MicroRNA-133b对非小细胞肺癌生物学行为的影响和机制研究
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摘要
背景和目的：
肺癌在我国发病率和死亡率都有明显增高，其中大部分是非小细胞肺癌(NSCLC)。MicroRNA (miRNA)和表皮生长因子受体（EGFR）的表达异常对于NSCLC的发生发展均是一个非常重要的因素。我们应用组织标本和细胞株，研究miR-133b对于肺癌细胞增殖、侵袭转移能力和药物敏感性等生物学行为的影响，通过细胞转染等方法分析miR-133b与EGFR信号通路分子间的相互关系及可能作用机制。
方法：
1、应用实时定量逆转录多聚酶链式反应（realtime RT-PCR）检测肺癌组织标本和匹配的正常肺组织标本中miR-133b和EGFR mRNA的表达水平；应用免疫组化化学法（IHC）分析肺癌组织标本中EGFR蛋白的表达水平。
2、选用生物信息学和双荧光素酶报告基因法确证miR-133b与EGFR mRNA3′非编码区域UTR的靶向结合作用。
3、采用阳离子脂质体法在四种肺癌细胞株（H1650、A549、H1975和PC-9）中转染miR-133b模拟物或者抑制物，使其过表达或者抑制。随后：（1）应用流式细胞分析（FCM）方法检测癌细胞的凋亡状况；（2）应用四氮唑盐法（MTT比色法）检测癌细胞的增殖活性和对于吉非替尼的药物敏感性；（3）应用划痕法、Transwell/Matrigel试验检测癌细胞的侵袭转移能力；（4）应用realtime RT-PCR法检测癌细胞miR-133b、EGFR及其下游基因mRNA表达（；5）应用Western-blots法检测EGFR及其下游信号通路分子蛋白表达量。
结果：
1、在27例匹配的肿瘤组织（T）和相应非肿瘤正常肺组织（N）的检测中，NSCLC癌组织中miR-133b低表达；miR-133的表达水平和区域淋巴结受累程度、分期及脏层胸膜或脉管侵犯之间呈负相关；miR-133b的表达水平和EGFR mRNA转录产物存在着显著的负相关。EGFR mRNA水平和区域淋巴结受累程度之间正相关，EGFR蛋白水平和脏层胸膜或脉管侵犯之间正相关；EGFR蛋白阳性率为66.7%(18/27)与mRNA过表达存在基本一致性。
2、生物信息学分析显示在EGFR mRNA3′-UTR的50~56位置，具有一个与miR-133b完全互补的7个核酸的种子序列；通过构建和转染EGFR@pMIR-Report-Luc质粒和miR-133b进入细胞，导致了较对照组标化荧光下降。
3、转染miR-133b模拟物或者抑制物后，四种肺癌细胞的凋亡均较对照组明显增加；并且模拟物引起的凋亡也较抑制物明显增加。
4、转染miR-133b模拟物后，四种肺癌细胞的侵袭转移能力降低，反之转染miR-133b抑制物后则提高了肺癌细胞的侵袭转移能力，并且对PC-9和A549细胞的调节作用更明显。
5、H1650、H1975和PC-9肺癌细胞中，转染miR-133b模拟物后表现为对吉非替尼的明显敏感，而在A549、H1975和PC-9肺癌细胞中，转染miR-133b抑制物后表现为对吉非替尼的明显耐药。
6、四种肺癌细胞中EGFR mRNA和蛋白水平均受到miR-133b过表达或抑制的调节，在PC-9细胞中转染miR-133b模拟物后，EGFR mRNA的下调更明显。在PC-9和A549肺癌细胞中，转染miR-133b模拟物/抑制物后，EGFR、AKT和ERK12磷酸化水平明显下调/上调，而在H1650和H1975细胞中上述改变不明显。
结论：
1、MiR-133b低表达促进了NSCLC的增殖、侵袭转移和对EGFR-TKI的耐药。
2、MiR-133b通过靶向作用于EGFR，在转录后水平调节了内生EGFR蛋白表达水平，进而主要影响EGFR依赖的肺癌细胞中EGFR下游通路的分子活性来产生上述功能变化。该研究为此类肿瘤的靶向治疗提供了重要的理论基础。
Background:
Morbidity and mortality of lung cancer in China has increased significantly, and mostof them were non-small cell lung cancer (NSCLC). MicroRNAs (miRNAs) play keyroles in tumorigenesis and tumor progression. Both the deregulation of miRNAs andepidermal growth factor receptor (EGFR) are emerging as important areas ofnon-small cell lung cancer (NSCLC). With the tissues and cell lines, the relationshipof the miR-133b expression and the proliferation, invasion and sensitivity toEGFR-TKI of NSCLC was evaluated. After transfected with miR-133b, the possiblemechanisms of miR-133b regulating EGFR signaling pathway were studied.
