miR-137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin-resistant neuroblastoma cells.
miR-137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin-resistant neuroblastoma cells.
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化疗是癌症最常见的治疗方法。然而，多药耐药(MDR)仍然是有效化疗的主要障碍，限制了传统化疗药物和新型生物药物的疗效。组成性雄烷受体(CAR)是一种异种传感器，是MDR的关键调节因子。它通过调节I期药物代谢酶和三磷酸腺苷结合盒(ABC)转运蛋白的表达而在异物解毒中发挥作用，这两种转运蛋白在肿瘤中的过表达及其在耐药中的作用使其成为减少MDR的潜在治疗靶点。MicroRNAs(MiRNAs)是基因表达的内源性负调控因子，参与了包括耐药在内的大多数细胞过程。在这里，我们报告了miR-137和CAR在亲代和阿霉素耐药神经母细胞瘤细胞中的表达呈负相关，其中miR-137在耐药细胞中下调。MIR-137过表达导致CAR蛋白和mRNA的下调(通过mRNA降解)；它使阿霉素耐药细胞对阿霉素敏感(表现为增殖减少，细胞凋亡增加，G2期细胞周期停滞增加)，并降低了神经母细胞瘤异种移植瘤的体内生长速度。我们在肝细胞癌和结肠癌的细胞模型中观察到了类似的结果，表明miR-137的阿霉素增敏作用不是肿瘤类型特异性的。最后，我们首次展示了一个负反馈环，通过该环，miR-137下调CAR表达，CAR下调miR-137表达。在对阿霉素耐药的神经母细胞瘤细胞中，miR-137启动子的高甲基化和CAR-137对miR-137的负调控在一定程度上降低了miR-137的表达，增加了CAR和MDR1的表达。这些发现表明miR-137是癌症对阿霉素治疗反应的关键调节因子，他们认为miR-137是一个非常有希望的降低车载阿霉素耐药性的靶点。
Chemotherapy is the most common treatment for cancer. However, multidrug resistance (MDR) remains a major obstacle to effective chemotherapy, limiting the efficacy of both conventional chemotherapeutic and novel biologic agents. The constitutive androstane receptor (CAR), a xenosensor, is a key regulator of MDR. It functions in xenobiotic detoxification by regulating the expression of phase I drug metabolizing enzymes and ATP-binding cassette (ABC) transporters, whose overexpression in cancers and whose role in drug resistance make them potential therapeutic targets for reducing MDR. MicroRNAs (miRNAs) are endogenous negative regulators of gene expression and have been implicated in most cellular processes, including drug resistance. Here we report the inversely related expression of miR-137 and CAR in parental and doxorubicin-resistant neuroblastoma cells, wherein miR-137 is down-regulated in resistant cells. miR-137 over-expression resulted in down-regulation of CAR protein and mRNA (via mRNA degradation); it sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis, and increased G2-phase cell cycle arrest) and reduced the in vivo growth rate of neuroblastoma xenografts. We observed similar results in cellular models of hepatocellular and colon cancers, indicating that the doxorubicin-sensitizing effect of miR-137 is not tumor type-specific. Finally, we show for the first time a negative feedback loop whereby miR-137 down-regulates CAR expression and CAR down-regulates miR-137 expression. Hypermethylation of the miR-137 promoter and negative regulation of miR-137 by CAR contribute in part to reduced miR-137 expression and increased CAR and MDR1 expression in doxorubicin-resistant neuroblastoma cells. These findings demonstrate that miR-137 is a crucial regulator of cancer response to doxorubicin treatment, and they identify miR-137 as a highly promising target to reduce CAR-driven doxorubicin resistance.
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影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
影响因子：
5.8
作者：
Chen, Yakun;Tang, Yong;Guo, Changxiong;Wang, Jiuhui;Boral, Debasish;Nie, Daotai
通讯作者：
Nie, Daotai
DOI：
10.1158/1078-0432.ccr-09-3215
发表时间：
2010-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Buckley PG;Alcock L;Bryan K;Bray I;Schulte JH;Schramm A;Eggert A;Mestdagh P;De Preter K;Vandesompele J;Speleman F;Stallings RL
通讯作者：
Stallings RL
影响因子：
3.7
作者：
Bray I;Bryan K;Prenter S;Buckley PG;Foley NH;Murphy DM;Alcock L;Mestdagh P;Vandesompele J;Speleman F;London WB;McGrady PW;Higgins DG;O'Meara A;O'Sullivan M;Stallings RL
通讯作者：
Stallings RL
DOI：
10.1073/pnas.0407729102
发表时间：
2005-01-25
影响因子：
11.1
作者：
Estève, PO;Chin, HG;Pradhan, S
通讯作者：
Pradhan, S