The pathogenesis of hepatocellular carcinoma (HCC) involves many molecular pathways. Glycine N-methyltransferase (GNMT) is downregulated in almost all HCC and its gene knockout mice developed HCC with high penetrance. We identified PREX2, a novel PTEN inhibitor, as a GNMT-interacting protein. Such interaction enhanced degradation of PREX2 through an E3 ligase HectH9-mediated proteasomal ubiquitination pathway. Depletion of GNMT or HectH9 resulted in AKT activation in a PREX2 dependent manner and enhanced cell proliferation. An elevated PREX2 protein expression accompanied by activation of AKT was observed in the liver of Gnmt knockout mice. PREX2 protein expression was upregulated in 54.9% of human HCC samples, while its mRNA level was comparable in tumor and tumor-adjacent tissue, suggesting a post-translational alteration of PREX2 expression. Higher level of PREX2 in the tumor tissues was associated with poorer survival. These results reveal a novel mechanism in which GNMT participates in AKT signaling and HCC tumorigenesis by promoting HectH9-mediated PREX2 degradation.
Sarcomatoid hepatocellular carcinoma (SHC) is a rare type of HCC with significantly poorer survival than ordinary HCC. Little is known about the mechanism associated with SHC and its biomarkers and therapy. Here, we established a mouse liver cancer cell line and designated as Ymac-1. A sarcomatous appearance was observed in the allograft tumor arose from Ymac-1. Liver-secreted plasma proteins were found in Ymac-1 cultured supernatant by proteomics analysis. The positive staining of CK7, CK8, Vimentin and the suppressed expression of AFP indicated that Ymac-1 is a SHC cell line. Compared to its original tumor, an elevated level of EMT markers, N-cadherin and Vimentin, was found in Ymac-1. Ymac-1 displayed a higher migration rate and side population percentage than a mouse ordinary HCC cell line-Hepa1-6. Microarray analysis was performed to identify potential biomarkers/therapeutic targets for SHC. G6pd, a vital enzyme in pentose phosphate pathway, is highly expressed in Ymac-1. Depletion of G6pd in Ymac-1 reduced CD133 expression and sphere formation. Positive correlations between G6PD and CD133 were observed in human specimen. Higher expression of both G6PD and CD133 in tumor were associated with poor survival. In summary Ymac-1 can be a useful SHC cell model for novel biomarker and therapy development.
Cancer stem cells (CSCs), a subpopulation possess tumor initiation and self-renewal capacity, are responsible for recurrence, metastases and drug resistance. Thus, it is important to understand their biology for identification of new therapeutic approaches. Liver surgery and/or transarterial (chemo) embolization (TAE/TACE) therapy usually generate a microenvironment that fosters aggressive tumor recurrence. These areas are characterized by chronic hypoxia and possibly low glucose concentration. Here, we tested the hypothesis that whether hypoxia along with low glucose environment promote the expansion of CSC population in HCC cells. We cultured human liver cancer cell line-Huh7 cells in normoxia or hypoxia condition with high or low glucose medium. The EMT markers (N-cadherin and Vimentin) but not stemness genes (CD44 and CD133) were upregulated in hypoxia condition. However, all genes were significantly induced under low glucose/hypoxia condition. In addition, results from sphere assay showed that low glucose/hypoxia condition dramatically improved the sphere formation ability of Huh7 cells, while low glucose or hypoxia along cannot promote sphere formation. Moreover, Huh7 cells cultured in low glucose/hypoxia condition displayed a lower sensitivity to cisplatin and doxorubicin treatment compared to cells maintained in high glucose/normoxia condition. Therefore, our findings suggested that low glucose concentration and hypoxia environment remarkably promote the enrichment of liver CSCs which could be useful for developing novel therapeutic modalities. Citation Format: Chih Chung Lai, Tsu-Hsiang Shia, Yu-Peng Liu, Chia-Hung Yen. Low glucose and hypoxia environment promote the enrichment of liver cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2534.
Drug resistance is the main cause of cancer recurrence and a major obstacle to the success of anticancer therapy. NRF2, a pivotal transcription factor regulates antioxidant response and detoxification, has been shown to participate in the development of cancer drug resistance. Functional suppression of NRF2 rendered cancer cell more susceptible to anticancer treatments. Beilschmiedia tsangii Merr. (Lauraceae) is a medium-sized evergreen tree. It has been reported that Beilschmiedia extract showed a strong antioxidant activity. In continuation of our bioactivity studies on this species, we tested the effects of 23 compounds isolated from the B. tsangii on NRF2 activity. We identified rel-(7R,8R,7′R,8′R)-3,4,3′,4′-dimethylene-dioxy-5,5′-dimethoxy-7,7′-epoxylignan (BT04) significantly inhibited NRF2 activity in liver cancer cell (Huh7) with an IC50 value of 17 μM, but not in keratinocyte (HacaT cell). By contrast, luteolin, a known NRF2 inhibitor, suppressed NRF2 activity in both Huh7 cell and HacaT cell. Moreover, the mRNA level of NRF2 target genes, NQO1 and HO1, were significantly decreased in Huh7 upon BT04 treatment, while those NRF2 target genes remained unchanged in BT04-treated HacaT cell. A moderate cytotoxic effect of BT04 on Huh7 cell was also observed. Accordingly, our result suggested that BT04 can specifically inhibit NRF2 activity in liver cancer, which in turn indicated that BT04 could be a potential adjuvant to improve chemoresistance. Citation Format: Yi Siao Chen, Chih Chung Lai, Yi Ping Kuo, Hsun Shuo Chang, Ih Sheng Chen, Chia-Hung Yen. Identification of compound isolated from Beilschmiedia tsangii as a liver cancer specific NRF2 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 190. doi:10.1158/1538-7445.AM2017-190
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