Cancer Prevention Research, 2011, 4(1):76.

MicroRNAs 221/222 and Genistein mediated regulation of ARHI tumor suppressor gene in prostate cancer

Yi Chen, et al

Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California

ARHI is an imprinted tumor suppressor gene and is downregulated in various malignancies. However, ARHI expression, function, and mechanisms of action in prostate cancer have not been reported. Here, we report that ARHI mRNA and protein levels were downregulated in prostate cancer tissues compared with adjacent normal tissues. Overexpression of ARHI inhibited cell proliferation, colony formation, invasion, and induced apoptosis. Further studies on a new mechanism of ARHI downregulation showed a significant inverse relationship between ARHI and miR-221 and 222, which were upregulated in prostate cancer cell lines. Transfection of miR-221 and 222 inhibitors into PC-3 cells caused a significant induction of ARHI expression. A direct interaction of miR-221 or 222 with a target site on the 3'UTR of ARHI was confirmed by a dual luciferase pMIR-REPORT assay. Finally, we also found that genistein upregulates ARHI by downregulating miR-221 and 222 in PC-3 cells. In conclusion, ARHI is a tumor suppressor gene downregulated in prostate cancer, and overexpression of ARHI can inhibit cell proliferation, colony formation, and invasion. This study demonstrates for the first time that prostate cancer cells have decreased level of ARHI which could be caused by direct targeting of 3'UTR of ARHI by miR221/222. Genistein, a potential nontoxic chemopreventive agent, restores expression of ARHI and may be an important dietary therapeutic agent for treating prostate cancer.

美国《癌症防护研究》，2011年1月

microRNA 221/222 和金雀异黄素在前列腺癌中介导调节 ARHI 肿瘤抑癌基因

陈毅等

美国加利福尼亚大学分校旧金山退伍军人事务医学中心泌尿外科

ARHI 是一种印迹抑癌基因，在各种恶性肿瘤中被下调。然而，ARHI 在前列腺癌中的表达、 功能和活性机制没有被报道过。在这里，我们报道了 ARHI 的mRNA 和蛋白水平在前列腺癌组织中与邻近正常组织相比有所下调。ARHI 的过度表达抑制了细胞增殖、 菌落形成， 侵袭，并诱导细胞凋亡。对ARHI 下调新机理的进一步研究表明 ARHI 和在前列腺癌细胞中上调的miR-221与222之间的关系明显相反。miR-221 和 222 抑制剂转录到PC-3 细胞会明显诱导 ARHI的 表达。通过双荧光素酶 pMIR -REPORT检测证实了miR- 221 或 222 与目标靶点ARHI上的 3' UTR的直接相互作用。最后，我们还发现，染料木黄酮在PC 3细胞中通过下调miR-221 和 222使ARHI上调。总之，ARHI是一种在前列腺癌中下调的肿瘤抑癌基因，并且 ARHI 的过度表达可以抑制细胞增殖、 菌落形成和侵袭。这项研究第一次表明前列腺癌细胞降低了 ARHI 的水平并可能通过 miR-221/222作为ARHI的3' UTR 的直接靶标。金雀异黄素，一种潜在的无毒化学预防试剂，可以恢复 ARHI 的表达，成为治疗前列腺癌的重要饮食治疗试剂。