CD44和NANOG在上皮性卵巢癌中的表达及其临床意义
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摘要
目的:探讨上皮性卵巢癌(epithelial ovarian cancer,EOC)中CD44及转录因子NANOG的表达及其临床意义。方法:用免疫组织化学法检测良性卵巢肿瘤和EOC组织中CD44及NANOG的表达,并对EOC中CD44和NANOG的表达水平做相关性分析。Western blot法检测不同浓度顺铂对卵巢癌SKOV3细胞中CD44及NANOG蛋白表达水平的影响。结果:CD44和NANOG在EOC中的阳性表达率均明显高于良性卵巢肿瘤组织(P<0.01);EOC中CD44与NANOG的表达水平呈正相关(r=0.346,P<0.01)。CD44在EOC中的阳性表达率与临床分期和淋巴结转移有关(P<0.05),而与年龄、病理分级、病理类型和肿瘤位置无关;NANOG在EOC中的阳性表达率与病理分级和临床分期有关(P<0.05),而与年龄、病理类型、淋巴结转移和肿瘤位置无关。顺铂可诱导卵巢癌SKOV3细胞中CD44和NANOG表达上调(P<0.05)。结论:CD44和NANOG在EOC中高表达,且与EOC发生和发展有关。顺铂可诱导卵巢癌SKOV3细胞中肿瘤干细胞标记物CD44及胚胎干细胞多能性基因产物NANOG表达升高。肿瘤干细胞的产生可能是促进EOC发生、发展及化疗耐药的潜在机制。
AIM: To investigate the expression of CD44 and transcription factor NANOG in epithelial ovarian cancer( EOC) and its clinical significance. METHODS: The expression of CD44 and NANOG in EOC and benign ovarian tumor tissues were detected by immunohistochemical method. The correlation between the expression of CD44 and NANOG in EOC was analyzed. The expression of CD44 and NANOG in ovarian cancer cell line SKOV3 after treatment with cisplatin at different concentrations were detected by Western blot. RESULTS: The positive expression rates of CD44 and NANOG in EOC were significantly higher than those in benign ovarian tumor tissues( P < 0. 01). In EOC,positive correlation was observed between the expression of CD44 and NANOG( r = 0. 346,P < 0. 01). The positive expression rate of CD44 was associated with clinical stage and lymphatic metastasis( P < 0. 05),and had no relationship with age,histological grade,pathological types and the location of tumors. The positive expression rate of NANOG was associated with clinical stage and histological grade( P < 0. 05),and had no relationship with age,lymphatic metastasis,pathological types and the location of tumors. Increased expression of CD44 and NANOG were detected in ovarian cancer cell line SKOV3 after treatment with cisplatin( P < 0. 05). CONCLUSION: The over-expression of CD44 and NANOG are associated with the occurrence and development of EOC. The expression of cancer stem cells marker CD44 and the pluripotent gene product pertaining to embryonic stem cells NANOG are increased in cisplatin-induced SKOV3 cells. Cancer stem cells and the expression of stemness-related gene may well be the underlying pathogenesis that promotes the onset,progression,and chemotherapy resistance of EOC.
AIM: To investigate the expression of CD44 and transcription factor NANOG in epithelial ovarian cancer( EOC) and its clinical significance. METHODS: The expression of CD44 and NANOG in EOC and benign ovarian tumor tissues were detected by immunohistochemical method. The correlation between the expression of CD44 and NANOG in EOC was analyzed. The expression of CD44 and NANOG in ovarian cancer cell line SKOV3 after treatment with cisplatin at different concentrations were detected by Western blot. RESULTS: The positive expression rates of CD44 and NANOG in EOC were significantly higher than those in benign ovarian tumor tissues( P < 0. 01). In EOC,positive correlation was observed between the expression of CD44 and NANOG( r = 0. 346,P < 0. 01). The positive expression rate of CD44 was associated with clinical stage and lymphatic metastasis( P < 0. 05),and had no relationship with age,histological grade,pathological types and the location of tumors. The positive expression rate of NANOG was associated with clinical stage and histological grade( P < 0. 05),and had no relationship with age,lymphatic metastasis,pathological types and the location of tumors. Increased expression of CD44 and NANOG were detected in ovarian cancer cell line SKOV3 after treatment with cisplatin( P < 0. 05). CONCLUSION: The over-expression of CD44 and NANOG are associated with the occurrence and development of EOC. The expression of cancer stem cells marker CD44 and the pluripotent gene product pertaining to embryonic stem cells NANOG are increased in cisplatin-induced SKOV3 cells. Cancer stem cells and the expression of stemness-related gene may well be the underlying pathogenesis that promotes the onset,progression,and chemotherapy resistance of EOC.
