miR-30d对胰岛素产生和分泌的调控机制研究
摘要
microRNAs (miRNAs)是一类长约22nt的非编码RNA，它在转录后水平调控靶基因的表达而参与组织器官发育、细胞的分裂与增殖、凋亡、肿瘤及其他疾病的调控。研究表明，miRNAs参与胰岛发育、β细胞增殖、胰岛素的产生与分泌，从而调控糖尿病的发展过程，但目前miRNAs对胰岛素产生和分泌的调控机制尚不清楚。研究miRNAs靶基因参与的信号通路，探索miRNAs对靶基因及相关疾病的调控机制，已成为现代生物学研究的热点。本论文以小鼠胰岛瘤细胞MIN6和糖尿病小鼠模型db/db小鼠为研究对象，研究miR-30d在体内外对靶基因的调控和诱导胰岛素信号传导、胰岛素产生和分泌的机制。研究结果如下。
1.原位杂交和real-time PCR检测miR-30d在db/db小鼠胰岛中的表达，结果表明，miR-30d在糖尿病小鼠中表达量降低，而与细胞凋亡有关的let-7显著升高。双荧光素酶试验结果显示，过表达miR-30d能够显著增加RIP启动的荧光素酶活性。以上结果说明，miR-30d通过促进胰岛素基因转录调控糖尿病的发生和发展。
2. Western blot和real-time PCR检测在MIN6中过表达miR-30d对MafA的作用，结果表明，高糖促进MafA表达，过表达miR-30d能够促进MafA的转录和表达。免疫荧光试验表明，过表达miR-30d显著激活MafA在MIN6细胞中的表达。Real-time PCR检测小鼠胰岛中过表达miR-30d对MafA和胰岛素的作用，结果显示过表达miR-30d可显著促进MafA和胰岛素基因转录。Western blot结果显示miR-30d可促进MafA的表达。
3. Western blot检测miR-30d和TNF-α对MafA、Pdx-1和IRS2作用，结果显示TNF-α可显著抑制MafA、Pdx-1、IRS2的表达，而过表达miR-30d可降低TNF-α对MafA和IRS2的抑制作用，抑制miR-30d则使TNF-α进一步抑制MafA和IRS2表达，但对Pdx-1没有作用。将同样处理的细胞进行胰岛素分泌试验，结果表明，TNF-α可显著抑制胰岛素的分泌，过表达miR-30d可部分恢复胰岛素分泌水平。
4. Western blot检测miR-30d对Map4k4的影响。结果表明，过表达miR-30d可抑制Map4k4的转录和表达。双荧光素酶试验结果表明，过表达miR-30d导致Map4k4-WT荧光素活性降低，而Map4k4-miR30d结合位点发生点突变的Map4k4-mut的荧光素酶活性没有降低。这说明miR-30d可与Map4k43′UTR结合而抑制转录和表达，从而Map4k4是miR-30d的直接靶基因。原位杂交检测db/db小鼠胰岛中Map4k4和miR-30d的表达，结果表明糖尿病小鼠胰岛中Map4k4染色显著增加，miR-30d染色显著减弱。Real-timePCR和western blot检测Map4k4在小鼠胰岛中的表达水平，结果表明，在db/db小鼠胰岛中Map4k4转录和表达均增加。
5. Western blot和real-time PCR检测Map4k4的表达，结果表明，TNF-α处理的MIN6细胞中Map4k4的蛋白水平和mRNA水平均增加，说明TNF-α可诱导Map4k4转录和表达。Real-time PCR、western blot检测沉默Map4k4对胰岛素、MafA、Pdx-1及IRS2作用，结果沉默Map4k4能够显著恢复胰岛素、MafA和IRS2的表达，但对Pdx-1没有影响。
本研究发现miR-30d通过与靶基因Map4k4的作用而上调胰岛素转录因子MafA，从而促进胰岛素的表达和分泌，降低TNF-α诱导的胰岛素基因转录、产生及分泌抑制，揭示了miR-30d对糖尿病发生的调控机制，为糖尿病治疗提供新的思路。
microRNAs (miRNAs) are non-coding RNA with22nt in length that play a role indevelopment, cell differentiation and proliferation, apoptosis, cancer and other diseases atpost-transcription level. Reported miRNAs regulate diabetes process by targeting genesimportant for pancreas development, beta cell proliferation, insulin production, secretion,while the mechanisms by which miRNAs regulate insulin production and secretion are notclear. miRNAs modulate insulin signaling by gene regulation, so currently lots of biologicalstudies are fucosing on miRNA gene regulation to targets and related deseases.
In this study, we employed MIN6and db/db mice to evaluate effects that miR-30dregulates target and signaling and mechanism of insulin production and secretion. From theexperiments, the following results were obtained:
1. In situ Hybridization and real-time PCR were performed to measure miR-30d level indb/db mouse. miR-30d is down regulated in diabetic mice, while let-7which is related toapoptosis increases dramatically. Dual-luciferase experimental data showed thatoverexpression of miR-30d increased RIP-driven luciferase activity. These resultsdemonstrated that miR-30d plays a role in development diabetes by promoting insulin genetranscription.
