miR-451在结直肠癌中的表达及生物学行为研究
摘要
研究背景与目的:结直肠癌是常见的消化道恶性肿瘤,迅速生长而易于转移,但是它的发病机理仍然不清楚。microRNAs(miRNAs)是内源性非编码的小RNA分子,具有重要的生理及病理意义。虽然目前有研究表明miR-451在结直肠癌中表达下调,但是miR-451在结直肠癌中的作用仍然不明确。
方法:取14例结直肠癌及癌旁正常组织,荧光定量PCR方法检测组织中miR-451表达情况,分析miR-451表达与临床病理参数之间的相关性。定量PCR检测正常结直肠组织与结直肠癌细胞SW480、SW620中miR-451表达情况。转染miR-451及miR-451negative control到结直肠癌细胞,实验分为4组:miR-451 mimics转染组(使用Lipo 2000转染miR-451 mimics)、NC组(使用Lipo 2000转染miR negative control),空白转染组(只加与前组等量的Lipo 2000,无miRNA片段),对照组(细胞常规培养,不加Lipo 2000和miRNA片段)。荧光定量PCR法检测转染24h后miR-451表达量的改变,CCK-8试剂盒分别检测转染24h、48h、72h后细胞的增殖能力;流式细胞仪检测转染48h后细胞的凋亡情况;Transwell侵袭实验检测细胞侵袭能力的改变;免疫印迹技术检测转染48h后靶蛋白的表达情况。
结果:14例结直肠癌组织中,相对于正常黏膜,9例(64.3%)miR-451表达下调。结直肠癌组织中miR-451表达比正常黏膜平均下调3.98倍,差异有统计学意义(P<0.05)。miR-451的表达与患者年龄、性别、临床分期、组织分级、肿瘤直径、淋巴结转移无关(P >0.05)。相对于正常粘膜,结直肠癌细胞中miR-451表达也显著下调(P <0.01)。转染24h后,SW480及SW620细胞的miR-451 mimics转染组miR-451表达分别为144.33±44.31、67.96±13.33,显著高于NC组(P<0.01);CCK-8检测结果表明,SW480细胞中,miR-451 mimics转染组中细胞增殖与另外3组相比差异不明显(P>0.05);SW620细胞中,miR-451 mimics转染组中细胞增殖在48h、72h明显抑制(P<0.01);转染48h后,SW480与SW620细胞的miR-451 mimics转染组细胞凋亡率分别为(6.33±2.89)%和(9.63±5.58)%,与另外3组比较,细胞凋亡能力无明显改变(P>0.05);Transwell小室中作用48h,SW480与SW620细胞的miR-451 mimics转染组侵袭细胞数分别为(17.2±1.8)个/视野、(37.4±6.1)个/视野,侵袭能力较另外3组明显减弱(P<0.01);转染48h后,SW480与SW620细胞的miR-451 mimics转染组中MIF蛋白相对表达量分别为(0.606±0.028)、(0.779±0.034),与另外3组相比,差异有显著统计学意义(P<0.01)。
结论:相对于正常黏膜组织,miR-451在结直肠癌组织及细胞中表达下调;上调miR-451表达可抑制结直肠癌细胞的增殖、侵袭能力,miR-451可能对结直肠癌的诊断和治疗起重要的作用。
Objective: Colorectal carcinoma (CRC), extremely common and aggressive tumor, is rapidly growing and highly infiltrative, but the molecular basis of its pathogenesis is not well defined. microRNAs (miRNAs) are endogenously expressed noncoding RNAs with important biological and pathological functions. Although study has shown that miR-451 is obviously down-regulated in CRC, the role of miR-451 in CRC is still elusive.
Methods: The expression of miR-451 was done on 14 human CRC and matched non-neoplastic mucosa samples using Real-time quantitative RT-PCR (qRT-PCR) approach, and the relationship between miR-451 level and various clinical parameters were analyzed. To investigate the effect of human miR-451 on the proliferation, apoptosis and invasion potential of CRC cell line SW480 and SW620, the experiment was divided into four groups: the miR-451 mimics group, negative control group, blank transfection group and blank control group. Synthetic miR-451 mimics was transfected into cells via lipofectamine 2000, and the expression change of miR-451 was measured by qRT-PCR. Cellular proliferation capacity was assayed by the Cell counting kit-8 (CCK-8), the apoptotic rate was tested by flow cytometry (FCM) and invasion capacity were analysed by transwell assay. The effect of miR-451 mimics on expression of the macrophage migration inhibitory factor (MIF) protein was measured by Western blot assay.
