PDF(Pubmed)
Abstract：
The interruption of normal cell cycle execution acts as an important part to the development of leukemia. It was reported that microRNAs (miRNAs) were closely related to tumorigenesis and progression, and their aberrant expression had been demonstrated to play a crucial role in numerous types of cancer. Our previous study showed that miR-1246 was preferentially overexpressed in chemo-resistant leukemia cell lines, and participated in process of cell cycle progression and multidrug resistant regulation. However, the underlying mechanism remains unclear. In present study, bioinformatics prediction and dual luciferase reporter assay indicated that CADM1 was a direct target of miR-1246. Evidently decreased expression of CADM1 was observed in relapsed primary leukemia patients and chemo-resistant cell lines. Our results furtherly proved that inhibition of miR-1246 could significantly enhance drug sensitivity to Adriamycin (ADM), induce cell cycle arrest at G0/G1 phase, promote cell apoptosis, and relieve its suppression on CADM1 in K562/ADM and HL-60/RS cells. Interference with CADM1 could reduce the increased drug sensitivity induced by miR-1246 inhibition, and notably restore drug resistance by promoting cell cycle progression and cell survival via regulating CDKs/Cyclins complexes in chemo-resistant leukemia cells. Above all, our results demonstrated that CADM1 attenuated the role of miR-1246 in promoting cell cycle progression and cell survival, thus influencing multidrug resistance within chemo-resistant leukemia cells via CDKs/Cyclins. Higher expression of miR-1246 and lower expression of CADM1 might be risk factors for leukemia.
摘要：
正常细胞周期执行的中断是白血病发展的重要组成部分。据报道,microRNAs(miRNAs)与肿瘤发生、发展密切相关,它们的异常表达已被证明在许多类型的癌症中起着至关重要的作用。我们之前的研究表明，miR-1246在化疗耐药的白血病细胞系中优先过表达，并参与细胞周期进程和多药耐药调控。然而,潜在机制尚不清楚.在目前的研究中,生物信息学预测和双荧光素酶报告基因实验表明,CADM1是miR-1246的直接靶标。在复发的原发性白血病患者和化学耐药细胞系中观察到CADM1的表达明显降低。我们的研究结果进一步证明抑制miR-1246可以显著增强药物对阿霉素(ADM)的敏感性,诱导细胞周期停滞在G0/G1期，促进细胞凋亡，减轻其对K562/ADM和HL-60/RS细胞CADM1的抑制作用。干扰CADM1可降低miR-1246抑制导致的药物敏感性增加,并通过调节化学抗性白血病细胞中的CDKs/Cyclins复合物促进细胞周期进程和细胞存活来显著恢复药物抗性。最重要的是,我们的结果表明，CADM1减弱了miR-1246在促进细胞周期进程和细胞存活中的作用，从而通过CDKs/Cyclins影响化疗耐药白血病细胞内的多药耐药性。miR-1246的高表达和CADM1的低表达可能是白血病的危险因素。
