Annexin A2 as a biomarker for hepatocellular carcinoma in Egyptian patients
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摘要
AIM To investigate the clinical utility of serum annexin A2(ANXA2) as a diagnostic marker for early hepatocellular carcinoma(HCC).METHODS This study was performed in HCC Clinic of Ain Shams University Hospitals, Cairo, Egypt and included: Group 1: Fifty patients with early stage HCC(Barcelona Clinic Liver Cancer stage A); Group 2: Twenty five patients with chronic liver disease; and Control Group: Fifteen healthy, age-and sex-matched subjects who were seronegative for viral hepatitis markers. The followinglaboratory investigations were done: Viral hepatitis markers [hepatitis B surface antigen and hepatitis C virus(HCV) antibodies], HCV RNA in HCV antibody-positive patients, serum alpha fetoprotein(AFP), and serum ANXA2 levels.RESULTS In this study, 88% of HCC patients(n = 44) were HCVpositive, while HBV infection represented only 8% of all HCC patients(n = 4); and two patients were negative for both viral markers. A highly significant difference was found between patients with HCC and chronic liver disease as well as controls with regard to serum ANXA2 levels(130, IQR 15-240; 15, IQR 15-17; and 17, IQR 15-30 ng/m L, respectively). The area under the curve of ANXA2 was 0.865; the cut-off value was established to be 18 ng/mL with a diagnostic sensitivity of 74% and a specificity of 88%, while the sensitivity and specificity of AFP at the cut-off value of 200 ng/dL were 20% and 100%, respectively.CONCLUSION Serum ANXA2 may serve as a biomarker for the early detection of HCC.
AIM To investigate the clinical utility of serum annexin A2(ANXA2) as a diagnostic marker for early hepatocellular carcinoma(HCC).METHODS This study was performed in HCC Clinic of Ain Shams University Hospitals, Cairo, Egypt and included: Group 1: Fifty patients with early stage HCC(Barcelona Clinic Liver Cancer stage A); Group 2: Twenty five patients with chronic liver disease; and Control Group: Fifteen healthy, age-and sex-matched subjects who were seronegative for viral hepatitis markers. The followinglaboratory investigations were done: Viral hepatitis markers [hepatitis B surface antigen and hepatitis C virus(HCV) antibodies], HCV RNA in HCV antibody-positive patients, serum alpha fetoprotein(AFP), and serum ANXA2 levels.RESULTS In this study, 88% of HCC patients(n = 44) were HCVpositive, while HBV infection represented only 8% of all HCC patients(n = 4); and two patients were negative for both viral markers. A highly significant difference was found between patients with HCC and chronic liver disease as well as controls with regard to serum ANXA2 levels(130, IQR 15-240; 15, IQR 15-17; and 17, IQR 15-30 ng/m L, respectively). The area under the curve of ANXA2 was 0.865; the cut-off value was established to be 18 ng/mL with a diagnostic sensitivity of 74% and a specificity of 88%, while the sensitivity and specificity of AFP at the cut-off value of 200 ng/dL were 20% and 100%, respectively.CONCLUSION Serum ANXA2 may serve as a biomarker for the early detection of HCC.
AIM To investigate the clinical utility of serum annexin A2(ANXA2) as a diagnostic marker for early hepatocellular carcinoma(HCC).METHODS This study was performed in HCC Clinic of Ain Shams University Hospitals, Cairo, Egypt and included: Group 1: Fifty patients with early stage HCC(Barcelona Clinic Liver Cancer stage A); Group 2: Twenty five patients with chronic liver disease; and Control Group: Fifteen healthy, age-and sex-matched subjects who were seronegative for viral hepatitis markers. The followinglaboratory investigations were done: Viral hepatitis markers [hepatitis B surface antigen and hepatitis C virus(HCV) antibodies], HCV RNA in HCV antibody-positive patients, serum alpha fetoprotein(AFP), and serum ANXA2 levels.RESULTS In this study, 88% of HCC patients(n = 44) were HCVpositive, while HBV infection represented only 8% of all HCC patients(n = 4); and two patients were negative for both viral markers. A highly significant difference was found between patients with HCC and chronic liver disease as well as controls with regard to serum ANXA2 levels(130, IQR 15-240; 15, IQR 15-17; and 17, IQR 15-30 ng/m L, respectively). The area under the curve of ANXA2 was 0.865; the cut-off value was established to be 18 ng/mL with a diagnostic sensitivity of 74% and a specificity of 88%, while the sensitivity and specificity of AFP at the cut-off value of 200 ng/dL were 20% and 100%, respectively.CONCLUSION Serum ANXA2 may serve as a biomarker for the early detection of HCC.