Results: miR-451 expression is significantly decreased in 9 of 14 (64.3%) tumor tissues compared to that in their matched non-neoplastic mucosa tissues(P<0.01). Furthermore, CRC cell lines SW480 and SW620 showed a low expression of miR-451(P<0.01). However, no statistically significant correlation was found between miR-451 level and any of the various clinicopathologic characteristics such as sex, age, clinical stage, histological grade, tumor size and lymph node status. In vitro assay, compared with the negative control groups, miR-451 expression in the miR-451 mimics group of SW480 (144.33±44.31) and SW620 cells (67.96±13.33) increased significantly (P<0.01). The cell growth inhibition of miR-451 mimics group was demonstrated from 48h after SW620 cells treated with transfection by CCK-8 results (P<0.01), however, in SW480 cells, no significant change was found (P>0.05). In SW480 and SW620 cells, FCM analysis showed that the apoptotic rate in the miR-451 mimics group were (6.33±2.89)% and (9.63±5.58)%, separately, which were similar to the other three groups (P>0.05). In transwell assay, the invasion capability in the miR-451 mimics group were (17.2±1.8) /per field and (37.4±6.1)/per field, separately, which were lower than the other three groups (P<0.01). Western blot assay presented that MIF protein expression in the miR-451 mimics group were (0.606±0.028) and (0.779±0.034), separately, which were down-regulated when compared with the other three groups(P<0.01).
Conclusion: miR-451 is downregulated in human CRC tissues, restoration of miR-451 affects proliferation and invasion of CRC cells. This new information may suggest the potential role of miR-451 in the diagnosis and treatment of colorectal carcinoma.
方法:取14例结直肠癌及癌旁正常组织,荧光定量PCR方法检测组织中miR-451表达情况,分析miR-451表达与临床病理参数之间的相关性。定量PCR检测正常结直肠组织与结直肠癌细胞SW480、SW620中miR-451表达情况。转染miR-451及miR-451negative control到结直肠癌细胞,实验分为4组:miR-451 mimics转染组(使用Lipo 2000转染miR-451 mimics)、NC组(使用Lipo 2000转染miR negative control),空白转染组(只加与前组等量的Lipo 2000,无miRNA片段),对照组(细胞常规培养,不加Lipo 2000和miRNA片段)。荧光定量PCR法检测转染24h后miR-451表达量的改变,CCK-8试剂盒分别检测转染24h、48h、72h后细胞的增殖能力;流式细胞仪检测转染48h后细胞的凋亡情况;Transwell侵袭实验检测细胞侵袭能力的改变;免疫印迹技术检测转染48h后靶蛋白的表达情况。
结果:14例结直肠癌组织中,相对于正常黏膜,9例(64.3%)miR-451表达下调。结直肠癌组织中miR-451表达比正常黏膜平均下调3.98倍,差异有统计学意义(P<0.05)。miR-451的表达与患者年龄、性别、临床分期、组织分级、肿瘤直径、淋巴结转移无关(P >0.05)。相对于正常粘膜,结直肠癌细胞中miR-451表达也显著下调(P <0.01)。转染24h后,SW480及SW620细胞的miR-451 mimics转染组miR-451表达分别为144.33±44.31、67.96±13.33,显著高于NC组(P<0.01);CCK-8检测结果表明,SW480细胞中,miR-451 mimics转染组中细胞增殖与另外3组相比差异不明显(P>0.05);SW620细胞中,miR-451 mimics转染组中细胞增殖在48h、72h明显抑制(P<0.01);转染48h后,SW480与SW620细胞的miR-451 mimics转染组细胞凋亡率分别为(6.33±2.89)%和(9.63±5.58)%,与另外3组比较,细胞凋亡能力无明显改变(P>0.05);Transwell小室中作用48h,SW480与SW620细胞的miR-451 mimics转染组侵袭细胞数分别为(17.2±1.8)个/视野、(37.4±6.1)个/视野,侵袭能力较另外3组明显减弱(P<0.01);转染48h后,SW480与SW620细胞的miR-451 mimics转染组中MIF蛋白相对表达量分别为(0.606±0.028)、(0.779±0.034),与另外3组相比,差异有显著统计学意义(P<0.01)。
结论:相对于正常黏膜组织,miR-451在结直肠癌组织及细胞中表达下调;上调miR-451表达可抑制结直肠癌细胞的增殖、侵袭能力,miR-451可能对结直肠癌的诊断和治疗起重要的作用。
Objective: Colorectal carcinoma (CRC), extremely common and aggressive tumor, is rapidly growing and highly infiltrative, but the molecular basis of its pathogenesis is not well defined. microRNAs (miRNAs) are endogenously expressed noncoding RNAs with important biological and pathological functions. Although study has shown that miR-451 is obviously down-regulated in CRC, the role of miR-451 in CRC is still elusive.