引文
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[12]周嘉嘉,陈汝福,邓小耿,等.沉默NANOG表达对人肝癌细胞Hep G2中cyclin D1表达及细胞增殖的影响[J].中国病理生理杂志,2014,30(2):245-249.
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[14]Bourguignon LY,Spevak CC,Wong G,et al.Hyaluronan-CD44 interaction with protein kinase Cεpromotes oncogenic signaling by the stem cell marker Nanog and the production of micro RNA-21,leading to down-re-gulation of the tumor suppressor protein PDCD4,anti-apoptosis,and chemotherapy resistance in breast tumor cells[J].J Biol Chem,2009,284(39):26533-26546.
[15]Wiechert A,Saygin C,Thiagarajan PS,et al.Cisplatin induces stemness in ovarian cancer[J].Oncotarget,2016,7(21):30511-30522.
[16]Chiou SH,Wang ML,Chou YT,et al.Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation[J].Cancer Res,2010,70(24):10433-10444.
[17]Lu CS,Shieh GS,Wang CT,et al.Chemotherapeuticsinduced Oct4 expression contributes to drug resistance and tumor recurrence in bladder cancer[J].Oncotarget,2017,8(19):30844-30858.
[2]Sacks JD,Barbolina MV.Expression and function of CD44 in epithelial ovarian carcinoma[J].Biomolecules,2015,5(4):3051-3066.
[3]Z9ller M.CD44:can a cancer-initiating cell profit from an abundantly expressed molecule?[J].Nat Rev Cancer,2011,11(4):254-267.
[4]Cavaleri F,Scholer HR.Nanog:a new recruit to the embryonic stem cell orchestra[J].Cell,2003,113(5):551-552.
[5]Visvader JE,Lindeman GJ.Cancer stem cells in solid tumours:accumulating evidence and unresolved questions[J].Nat Rev Cancer,2008,10(8):755-768.
[6]Bonnet D,Dick JE.Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J].Nat Med,1997,3(7):730-737.
[7]Zhang S,Balch C,Chan MW,et al.Identification and characterization of ovarian cancer-initiating cells from primary human tumors[J].Cancer Res,2008,68(11):4311-4320.
[8]Revelante N,Gilmartin M.Regulation of and regulation by CD44:a paradigm complex regulatory network[J].Int Trends Immun,2013,6(4):43-58.
[9]Gao Y,Foster R,Yang X,et al.Up-regulation of CD44in the development of metastasis,recurrence and drug resistance of ovarian cancer[J].Oncotarget,2015,6(11):9313-9326.
[10]Du YR,Chen Y,Gao Y,et al.Effects and mechanisms of anti-CD44 monoclonal antibody A3D8 on proliferation and apoptosis of sphere-forming cells with stemness from human ovarian cancer[J].Int J Gynecol Cancer,2013,23(8):136-1375.
[11]Loh YH,Wu Q,Chew JL,et al.The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells[J].Nat Genet,2006,38(4):431-440.
[12]周嘉嘉,陈汝福,邓小耿,等.沉默NANOG表达对人肝癌细胞Hep G2中cyclin D1表达及细胞增殖的影响[J].中国病理生理杂志,2014,30(2):245-249.
[13]Siu MK,Wong ES,Kong DS,et al.Stem cell transcription factor NANOG controls cell migration and invasion via dysregulation of E-cadherin and Fox J1 and contributes to adverse clinical outcome in ovarian cancers[J].Oncogene,32(30):3500-3509.
[14]Bourguignon LY,Spevak CC,Wong G,et al.Hyaluronan-CD44 interaction with protein kinase Cεpromotes oncogenic signaling by the stem cell marker Nanog and the production of micro RNA-21,leading to down-re-gulation of the tumor suppressor protein PDCD4,anti-apoptosis,and chemotherapy resistance in breast tumor cells[J].J Biol Chem,2009,284(39):26533-26546.
[15]Wiechert A,Saygin C,Thiagarajan PS,et al.Cisplatin induces stemness in ovarian cancer[J].Oncotarget,2016,7(21):30511-30522.
[16]Chiou SH,Wang ML,Chou YT,et al.Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation[J].Cancer Res,2010,70(24):10433-10444.
[17]Lu CS,Shieh GS,Wang CT,et al.Chemotherapeuticsinduced Oct4 expression contributes to drug resistance and tumor recurrence in bladder cancer[J].Oncotarget,2017,8(19):30844-30858.