Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells.
Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells.
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DOI：
10.1186/1476-4598-9-96
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发表时间：
2010-04-30
期刊：
影响因子：
37.3
通讯作者：
Ju J
中科院分区：
文献类型：
--
作者：
Song B;Wang Y;Titmus MA;Botchkina G;Formentini A;Kornmann M;Ju J
非编码 microRNA (miRNA) 介导的翻译控制在细胞抗癌药物治疗耐药机制中发挥着关键作用。二氢叶酸还原酶 (DHFR) 和胸苷酸合酶 (TYMS, TS) 是过去 50 年来抗叶酸和氟嘧啶化疗的两个最重要靶点。在本研究中，我们研究了 miR-215 在 DHFR 抑制剂甲氨蝶呤 (MTX) 和 TS 抑制剂 Tomudex (TDX) 化疗耐药中的作用。 DHFR 和 TS 的蛋白水平均被 miR-215 抑制，而不改变靶标 mRNA 转录物水平。有趣的是，尽管 DHFR 和 TS 蛋白下调，但 miR-215 的异位表达导致对 MTX 和 TDX 的敏感性降低。矛盾的是，针对 DHFR 或 TS 的基因特异性小干扰 RNA (siRNA) 却具有相反的效果，增加了对 MTX 和 TDX 的敏感性。进一步的研究表明，miR-215 的过度表达会抑制细胞增殖并引发细胞周期停滞在 G2 期，并且这种效应伴随着 p53 依赖性的 p21 上调。对细胞增殖的抑制作用在含有野生型p53的细胞系中更为明显，但在用针对DHFR或TS的siRNA转染的细胞中没有观察到。此外，无齿蛋白同源物（DTL），一种细胞周期调节的核和中心体蛋白，被证实是 miR-215 的关键靶标之一，并且 siRNA 敲低 DTL 导致 G2 阻滞、p53 和 p21 诱导增强，并减少细胞增殖。此外，接受针对 DTL 的 siRNA 的细胞表现出对 MTX 和 TDX 的化学耐药性增加。与对照大量 CD133+/CD44+ 结肠癌细胞相比，CD133+HI/CD44+HI 结肠癌干细胞中的内源性 miR-215 升高约 3 倍，这些细胞表现出缓慢的增殖速率和化疗耐药性。综上所述，我们的结果表明，miR-215 通过抑制 DTL 表达，引起 G2 阻滞，从而诱导细胞增殖减少，从而导致对 MTX 和 TDX 的化疗耐药性增加。这项研究的结果表明，miR-215可能在肿瘤化疗耐药机制中发挥重要作用，并且它可能具有作为新型生物标志物候选者的独特潜力。
Translational control mediated by non-coding microRNAs (miRNAs) plays a key role in the mechanism of cellular resistance to anti-cancer drug treatment. Dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS, TS) are two of the most important targets for antifolate- and fluoropyrimidine-based chemotherapies in the past 50 years. In this study, we investigated the roles of miR-215 in the chemoresistance to DHFR inhibitor methotrexate (MTX) and TS inhibitor Tomudex (TDX). The protein levels of both DHFR and TS were suppressed by miR-215 without the alteration of the target mRNA transcript levels. Interestingly, despite the down-regulation of DHFR and TS proteins, ectopic expression of miR-215 resulted in a decreased sensitivity to MTX and TDX. Paradoxically, gene-specific small-interfering RNAs (siRNAs) against DHFR or TS had the opposite effect, increasing sensitivity to MTX and TDX. Further studies revealed that over-expression of miR-215 inhibited cell proliferation and triggered cell cycle arrest at G2 phase, and that this effect was accompanied by a p53-dependent up-regulation of p21. The inhibitory effect on cell proliferation was more pronounced in cell lines containing wild-type p53, but was not seen in cells transfected with siRNAs against DHFR or TS. Moreover, denticleless protein homolog (DTL), a cell cycle-regulated nuclear and centrosome protein, was confirmed to be one of the critical targets of miR-215, and knock-down of DTL by siRNA resulted in enhanced G2-arrest, p53 and p21 induction, and reduced cell proliferation. Additionally, cells subjected to siRNA against DTL exhibited increased chemoresistance to MTX and TDX. Endogenous miR-215 was elevated about 3-fold in CD133+HI/CD44+HI colon cancer stem cells that exhibit slow proliferating rate and chemoresistance compared to control bulk CD133+/CD44+ colon cancer cells. Taken together, our results indicate that miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX. The findings of this study suggest that miR-215 may play a significant role in the mechanism of tumor chemoresistance and it may have a unique potential as a novel biomarker candidate.
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影响因子：
23.9
作者：
Liu Y;Elf SE;Miyata Y;Sashida G;Liu Y;Huang G;Di Giandomenico S;Lee JM;Deblasio A;Menendez S;Antipin J;Reva B;Koff A;Nimer SD
通讯作者：
Nimer SD
DOI：
10.1111/j.1349-7006.2001.tb01050.x
发表时间：
2001-01-01
期刊：
JAPANESE JOURNAL OF CANCER RESEARCH
影响因子：
--
作者：
Kano, Y;Akutsu, M;Furukawa, Y
通讯作者：
Furukawa, Y
影响因子：
4.3
作者：
Banks, Damon;Wu, Min;Zhang, Hui
通讯作者：
Zhang, Hui
DOI：
10.1016/0190-9622(91)70199-c
发表时间：
1991-08-01
影响因子：
13.8
作者：
OLSEN, EA
通讯作者：
OLSEN, EA
影响因子：
64.8
作者：
He, Lin;He, Xingyue;Hannon, Gregory J.
通讯作者：
Hannon, Gregory J.