引文
1 Miller FD,Abu-Raddad LJ.Evidence of intense ongoing endemic transmission of hepatitis C virus in Egypt.Proc Natl Acad Sci USA 2010;107:14757-14762[PMID:20696911 DOI:10.1073/pnas.1008877107]
2 El-Serag HB.Hepatocellular carcinoma.N Engl J Med 2011;365:1118-1127[PMID:21992124 DOI:10.1056/NEJMra1001683]
3 Malaguarnera M,Vacante M,Fichera R,Cappellani A,Cristaldi E,Motta M.Chromogranin A(Cg A)serum level as a marker of progression in hepatocellular carcinoma(HCC)of elderly patients.Arch Gerontol Geriatr 2010;51:81-85[PMID:19766330 DOI:10 .1016/j.archger.2009.08.004]
4 Bharadwaj A,Bydoun M,Holloway R,Waisman D.Annexin A2 heterotetramer:structure and function.Int J Mol Sci 2013;14:6259-6305[PMID:23519104 DOI:10.3390/ijms14036259]
5 Lokman NA,Ween MP,Oehler MK,Ricciardelli C.The role of annexin A2 in tumorigenesis and cancer progression.Cancer Microenviron 2011;4:199-208[PMID:21909879 DOI:10.1007/s12307-011-0064-9]
6 Zhang HJ,Yao DF,Yao M,Huang H,Wu W,Yan MJ,Yan XD,Chen J.Expression characteristics and diagnostic value of annexin A2 in hepatocellular carcinoma.World J Gastroenterol 2012;18:5897-5904[PMID:23139605 DOI:10.3748/wjg.v18.i41.5897]
7 Zhang Q,Ye Z,Yang Q,He X,Wang H,Zhao Z.Upregulated expression of annexin II is a prognostic marker for patients with gastric cancer.World J Surg Oncol 2012;10:103[PMID:22681645DOI:10.1186/1477-7819-10-103]
8 Yang SL,Chou YT,Wu CN,Ho MS.Annexin II binds to capsid protein VP1 of enterovirus 71 and enhances viral infectivity.J Virol 2011;85:11809-11820[PMID:21900167 DOI:10.1128/JVI.00297-11]
9 Sun Y,Gao G,Cai J,Wang Y,Qu X,He L,Liu F,Zhang Y,Lin K,Ma S,Yang X,Qian X,Zhao X.Annexin A2 is a discriminative serological candidate in early hepatocellular carcinoma.Carcino-genesis 2013;34:595-604[PMID:23188673 DOI:10.1093/carcin/bgs372]
10 Ji NY,Park MY,Kang YH,Lee CI,Kim DG,Yeom YI,Jang YJ,Myung PK,Kim JW,Lee HG,Kim JW,Lee K,Song EY.Evaluation of annexin II as a potential serum marker for hepatocellular carcinoma using a developed sandwich ELISA method.Int J Mol Med 2009;24:765-771[PMID:19885616]
11 Forner A,Reig ME,de Lope CR,Bruix J.Current strategy for staging and treatment:the BCLC update and future prospects.Semin Liver Dis 2010;30:61-74[PMID:20175034 DOI:10.1055/s-0030-1247133]
12 European Association For The Study Of The Liver;European Organisation For Research And Treatment Of Cancer.EASL-EORTC clinical practice guidelines:management of hepatocellular carcinoma.J Hepatol 2012;56:908-943[PMID:22424438 DOI:10 .1016/j.jhep.2011.12.001]
13 Riener MO,Stenner F,Liewen H,Soll C,Breitenstein S,Pestalozzi BC,Samaras P,Probst-Hensch N,Hellerbrand C,Müllhaupt B,Clavien PA,Bahra M,Neuhaus P,Wild P,Fritzsche F,Moch H,Jochum W,Kristiansen G.Golgi phosphoprotein 2(GOLPH2)expression in liver tumors and its value as a serum marker in hepatocellular carcinomas.Hepatology 2009;49:1602-1609[PMID:19291786 DOI:10.1002/hep.22843]
