Enforced expression of miR-101 inhibits prostate cancer cell growth by modulating the COX-2 pathway in vivo.
Enforced expression of miR-101 inhibits prostate cancer cell growth by modulating the COX-2 pathway in vivo.
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DOI：
10.1158/1940-6207.capr-10-0333
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Pang X
中科院分区：
文献类型：
--
作者：
Hao Y;Gu X;Zhao Y;Greene S;Sha W;Smoot DT;Califano J;Wu TC;Pang X
人们普遍认为慢性炎症与肿瘤发生有关。考克斯-2是产生炎症的类胡萝卜素的关键调节因子，促进细胞增殖和生长;因此，考克斯-2的过表达经常在肿瘤组织中发现。因此，更好地理解考克斯-2的调节机制可能会导致新的靶向癌症治疗。本研究旨在探讨microRNA-101（miR-101）调控考克斯-2表达的机制以及外源性miR-101对考克斯-2相关肿瘤的治疗潜力。通过使用慢病毒转导作为体外和体内研究的工具，产生稳定表达外源性miR-101的前列腺癌细胞系（BPH 1CmiR 101）。我们发现miR-101通过直接结合考克斯-2 mRNA的3′-非翻译区（3′-UTR）抑制考克斯-2的转录后表达。利用反义DNA证实了miR-101的调控功能。因此，外源性miR-101能够有效抑制培养的前列腺癌细胞和前列腺肿瘤异种移植物的生长。BPH 1CmiR 101组的平均肿瘤重量（0.22 g）显著低于BPH 1Cvec组（0.46 g）。同时检测细胞周期蛋白、增殖细胞核抗原（PCNA）、表皮生长因子受体（EGFR）等细胞生长调节因子的表达水平。总之，考克斯-2是miR-101调节转录后的直接靶点。外源性miR-101在体内外抑制前列腺癌细胞的增殖和生长。这些数据表明，外源性miR-101可能通过直接抑制考克斯-2的表达而提供一种新的癌症治疗。
It is commonly agreed that there is an association of chronic inflammation with tumorigenesis. COX-2, a key regulator of inflammation-producing prostaglandins, promotes cell proliferation and growth; thus, overexpression of COX-2 is often found in tumor tissues. Therefore, a better understanding of the regulatory mechanism(s) of COX-2 could lead to novel targeted cancer therapies. In this study, we investigated the mechanism of microRNA-101 (miR-101)-regulated COX-2 expression and the therapeutic potential of exogenous miR-101 for COX-2-associated cancer. A stably expressing exogenous miR-101 prostate cancer cell line (BPH1CmiR101) was generated by using lentiviral transduction as a tool for in vitro and in vivo studies. We found that miR-101 inhibited COX-2 posttranscriptional expression by directly binding to the 3′-untranslated region (3′-UTR) of COX-2 mRNA. The regulatory function of miR-101 was also confirmed by using antisense DNA. As a result, exogenous miR-101 is able to effectively suppress the growth of cultured prostate cancer cells and prostate tumor xenografts. The average tumor weight was significantly lower in the BPH1CmiR101 group (0.22 g) than the BPH1Cvec group (0.46 g). Expression levels of the cell growth regulators, such as cyclin proteins, PCNA (proliferating cell nuclear antigen), EGFR (epidermal growth factor receptor), were also studied. In conclusion, COX-2 is a direct target in miR-101 regulation of posttranscription. Exogenous miR-101 suppresses the proliferation and growth of prostate cancer cells in vitro and in vivo. These data suggest that exogenous miR-101 may provide a new cancer therapy by directly inhibiting COX-2 expression.