自噬蛋白Parkin和P62在结直肠癌中的表达
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摘要
目的观察自噬蛋白Parkin和P62在人结直肠癌组织中的表达及其与临床病理特征之间的关系。方法收集2012年至2015年武汉大学中南医院手术切除的50例结直肠癌标本及50例癌旁正常结肠组织,用免疫组化SP法检测标本中Parkin蛋白和P62蛋白的表达,分析其表达差异及与临床病理特征之间的关系。结果免疫组化法检测Parkin蛋白和P62蛋白均主要表达于细胞浆。Parkin蛋白在结直肠癌中的阳性表达率为36.0%,在癌旁正常组织中的阳性表达率为72.0%,差异有统计学意义(χ~2=13.043,P=0.000)。P62蛋白在结直肠癌中的阳性表达率为70.0%,在癌旁正常组织中的阳性表达率为42.0%,差异有统计学意义(χ~2=7.955,P=0.005)。Parkin蛋白在组织高分化中阳性表达率高于低分化(P<0.05);P62蛋白在临床分期Ⅲ/Ⅳ期中阳性表达率高于Ⅰ/Ⅱ期(P<0.05)。Spearman相关分析显示,P62蛋白的表达与Parkin蛋白的表达无相关性(r=0.09,P>0.05)。结论肿瘤细胞自噬活性的提高可能参与人结直肠癌的发展,Parkin蛋白和P62蛋白表达可能是肿瘤细胞发生、进展的潜在标志物。临床病理检测Parkin蛋白和P62蛋白的表达,对判断患者预后及结直肠癌分子靶向治疗有潜在的临床意义。
Objective To investigate the expression of autophagic protein Parkin and P62 in human colorectal cancer tissue and the relationship with clinicopathologic characteristics.Methods Fifty specimens of colorectal cancer and 50 normal colonic tissues adjacent to cancer by surgical resection were collected from Zhongnan Hospital of Wuhan University from 2012 to 2015.Immunohistochemical SP method was used to detect the expression of Parkin and P62 in specimens,and to analyze the difference of expression and its relationship with clinicopathological characteristics.Results Immunohistochemistry showed that both Parkin and P62 protein was mainly expressed in cytoplasm.The positive expression rate of Parkin in colorectal cancer tissue was significantly lower than that in adjacent normal tissue(36.0% vs 72.0%,χ~2=13.043,P=0.000).The positive expression rate of P62 in colorectal cancer tissue was significantly higher than that in adjacent normal tissue(70.0% vs 42.0%,χ~2=7.955,P=0.005).The positive expression rate of Parkin protein was higher in well-differentiated tissues than that in poorly differentiated tissues(P<0.05);the positive expression rate of P62 protein in clinical stage Ⅲ/Ⅳ was higher than that in stage Ⅰ/Ⅱ(P<0.05).Spearman correlation analysis showed that there was no correlation between the expression of P62 protein and Parkin protein(r=0.09,P>0.05).Conclusions Increased autophagic activity of cancer cells may be involved in the development of human colorectal cancer.Parkin protein and P62 protein expression may be potential markers of tumorigenesis and progression.Clinicopathology detection of Parkin protein and P62 protein expression has potential clinical significance for predicting prognosis of patients and molecular targeted therapy of colorectal cancer.
Objective To investigate the expression of autophagic protein Parkin and P62 in human colorectal cancer tissue and the relationship with clinicopathologic characteristics.Methods Fifty specimens of colorectal cancer and 50 normal colonic tissues adjacent to cancer by surgical resection were collected from Zhongnan Hospital of Wuhan University from 2012 to 2015.Immunohistochemical SP method was used to detect the expression of Parkin and P62 in specimens,and to analyze the difference of expression and its relationship with clinicopathological characteristics.Results Immunohistochemistry showed that both Parkin and P62 protein was mainly expressed in cytoplasm.The positive expression rate of Parkin in colorectal cancer tissue was significantly lower than that in adjacent normal tissue(36.0% vs 72.0%,χ~2=13.043,P=0.000).The positive expression rate of P62 in colorectal cancer tissue was significantly higher than that in adjacent normal tissue(70.0% vs 42.0%,χ~2=7.955,P=0.005).The positive expression rate of Parkin protein was higher in well-differentiated tissues than that in poorly differentiated tissues(P<0.05);the positive expression rate of P62 protein in clinical stage Ⅲ/Ⅳ was higher than that in stage Ⅰ/Ⅱ(P<0.05).Spearman correlation analysis showed that there was no correlation between the expression of P62 protein and Parkin protein(r=0.09,P>0.05).Conclusions Increased autophagic activity of cancer cells may be involved in the development of human colorectal cancer.Parkin protein and P62 protein expression may be potential markers of tumorigenesis and progression.Clinicopathology detection of Parkin protein and P62 protein expression has potential clinical significance for predicting prognosis of patients and molecular targeted therapy of colorectal cancer.