14 Page AJ,Cosgrove DC,Philosophe B,Pawlik TM.Hepatocellular carcinoma:diagnosis,management,and prognosis.Surg Oncol Clin N Am 2014;23:289-311[PMID:24560111 DOI:10.1016/j.soc.2013.10.006]
15 Zhu K,Dai Z,Zhou J.Biomarkers for hepatocellular carcinoma:progression in early diagnosis,prognosis,and personalized therapy.Biomark Res 2013;1:10[PMID:24252133 DOI:10.1186/2050-7771-1-10]
16 Thapa BR,Walia A.Liver function tests and their interpretation.Indian J Pediatr 2007;74:663-671[PMID:17699976]
17 Bolog N,Andreisek G,Oancea I,Mangrau A.CT and MR imaging of hepatocellular carcinoma.J Gastrointestin Liver Dis 2011;20:181 -189[PMID:21725516]
18 Toyoda H,Kumada T,Tada T,Kaneoka Y,Maeda A,Kanke F,Satomura S.Clinical utility of highly sensitive Lens culinaris agglutinin-reactive alpha-fetoprotein in hepatocellular carcinoma patients with alpha-fetoprotein<20 ng/m L.Cancer Sci 2011;102 :1025-1031[PMID:21244578 DOI:10.1111/j.1349-7006.2011.01875.x]
19 Cui Z,Yu X,Guo L,Wei Y,Zheng S,Li W,Chen P,Zhu J,Peng J.Combined analysis of serum alpha-fetoprotein and MAGE-A3-specific cytotoxic T lymphocytes in peripheral blood for diagnosis of hepatocellular carcinoma.Dis Markers 2013;35:915-923[PMID:24427779 DOI:10.1155/2013/907394]
20 Bruix J,Sherman M,Llovet JM,Beaugrand M,Lencioni R,Burroughs AK,Christensen E,Pagliaro L,Colombo M,Rodés J.Clinical management of hepatocellular carcinoma.Conclusions of the Barcelona-2000 EASL conference.European Association for the Study of the Liver.J Hepatol 2001;35:421-430[PMID:11592607]
21 Gurluler E,Guner OS,Tumay LV,Turkel Kucukmetin N,Hizli B,Zorluoglu A.Serum annexin A2 levels in patients with colon cancer in comparison to healthy controls and in relation to tumor pathology.Med Sci Monit 2014;20:1801-1807[PMID:25287627DOI:10.12659/MSM.892319]
22 Liu Y,Myrvang HK,Dekker LV.Annexin A2 complexes with S100proteins:structure,function and pharmacological manipulation.Br J Pharmacol 2015;172:1664-1676[PMID:25303710 DOI:10 .1111/bph.12978]
23 Zidan A,Scheuerlein H,Schüle S,Settmacher U,Rauchfuss F.Epidemiological pattern of hepatitis B and hepatitis C as etiological agents for hepatocellular carcinoma in iran and worldwide.Hepat Mon 2012;12:e6894[PMID:23233864 DOI:10.5812/hepatmon.6894]
24 Zekri AR,Hassan ZK,Bahnassy AA,Sherif GM,ELdahshan D,Abouelhoda M,Ali A,Hafez MM.Molecular prognostic profile of Egyptian HCC cases infected with hepatitis C virus.Asian Pac J Cancer Prev 2012;13:5433-5438[PMID:23317196]
25 Abdelgawad IA,Mossallam GI,Radwan NH,Elzawahry HM,Elhifnawy NM.Can Glypican3 be diagnostic for early hepato-cellular carcinoma among Egyptian patients?Asian Pac J Cancer Prev 2013;14:7345-7349[PMID:24460300]
26 Shaker MK,Abdella HM,Khalifa MO,El Dorry AK.Epide-miological characteristics of hepatocellular carcinoma in Egypt:a retrospective analysis of 1313 cases.Liver Int 2013;33:1601-1606[PMID:23714212 DOI:10.1111/liv.12209]
