Cbl-b/miR-103-107/caveolin-1通路调节胃癌多药耐药的机制

In previous studies, we reported a novel mechanism of the translocation of Cbl-b proteins from the nucleoli to the cytoplasms controlling the gastric carcinoma multi-drug resistance (MDR), in which adriamycin activated nuclear Cbl-b to translocate into cytoplasms. The cytoplastic Cbl-b proteins then binded and directly degradated the activated c-Src, leading to disfunction of c-Src-dependent phosphorylation of caveolin-1 (pY14), and effectively inhibited the c-Src/caveolin-1/P-gp complex and the P-gp efflux functions. On the other hand, the results demonstrated an important role for Cbl-b in reversing P-gp-mediated MDR through suppression of the PI3-K/Akt signaling pathway and the down-regulation of P-gp expression. More data confirmed that Cbl-b was localization in nucleic in gastric carcinoma MDR cells, which maybe a new approach reversing MDR through the genetics or the epigenetics manner. Recently, caveolin-1, a critical component of lipid rafts, has been identified as a direct target gene of miR-103-107 (Nature, 2011). Here, we showed that the expression of microRNAs 103 and 107 is upregulated in overexpression Cbl-b protein cell lines by the microarray data and real-time RT-PCR compared with controls. These results suggested that Cbl-b upregulated the expression of miR-103-107 and then subsequently inhibited the expression of caveolin-1, which affected the c-Src/caveolin-1/P-gp mediated MDR. To investigate the regulatory role of Cbl-b/miR-103-107/caveolin-1 pathway in MDR gastric cancinomas and the underlying mechanisms, can help us better understant the mechanisms of gastric cancinoma MDR and find a novel MDR reversing strategies.

我们原创性研究证实Cbl-b主要在胞浆中发挥作用:1.Cbl-b泛素化降解胞浆中c-Src,抑制c-Src/caveolin-1/P-gp复合物形成,抑制P-gp功能;2.Cbl-b抑制PI3-K/Akt通路,下调P-gp蛋白表达,逆转胃癌多药耐药。进一步数据证实:耐药细胞中Cbl-b位于胞核,提示Cbl-b还可能通过调节细胞的遗传或表遗传,进而影响耐药。最新研究报告miR-103-107下调caveolin-1的表达,而我们进一步数据证实,耐药株中miR-103-107低表达,过表达Cbl-b上调miR-103-107,提示Cbl-b通过上调miR-103-107,间接抑制了caveolin-1的表达,进而影响c-Src/caveolin-1/P-gp介导的耐药。阐明Cbl-b/miR-103-107/caveolin-1通路调节胃癌MDR机制,将为寻找新的药物靶标及个体化用药提供依据.

多药耐药（MDR）是导致胃癌化疗失败的重要原因。近期我们的原创性研究结果已证实：① 经典耐药蛋白P-gp必须依赖在细胞膜的脂筏内形成功能性构型，进而发挥其药物外排“泵”功能；② 进一步分析脂筏内相关蛋白的相互作用，发现三聚复合物c-Src/caveolin-1/P-gp的形成是维持胃癌耐药表型的关键步骤；③ 脂筏相关蛋白c-Src发生416位点的酪氨酸磷酸化后，能够与Cbl-b特异性结合，进而发生泛素化降解。④ Caveolin-1是细胞膜上内陷微区域的主要结构蛋白，参与许多细胞生命活动。目前在对一些人类耐药肿瘤细胞系研究中均发现caveolin-1上调。提示caveolin-1过表达与肿瘤MDR密切相关。通过检测胃癌耐药细胞SGC7901/ADR及其亲本敏感细胞中的caveolin-1表达水平，我们发现胃癌耐药细胞SGC7901/ADR中，caveolin-1的表达显著高于亲本敏感细胞SGC7901；过表达Cbl-b可显著下调caveolin-1的表达水平。进一步的研究证实caveolin-1是miR-103/107家族共同调控的靶基因，Cbl-b调控的miR-103/107家族是一类新的参与胃癌耐药的重要分子，其通过靶向caveolin-1在胃癌MDR中发挥重要的作用。上述研究结果对我们全面认识胃癌耐药的机理、确定逆转胃癌耐药的新靶点，从而提高胃癌的治疗效果具有重要意义。