MicroRNA-101与环氧化酶-2在胃癌组织中的表达及意义
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摘要
背景：microRNAs(miRNAs)是一类非编码蛋白质的单链小RNA，其主要功能是调节转录后的翻译过程，在人类多种肿瘤的发生、发展中起着癌基因或抑癌基因的作用。miRNA-101在胃癌、肝癌、结肠癌和前列腺癌等多种恶性肿瘤中低表达，可能发挥抑癌基因的作用。我们的前期研究发现，环氧合酶-2（cyclooxygenase-2, COX-2）在胃癌发生、浸润和转移中发挥重要作用，外源性miRNA-101抑制胃癌细胞的增殖和COX-2表达，动物实验证明miRNA-101抑制胃癌移植瘤生长，同时抑制COX-2在移植瘤的表达。然而，miRNA-101和COX-2在人胃癌组织中的表达及其与胃癌临床病理特征的相关性尚不清楚。目的：探讨miRNA-101和COX-2在人胃癌组织中的表达及其与临床病理特征的相关性。方法：
1.研究对象：收集30例经手术切除证实的新鲜胃癌及癌旁正常组织标本作为研究对象。
2.实时荧光定量多聚酶链反应：提取胃癌及癌旁正常组织中的总RNA并逆转录，实时荧光定量多聚酶链反应检测组织中目的基因COX-2mRNA的表达水平，以GAPDH的表达作为内对照；提取胃癌及癌旁正常组织中的miRNA-101，实时荧光定量多聚酶链反应检测组织中miRNA-101的表达水平，以U6的表达作为内对照。
3.免疫印迹法：检测胃癌及癌旁正常组织中目的基因蛋白COX-2的表达水平。
结果：
1. miRNA-101在胃癌组织中的相对表达量显著低于癌旁正常组织。
2. COX-2mRNA在胃癌组织中的相对表达量显著高于癌旁正常组织。COX-2mRNA与miRNA-101的表达在胃癌和癌旁正常组织中均呈显著负相关。
3. TNM分期中III-IV期和伴有淋巴结转移的胃癌标本中，miRNA-101相对表达量显著低于I-II期和无淋巴结转移病例。
4. COX-2mRNA在III-IV期和伴有淋巴结转移胃癌标本的表达水平显著高于I-II期和无淋巴结转移病例。结论：miRNA-101表达下调伴COX-2过表达与胃癌的浸润和转移密切相关。
背景：特异性COX-2抑制剂能有效抑制胃癌细胞增殖、诱导细胞凋亡，然而数项大规模前瞻性研究发现，长期使用COX-2抑制剂可能增加心血管事件发生的风险，使其在临床上的应用受到了限制。熊果酸(ursolic acid, UA)是一种五环三萜类化合物，广泛存在于多种天然植物中，对胃癌、肝癌、肺癌、膀胱癌等多种实体瘤细胞和白血病细胞具有抑制增殖、促凋亡、抗血管生成及细胞毒作用。我们的前期研究发现，熊果酸和选择性COX-2抑制剂NS398能够抑制胃癌细胞SGC-7901的增殖和COX-2表达，但是它们对于COX-2阴性的胃癌细胞增殖的影响尚未知。观察熊果酸对COX-2阴性的胃癌细胞增殖的影响，将为熊果酸应用于胃癌的防治提供理论基础。目的：选择高表达COX-2的胃癌细胞株SGC-7901和不表达COX-2的胃癌细胞株MGC-803，观察熊果酸和选择性COX-2抑制剂NS-398对上述两种细胞增殖的影响。
方法：
1.将SGC-7901细胞和MGC-803细胞接种在RPMI-1640培养液中常规培养24h，换无血清培养基继续培养24h。
2.在上述两种细胞中分别加入熊果酸（终浓度为10、20、40、80μmol/L）或NS-398（终浓度50、100、200、400μmol/L），继续培养12h、24h和48h。
3. MTT法观察细胞增殖情况。
结果：
1.熊果酸呈时间和剂量依赖性抑制SGC-7901和MGC-803细胞的增殖。
2. NS-398呈时间和剂量依赖性抑制SGC-7901和MGC-803细胞的增殖。
结论：熊果酸和NS-398对高表达COX-2的胃癌细胞株SGC-7901和不表达COX-2的胃癌细胞株MGC-803均有增殖抑制作用。
背景：绝大多数大肠癌是由息肉恶变而来，大肠息肉的早期发现和及时治疗是改善大肠癌预后的有效途径。随着年龄的增加，老年人群中大肠腺瘤性息肉的发病率逐渐增加[1,2]。自20世纪90年代德国ERBE公司研发的氩离子凝固装置应用于胃肠道疾病的治疗以来，内镜下氩离子凝固术（argon plasma coagulation，APC）已经广泛用于治疗消化道息肉，这种技术可以减少手术率。目的：探讨内镜下氩离子凝固术（argon plasma coagulation，APC）治疗老年人大肠息肉的安全性和有效性。方法：
1.2008年10月至2011年6月，采用德国ERBE公司生产的APC（VIO200D型）内镜专用氩气刀，对肠镜检查发现大肠息肉的258例病人进行内镜下治疗。
2.直径≤0.5cm的扁平息肉，予氩离子凝固导管电凝灼除病灶。凝固次数视病灶大小及质地而定。
