中国作者重要发表 - miR-192通过p53-microRNA环调节二氢叶酸还原酶和细胞增殖



miR-192通过p53-microRNA环调节二氢叶酸还原酶和细胞增殖





miR-192 Regulates dihydrofolate reductase and cellular proliferation through the p53-microRNA circuit





Song B., Wang Y., Kudo K., Gavin E.J., Xi Y., Ju J. 2009/5/29 18:40:37

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Clinical Cancer Research, 2008, Volume 14, Issue 24




Purpose: The purpose of this study is to investigate the molecular mechanism of miR-192 in colon cancer. Experimental Design: Human colon cancer cell lines with different p53 status were used as our model system to study the effect of miR-192 on cell proliferation, cell cycle control, and mechanism of regulation. Results: Our results show that one of the key miR-192 target genes is dihydrofolate reductase (DHFR). miR-192 affects cellular proliferation through the p53-miRNA circuit. Western immuno-blot analyses indicated that the expression of DHFR was significantly decreased by miR-192. Further investigation revealed that such suppression was due to translational arrest rather than mRNA degradation. More profound inhibition of cellular proliferation was observed by ectopic expression of miR-192 in colon cancer cell lines containing wild-type p53 than cells containing mutant p53. Thus, the effect of miR-192 on cellular proliferation is mainly p53 dependent. Over-expression of miR-192 triggered both G1 and G2 arrestin HCT-116 (wt-p53) cells but not in HCT-116 (null-p53) cells. The cell cycle checkpointcontrol genes p53 and p21 were highly over-expressed in cells that overexpressed miR-192. Endogenous miR-192 expression was increased in HCT-116 (wt-p53) and RKO (wt-p53) cells treated with methotrexate, which caused an induction of p53 expression. Chromatin immunoprecipitation-quantitative reverse transcription-PCR analysis revealed that the p53 protein interacted with the miR-192 promoter sequence. Conclusion: These results indicate that miR-192 may be another miRNA candidate that is involved in the p53 tumor suppressor network with significant effect on cell cycle control and cell proliferation. © 2008 American Association for Cancer Research.



Correspondence Address: Ju, J.; Department of Pathology, Medical Center, Stony Brook University, Stony Brook, NY 11794-8691; email: jiju@notes.cc.sunysb.edu



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王燕燕王曙

上海交通大学附属瑞金医院内分泌科

患者，女，69岁。2009年1月无明显诱因下出现乏力，当时程度较轻，未予以重视。2009年3月患者乏力症状加重，尿色逐渐加深，大便习惯改变，颜色变淡。4月18日入我院感染科治疗，诉轻度头晕、心慌，体重减轻10kg。无肝区疼痛，无发热，无腹痛、腹泻、腹胀、里急后重，无恶性、呕吐等。入院半月前于外院就诊，查肝功能：ALT 601IU/L，AST 785IU/L，TBIL 97.7umol/L，白蛋白 41g/L，甲状腺功能：游离T3 30.6pmol/L，游离T4 51.9pmol/L，心电图示快速房颤。

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