泛素化特异性蛋白酶18在结直肠癌中的表达及其临床意义
|
摘要
目的检测USP18在结直肠癌新鲜组织及石蜡组织样本中的表达情况,分析USP18的表达与结直肠癌的恶性进程的关系及其临床应用价值。方法时荧光定量PCR法及免疫印迹实验检测USP18在40例结直肠癌新鲜组织及癌旁正常组织中mRNA及蛋白表达水平,免疫组织化学染色检测USP18在114例结直肠癌石蜡标本中的蛋白表达情况,并分析其与结直肠癌的临床病理相关指标的关系。结果在结直肠癌组织中USP18mRNA及蛋白表达水平显著高于正常结直肠黏膜组织;此外,USP18的表达水平与结直肠癌分化程度、淋巴结转移以及远处转移呈负相关关系(P<0.05)。结论 USP18的表达在结直肠癌组织中明显上调,其高表达与结直肠癌进展密切相关,可作为预测结直肠癌进展和转移的分子标记物之一。
Objective To detect the expression of ubiquitin-specific peptidase 18(USPl8) in the fresh tissue of colorectal cancer(CRC) and in paraffin-embedded tissue specimens and to analyze the relation of the expression level ofUSP18 with the malignant processes of CRC and the clinical application value. Methods The mRCR and protein expressions of USP18 in 40 cases of CRC fresh tissues and the paracancerous normal tissues were detected by real time fluorescence quantitative PCR(FQ-PCR) and Western boltting while the protein expression of USP18 in 114 paraffin-embedded CRC specimens was detected by immunohistochemistry; an analysis was made to the relation between the expressions and related clinical pathological indexes. Results The mRNA and protein expression of USP18 in CRC tissues were much higher than those in the paracanocerous normal mucosal tissues; the expression level of USP18 was negatively correlated to CRC differentiation,lymph metastasis and distant metastasis(P<0. 05). Conclusions T he expression of USP18 is up-regulated in CRC tissues and the high expression is closely correlated to CRC progression; it can be taken as one of novel molecular markers for prediction of CRC progression and metastasis.
Objective To detect the expression of ubiquitin-specific peptidase 18(USPl8) in the fresh tissue of colorectal cancer(CRC) and in paraffin-embedded tissue specimens and to analyze the relation of the expression level ofUSP18 with the malignant processes of CRC and the clinical application value. Methods The mRCR and protein expressions of USP18 in 40 cases of CRC fresh tissues and the paracancerous normal tissues were detected by real time fluorescence quantitative PCR(FQ-PCR) and Western boltting while the protein expression of USP18 in 114 paraffin-embedded CRC specimens was detected by immunohistochemistry; an analysis was made to the relation between the expressions and related clinical pathological indexes. Results The mRNA and protein expression of USP18 in CRC tissues were much higher than those in the paracanocerous normal mucosal tissues; the expression level of USP18 was negatively correlated to CRC differentiation,lymph metastasis and distant metastasis(P<0. 05). Conclusions T he expression of USP18 is up-regulated in CRC tissues and the high expression is closely correlated to CRC progression; it can be taken as one of novel molecular markers for prediction of CRC progression and metastasis.
引文
[1] SIEGEL RL, MILLER KD, JEMAL A. Cancer Statistics,2017[J]. CA Cancer J Clin,2017,67(1):7-30.
[2] SIEGEL R,DESANTIS C,JEMAL A. Colorectal cancer statistics,2014[J]. Ca A Cancer Journal for Clinicians,2014,64(2):104-117.
[3] BOSMAN SJ,VERMEER TA,DUDINK RL,et al. Abdominosacral resection:long-term outcome in 86 patients with locally advanced or locally recurrent rectal cancer[J]. Eur J Surg Oncol,2014,40(6):699-705.
[4] SANTIN I,MOORE F,GRIECO FA,et al. USP18 is a key regulator of the interferon-driven gene network modulating pancreatic beta cell inflammation and apoptosis[J]. Cell Death Dis,2012,3(11):e419.
[5] HONKE N,SHAABANI N,DE ZHANG,et al. Multiple functions of USP18[J]. Cell Death Dis,2016,7(11):e2444.
[6] KIM YH,KIM WT,JEONG P,et al. Novel combination markers for predicting survival in patients with muscle invasive bladder cancer:USP18 and DGCR2[J]. J Korean Med Sci,2014,29(3):351-356.
[7] CAI J,LIU T,JIANG X,et al. Downregulation of USP18 inhibits growth and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma cells by suppressing BCL2L1[J]. Exp Cell Res,2017,15;358(2):315-322.
[8] SCHWER H,LIU LQ,ZHOU L,et al. Cloning and characterization of a novel human ubiquitin-specific protease,a homologue of murine UBP43(Usp18)[J]. Genomics,2000,65(1):44-52.
[9] MALAKHOVA OA,KIM KI,LUO JK,et al. UBP43 is a novel regulator of interferon signaling independent of its ISGl5 isopeptidase activity[J]. EMBO J,2006,25(11):2358-2367.
[10] HONG B,LI H,LU Y,et al. USP18 is crucial for IFN-γ-mediated inhibition of B16 melanoma tumorigenesis and antitumor immunity[J]. Mol Cancer,2014,13(1):1-12.
[11] BURKART C,ARIMOTO K,TANG T,et al. Usp18deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-l and elevated secretion of Cxcl10[J]. EMBO Mol Med,2013,5(7):967–982.