3.直径>0.5cm的扁平息肉，在息肉基底部注射1∶10000的肾上腺素生理盐水和美兰（1∶100）混合液，使得病灶抬举良好，予一次性电圈套器将抬举的病灶完整套扎，较深大的创面予钛夹闭合。
4.带蒂或亚蒂的息肉，予一次性电圈套器套扎高频电切除。
5.尽量将所有切除标本回收送病理学检查，注意观察病人的并发症。结果：
1.258例老年病人共检出525枚息肉，全部APC治愈。
2.根据息肉大小和形态，APC灼除302枚（57.5%），APC切除89枚（17%），黏膜下注射后APC切除134枚（25.5%），局部渗血者行APC电凝或钛夹止血。
3.术后2例（0.8%）出现少量便血，予药物治疗后出血停止，无穿孔和大出血等严重并发症。
4.随着息肉体积增大，绒毛管状腺瘤的发生率增加而管状腺瘤的发生率下降，轻度异型增生的比例下降而中度异型增生比例增加。结论：APC可作为老年人大肠息肉的首选治疗，安全性高，并发症少。
Background: MicroRNAs (miRNAs) are short single-stranded non-coding RNAsthat influence post-transcriptional gene regulation by affecting mRNA stability and/ortranslational repression of their target mRNAs. Alterations of the expression patternof miRNAs that regulate genes involved in cellular proliferation, differentiation orapoptosis, have been found in different human tumors including gastric cancer,suggesting that they may represent a novel class of oncogenes or tumor suppressorgenes. Previous studies showed that Cyclooxygenase-2(COX-2) is over-expressed ingastric cancer, and could be one of the key molecules that might contribute to thegrowth and invasiveness of gastric cancer cells. It has been reported that miR-101down-regulation is involved in COX-2over-expression in human gastric cancer cellsin animal models.Objective: To investigate the expression of microRNA-101(miRNA-101) andCOX-2in gastric cancer and their relationship with clinicopathologic characteristicsof the patients.Methods:
1. Objects: Thirty gastric cancer specimens and matched normal gastric tissuespecimens were obtained surgically from patients.
2. Real time quantitative fluorescence PCR(qRT-PCR): Total RNA was extractedfrom30resected gastric cancer specimens and matched normal tissues specimens,according to the manufacturer’s instructions, followed by reverse transcription.qRT-PCR was carried out to exam the relative expression of target genes miRNA-101and COX-2mRNA. The relative expressions of target gene COX-2mRNA were normalized to that of U6. The relative expressions of target geneCOX-2mRNA were normalized to that of glyceraldehydes-3-phosphatedehydrogenase (GAPDH).
