cFLIP、caspase-8在结直肠癌组织中的表达和意义
摘要
目的:检测细胞型Fas相关死亡域蛋白样白细胞介素-1β转换酶抑制蛋白(cFLIP)、半胱氨酸天冬氨酸特异性蛋白酶-8(caspase-8)mRNA在结直肠癌组织中的表达,分析两种基因与结直肠癌发生发展的关系,探讨其在结直肠癌的诊断和治疗中的作用和意义。
方法:采用实时荧光定量聚合酶链(SYBR Green I QRT-PCR)技术检测cFLIP、caspase-8mRNA在32例结直肠癌组织、10例癌旁组织及10例正常粘膜中的表达。
结果:cFLIP、caspase-8在癌组织中的相对表量分别为(1.913±0.845)、(1.856±0.810),两者在癌旁组织中的相对表量分别为(1.521±0.447)、(1.597±0.578),两者在癌、癌旁组织中的表达均高于癌旁正常组织(p＜0.05)。其中cFLIP在癌组织中的表达与临床病理参数(性别、年龄、分化程度、肿瘤直径、有无淋巴结转移、有无远处转移、浸润程度,分布部位)无关(p＞0.05),caspase-8在有淋巴结转移组中的相对表达量(2.009±0.765)高于无淋巴结转移组(1.315±0.770),其与其它的临床病理参数(性别、年龄、分化程度、肿瘤直径、有无远处转移、浸润程度、分布部位)无关(p＞0.05).
结论:cFLIP、caspase-8高表达在结直肠癌的发生发展中起重要作用,两者可能无线性关系。cFLIP表达与肿瘤的临床病理参数无关,caspase-8在有淋巴结转移组的相对表达量高于无淋巴结转移组,提示其与结直肠癌的侵袭转移及预后密切相关。因此认为cFLIP、caspase-8与肿瘤的发生发展、预后有关,有望成为肿瘤诊断和治疗的新靶标。
Objective: To explore the effect and significance of Fas- associated death domain-like interleukin-1 converting enzyme (FLICE)- like inhibitory protein (cFLIP) and cystine asparate specific protease-8 (caspase-8) in diagnosing and treating with colorectal neoplasms, we investigated the expression of in colorectal neoplasms at mRNA level, and analyzed relationship between the occurrence and development of colorectal neoplasms with them,
Methods: The expression of cFLIP、caspase-8 was detected in colorectal neoplasms, nearby tissues and matched normal tissues, at mRNA level, was detected by SYBR Green I quantitatie realtime polymerase chain reaction technique.
Result: The relative expression amount of cFLIP, caspase-8 in colorectal neoplasms tissues were (1.913±0.845) , (1.856±0.810) , respectively; The relative expression amount of cFLIP, caspase-8 in nearby tissues was (1.521±0.447), (1.597±0.578) , respectively. The expression of them in neoplasms and nearby tissues was higher than that in normal tissues(p < 0.05). No relationship could be exist in cFLIP and clinicopathological parameters (including sex, age, differentiation degrees, size, lymph node metastasis, distant metastasis, invasion, distribution) (P>0.05), while caspase-8 in group with lymph node metastasis seemed much higher than that in group without lymph node metastasis (P<0.05), and there were no statistical differencese among groups devided by other different clinicopathological parameters (P>0.05).
Conclusion: The overexpresstion of cFLIP and caspase-8 played a great role in the occurrence and development of colorectal neoplasms, but there might be no linear relationship between them. We couldn't observe cFLIP correlated with clinicopathological parameters, while caspase-8 in group with lymph node metastasis was higher than that in group without lymph node metastasis. It suggested that caspase-8 had close relationship with the malignant degree and prognosis of colorectal neoplasms. To sum up, we concluded cFLIP and caspase-8 had close relationship with the occurrence, development and prognosis of colorectal neoplasms, and them could be new targets of the diagnosis and treatment of colorectal tumors in the future, hopefully.