2. The ensuring effect of miR-30d upon the expression of MafA was examined bywestern blot and real-time PCR. It shows that the expression of MafA in high glucoseincreases and overexpression of miR-30d increased MafA transcription and expression.Immunofluorescent experiment shows miR-30d overexpression activates MafA proteinexpression at the single cell level. Using real-time PCR analysis the effect of miR-30doverexpression on MafA, the results show that overexpression of miR-30d promotestranscription of MafA and insulin. Western blot analysis shows miR-30d increases MafAexpression.
3. Effects of miR-30d and TNF-α on MafA、Pdx-1and IRS2were detected by westernblot. It shows that TNF-α significantly inhibited MafA, Pdx-1and IRS2expression, whileoverexpression of miR-30d decreased in partial inhibition of MafA and IRS2. Inhibition of miR-30d induced further suppression of MafA and IRS2by TNF-α. Insulin secretion wasmeasured in MIN6cells with the same treatment. We observed that insulin secretion wassignificantly impaired by TNF-α, and that overexpression of miR-30d could only partiallyrestore this impairment.
4. The effect of miR-30d on the expression of Map4k4was tested by western blot.Overexpression or miR-30d decreased the transcription and expression ofMap4k4.Overexpression of miR30d decreased the Map4k4-WT reporter activity, while theluciferase activity of point mutations in Map4k4-miR30d binding site (Map4k4-mut)doesn’t decrease. It shows that Map4k4is a direct target of miR-30d.In situ hybridizationanalysis with pancreas sections of diabetic mice was performed to measure Map4k4proteinand miR-30d level. Map4k4expression was significantly increased in the diabetic islets,while miR-30d decreased dramaticlly.The isolated islets were further analyzed for theexpression of Map4k4by Western blot and real-time PCR, and the results demonstrated thatboth Map4k4protein and mRNA levels were increased.
5. We confirmed that both Map4k4protein and mRNA level were increased in MIN6cells treated by TNF-α. It shows TNF-α induces transcription and expression of Map4k4.
The effects of silencing Map4k4on insulin, MafA, Pdx-1and IRS2was tested and datashow that silencing of Map4k4was able to restore pre-insulin2, MafA and IRS2expressionsignificantly, but no effect on Pdx-1.
This study illustrated that miR-30d up-regulates insulin transcription factor via targetingMap4k4and furtherly promotes insulin gene expression and secretion. miR-30d can decreaseTNF-α-induced suppression of insulin transcription, production and secretion. The dataillustrate that the multi-functional miR-30d reveals the mechanism of diabetes developmentand provides a potential novel therapeutic target in the interventional approach to treatment ofdiabetes.
1.原位杂交和real-time PCR检测miR-30d在db/db小鼠胰岛中的表达，结果表明，miR-30d在糖尿病小鼠中表达量降低，而与细胞凋亡有关的let-7显著升高。双荧光素酶试验结果显示，过表达miR-30d能够显著增加RIP启动的荧光素酶活性。以上结果说明，miR-30d通过促进胰岛素基因转录调控糖尿病的发生和发展。
2. Western blot和real-time PCR检测在MIN6中过表达miR-30d对MafA的作用，结果表明，高糖促进MafA表达，过表达miR-30d能够促进MafA的转录和表达。免疫荧光试验表明，过表达miR-30d显著激活MafA在MIN6细胞中的表达。Real-time PCR检测小鼠胰岛中过表达miR-30d对MafA和胰岛素的作用，结果显示过表达miR-30d可显著促进MafA和胰岛素基因转录。Western blot结果显示miR-30d可促进MafA的表达。
3. Western blot检测miR-30d和TNF-α对MafA、Pdx-1和IRS2作用，结果显示TNF-α可显著抑制MafA、Pdx-1、IRS2的表达，而过表达miR-30d可降低TNF-α对MafA和IRS2的抑制作用，抑制miR-30d则使TNF-α进一步抑制MafA和IRS2表达，但对Pdx-1没有作用。将同样处理的细胞进行胰岛素分泌试验，结果表明，TNF-α可显著抑制胰岛素的分泌，过表达miR-30d可部分恢复胰岛素分泌水平。
4. Western blot检测miR-30d对Map4k4的影响。结果表明，过表达miR-30d可抑制Map4k4的转录和表达。双荧光素酶试验结果表明，过表达miR-30d导致Map4k4-WT荧光素活性降低，而Map4k4-miR30d结合位点发生点突变的Map4k4-mut的荧光素酶活性没有降低。这说明miR-30d可与Map4k43′UTR结合而抑制转录和表达，从而Map4k4是miR-30d的直接靶基因。原位杂交检测db/db小鼠胰岛中Map4k4和miR-30d的表达，结果表明糖尿病小鼠胰岛中Map4k4染色显著增加，miR-30d染色显著减弱。Real-timePCR和western blot检测Map4k4在小鼠胰岛中的表达水平，结果表明，在db/db小鼠胰岛中Map4k4转录和表达均增加。
5. Western blot和real-time PCR检测Map4k4的表达，结果表明，TNF-α处理的MIN6细胞中Map4k4的蛋白水平和mRNA水平均增加，说明TNF-α可诱导Map4k4转录和表达。Real-time PCR、western blot检测沉默Map4k4对胰岛素、MafA、Pdx-1及IRS2作用，结果沉默Map4k4能够显著恢复胰岛素、MafA和IRS2的表达，但对Pdx-1没有影响。
本研究发现miR-30d通过与靶基因Map4k4的作用而上调胰岛素转录因子MafA，从而促进胰岛素的表达和分泌，降低TNF-α诱导的胰岛素基因转录、产生及分泌抑制，揭示了miR-30d对糖尿病发生的调控机制，为糖尿病治疗提供新的思路。
