognostic prediction, and screening in HCC. 4 Therefore, exploring the molecular mechanisms of the inactivation of TSGs involved in HCC development could improve the treatment of HCC in the future.
Honokiol, a hydroxylated biphenyl compound isolated from the Chinese herb Magnolia officinalis, has been reported to have anticancer activities in a variety of cancer cell lines. The present study aimed to evaluate the anticancer effect and possible molecular mechanisms of honokiol in a glioblastoma multiforme (GBM) cell line. The anticancer activities of honokiol were investigated in the DBTRG-05MG GBM cell line. The effect of honokiol on cell growth was determined using a sulforhodamine B assay. Flow cytometry and immunoblotting were used to measure honokiol-induced apoptosis (programmed cell death type I) and autophagy (programmed cell death type II). Honokiol was observed to reduce DBTRG-05MG cell viability in a dose-dependent manner. At a dose of 50 μM, honokiol markedly decreased the expression of Rb protein and led to the cleavage of poly(ADP-ribose) polymerase and Bcl-xL to promote apoptosis in the cancer cells. In addition, markers of autophagy, including Beclin-1 and LC3-II, were also significantly increased. In addition to apoptosis, honokiol was also able to induce autophagy in the DBTRG-05MG cells. The mechanisms that are responsible for the correlation between honokiol-induced apoptosis and autophagy require further investigation. Such efforts may provide a potential strategy for improving the clinical outcome of GBM treatment.
Carbonic anhydrase III (CAIII) is distinguished from the other members of the CA family by low carbon dioxide hydratase activity, resistance to the CA inhibitor acetazolamide, and a predominant expression in the liver of males. In this report the effects of CAIII expression on liver cancer cells invasiveness were explored. Overexpression of CAIII in the HCC cell line SK-Hep1 resulted in increased anchorage-independent growth and invasiveness. And siRNA-mediated silencing of CAIII expression decreased the invasive ability of SK-Hep1 cells. Furthermore, CAIII transfectants showed elevated focal adhesion kinase (FAK) and Src activity. Silencing of FAK expression in CAIII transfectants led to suppression of HCC cell invasion. More importantly, the CAIII transfectants acidified the culture medium at an accelerated speed than the control cells did. Taken together, these data suggest that the CAIII-promoted invasive ability of HCC cells may probably be mediated through, at least in part, the FAK signaling pathway via intracellular and/or extracellular acidification.
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