Methods:
1. Expression levels of miR-133b and EGFR mRNA were detected by qRT-PCR inpaired NSCLC specimens and matched normal lung tissue; the expression levels ofEGFR protein were evaluated by immunohistochemical in NSCLC specimens.
2. Bioinformatics and Dual Luciferase Report Gene System were used to confirm thatmiR-133b could actually bind the sites of EGFR mRNA in3' non-coding region（UTR）.
3. After transfection of miR-133b mimic or inhibitor through cationic liposome infour lung cancer cell lines (H1650, A549, H1975and PC-9), miR-133b wasoverexpressed or inhibited. Then,(1) the apoptosis of cancer cells was detected byFlow cytometry (FCM);(2) the proliferative activity and the sensitivity to gefitinib ofcancer cells was evalutated by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay;(3) the migration/invasion of cancer cells wasassessed by the scratch test and Transwell Cell Migration/Invasion Matrigel Assay;(4)the expression levels of the miR-133b, EGFR mRNA and its downstream signalingmolecules were detected by qRT-PCR;(5) the protein expression levels of EGFR andits downstream signaling pathway were detected by Western blots.
Results:
1. In27lung cancer tissues (T) and corresponding nonneoplastic lung tissues (N), themiR-133b expression level in NSCLC tissues was significantly lower than that inpaired nonneoplastic lung tissues. Negative correlation was found between miR-133bexpression levels and the extent of regional lymph node involvement, stage andvisceral pleura or vessel invasion. Notably, a significant inverse correlation wasfound between miR-133b levels and EGFR mRNA transcripts. Positive correlationwas found between EGFR mRNA levels and the extent of regional lymph nodeinvolvement, and positive correlation was also found between EGFR protein levelsand visceral pleura or vascular invasion; the positive rate of EGFR protein (66.7%,18/27) was basically consistent with mRNA overexpression.
2. It was shown that EGFR mRNA contained a miR-133b7-nucleotide seed match inthe position50-56of EGFR3′-UTR by bioinformatics analysis; Construction andtransfection of EGFR@pMIR-Report-Luc plasmid and miRNA-133b into cells led tosignificant reduction in normalized luciferase values compared to controls includingpRL-TK reporter plasmids.
3. After transfected with miR-133b mimic/inhibitor, the percentage of apoptotic lungcancer cells, compared with control, was significantly increased in four lung cancercells; moreover, the mimic induced significantly more apoptosis than the inhibitor.
4. After transfected with miR-133b mimic, the cell migration/invasiveness wasdecrease in four cancer cells. On the contrary, the loss of miR-133b would promotethe migration/invasiveness of NSCLC cells. We also found stronger regulations in thePC-9and A549cells.
5. Significant sensitivity to gefitinib was found in H1650, H1975and PC-9cellstransfected with miR-133b mimic compared to the controls. Significant resistance togefitinib was found in A549, H1975and PC-9cells transfected with miR-133binhibitor compared to the controls.
6. In four lung cancer cells, the level of EGFR mRNA and protein was regulated bymiR-133b overexpression/inhibition. In PC-9cell, EGFR mRNA level wassignificantly down-regulated by transfected with the miR-133b mimic. MiR-133bmimic/inhibitor could significantly abolish/establish the phosphorylation of EGFR,AKT and ERK12in PC-9and A549cells. However, no definite changes of thepEGFR, pAkt, and pERK12expression were found in H1650and H1975cells.
Conclusion:
1. Our data supports that the down-regulation of miR-133b could promote cell growth,migration/invasion and resistance to gefitinib in NSCLC.
2. MiR-133b can target and inhibit the endogenous EGFR protein translation at thepost-transcriptional level, and then regulate the EGFR signaling pathway, especiallyin EGFR-addicted NSCLC cells. Thus it caused the phenotypic changes in cancercells as described above. This finding has important implications in the developmentof targeted therapeutics for a number of EGFR-addicted cancers.