方法:采用实时荧光定量聚合酶链(SYBR Green I QRT-PCR)技术检测cFLIP、caspase-8mRNA在32例结直肠癌组织、10例癌旁组织及10例正常粘膜中的表达。
结果:cFLIP、caspase-8在癌组织中的相对表量分别为(1.913±0.845)、(1.856±0.810),两者在癌旁组织中的相对表量分别为(1.521±0.447)、(1.597±0.578),两者在癌、癌旁组织中的表达均高于癌旁正常组织(p＜0.05)。其中cFLIP在癌组织中的表达与临床病理参数(性别、年龄、分化程度、肿瘤直径、有无淋巴结转移、有无远处转移、浸润程度,分布部位)无关(p＞0.05),caspase-8在有淋巴结转移组中的相对表达量(2.009±0.765)高于无淋巴结转移组(1.315±0.770),其与其它的临床病理参数(性别、年龄、分化程度、肿瘤直径、有无远处转移、浸润程度、分布部位)无关(p＞0.05).
结论:cFLIP、caspase-8高表达在结直肠癌的发生发展中起重要作用,两者可能无线性关系。cFLIP表达与肿瘤的临床病理参数无关,caspase-8在有淋巴结转移组的相对表达量高于无淋巴结转移组,提示其与结直肠癌的侵袭转移及预后密切相关。因此认为cFLIP、caspase-8与肿瘤的发生发展、预后有关,有望成为肿瘤诊断和治疗的新靶标。
Objective: To explore the effect and significance of Fas- associated death domain-like interleukin-1 converting enzyme (FLICE)- like inhibitory protein (cFLIP) and cystine asparate specific protease-8 (caspase-8) in diagnosing and treating with colorectal neoplasms, we investigated the expression of in colorectal neoplasms at mRNA level, and analyzed relationship between the occurrence and development of colorectal neoplasms with them,
Methods: The expression of cFLIP、caspase-8 was detected in colorectal neoplasms, nearby tissues and matched normal tissues, at mRNA level, was detected by SYBR Green I quantitatie realtime polymerase chain reaction technique.
Result: The relative expression amount of cFLIP, caspase-8 in colorectal neoplasms tissues were (1.913±0.845) , (1.856±0.810) , respectively; The relative expression amount of cFLIP, caspase-8 in nearby tissues was (1.521±0.447), (1.597±0.578) , respectively. The expression of them in neoplasms and nearby tissues was higher than that in normal tissues(p < 0.05). No relationship could be exist in cFLIP and clinicopathological parameters (including sex, age, differentiation degrees, size, lymph node metastasis, distant metastasis, invasion, distribution) (P>0.05), while caspase-8 in group with lymph node metastasis seemed much higher than that in group without lymph node metastasis (P<0.05), and there were no statistical differencese among groups devided by other different clinicopathological parameters (P>0.05).
Conclusion: The overexpresstion of cFLIP and caspase-8 played a great role in the occurrence and development of colorectal neoplasms, but there might be no linear relationship between them. We couldn't observe cFLIP correlated with clinicopathological parameters, while caspase-8 in group with lymph node metastasis was higher than that in group without lymph node metastasis. It suggested that caspase-8 had close relationship with the malignant degree and prognosis of colorectal neoplasms. To sum up, we concluded cFLIP and caspase-8 had close relationship with the occurrence, development and prognosis of colorectal neoplasms, and them could be new targets of the diagnosis and treatment of colorectal tumors in the future, hopefully.
引文
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1 Irmler M,Thome M,Hahne M,et al.Inhibition of death receptor signal by celluar FLIP[J].Nature,1997,388(6624):190-195.
