Yiming Li

ABCG2, which encodes an ATP-binding cassette transporter protein, is associated with the phenotype of cancer stem cells and is used to define the pluripotential side population cells by flow cytometry and slide-cytometry. MicroRNAs control a wide array of biological processes (e.g., cell differentiation, proliferation and apoptosis) whose dysregulation is a hallmark of cancer. MicroRNA-328 (miR-328) is underexpressed in many cancers including glioblastoma multiforme and contributes to tumor resistance to chemotherapy. ABCG2 is associated with multi-drug resistance and is also highly expressed in glioblastoma. Some preliminary studies have shown that ABCG2 is the target gene for miRNA-328. Thus, we hypothesize that modulating ABCG2 expression by targeting miRNA-328 in glioblastoma cancer stem cells could represent a promising strategy for therapeutic manipulation to increase the efficacy of chemotherapeutic agents for glioblastoma, a highly lethal type of cancer.

Accumulating evidence has shown that micro-RNAs (miRNAs) are involved in multiple processes in cancer development and progression. Upregulation of miRNA-494 (miR-494) has been identified as an oncogenic miRNA and is associated with poor prognosis in several types of human cancer. However, the specific function of miR-494 in colorectal cancer remains unclear. In this study we found that the expression of miR-494 in colorectal cancer tissues and cell lines was much higher than in normal control tissues and cells, respectively. In addition, upregulation of miR-494 more frequently occurred in tissue specimens with adverse clinical stage and the presence of distant metastasis. Moreover, multivariate survival analyses demonstrated that overexpression of miR-494 is an independent prognostic factor for both progression-free and overall survival. In addition miR-494 promoted invasion and migration in colorectal cancer cells, and miR-494 directly inhibited the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression by targeting its 3'-untranslated region (3'-UTR). Moreover, PTEN is down regulated and inversely correlated with miR-494 expression in tissues. Thus, for the first time, we provided convincing evidence that upregulation of miR-494 was associated with tumor aggressiveness and tumor metastasis and promoted cell migration and invasion by targeting PTEN gene in colorectal cancer, and miR-494 is an independent prognostic marker for colorectal cancer patients.

Glycolytic intermediary metabolites such as fructose-1,6-bisphosphate can serve as signals, controlling metabolic states beyond energy metabolism. However, whether glycolytic metabolites also play a role in controlling cell fate remains unexplored. Here, we find that low levels of glycolytic metabolite 3-phosphoglycerate (3-PGA) can switch phosphoglycerate dehydrogenase (PHGDH) from cataplerosis serine synthesis to pro-apoptotic activation of p53. PHGDH is a p53-binding protein, and when unoccupied by 3-PGA interacts with the scaffold protein AXIN in complex with the kinase HIPK2, both of which are also p53-binding proteins. This leads to the formation of a multivalent p53-binding complex that allows HIPK2 to specifically phosphorylate p53-Ser46 and thereby promote apoptosis. Furthermore, we show that PHGDH mutants (R135W and V261M) that are constitutively bound to 3-PGA abolish p53 activation even under low glucose conditions, while the mutants (T57A and T78A) unable to bind 3-PGA cause constitutive p53 activation and apoptosis in hepatocellular carcinoma (HCC) cells, even in the presence of high glucose. In vivo, PHGDH-T57A induces apoptosis and inhibits the growth of diethylnitrosamine-induced mouse HCC, whereas PHGDH-R135W prevents apoptosis and promotes HCC growth, and knockout of Trp53 abolishes these effects above. Importantly, caloric restriction that lowers whole-body glucose levels can impede HCC growth dependent on PHGDH. Together, these results unveil a mechanism by which glucose availability autonomously controls p53 activity, providing a new paradigm of cell fate control by metabolic substrate availability.