Methods: The expression of miR-451 was done on 14 human CRC and matched non-neoplastic mucosa samples using Real-time quantitative RT-PCR (qRT-PCR) approach, and the relationship between miR-451 level and various clinical parameters were analyzed. To investigate the effect of human miR-451 on the proliferation, apoptosis and invasion potential of CRC cell line SW480 and SW620, the experiment was divided into four groups: the miR-451 mimics group, negative control group, blank transfection group and blank control group. Synthetic miR-451 mimics was transfected into cells via lipofectamine 2000, and the expression change of miR-451 was measured by qRT-PCR. Cellular proliferation capacity was assayed by the Cell counting kit-8 (CCK-8), the apoptotic rate was tested by flow cytometry (FCM) and invasion capacity were analysed by transwell assay. The effect of miR-451 mimics on expression of the macrophage migration inhibitory factor (MIF) protein was measured by Western blot assay.
Results: miR-451 expression is significantly decreased in 9 of 14 (64.3%) tumor tissues compared to that in their matched non-neoplastic mucosa tissues(P<0.01). Furthermore, CRC cell lines SW480 and SW620 showed a low expression of miR-451(P<0.01). However, no statistically significant correlation was found between miR-451 level and any of the various clinicopathologic characteristics such as sex, age, clinical stage, histological grade, tumor size and lymph node status. In vitro assay, compared with the negative control groups, miR-451 expression in the miR-451 mimics group of SW480 (144.33±44.31) and SW620 cells (67.96±13.33) increased significantly (P<0.01). The cell growth inhibition of miR-451 mimics group was demonstrated from 48h after SW620 cells treated with transfection by CCK-8 results (P<0.01), however, in SW480 cells, no significant change was found (P>0.05). In SW480 and SW620 cells, FCM analysis showed that the apoptotic rate in the miR-451 mimics group were (6.33±2.89)% and (9.63±5.58)%, separately, which were similar to the other three groups (P>0.05). In transwell assay, the invasion capability in the miR-451 mimics group were (17.2±1.8) /per field and (37.4±6.1)/per field, separately, which were lower than the other three groups (P<0.01). Western blot assay presented that MIF protein expression in the miR-451 mimics group were (0.606±0.028) and (0.779±0.034), separately, which were down-regulated when compared with the other three groups(P<0.01).
Conclusion: miR-451 is downregulated in human CRC tissues, restoration of miR-451 affects proliferation and invasion of CRC cells. This new information may suggest the potential role of miR-451 in the diagnosis and treatment of colorectal carcinoma.
引文
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[1] Chen CZ, Li L, Lodish HF, et al. MicroRNAs modulate hematopoietic lineage differentiation. Science, 2004, 303(5654): 83-86.
[2] Berezikov E, Guryev V, van de Belt J, et al. Phylogenetic shadowing and computational identification of human microRNA genes. Cell, 2005, 120(1): 21-24.
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[9] Zhang Z, Chang H, Li Y, et al. MicroRNAs: potential regulators involved in human anencephaly. Int J Biochem Cell Biol. 2010, 42(2):367-74
[10] Bostjancic E, Zidar N, Glavac D. MicroRNA microarray expression profiling inhuman myocardial infarction. Dis Markers. 2009, 27(6):255-68.
[11] Bruchova H, Yoon D, Agarwal AM, et al. Regulated expression of microRNAs in normal and polycythemia vera erythropoiesis. Exp Hematol. 2007, 35(11):1657-1667
[12] Bruchova-Votavova H, Yoon D, Prchal JT. miR-451 enhances erythroid differentiation in K562 cells. Leuk Lymphoma. 2010, 51(4):686-93.