2 Higuchi H,Yoon JH,Grambihler A,et al.Bile Acids stimulate cFLIP phosphorylation enhancing TRAIL-mediated apoptosis[J].Biol J Chem,2003,278(1):454-461
3 高文超,范列英,蔡清萍等.cFLIP蛋白在大肠癌细胞中的表达及其对大肠癌细胞凋亡的影响[J].中华实验外科杂志,2004,21(7):795-797
4 Matsuda-Minehata F,Goto Y,InDue N,et al.Antiapoptotic activity of porcine cFLIP in ovarian granulosa cell lines[J].Mol Reprod Oev,2007,74:1165-1170
5 Metsuda F,InDue N,Goto Y,et al.CFLIP regulates death receptor-mediated apoptosis in an ovarian granulose cell line by inhibiting procaspase-8 cleavage[J].J Reprod Dev,2008,54(4):314-320
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7 Jonsson G,Paulie S,Grandien A,et al.High level of cFLIP correlates with resistance to death receptor- induced apoptosis in bladder carcinoma cells[J].Anticancer research,2003,23:1213-1218
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12 Ryu BK,Lee MG,Chi SG,et al.Increased expression of cFLIP-L in colonic adenocarcinoma[J].J Pathol,2001,194(1):15-19
13 沈宏亮,丁尔迅,李松明,等.大肠癌组织中cFLIP_1 mRNA的表达及临床意义[J].第二军医大学学报,2007,28(2):154-157
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22 Brooks AD,Sayers TJ.Reduction of the antiapoptotic protein cFLIP enhances the susceptibility of human renal cancer cells to TRAIL apoptosis[J].Cancer Immunol Immunother,2005,54:499-505
23 Shai J.White,Ping Lu,Gina M.Keller,et al.Targeting the Short Form of cFLIP by RNA Interference is Sufficient to Enhance TRAIL Sensitivity in PC3 Prostate Carcinoma Cells[J].Cancer Biol Therapy,2006,5(12):1618-1623,
24 Geserick P,Drewniok C,Hupe M,et al.Suppression of cFLIP is sufficient to sensitize human melanoma cells to TRAIL-and CD95L-mediated apoptosis[J].Oncogene,2008,27:3211-3220
25 Kreuz S,Siegmund D,Scheurich P,et al.NF-κB Inducers Upregulate cFLIP,a Cycloheximid- e-Sensitive Inhibitor of Death Receptor Signaling[J].Mole Cell Biol,2001,21(12):.3964-3973
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30 Kreuz S,Siegmund D,Scheurich P,et al.NF-κB inducers upregulate cFLIP,a Cycloheximide-sensitive inhibitor of Death Receptor Signaling[J].Mole Cell Biol,2001,21(12):3964-3973
31 Sun CL,Chao CCK.Cross- resistance to death ligand- induced apoptosis in cisplatin -selected HeLa cells associated with overexpression of DDB2 and subsequent induction of cFLIP[J].Molecu Pharmacology,2005,67(4):1307-1314
[2]Kerr J,Wyllie A,Currie A,et al.A basic biological phenomenon with wide ranging implications in tissue kinetics[J].Brit J Cancer,1972,26:239-57.
[3]Jaattela M.Escaping cell death:survival proteins in cancer[J].Exp Cell Res,1999,248(1):30
[4]Grenet J,Teitz T,Wei T,et al.Structure and chromosome localization of the human CASP8gene[J].Gene,1999,226(2):225-232.
[5]Kim HS,Lee JW,Soung YH,et al.Inactivating mutations of caspase-8 gene in colorectal carcinomas [J].Gastroenterology,2003,125(3):708-715
[6]沈宏亮,丁尔迅,李松明,等.大肠癌组织中cFLIP_L mRNA的表达及临床意义[J].第二军医大学学报,2007,28(2):154-157
[7]Clegg RM.Fluorescence resonance energy transfer[J].Curr Opin Biotechnol,1995,6(1):103-110
[8]Kenneth J,Livak,Schmittgen TD.Analysis of relative gene expression data using real-time quantitative PCR and the 2~(-ΔΔCt) Method[J].Methods,2001,25,402-408
[9]Irmler M,Thome M,Hahne M,et al.Inhibition of death receptor signal by celluar FLIP[J].Nature,1997,388(6624):190-195.
[10]高文超,范列英,蔡清萍等.cFLIP蛋白在大肠癌细胞中的表达及其对大肠癌细胞凋亡的影响[J].中华实验外科杂志,2004,21(7):795-797
[11]Metsuda F,Inoue N,Goto Y,et al.CFLIP regulates death receptor-mediated apoptosis in an ovarian granulose cell line by inhibiting procaspase-8 cleavage[J].J Reprod Dev,2008,54(4):314-320
[12]Jonsson G,Paulie S,Grandien A,et al.High level of cFLIP correlates with resistance to death receptor- induced apoptosis in bladder carcinoma cells[J].Anticancer research,2003,23:1213-1218
[13]Clarke P,Tyler KL.Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis[J].Apoptosis,2007,12:211-223
[14]Higuchi H,Yoon JH,Grambihler A,et al.Bile Acids stimulate cFLIP phosphorylation enhanceing TRAIL-mediated apoptosis[J].Biol J Chem,2003,278(1):454-461
[15]B(a|¨)umler C,Duan F,Onel K,et al.Differential recruitment of caspase 8 to cFlip confers sensitivity or resistance to Fas-mediated apoptosis in a subset of familial lymphoma patients[J].Leuk Resear,2003,27:841-851
[16]Ryu BK,Lee MG,Chi SG,et al.Increased expression of cFLIP-L in colonic adenocarcinoma [J].J Pathol,2001,194(1):15-19
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