[12] SHAHIDUL MM,CRISTY RE,HUFF V. Ubiquitin specific protease 18(Usp18)is a WT1 transcriptional target[J]. Exp Cell Res,2013,319(5):612-622
[13] GUO Y,CHINYENGETERE F,DOLINKO AV,et al.Evidence for the ubiquitin protease UBP43 as an antineoplastic target[J]. Mol Cancer Ther,2012,11(9):1968-77.
[14] YAN M,LUO JK,RITCHIE KJ,et al. Ubp43 regulates BCR-ABL leukemogenesis via the type 1 interferon receptor signaling[J]. Blood. 2007,110(1):305-312.
[15] POTU H,SGORBISSA A,BRANCOLINI C. Identification of USP18 as an important regulator of the susceptibility to IFN-alpha and drug-induced apoptosis[J]. Cancer Res. 2010,70(2):655-665.
[16] SGORBISSA A,TOMASELLA A,POTU H,et al.Type I IFNs signaling and apoptosis resistance in glioblastoma cells[J]. Apoptosis. 2011,16(12):1229-1244.
[17] GUO Y,DOLINKO AV,CHINYENGETERE F,et al.Blockade of the ubiquitin protease UBP43 destabilizes transcription factor PML/RARalpha and inhibits the growth of acute promyelocytic leukemia[J]. Cancer Res. 2010,70(23):9875-9885.
[18] BIDWELL BN,SLANEY CY,WITHANA NP,et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape[J].Nat Med. 2012,18(8):1224-1231
[19] JEON YJ,JO MG,YOO HM,et al. Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15[J]. J Clin Invest. 2012, 122(7):2622-2636.
[20] CHIANG JY,JANG IK,HODES R,et al. Ablation of Cbl-b provides protection against transplanted and spontaneous tumors[J]. J Clin Invest. 2007,117(4):1029-1036.
[2] SIEGEL R,DESANTIS C,JEMAL A. Colorectal cancer statistics,2014[J]. Ca A Cancer Journal for Clinicians,2014,64(2):104-117.
[3] BOSMAN SJ,VERMEER TA,DUDINK RL,et al. Abdominosacral resection:long-term outcome in 86 patients with locally advanced or locally recurrent rectal cancer[J]. Eur J Surg Oncol,2014,40(6):699-705.
[4] SANTIN I,MOORE F,GRIECO FA,et al. USP18 is a key regulator of the interferon-driven gene network modulating pancreatic beta cell inflammation and apoptosis[J]. Cell Death Dis,2012,3(11):e419.
[5] HONKE N,SHAABANI N,DE ZHANG,et al. Multiple functions of USP18[J]. Cell Death Dis,2016,7(11):e2444.
[6] KIM YH,KIM WT,JEONG P,et al. Novel combination markers for predicting survival in patients with muscle invasive bladder cancer:USP18 and DGCR2[J]. J Korean Med Sci,2014,29(3):351-356.
[7] CAI J,LIU T,JIANG X,et al. Downregulation of USP18 inhibits growth and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma cells by suppressing BCL2L1[J]. Exp Cell Res,2017,15;358(2):315-322.
[8] SCHWER H,LIU LQ,ZHOU L,et al. Cloning and characterization of a novel human ubiquitin-specific protease,a homologue of murine UBP43(Usp18)[J]. Genomics,2000,65(1):44-52.
[9] MALAKHOVA OA,KIM KI,LUO JK,et al. UBP43 is a novel regulator of interferon signaling independent of its ISGl5 isopeptidase activity[J]. EMBO J,2006,25(11):2358-2367.
[10] HONG B,LI H,LU Y,et al. USP18 is crucial for IFN-γ-mediated inhibition of B16 melanoma tumorigenesis and antitumor immunity[J]. Mol Cancer,2014,13(1):1-12.
[11] BURKART C,ARIMOTO K,TANG T,et al. Usp18deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-l and elevated secretion of Cxcl10[J]. EMBO Mol Med,2013,5(7):967–982.
[12] SHAHIDUL MM,CRISTY RE,HUFF V. Ubiquitin specific protease 18(Usp18)is a WT1 transcriptional target[J]. Exp Cell Res,2013,319(5):612-622
[13] GUO Y,CHINYENGETERE F,DOLINKO AV,et al.Evidence for the ubiquitin protease UBP43 as an antineoplastic target[J]. Mol Cancer Ther,2012,11(9):1968-77.
[14] YAN M,LUO JK,RITCHIE KJ,et al. Ubp43 regulates BCR-ABL leukemogenesis via the type 1 interferon receptor signaling[J]. Blood. 2007,110(1):305-312.
[15] POTU H,SGORBISSA A,BRANCOLINI C. Identification of USP18 as an important regulator of the susceptibility to IFN-alpha and drug-induced apoptosis[J]. Cancer Res. 2010,70(2):655-665.
[16] SGORBISSA A,TOMASELLA A,POTU H,et al.Type I IFNs signaling and apoptosis resistance in glioblastoma cells[J]. Apoptosis. 2011,16(12):1229-1244.
[17] GUO Y,DOLINKO AV,CHINYENGETERE F,et al.Blockade of the ubiquitin protease UBP43 destabilizes transcription factor PML/RARalpha and inhibits the growth of acute promyelocytic leukemia[J]. Cancer Res. 2010,70(23):9875-9885.
[18] BIDWELL BN,SLANEY CY,WITHANA NP,et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape[J].Nat Med. 2012,18(8):1224-1231
[19] JEON YJ,JO MG,YOO HM,et al. Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15[J]. J Clin Invest. 2012, 122(7):2622-2636.
[20] CHIANG JY,JANG IK,HODES R,et al. Ablation of Cbl-b provides protection against transplanted and spontaneous tumors[J]. J Clin Invest. 2007,117(4):1029-1036.