3. Immunoblotting test: Western blot was carried out to identify the expression ofCOX-2in gastric cancer specimens and matched normal gastric tissue.Results:
1. The relative level of miRNA-101in the cancerous tissue was significantly lowerthan those in the normal gastric mucosa.
2. The relative level of COX-2mRNA in the cancerous tissue was significantlyhigher than those in the normal gastric mucosa. The expression of miRNA-101wasnegatively correlated with COX-2mRNA in cancer tissues and normal tissues.
3. The expression levels of miRNA-101were significantly lower in the patients withstages III-IV or lymph node metastasis than that in those with stages I-II or withoutsuch metastasis.
4. COX-2mRNA expression was significantly higher in the patients with stagesIII-IV or lymph node metastasis than that in those with stages I-II or without suchmetastasis.Conclusion： Reduced miRNA-101expression correlated to high levels of COX-2ingastric cancer tissues is closely related to tumor invasion and lymph node metastasis.
Background: The specific cyclooxygenase (COX)-2inhibitor have theanti-proliferative and pro-apoptotic effects on gastric cancer cells. There aresomerandomized, double-blind, placebo-controlled trials with COX-2inhibitors(coxibs) showing an increased rate of thrombotic vascular events in patients treatedwith coxibs. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, islargely distributed in medical herbs. UA has a wide range of anticancer functionssuch as proapoptosis, antiangiogenesis, antimetastasis and cytotoxicity in stomach,liver, lung and bladder cancers. Our previous study indicated that UA and NS398inhibited the proliferation and induced the apoptosis of COX-2positive gastric cancercell line SGC-7901, along with down-regulating the expression of COX-2. This studyis designed to evaluate the effects of UA and NS398on COX-2negative gastriccancer cell line MGC-803, which is in an attempt to develop potent antitumor agents.
Objective: To investigate the effects of UA and COX-2inhibitor NS398on theproliferation of COX-2positive gastric cancer cell line SGC-7901and COX-2negative gastric cancer cell line MGC-803.Methods: SGC-7901cells and MGC-803cells were seeded in RPMI-1640supplemented with10%heat-inactivated fetal calfserum and routinely incubated for24h. After serum-free starvation for24h, the cellswere cultured with either UA at the Final concentration of10,20,40,80μmol/L orNS-398at the final concentration of50,100,200,400μmol/L for12,24and48h respectively. Cell proliferation was determined using methyl thiazolyl tetrazolium(MTT) colorimetric assay.
Results: Both UA and NS398significantly inhibited SGC-7901and MGC-803cellproliferation in a dose-and time-dependent manner.
Conclusion: Both UA and COX-2inhibitor NS398significantly inhibited cellproliferation of COX-2positive gastric cancer cell line SGC-7901and COX-2negative gastric cancer cell line MGC-803.
Background: Nearly all colorectal cancers are thought to arise from adenomatouspolyps. The conclusions from the National Polyp Study strongly support the conceptthat the removal of polyps may prevent the future development of colorectal cancer.With age increasing, there is a higher prevalence of colonic adenomatous polyps inelderly individuals. Argon plasma coagulation(APC), invented by ERBE German, hasbeen introduced to therapy of gastroenterology in1990’s. APC is useful in themanagement of adenomas in gastrointestinal tract, which can reduce surgery.Objects: To evaluate the safety and efficacy of endoscopic argon plasma coagulation(APC) in the management of elderly patients with colorectal polyps.Methods: Colorectal polyps found in electronic enteroscopy were treated with argonplasma generated by ERBE APC (VIO200D) made in German ERBE Company.
Results:
1. A total of525polyps in258elderly patients were all cured by APC.
2.302(57.5%) sessile flat polyps with diameter0.2cm to0.5cm were ablated withAPC，89(17%) semi-pedunculated and pedunculated polyps were resected by high-frequency electrosection, and134sessile (25.5%) polyps with diameter0.6cm to5.0cm were resected after submucosal injection with epinephrine plus methylene bluenormal saline on focal membrane. APC electric coagulation or titanium clip would beemployed if bleeding appeared in partial wounds.