27 El-Tayeh SF,Hussein TD,El-Houseini ME,Amer MA,El-Sherbini M,Elshemey WM.Serological biomarkers of hepato-cellular carcinoma in Egyptian patients.Dis Markers 2012;32:255 -263[PMID:22430192 DOI:10.3233/DMA-2011-0883]
28 Awadallah AM,Issa HA,Soliman MS.Evaluation of Serum Chromogranin-A as a Useful Tumor Marker for Diagnosis of Hepatocellular Carcinoma.J Am Sci 2011;7:999
29 Bruix J,Sherman M.Management of hepatocellular carcinoma:an update.Hepatology 2011;53:1020-1022[PMID:21374666 DOI:10 .1002/hep.24199]
30 Ibrahim MA,Hashem ME,Mostafa EF,Refaey MM,Hamed EF,Islam Ibrahim I,Almahdy MA.Annexin A2 versus AFP as an efficient diagnostic serum marker for hepatocellular carcinoma.J Gastroenterol Hepatol 2013;2:780-785
31 Wang CY,Lin CF.Annexin A2:its molecular regulation and cellular expression in cancer development.Dis Markers 2014;2014:308976[PMID:24591759 DOI:10.1155/2014/308976]
32 Mohammad HS,Kurokohchi K,Yoneyama H,Tokuda M,Morishita A,Jian G,Shi L,Murota M,Tani J,Kato K,Miyoshi H,Deguchi A,Himoto T,Usuki H,Wakabayashi H,Izuishi K,Suzuki Y,Iwama H,Deguchi K,Uchida N,Sabet EA,Arafa UA,Hassan AT,El-Sayed AA,Masaki T.Annexin A2 expression and phosphorylation are up-regulated in hepatocellular carcinoma.Int J Oncol 2008;33:1157-1163[PMID:19020748]
33 El-Abd N,Fawzy A,Elbaz T,Hamdy S.Evaluation of annexin A2and as potential biomarkers for hepatocellular carcinoma.Tumour Biol 2016;37:211-216[PMID:26189841 DOI:10.1007/s13277-015 -3524-x]
2 El-Serag HB.Hepatocellular carcinoma.N Engl J Med 2011;365:1118-1127[PMID:21992124 DOI:10.1056/NEJMra1001683]
3 Malaguarnera M,Vacante M,Fichera R,Cappellani A,Cristaldi E,Motta M.Chromogranin A(Cg A)serum level as a marker of progression in hepatocellular carcinoma(HCC)of elderly patients.Arch Gerontol Geriatr 2010;51:81-85[PMID:19766330 DOI:10 .1016/j.archger.2009.08.004]
4 Bharadwaj A,Bydoun M,Holloway R,Waisman D.Annexin A2 heterotetramer:structure and function.Int J Mol Sci 2013;14:6259-6305[PMID:23519104 DOI:10.3390/ijms14036259]
5 Lokman NA,Ween MP,Oehler MK,Ricciardelli C.The role of annexin A2 in tumorigenesis and cancer progression.Cancer Microenviron 2011;4:199-208[PMID:21909879 DOI:10.1007/s12307-011-0064-9]
6 Zhang HJ,Yao DF,Yao M,Huang H,Wu W,Yan MJ,Yan XD,Chen J.Expression characteristics and diagnostic value of annexin A2 in hepatocellular carcinoma.World J Gastroenterol 2012;18:5897-5904[PMID:23139605 DOI:10.3748/wjg.v18.i41.5897]
7 Zhang Q,Ye Z,Yang Q,He X,Wang H,Zhao Z.Upregulated expression of annexin II is a prognostic marker for patients with gastric cancer.World J Surg Oncol 2012;10:103[PMID:22681645DOI:10.1186/1477-7819-10-103]
8 Yang SL,Chou YT,Wu CN,Ho MS.Annexin II binds to capsid protein VP1 of enterovirus 71 and enhances viral infectivity.J Virol 2011;85:11809-11820[PMID:21900167 DOI:10.1128/JVI.00297-11]