[13] Hui AB, Lenarduzzi M, Krushel T, et al. Comprehensive MicroRNA profiling for head and neck squamous cell carcinomas. Clin Cancer Res. 2010, 16(4):1129-1139
[14] Zhu H, Wu H, Liu XP et al. Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells. biochemical pharmacology, 2008, 76:582-588
[15] Kovalchuk O, Filkowski J, Meservy J, et al. Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther, 2008;7(7):2152–2159
[16] Bian HB, Pan X, Yang JS, et al. Upregulation of microRNA-451 increases cisplatin sensitivity of non-small cell lung cancer cell line (A549). J Exp Clin Cancer Res, 2011, 30:20
[17] Bandres E, Bitarte N, Arias F, et al. microRNA-451 Regulates Macrophage Migration Inhibitory Factor Production and Proliferation of Gastrointestinal Cancer Cells. Clin Cancer Res , 2009, 15(7) :2281-2290
[18] Gal H, Pandi G, Kanner A.A, et al. MIR-451 and Imatinib mesylate inhibit tumor growth of Glioblastoma stem cells, Biochem. Biophys. Res. Commun. 2008, 376 (1): 86-90.
[19] Godlewski J, Nowicki MO, Bronisz A, et al. MicroRNA-451 Regulates LKB1/AMPK Signaling and Allows Adaptation to Metabolic Stress in Glioma Cells . Molecular Cell, 2010, 37(5):620-632.
[20] Wang R, Wang ZX, Yang JS, et al. MicroRNA-451 functions as a tumor suppressor in human non-small cell lung cancer by targeting ras-related protein 14 (RAB14). Oncogene, 2011,
[21] Heinzelmann J, Henning B, Sanjmyatav J, et al. Specific miRNA signatures are associated with metastasis and poor prognosis in clear cell renal cell carcinoma. World J Urol. 2011,
[2] Weitz J, Koch M, Debus J, et al. Colorectal cancer [J]. Lancet, 2005, 365(9454):153-165.
[3] Chen CZ, Li L, Lodish HF, et al. MicroRNAs modulate hematopoietic lineage differentiation[J]. Science, 2004, 303(5654): 83-86.
[4] Lee RC, Feinbaum RL, Ambms V. The C elegans hetemchronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14[J]. Cell, 1993, 75(5):843-854.
[5] Berezikov E, Guryev V, van de Belt J, et al. Phylogenetic shadowing and computational identification of human microRNA genes [J]. Cell, 2005, 120(1): 21-24.
[6] Bandres E, Cubedo E, Agirre X, et a1. Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues[J]. Mol Cancer, 2006, 5:29
[7] Rossi L, Bonmassar E, Faraoni I. Modification of miR gene expression pattern in human colon cancer cells following exposure to 5-fluoreuracil in vitro [J]. Pharmacol Res, 2007, 56(3):248-253
[8] Akao Y, Nakagawa Y, Naoe T. Let-7 microRNA functions as a potential growth suppressor in human colon cancer cells [J]. Biol Pharm Bull, 2006, 29(5):903-906
[9] Motoyama K, Inoue H, Takatsuno Y, et al. Over-and under-expressed microRNAs in human colorectal cancer[J]. Int J Oncol, 2009, 34(4):1069-1075.
[10] Wang CJ, Zhou ZG, Wang L, et al. Clinicopathological significance of microRNA-31, -143 and -145 expression in colorectal cancer [J]. Dis Markers, 2009, 26(1):27–34.
[11] Hu G, Chen D, Li X, et al. miR-133b regulates the MET proto-oncogene and inhibits the growth of colorectal cancer cells in vitro and in vivo [J]. Cancer Biol Ther, 2010, 10(2): 190-197
[12] Bandres E, Bitarte N, Arias F, et al. microRNA-451 Regulates Macrophage Migration Inhibitory Factor Production and Proliferation of GastrointestinalCancer Cells[J]. Clin Cancer Res, 2009, 15(7):2281-2290.
[13] Bartel D P. MicroRNAs: genomics, biogenesis, mechanism, and function [J]. Cell, 2004, 116(2):287-297
[14] Gregory RI, Shiekhattar R. MicroRNA biogenesis and cancer [J]. Cancer Res, 2005, 65(9):3509-3512
[15] Gregory RI, Yan KP, Amuthan G, et a1. The Microprocessor complex mediates the genesis of microRNAs [J]. Nature, 2004, 432(7014):235-240
[16] Ambros V. The functions of animal MicroRNAs [J]. Nature, Review, 2004, 431(7006):350-355.
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