3. Minor bleeding occurred in two patients (0.8%), there were no majorcomplications (perforations or bleeding requiring transfusion).
4. With the size of the polyps growing, the incidence of tubulo-villous adenomasincreases, while the incidence of tubular adenomas decreases. Meanwhile, theincidence of moderate-dysplasia adenomas increases, as well as the incidence ofwild-dysplasia adenomas decreases.
Conclusion: APC is a well tolerated and effective treatment in elderly patients withcolorectal polyps.
1.研究对象：收集30例经手术切除证实的新鲜胃癌及癌旁正常组织标本作为研究对象。
2.实时荧光定量多聚酶链反应：提取胃癌及癌旁正常组织中的总RNA并逆转录，实时荧光定量多聚酶链反应检测组织中目的基因COX-2mRNA的表达水平，以GAPDH的表达作为内对照；提取胃癌及癌旁正常组织中的miRNA-101，实时荧光定量多聚酶链反应检测组织中miRNA-101的表达水平，以U6的表达作为内对照。
3.免疫印迹法：检测胃癌及癌旁正常组织中目的基因蛋白COX-2的表达水平。
结果：
1. miRNA-101在胃癌组织中的相对表达量显著低于癌旁正常组织。
2. COX-2mRNA在胃癌组织中的相对表达量显著高于癌旁正常组织。COX-2mRNA与miRNA-101的表达在胃癌和癌旁正常组织中均呈显著负相关。
3. TNM分期中III-IV期和伴有淋巴结转移的胃癌标本中，miRNA-101相对表达量显著低于I-II期和无淋巴结转移病例。
4. COX-2mRNA在III-IV期和伴有淋巴结转移胃癌标本的表达水平显著高于I-II期和无淋巴结转移病例。结论：miRNA-101表达下调伴COX-2过表达与胃癌的浸润和转移密切相关。
背景：特异性COX-2抑制剂能有效抑制胃癌细胞增殖、诱导细胞凋亡，然而数项大规模前瞻性研究发现，长期使用COX-2抑制剂可能增加心血管事件发生的风险，使其在临床上的应用受到了限制。熊果酸(ursolic acid, UA)是一种五环三萜类化合物，广泛存在于多种天然植物中，对胃癌、肝癌、肺癌、膀胱癌等多种实体瘤细胞和白血病细胞具有抑制增殖、促凋亡、抗血管生成及细胞毒作用。我们的前期研究发现，熊果酸和选择性COX-2抑制剂NS398能够抑制胃癌细胞SGC-7901的增殖和COX-2表达，但是它们对于COX-2阴性的胃癌细胞增殖的影响尚未知。观察熊果酸对COX-2阴性的胃癌细胞增殖的影响，将为熊果酸应用于胃癌的防治提供理论基础。目的：选择高表达COX-2的胃癌细胞株SGC-7901和不表达COX-2的胃癌细胞株MGC-803，观察熊果酸和选择性COX-2抑制剂NS-398对上述两种细胞增殖的影响。
方法：
1.将SGC-7901细胞和MGC-803细胞接种在RPMI-1640培养液中常规培养24h，换无血清培养基继续培养24h。
2.在上述两种细胞中分别加入熊果酸（终浓度为10、20、40、80μmol/L）或NS-398（终浓度50、100、200、400μmol/L），继续培养12h、24h和48h。
3. MTT法观察细胞增殖情况。
结果：
1.熊果酸呈时间和剂量依赖性抑制SGC-7901和MGC-803细胞的增殖。
2. NS-398呈时间和剂量依赖性抑制SGC-7901和MGC-803细胞的增殖。
结论：熊果酸和NS-398对高表达COX-2的胃癌细胞株SGC-7901和不表达COX-2的胃癌细胞株MGC-803均有增殖抑制作用。
背景：绝大多数大肠癌是由息肉恶变而来，大肠息肉的早期发现和及时治疗是改善大肠癌预后的有效途径。随着年龄的增加，老年人群中大肠腺瘤性息肉的发病率逐渐增加[1,2]。自20世纪90年代德国ERBE公司研发的氩离子凝固装置应用于胃肠道疾病的治疗以来，内镜下氩离子凝固术（argon plasma coagulation，APC）已经广泛用于治疗消化道息肉，这种技术可以减少手术率。目的：探讨内镜下氩离子凝固术（argon plasma coagulation，APC）治疗老年人大肠息肉的安全性和有效性。方法：
1.2008年10月至2011年6月，采用德国ERBE公司生产的APC（VIO200D型）内镜专用氩气刀，对肠镜检查发现大肠息肉的258例病人进行内镜下治疗。
2.直径≤0.5cm的扁平息肉，予氩离子凝固导管电凝灼除病灶。凝固次数视病灶大小及质地而定。
3.直径>0.5cm的扁平息肉，在息肉基底部注射1∶10000的肾上腺素生理盐水和美兰（1∶100）混合液，使得病灶抬举良好，予一次性电圈套器将抬举的病灶完整套扎，较深大的创面予钛夹闭合。
4.带蒂或亚蒂的息肉，予一次性电圈套器套扎高频电切除。
5.尽量将所有切除标本回收送病理学检查，注意观察病人的并发症。结果：
1.258例老年病人共检出525枚息肉，全部APC治愈。
2.根据息肉大小和形态，APC灼除302枚（57.5%），APC切除89枚（17%），黏膜下注射后APC切除134枚（25.5%），局部渗血者行APC电凝或钛夹止血。
3.术后2例（0.8%）出现少量便血，予药物治疗后出血停止，无穿孔和大出血等严重并发症。