引文
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[2] 高雅,邢皓,于爱鸣.自噬与肿瘤[J].中国科技信息,2012(14):115,136.
[3] 李丹,李翀,蒋敬庭.自噬在肿瘤发生与发展中的调控机制[J].临床肿瘤学杂志,2013,18(6):561-564.
[4] Yu M,Gou WF,Zhao S,et al.Beclin 1 expression is an independent prognostic factor for gastric carcinomas[J].Tumour Biol,2013,34(2):1071-1083.
[5] Kitada T,Asakawa S,Hattori N,et al.Mutations in the Parkin gene cause autosomal recessive juvenile Parkinsonism[J].Nature,1998,392(6676):605-608.
[6] Picchio MC,Martin ES,Cesari R,et al.Alterations of the tumor suppressor gene Parkin in non-small cell lung cancer[J].Clin Cancer Res,2004,10(8):2720-2724.
[7] Denison SR,Callahan G,Becker NA,et al.Characterization of FRA6E and its potential role in autosomal recessive juvenile Parkinsonism and ovarian cancer[J].Genes Chromosomes Cancer,2003,38(1):40-52.
[8] Poulogiannis G,McIntyre RE,Dimitriadi M,et al.PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice[J].Proc Natl Acad Sci USA,2010,107(34):15145-15150.
[9] Veeriah S,Taylor BS,Meng SS,et al.Somatic mutations of the Parkinson′s disease-associated gene PARK2 in glioblastoma and other human malignancies[J].Nat Genet,2010,42(1):77-82.
[10] Kirkin V,McEwan DG,Novak I,et al.A role for ubiquitin in selective autophagy[J].Mol Cell,2009,34(3):259-269.
[11] Huang F,Nie CL,Yang Y,et al.Selenite induces redox-dependent Bax activation and apoptosis in colorectal cancer cells[J].Free Radic Biol Med,2009,46(8):1186-1196.
[12] Cesari R,Martin ES,Calin GA,et al.Parkin,a gene implicated in autosomal recessive juvenile Parkinsonism,is a candidate tumor suppressor gene on chromosome 6q25-q27[J].Proc Natl Acad Sci USA,2003,100(10):5956-5961.
[13] Wang F,Denison S,Lai JP,et al.Parkingene alterations in hepatocellular carcinoma[J].Genes Chromosom Cancer,2004,40(2):85-96.
[14] Liu JL,Chen FF,Lung J,et al.Prognostic significance of p62/SQSTM1 subcellular localization and LC3B in oral squamous cell carcinoma[J].Br J Cancer,2014,111(5):944-954.
[15] Burdelski C,Reiswich V,Hube-Magg C,et al.Cytoplasmic accumulation of sequestosome 1(p62) is a predictor of biochemical recurrence,rapid tumor cell proliferation,and genomic instability in prostate cancer[J].Clin Cancer Res,2015,21(15):3471-3479.
[16] Komatsu M,Kurokawa H,Waguri S,et al.The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1[J].Nat Cell Biol,2010,12(3):213.
[17] Eskelinen EL.The dual role of autophagy in cancer[J].Curr Opin Pharmacol,2011,11(4):294-300.
[18] Mathew R,Karp CM,Beaudoin B,et al.Autophagy suppresses tumorigenesis through elimination of p62[J].Cell,2009,137(6):1062-1075.
[19] Mah LY,Ryan KM.Autophagy and cancer[J].Cold Spring Harb Perspect Biol,2012,4(1):a008821.
[20] Nihira K,Miki Y,Ono K,et al.An inhibition of p62/SQSTM1 caused autophagic cell death of several human carcinoma cells[J].Cancer Sci,2014,105(5):568-575.