Yulei Du

Zinc ribbon domain-containing 1 (ZNRD1) mediates multidrug resistance of leukemia cells through regulation of P-glycoprotein and Bcl-2

Here, we investigated the role of zinc ribbon domain-containing 1 (ZNRD1) in multidrug resistance (MDR) of leukemia cells and the possible underlying mechanisms. ZNRD1 was found overexpressed in the vincristine-induced MDR leukemia cell HL-60/vincristine moreso than its parental cell HL-60. Up-regulation of ZNRD1 expression could confer resistance of both P-glycoprotein (P-gp)-related and P-gp-nonrelated drugs on HL-60 cells and suppress Adriamycin-induced apoptosis accompanied by decreased accumulation and increased releasing amount of Adriamycin. ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells. In addition, inhibition of ZNRD1 expression by RNA interference or P-gp inhibitor could partially reverse ZNRD1-mediated MDR. The further study of the biological functions of ZNRD1 may be helpful for understanding the mechanisms of MDR of leukemia and developing possible strategies to treat leukemia. [Mol Cancer Ther 2005;4(12):1936–42]

The Expression of Hypoxia-Inducible Factor-1α in Hepatitis B Virus-Related Hepatocellular Carcinoma : Correlation with Patients' Prognosis and Hepatitis B Virus X Protein

Hypoxia inducible factor-1α (HIF-1α) was well correlated with carcinogenesis and tumor progression in many kinds of cancer. In this study, high expression of HIF-1α was found in 37 of the 72 (51.39%) tumor specimens, and significantly correlated with venous invasion and lymphonode invasion. Patients with high expression of HIF-1α had a significantly shorter overall survival rate and disease-free survival rate than those with low expression. Multivariate analysis showed high HIF-1α expression was a borderline independent factor of overall survival. HIF-1α expression was also found to be significantly correlated with the expression of hepatitis B virus X protein (HBx), and over-expressed HBx upregulated HIF-1α protein expression in vitro. These results suggested that HIF-1α, which was partially regulated by HBx, might be a prognostic marker of HBV-related HCC patients.

MAD2 as a key component of mitotic checkpoint: A probable prognostic factor for gastric cancer.

We studied the subcellular localization of MAD2 in normal human tissues and gastric cancers. MAD2 showed nuclear and cytoplasmic localization in normal tissues such as muscle, testis, thyroid gland, cerebrum, trachea, and skin; blood vessels in some organs were also MAD2+. In normal stomach, MAD2 was expressed mainly in cytoplasm but showed nuclear staining in the majority of gastric cancers. MAD2 was significantly overexpressed in gastric cancer compared with matched adjacent tissues (P < .001), and expression was related to differentiation and other clinical parameters of cancer (P < .001). The cancer/adjacent normal tissue (C/N) ratio of MAD2 expression was higher than 2 and more frequently observed in patients with lymph gland metastasis (P < .05) and related to cancer differentiation. Our findings suggest that the steady-state amount of MAD2 inside cells may serve as a molecular switch in mitotic checkpoint control and that the subcellular localizations of this spindle protein undergo a shift during malignant transformation. The change of MAD2 expression may be involved mainly in gastric carcinogenesis and associated with the prognosis of gastric cancer; a C/N of more than 2 may be associated with the worse prognosis for survival in gastric carcinoma.

Depression of MAD2 inhibits apoptosis and increases proliferation and multidrug resistance in gastric cancer cells by regulating the activation of phosphorylated survivin.

Mitotic arrest-deficient 2 (MAD2) is one of the essential mitotic spindle checkpoint regulators, and it can protect cells from aberrant chromosome segregation. The Mad2 gene is very rarely mutated in many kinds of human cancer, but aberrantly reduced expression of MAD2 has been correlated with defective mitotic checkpoints in several human cancers. We have previously found that the MAD2 expression level is also shown to be associated with the multidrug resistance of tumour cells. In this study, we constructed a small interfering RNA (siRNA) eukaryotic expression vector of MAD2 and downregulated MAD2 expression in the gastric cancer cell line SGC7901 by transfection of MAD2-siRNA. SGC7901 cells stably transfected with the MAD2-siRNA exhibited significantly increased expression of phosphorylated survivin protein and enhanced drug resistance. Furthermore, MAD2-siRNA suppressed the proliferation of SGC7901 cells and inhibited tumour formation in athymic nude mice. This study clearly reveals that downregulation of MAD2 could regulate the cell cycle, increase proliferation, and improve the drug resistance of gastric cancer cells by regulating the activation of phosphorylated survivin. It also suggests both that MAD2 might play an important role in the development of human gastric cancer and that silencing the MAD2 gene may help to deal with the multidrug resistance of gastric cancer cells.