4.随着息肉体积增大，绒毛管状腺瘤的发生率增加而管状腺瘤的发生率下降，轻度异型增生的比例下降而中度异型增生比例增加。结论：APC可作为老年人大肠息肉的首选治疗，安全性高，并发症少。
Background: MicroRNAs (miRNAs) are short single-stranded non-coding RNAsthat influence post-transcriptional gene regulation by affecting mRNA stability and/ortranslational repression of their target mRNAs. Alterations of the expression patternof miRNAs that regulate genes involved in cellular proliferation, differentiation orapoptosis, have been found in different human tumors including gastric cancer,suggesting that they may represent a novel class of oncogenes or tumor suppressorgenes. Previous studies showed that Cyclooxygenase-2(COX-2) is over-expressed ingastric cancer, and could be one of the key molecules that might contribute to thegrowth and invasiveness of gastric cancer cells. It has been reported that miR-101down-regulation is involved in COX-2over-expression in human gastric cancer cellsin animal models.Objective: To investigate the expression of microRNA-101(miRNA-101) andCOX-2in gastric cancer and their relationship with clinicopathologic characteristicsof the patients.Methods:
1. Objects: Thirty gastric cancer specimens and matched normal gastric tissuespecimens were obtained surgically from patients.
2. Real time quantitative fluorescence PCR(qRT-PCR): Total RNA was extractedfrom30resected gastric cancer specimens and matched normal tissues specimens,according to the manufacturer’s instructions, followed by reverse transcription.qRT-PCR was carried out to exam the relative expression of target genes miRNA-101and COX-2mRNA. The relative expressions of target gene COX-2mRNA were normalized to that of U6. The relative expressions of target geneCOX-2mRNA were normalized to that of glyceraldehydes-3-phosphatedehydrogenase (GAPDH).
3. Immunoblotting test: Western blot was carried out to identify the expression ofCOX-2in gastric cancer specimens and matched normal gastric tissue.Results:
1. The relative level of miRNA-101in the cancerous tissue was significantly lowerthan those in the normal gastric mucosa.
2. The relative level of COX-2mRNA in the cancerous tissue was significantlyhigher than those in the normal gastric mucosa. The expression of miRNA-101wasnegatively correlated with COX-2mRNA in cancer tissues and normal tissues.
3. The expression levels of miRNA-101were significantly lower in the patients withstages III-IV or lymph node metastasis than that in those with stages I-II or withoutsuch metastasis.