9 Sun Y,Gao G,Cai J,Wang Y,Qu X,He L,Liu F,Zhang Y,Lin K,Ma S,Yang X,Qian X,Zhao X.Annexin A2 is a discriminative serological candidate in early hepatocellular carcinoma.Carcino-genesis 2013;34:595-604[PMID:23188673 DOI:10.1093/carcin/bgs372]
10 Ji NY,Park MY,Kang YH,Lee CI,Kim DG,Yeom YI,Jang YJ,Myung PK,Kim JW,Lee HG,Kim JW,Lee K,Song EY.Evaluation of annexin II as a potential serum marker for hepatocellular carcinoma using a developed sandwich ELISA method.Int J Mol Med 2009;24:765-771[PMID:19885616]
11 Forner A,Reig ME,de Lope CR,Bruix J.Current strategy for staging and treatment:the BCLC update and future prospects.Semin Liver Dis 2010;30:61-74[PMID:20175034 DOI:10.1055/s-0030-1247133]
12 European Association For The Study Of The Liver;European Organisation For Research And Treatment Of Cancer.EASL-EORTC clinical practice guidelines:management of hepatocellular carcinoma.J Hepatol 2012;56:908-943[PMID:22424438 DOI:10 .1016/j.jhep.2011.12.001]
13 Riener MO,Stenner F,Liewen H,Soll C,Breitenstein S,Pestalozzi BC,Samaras P,Probst-Hensch N,Hellerbrand C,Müllhaupt B,Clavien PA,Bahra M,Neuhaus P,Wild P,Fritzsche F,Moch H,Jochum W,Kristiansen G.Golgi phosphoprotein 2(GOLPH2)expression in liver tumors and its value as a serum marker in hepatocellular carcinomas.Hepatology 2009;49:1602-1609[PMID:19291786 DOI:10.1002/hep.22843]
14 Page AJ,Cosgrove DC,Philosophe B,Pawlik TM.Hepatocellular carcinoma:diagnosis,management,and prognosis.Surg Oncol Clin N Am 2014;23:289-311[PMID:24560111 DOI:10.1016/j.soc.2013.10.006]
15 Zhu K,Dai Z,Zhou J.Biomarkers for hepatocellular carcinoma:progression in early diagnosis,prognosis,and personalized therapy.Biomark Res 2013;1:10[PMID:24252133 DOI:10.1186/2050-7771-1-10]
16 Thapa BR,Walia A.Liver function tests and their interpretation.Indian J Pediatr 2007;74:663-671[PMID:17699976]
17 Bolog N,Andreisek G,Oancea I,Mangrau A.CT and MR imaging of hepatocellular carcinoma.J Gastrointestin Liver Dis 2011;20:181 -189[PMID:21725516]
18 Toyoda H,Kumada T,Tada T,Kaneoka Y,Maeda A,Kanke F,Satomura S.Clinical utility of highly sensitive Lens culinaris agglutinin-reactive alpha-fetoprotein in hepatocellular carcinoma patients with alpha-fetoprotein<20 ng/m L.Cancer Sci 2011;102 :1025-1031[PMID:21244578 DOI:10.1111/j.1349-7006.2011.01875.x]
19 Cui Z,Yu X,Guo L,Wei Y,Zheng S,Li W,Chen P,Zhu J,Peng J.Combined analysis of serum alpha-fetoprotein and MAGE-A3-specific cytotoxic T lymphocytes in peripheral blood for diagnosis of hepatocellular carcinoma.Dis Markers 2013;35:915-923[PMID:24427779 DOI:10.1155/2013/907394]
20 Bruix J,Sherman M,Llovet JM,Beaugrand M,Lencioni R,Burroughs AK,Christensen E,Pagliaro L,Colombo M,Rodés J.Clinical management of hepatocellular carcinoma.Conclusions of the Barcelona-2000 EASL conference.European Association for the Study of the Liver.J Hepatol 2001;35:421-430[PMID:11592607]
