ANALYSIS OF MAP-KINASE IN THE BLADDER CANCER AND TARGETED MOLECULAR STRATEGIES BASED ON THE BLOCKADE OF THE MAP-KINASE PATHWAYS

背景：丝裂原活化蛋白激酶（MAPK）级联在细胞外信号转导到控制生长和分化的反应中起着至关重要的作用。MAPK激酶途径的特异性抑制剂对尿路上皮癌细胞周期依赖性激酶的抑制作用已被研究。材料与方法：对15例膀胱肿瘤患者正常尿液样本和20例膀胱肿瘤患者正常尿液样本以及20例膀胱肿瘤患者正常尿路上皮样本和40例膀胱肿瘤患者尿路上皮样本中Elk-1 mRNA的表达进行检测。我们通过研究MEK1/2抑制剂对6个人尿路上皮癌细胞系的抑制作用来研究MAPK在膀胱癌中的抑制作用。结果：正常尿液及正常尿路上皮粘膜均未检测到Elk-1 mrna的表达。另一方面，Elk-1 mRNA表达了所有人类移行细胞癌细胞系、20.0%的膀胱癌患者尿液样本和70.0%的膀胱癌样本。Elk-1 mRNA的表达与膀胱癌病理分级及分期无相关性。MEK1/2抑制剂处理的6例膀胱癌细胞中出现了几个TUNEL阳性细胞。用MAPK磷酸化法检测6种膀胱癌细胞系中MAPK通路的表达水平。MEK抑制剂通过TUNEL方法诱导UC细胞系轻微凋亡，但在MAPK检测中不抑制MAPK的磷酸化。结论：仅MAPK磷酸化可能不参与膀胱癌的癌变和肿瘤增殖。因此，细胞核中Elk-1的激活可能有助于致癌转化而不是肿瘤进展。

Background: The mitogen-activated protein kinase (MAPK) cascade plays a crucial role in the transduction of extra cellular signals into responses governing growth and differentiation. The effects of a specific inhibitor of the MAPK kinase pathway on inhibition of urothelial cancer cell cycle-dependent kinases have been examined. Materials and Methods: We evaluated the expression of Elk-1 mRNA in 15 normal urine samples or 20 urine sample of the patient with bladder cancer, and 20 normal urothelial or 40 bladder cancer specimens. We investigated inhibition effect of MAPK activation in bladder cancer by studying the effect of MEK1/2 inhibitor on a panel of six human urothelial carcinoma cell lines. Results: Elk-1 mRNAexpression was not detected in any of the normal urine samples and normal urothelial mucosa. In the other, Elk-1 mRNA expressed all of the human transitional cell carcinoma cell lines, 20.0% urine sample of the patient with bladder cancer and 70.0% bladder cancer specimens. No relations were observed between the Elk-1 mRNA expression and pathological grade or staging in bladder cancer specimens. Several TUNEL positive cells were present in specimens 6 bladder cancer cells treated with MEK1/2 inhibitor. The expression level of the MAPK pathway in six bladder cancer cell lines using MAPK phosphorylation assay were various. The MEK inhibitor induced slightly apoptosis in UC cell lines by TUNEL methods, but not inhibited phosphorylation of MAPK in the MAPK Assays. Conclusions: Only MAPK phosphorylation may not contribute to carcinogenesis and tumor proliferation in the bladder cancer. As a result, activation of Elk-1 in nucleus may contribute to carcinogenic transformation rather than in tumor progression.