4. COX-2mRNA expression was significantly higher in the patients with stagesIII-IV or lymph node metastasis than that in those with stages I-II or without suchmetastasis.Conclusion： Reduced miRNA-101expression correlated to high levels of COX-2ingastric cancer tissues is closely related to tumor invasion and lymph node metastasis.
Background: The specific cyclooxygenase (COX)-2inhibitor have theanti-proliferative and pro-apoptotic effects on gastric cancer cells. There aresomerandomized, double-blind, placebo-controlled trials with COX-2inhibitors(coxibs) showing an increased rate of thrombotic vascular events in patients treatedwith coxibs. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, islargely distributed in medical herbs. UA has a wide range of anticancer functionssuch as proapoptosis, antiangiogenesis, antimetastasis and cytotoxicity in stomach,liver, lung and bladder cancers. Our previous study indicated that UA and NS398inhibited the proliferation and induced the apoptosis of COX-2positive gastric cancercell line SGC-7901, along with down-regulating the expression of COX-2. This studyis designed to evaluate the effects of UA and NS398on COX-2negative gastriccancer cell line MGC-803, which is in an attempt to develop potent antitumor agents.
Objective: To investigate the effects of UA and COX-2inhibitor NS398on theproliferation of COX-2positive gastric cancer cell line SGC-7901and COX-2negative gastric cancer cell line MGC-803.Methods: SGC-7901cells and MGC-803cells were seeded in RPMI-1640supplemented with10%heat-inactivated fetal calfserum and routinely incubated for24h. After serum-free starvation for24h, the cellswere cultured with either UA at the Final concentration of10,20,40,80μmol/L orNS-398at the final concentration of50,100,200,400μmol/L for12,24and48h respectively. Cell proliferation was determined using methyl thiazolyl tetrazolium(MTT) colorimetric assay.
Results: Both UA and NS398significantly inhibited SGC-7901and MGC-803cellproliferation in a dose-and time-dependent manner.
Conclusion: Both UA and COX-2inhibitor NS398significantly inhibited cellproliferation of COX-2positive gastric cancer cell line SGC-7901and COX-2negative gastric cancer cell line MGC-803.
Background: Nearly all colorectal cancers are thought to arise from adenomatouspolyps. The conclusions from the National Polyp Study strongly support the conceptthat the removal of polyps may prevent the future development of colorectal cancer.With age increasing, there is a higher prevalence of colonic adenomatous polyps inelderly individuals. Argon plasma coagulation(APC), invented by ERBE German, hasbeen introduced to therapy of gastroenterology in1990’s. APC is useful in themanagement of adenomas in gastrointestinal tract, which can reduce surgery.Objects: To evaluate the safety and efficacy of endoscopic argon plasma coagulation(APC) in the management of elderly patients with colorectal polyps.Methods: Colorectal polyps found in electronic enteroscopy were treated with argonplasma generated by ERBE APC (VIO200D) made in German ERBE Company.
Results:
1. A total of525polyps in258elderly patients were all cured by APC.
2.302(57.5%) sessile flat polyps with diameter0.2cm to0.5cm were ablated withAPC，89(17%) semi-pedunculated and pedunculated polyps were resected by high-frequency electrosection, and134sessile (25.5%) polyps with diameter0.6cm to5.0cm were resected after submucosal injection with epinephrine plus methylene bluenormal saline on focal membrane. APC electric coagulation or titanium clip would beemployed if bleeding appeared in partial wounds.
3. Minor bleeding occurred in two patients (0.8%), there were no majorcomplications (perforations or bleeding requiring transfusion).
4. With the size of the polyps growing, the incidence of tubulo-villous adenomasincreases, while the incidence of tubular adenomas decreases. Meanwhile, theincidence of moderate-dysplasia adenomas increases, as well as the incidence ofwild-dysplasia adenomas decreases.
Conclusion: APC is a well tolerated and effective treatment in elderly patients withcolorectal polyps.
引文
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