21 Gurluler E,Guner OS,Tumay LV,Turkel Kucukmetin N,Hizli B,Zorluoglu A.Serum annexin A2 levels in patients with colon cancer in comparison to healthy controls and in relation to tumor pathology.Med Sci Monit 2014;20:1801-1807[PMID:25287627DOI:10.12659/MSM.892319]
22 Liu Y,Myrvang HK,Dekker LV.Annexin A2 complexes with S100proteins:structure,function and pharmacological manipulation.Br J Pharmacol 2015;172:1664-1676[PMID:25303710 DOI:10 .1111/bph.12978]
23 Zidan A,Scheuerlein H,Schüle S,Settmacher U,Rauchfuss F.Epidemiological pattern of hepatitis B and hepatitis C as etiological agents for hepatocellular carcinoma in iran and worldwide.Hepat Mon 2012;12:e6894[PMID:23233864 DOI:10.5812/hepatmon.6894]
24 Zekri AR,Hassan ZK,Bahnassy AA,Sherif GM,ELdahshan D,Abouelhoda M,Ali A,Hafez MM.Molecular prognostic profile of Egyptian HCC cases infected with hepatitis C virus.Asian Pac J Cancer Prev 2012;13:5433-5438[PMID:23317196]
25 Abdelgawad IA,Mossallam GI,Radwan NH,Elzawahry HM,Elhifnawy NM.Can Glypican3 be diagnostic for early hepato-cellular carcinoma among Egyptian patients?Asian Pac J Cancer Prev 2013;14:7345-7349[PMID:24460300]
26 Shaker MK,Abdella HM,Khalifa MO,El Dorry AK.Epide-miological characteristics of hepatocellular carcinoma in Egypt:a retrospective analysis of 1313 cases.Liver Int 2013;33:1601-1606[PMID:23714212 DOI:10.1111/liv.12209]
27 El-Tayeh SF,Hussein TD,El-Houseini ME,Amer MA,El-Sherbini M,Elshemey WM.Serological biomarkers of hepato-cellular carcinoma in Egyptian patients.Dis Markers 2012;32:255 -263[PMID:22430192 DOI:10.3233/DMA-2011-0883]
28 Awadallah AM,Issa HA,Soliman MS.Evaluation of Serum Chromogranin-A as a Useful Tumor Marker for Diagnosis of Hepatocellular Carcinoma.J Am Sci 2011;7:999
29 Bruix J,Sherman M.Management of hepatocellular carcinoma:an update.Hepatology 2011;53:1020-1022[PMID:21374666 DOI:10 .1002/hep.24199]
30 Ibrahim MA,Hashem ME,Mostafa EF,Refaey MM,Hamed EF,Islam Ibrahim I,Almahdy MA.Annexin A2 versus AFP as an efficient diagnostic serum marker for hepatocellular carcinoma.J Gastroenterol Hepatol 2013;2:780-785
31 Wang CY,Lin CF.Annexin A2:its molecular regulation and cellular expression in cancer development.Dis Markers 2014;2014:308976[PMID:24591759 DOI:10.1155/2014/308976]
32 Mohammad HS,Kurokohchi K,Yoneyama H,Tokuda M,Morishita A,Jian G,Shi L,Murota M,Tani J,Kato K,Miyoshi H,Deguchi A,Himoto T,Usuki H,Wakabayashi H,Izuishi K,Suzuki Y,Iwama H,Deguchi K,Uchida N,Sabet EA,Arafa UA,Hassan AT,El-Sayed AA,Masaki T.Annexin A2 expression and phosphorylation are up-regulated in hepatocellular carcinoma.Int J Oncol 2008;33:1157-1163[PMID:19020748]
33 El-Abd N,Fawzy A,Elbaz T,Hamdy S.Evaluation of annexin A2and as potential biomarkers for hepatocellular carcinoma.Tumour Biol 2016;37:211-216[PMID:26189841 DOI:10.1007/s13277-015 -3524-x]