AIM: To validate the utility of Annexin A10 as a surrogate marker of the serrated neoplasia pathway in invasive colorectal cancers(CRCs).METHODS: A total of 1133 primary CRC patients who underwent surgical resection a...AIM: To validate the utility of Annexin A10 as a surrogate marker of the serrated neoplasia pathway in invasive colorectal cancers(CRCs).METHODS: A total of 1133 primary CRC patients who underwent surgical resection at Seoul National University Hospital between January 2004 and December 2007 were enrolled.Expression of Annexin A10 was evaluated by immunohistochemistry using tissue microarray and paired to our findings on clinicopathologic and molecular characteristics of each individual.Cp G island methylator phenotype was determined by Methy Light assay and microsatellite instability was determined by high performance liquid chromatography.KRAS and BRAF mutation status was evaluated by direct sequencing and allele-specific PCR.Univariate and stage-specific survival analyses were performed to reveal the prognostic value of Annexin A10 expression.RESULTS: Annexin A10 expression was observed in 66(5.8%) of the 1133 patients.Annexin A10 expression was more commonly found in females and was associated with proximal location,ulcerative gross type,advanced T category,N category and TNM stage.CRCs with Annexin A10 expression showed an absence of luminal necrosis,luminal serration and mucin production.CRCs with Annexin A10 expression were associated with Cp G island methylator phenotype,microsatellite instability and BRAF mutation.In survival analysis,Annexin A10 expression was associated with poor overall survival and progression-free survival,especially in stage Ⅳ CRCs.CONCLUSION: Annexin A10 expression is associated with poor clinical behavior and can be used a supportive surrogate marker of the serrated neoplasia pathway in invasive CRCs.展开更多
Aberrant expression of annexin A2-SI00A10 heterotetramer （AIIt） associated with PML/RARα fusion protein causes lethal hyperfibrinolysis in acute promyelocytic leukemia （APL）, but the mechanism is unclear. To faci...Aberrant expression of annexin A2-SI00A10 heterotetramer （AIIt） associated with PML/RARα fusion protein causes lethal hyperfibrinolysis in acute promyelocytic leukemia （APL）, but the mechanism is unclear. To facilitate the investigation of regulatory association between ANXA2 and promyelocytic leukemia/retinoic acid receptor α （PML/RARα） fusion protein, this work was performed to determine the transcription start site of ANXA2 promoter with rapid amplification of 5＇-cDNA ends analysis. Zinc-induced U937/PR9 cells expressed PML/RARα fusion protein, and resultant increases in ANXA2 transcripts and translational expressions of both ANXA2 and S100A10, while S100A10 transcripts remained constitutive. The transactivation of ANXA2 promoter by PML/RARα fusion protein was 3.29 ± 0.13 fold higher than that by control pSG5 vector or wild-type RARer. The overexpression of ANXA2 in U937 transfected with full-length ANXA2 cDNA was associated with increased S100A10 subunit, although S100A10 transcripts remained constitutive. The tPA-dependent initial rate of plasmin generation （IRPG） in zinc-treated U937/PR9 increased by 2.13-fold, and cell invasiveness increased by 27.6%. Antibodies against ANXA2, S100A10, or combination of both all remarkably inhibited the IRPG and invasiveness in U937/PR9 and NB4. Treatment of zinc-induced U937/PR9 or circulating APL blasts with all-trans retinoic acid （ATRA） significantly reduced cell surface ANXA2 and S100A10 and associated reductions in IRPG and invasiveness. Thus, PML/RARα fusion protein transactivated the ANXA2 promoter to upregulate ANXA2 and accumulate S100A10. Increased AIIt promoted IRPG and invasiveness, both of which were partly abolished by antibodies against ANXA2 and S100A10 or by ATRA.展开更多
基金Supported by Grant from Basic Science Research Program through the National Research Foundation(NRF)funded by the Ministry of Education,No.2013R1A1A2059080a grant from the Korean Health Technology R&D Project,Ministry of Health&Welfare,No.HI13C1804+2 种基金Priority Research Centers Program through the NRF funded by the Ministry of Education,Science and Technology,No.2009-0093820the NRF grant funded by the Ministry of Science,ICT,and Future planning,No.2011-0030049a grant of the Korea Health Technology R&D Project,Ministry of Health&Welfare,Republic of Korea,No.HI14C1277."
文摘AIM: To validate the utility of Annexin A10 as a surrogate marker of the serrated neoplasia pathway in invasive colorectal cancers(CRCs).METHODS: A total of 1133 primary CRC patients who underwent surgical resection at Seoul National University Hospital between January 2004 and December 2007 were enrolled.Expression of Annexin A10 was evaluated by immunohistochemistry using tissue microarray and paired to our findings on clinicopathologic and molecular characteristics of each individual.Cp G island methylator phenotype was determined by Methy Light assay and microsatellite instability was determined by high performance liquid chromatography.KRAS and BRAF mutation status was evaluated by direct sequencing and allele-specific PCR.Univariate and stage-specific survival analyses were performed to reveal the prognostic value of Annexin A10 expression.RESULTS: Annexin A10 expression was observed in 66(5.8%) of the 1133 patients.Annexin A10 expression was more commonly found in females and was associated with proximal location,ulcerative gross type,advanced T category,N category and TNM stage.CRCs with Annexin A10 expression showed an absence of luminal necrosis,luminal serration and mucin production.CRCs with Annexin A10 expression were associated with Cp G island methylator phenotype,microsatellite instability and BRAF mutation.In survival analysis,Annexin A10 expression was associated with poor overall survival and progression-free survival,especially in stage Ⅳ CRCs.CONCLUSION: Annexin A10 expression is associated with poor clinical behavior and can be used a supportive surrogate marker of the serrated neoplasia pathway in invasive CRCs.
文摘Aberrant expression of annexin A2-SI00A10 heterotetramer （AIIt） associated with PML/RARα fusion protein causes lethal hyperfibrinolysis in acute promyelocytic leukemia （APL）, but the mechanism is unclear. To facilitate the investigation of regulatory association between ANXA2 and promyelocytic leukemia/retinoic acid receptor α （PML/RARα） fusion protein, this work was performed to determine the transcription start site of ANXA2 promoter with rapid amplification of 5＇-cDNA ends analysis. Zinc-induced U937/PR9 cells expressed PML/RARα fusion protein, and resultant increases in ANXA2 transcripts and translational expressions of both ANXA2 and S100A10, while S100A10 transcripts remained constitutive. The transactivation of ANXA2 promoter by PML/RARα fusion protein was 3.29 ± 0.13 fold higher than that by control pSG5 vector or wild-type RARer. The overexpression of ANXA2 in U937 transfected with full-length ANXA2 cDNA was associated with increased S100A10 subunit, although S100A10 transcripts remained constitutive. The tPA-dependent initial rate of plasmin generation （IRPG） in zinc-treated U937/PR9 increased by 2.13-fold, and cell invasiveness increased by 27.6%. Antibodies against ANXA2, S100A10, or combination of both all remarkably inhibited the IRPG and invasiveness in U937/PR9 and NB4. Treatment of zinc-induced U937/PR9 or circulating APL blasts with all-trans retinoic acid （ATRA） significantly reduced cell surface ANXA2 and S100A10 and associated reductions in IRPG and invasiveness. Thus, PML/RARα fusion protein transactivated the ANXA2 promoter to upregulate ANXA2 and accumulate S100A10. Increased AIIt promoted IRPG and invasiveness, both of which were partly abolished by antibodies against ANXA2 and S100A10 or by ATRA.