microRNAs (miRNAs) are non-coding RNA with22nt in length that play a role indevelopment, cell differentiation and proliferation, apoptosis, cancer and other diseases atpost-transcription level. Reported miRNAs regulate diabetes process by targeting genesimportant for pancreas development, beta cell proliferation, insulin production, secretion,while the mechanisms by which miRNAs regulate insulin production and secretion are notclear. miRNAs modulate insulin signaling by gene regulation, so currently lots of biologicalstudies are fucosing on miRNA gene regulation to targets and related deseases.
In this study, we employed MIN6and db/db mice to evaluate effects that miR-30dregulates target and signaling and mechanism of insulin production and secretion. From theexperiments, the following results were obtained:
1. In situ Hybridization and real-time PCR were performed to measure miR-30d level indb/db mouse. miR-30d is down regulated in diabetic mice, while let-7which is related toapoptosis increases dramatically. Dual-luciferase experimental data showed thatoverexpression of miR-30d increased RIP-driven luciferase activity. These resultsdemonstrated that miR-30d plays a role in development diabetes by promoting insulin genetranscription.
2. The ensuring effect of miR-30d upon the expression of MafA was examined bywestern blot and real-time PCR. It shows that the expression of MafA in high glucoseincreases and overexpression of miR-30d increased MafA transcription and expression.Immunofluorescent experiment shows miR-30d overexpression activates MafA proteinexpression at the single cell level. Using real-time PCR analysis the effect of miR-30doverexpression on MafA, the results show that overexpression of miR-30d promotestranscription of MafA and insulin. Western blot analysis shows miR-30d increases MafAexpression.
3. Effects of miR-30d and TNF-α on MafA、Pdx-1and IRS2were detected by westernblot. It shows that TNF-α significantly inhibited MafA, Pdx-1and IRS2expression, whileoverexpression of miR-30d decreased in partial inhibition of MafA and IRS2. Inhibition of miR-30d induced further suppression of MafA and IRS2by TNF-α. Insulin secretion wasmeasured in MIN6cells with the same treatment. We observed that insulin secretion wassignificantly impaired by TNF-α, and that overexpression of miR-30d could only partiallyrestore this impairment.
4. The effect of miR-30d on the expression of Map4k4was tested by western blot.Overexpression or miR-30d decreased the transcription and expression ofMap4k4.Overexpression of miR30d decreased the Map4k4-WT reporter activity, while theluciferase activity of point mutations in Map4k4-miR30d binding site (Map4k4-mut)doesn’t decrease. It shows that Map4k4is a direct target of miR-30d.In situ hybridizationanalysis with pancreas sections of diabetic mice was performed to measure Map4k4proteinand miR-30d level. Map4k4expression was significantly increased in the diabetic islets,while miR-30d decreased dramaticlly.The isolated islets were further analyzed for theexpression of Map4k4by Western blot and real-time PCR, and the results demonstrated thatboth Map4k4protein and mRNA levels were increased.
5. We confirmed that both Map4k4protein and mRNA level were increased in MIN6cells treated by TNF-α. It shows TNF-α induces transcription and expression of Map4k4.
The effects of silencing Map4k4on insulin, MafA, Pdx-1and IRS2was tested and datashow that silencing of Map4k4was able to restore pre-insulin2, MafA and IRS2expressionsignificantly, but no effect on Pdx-1.
This study illustrated that miR-30d up-regulates insulin transcription factor via targetingMap4k4and furtherly promotes insulin gene expression and secretion. miR-30d can decreaseTNF-α-induced suppression of insulin transcription, production and secretion. The dataillustrate that the multi-functional miR-30d reveals the mechanism of diabetes developmentand provides a potential novel therapeutic target in the interventional approach to treatment ofdiabetes.
引文
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