Abstract 3423: The role of PGC1-α and KLF4 in inhibiting the progression of human hepatoma cells

Hepatocellular carcinoma (HCC) is one of the most common cancers with high mortality worldwide. Hypoxia is considered as a driving force to trigger the progression of malignancy, such as epithelial-mesenchymal transition (EMT) process, tumor metastasis, and recurrence. Because of the high recurrence rate caused by frequent metastasis and the lack of effective systemic treatment, development of new biomarkers and therapeutic targets for HCC treatment is urgently needed. Loss of E-cadherin is an early and critical step in EMT process and tumor metastasis. Consequently, modulation of the expression of E-cadherin may be a potential way to prevent tumor metastasis. Recently, we have demonstrated that overexpression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) not only down-regulated the cyclin D1 expression and inhibited growth of hepatoma HepG2 cells, but also up-regulated the E-cadherin expression and concomitantly down-regulated the mesenchymal marker, and decreased the vimentin expression as well as the migration of HepG2 cells. In this study, we observed a significant increase in the expression level of Kruppel-like factor 4 (KLF4) in HepG2 cells when PGC-1α was overexpressed by adenovirus mediated gene transfer. Using wound healing assay and Western blotting, we further observed increased cell migration and decreased expression of KLF4 in HepG2, Hep3B, and HA22T/VGH hepatoma cell lines under hypoxia condition. Moreover, the KLF4 expression level in HepG2 cells under hypoxia and combined with drug treatment was also examined. We found that treatment of sodium nitroprusside, a nitric oxide donor, can protect HepG2 cells from hypoxia- and glucose depletion-induced cytotoxicity through repressing the KLF4 and Bip/Grp78 expression. After treatment with a cytotoxic dose (1 μM) of doxorubicin, the KLF4 expression of HepG2 cells was decreased under normoxia while it was increased under hypoxia. These results together suggest that PGC-1α may regulate the expression of E-cadherin via KLF4, and the KLF4 expression correlated with the response of HepG2 cells to doxorubicin under hypoxia. PGC-1α and KLF4 may serve as potential targets to inhibit the growth and metastasis of hepatoma cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3423. doi:10.1158/1538-7445.AM2011-3423