肺癌在我国发病率和死亡率都有明显增高，其中大部分是非小细胞肺癌(NSCLC)。MicroRNA (miRNA)和表皮生长因子受体（EGFR）的表达异常对于NSCLC的发生发展均是一个非常重要的因素。我们应用组织标本和细胞株，研究miR-133b对于肺癌细胞增殖、侵袭转移能力和药物敏感性等生物学行为的影响，通过细胞转染等方法分析miR-133b与EGFR信号通路分子间的相互关系及可能作用机制。
方法：
1、应用实时定量逆转录多聚酶链式反应（realtime RT-PCR）检测肺癌组织标本和匹配的正常肺组织标本中miR-133b和EGFR mRNA的表达水平；应用免疫组化化学法（IHC）分析肺癌组织标本中EGFR蛋白的表达水平。
2、选用生物信息学和双荧光素酶报告基因法确证miR-133b与EGFR mRNA3′非编码区域UTR的靶向结合作用。
3、采用阳离子脂质体法在四种肺癌细胞株（H1650、A549、H1975和PC-9）中转染miR-133b模拟物或者抑制物，使其过表达或者抑制。随后：（1）应用流式细胞分析（FCM）方法检测癌细胞的凋亡状况；（2）应用四氮唑盐法（MTT比色法）检测癌细胞的增殖活性和对于吉非替尼的药物敏感性；（3）应用划痕法、Transwell/Matrigel试验检测癌细胞的侵袭转移能力；（4）应用realtime RT-PCR法检测癌细胞miR-133b、EGFR及其下游基因mRNA表达（；5）应用Western-blots法检测EGFR及其下游信号通路分子蛋白表达量。
结果：
1、在27例匹配的肿瘤组织（T）和相应非肿瘤正常肺组织（N）的检测中，NSCLC癌组织中miR-133b低表达；miR-133的表达水平和区域淋巴结受累程度、分期及脏层胸膜或脉管侵犯之间呈负相关；miR-133b的表达水平和EGFR mRNA转录产物存在着显著的负相关。EGFR mRNA水平和区域淋巴结受累程度之间正相关，EGFR蛋白水平和脏层胸膜或脉管侵犯之间正相关；EGFR蛋白阳性率为66.7%(18/27)与mRNA过表达存在基本一致性。
2、生物信息学分析显示在EGFR mRNA3′-UTR的50~56位置，具有一个与miR-133b完全互补的7个核酸的种子序列；通过构建和转染EGFR@pMIR-Report-Luc质粒和miR-133b进入细胞，导致了较对照组标化荧光下降。
3、转染miR-133b模拟物或者抑制物后，四种肺癌细胞的凋亡均较对照组明显增加；并且模拟物引起的凋亡也较抑制物明显增加。
4、转染miR-133b模拟物后，四种肺癌细胞的侵袭转移能力降低，反之转染miR-133b抑制物后则提高了肺癌细胞的侵袭转移能力，并且对PC-9和A549细胞的调节作用更明显。
5、H1650、H1975和PC-9肺癌细胞中，转染miR-133b模拟物后表现为对吉非替尼的明显敏感，而在A549、H1975和PC-9肺癌细胞中，转染miR-133b抑制物后表现为对吉非替尼的明显耐药。
6、四种肺癌细胞中EGFR mRNA和蛋白水平均受到miR-133b过表达或抑制的调节，在PC-9细胞中转染miR-133b模拟物后，EGFR mRNA的下调更明显。在PC-9和A549肺癌细胞中，转染miR-133b模拟物/抑制物后，EGFR、AKT和ERK12磷酸化水平明显下调/上调，而在H1650和H1975细胞中上述改变不明显。
结论：
1、MiR-133b低表达促进了NSCLC的增殖、侵袭转移和对EGFR-TKI的耐药。
2、MiR-133b通过靶向作用于EGFR，在转录后水平调节了内生EGFR蛋白表达水平，进而主要影响EGFR依赖的肺癌细胞中EGFR下游通路的分子活性来产生上述功能变化。该研究为此类肿瘤的靶向治疗提供了重要的理论基础。
Background:
Morbidity and mortality of lung cancer in China has increased significantly, and mostof them were non-small cell lung cancer (NSCLC). MicroRNAs (miRNAs) play keyroles in tumorigenesis and tumor progression. Both the deregulation of miRNAs andepidermal growth factor receptor (EGFR) are emerging as important areas ofnon-small cell lung cancer (NSCLC). With the tissues and cell lines, the relationshipof the miR-133b expression and the proliferation, invasion and sensitivity toEGFR-TKI of NSCLC was evaluated. After transfected with miR-133b, the possiblemechanisms of miR-133b regulating EGFR signaling pathway were studied.
Methods:
1. Expression levels of miR-133b and EGFR mRNA were detected by qRT-PCR inpaired NSCLC specimens and matched normal lung tissue; the expression levels ofEGFR protein were evaluated by immunohistochemical in NSCLC specimens.
2. Bioinformatics and Dual Luciferase Report Gene System were used to confirm thatmiR-133b could actually bind the sites of EGFR mRNA in3' non-coding region（UTR）.
3. After transfection of miR-133b mimic or inhibitor through cationic liposome infour lung cancer cell lines (H1650, A549, H1975and PC-9), miR-133b wasoverexpressed or inhibited. Then,(1) the apoptosis of cancer cells was detected byFlow cytometry (FCM);(2) the proliferative activity and the sensitivity to gefitinib ofcancer cells was evalutated by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay;(3) the migration/invasion of cancer cells wasassessed by the scratch test and Transwell Cell Migration/Invasion Matrigel Assay;(4)the expression levels of the miR-133b, EGFR mRNA and its downstream signalingmolecules were detected by qRT-PCR;(5) the protein expression levels of EGFR andits downstream signaling pathway were detected by Western blots.
Results:
1. In27lung cancer tissues (T) and corresponding nonneoplastic lung tissues (N), themiR-133b expression level in NSCLC tissues was significantly lower than that inpaired nonneoplastic lung tissues. Negative correlation was found between miR-133bexpression levels and the extent of regional lymph node involvement, stage andvisceral pleura or vessel invasion. Notably, a significant inverse correlation wasfound between miR-133b levels and EGFR mRNA transcripts. Positive correlationwas found between EGFR mRNA levels and the extent of regional lymph nodeinvolvement, and positive correlation was also found between EGFR protein levelsand visceral pleura or vascular invasion; the positive rate of EGFR protein (66.7%,18/27) was basically consistent with mRNA overexpression.
2. It was shown that EGFR mRNA contained a miR-133b7-nucleotide seed match inthe position50-56of EGFR3′-UTR by bioinformatics analysis; Construction andtransfection of EGFR@pMIR-Report-Luc plasmid and miRNA-133b into cells led tosignificant reduction in normalized luciferase values compared to controls includingpRL-TK reporter plasmids.
3. After transfected with miR-133b mimic/inhibitor, the percentage of apoptotic lungcancer cells, compared with control, was significantly increased in four lung cancercells; moreover, the mimic induced significantly more apoptosis than the inhibitor.
4. After transfected with miR-133b mimic, the cell migration/invasiveness wasdecrease in four cancer cells. On the contrary, the loss of miR-133b would promotethe migration/invasiveness of NSCLC cells. We also found stronger regulations in thePC-9and A549cells.
5. Significant sensitivity to gefitinib was found in H1650, H1975and PC-9cellstransfected with miR-133b mimic compared to the controls. Significant resistance togefitinib was found in A549, H1975and PC-9cells transfected with miR-133binhibitor compared to the controls.
6. In four lung cancer cells, the level of EGFR mRNA and protein was regulated bymiR-133b overexpression/inhibition. In PC-9cell, EGFR mRNA level wassignificantly down-regulated by transfected with the miR-133b mimic. MiR-133bmimic/inhibitor could significantly abolish/establish the phosphorylation of EGFR,AKT and ERK12in PC-9and A549cells. However, no definite changes of thepEGFR, pAkt, and pERK12expression were found in H1650and H1975cells.
Conclusion:
1. Our data supports that the down-regulation of miR-133b could promote cell growth,migration/invasion and resistance to gefitinib in NSCLC.
2. MiR-133b can target and inhibit the endogenous EGFR protein translation at thepost-transcriptional level, and then regulate the EGFR signaling pathway, especiallyin EGFR-addicted NSCLC cells. Thus it caused the phenotypic changes in cancercells as described above. This finding has important implications in the developmentof targeted therapeutics for a number of EGFR-addicted cancers.
引文
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