HIF-1?在高原地区胃癌及胃黏膜癌前病变组织中的表达及临床意义
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摘要
目的探讨缺氧诱导因子-1a(hypoxia inducible factor-1a,HIF-1a)在高原地区胃癌及癌前病变患者中的表达与胃黏膜恶变过程中的临床联系及预后评价.方法利用RT-PCR检测7株胃癌细胞系及其27对胃癌和配癌旁正常组织中HIF-1a的表达;进一步利用组织微阵列和免疫组织化学染色检测37例萎缩性胃炎,34例胃黏膜肠化组织,146例胃癌和57例癌旁正常组织中HIF-1a的表达情况.结果RT-PCR检测显示,HIF-1a在7株胃癌细胞系存在差异表达.同时在胃癌组织的表达水平66.6%(18/27)高于癌旁正常组织14.8%(4/27)(P<0.001).免疫组织化学显示,HIF-1a在癌旁正常组织中表达阳性率为26.3%(15/57);萎缩性胃炎组织为64.8%(24/37);肠化生组织为61.7%(21/34);胃癌组织为56.8%(83/146).并且HIF-1a的表达与年龄相关(P<0.05),而与性别、胃癌的分化程度、胃癌患者临床分期等无关.Kaplan-Meier法和COX多因素回归分析提示HIF-1a高表达是术后胃癌患者独立的危险因素(P<0.001),RR=3.229(95%CI:2.024-5.151).结论HIF-1a表达在胃黏膜恶变过程中表达增加,并且与高原地区胃癌患者不良预后的密切相关.
AIM To detect the expression of hypoxia indurible factor-1α(HIF-1α) in gastric malignant transformation in people from high altitude area of Qinghai,China.METHODS RT-PCR was used to detect the expression of HIF-1α gene in 7 cell lines and 27 pairs of GC and matched tumor adjacent normal gastric mucosa tissues.Using tissue microarray including 57 normal gastric mucosa tissues,37 chronic atrophic gastritis tissues,34 intestinal metaplasia tissues,and 146 gastric cancer(GC)tissues,immunohistochemistry(IHC) was performed to detect the level of HIF-1α protein expression.RESULTS The expression of HIF-1α at the mRNA level was different in GC cell lines.HIF-1αexpression in AGS,SGC7901,and N87 cells was higher than that in MGC803,BGC823,PAMC82 and MKN45 cells.The level of HIF-1α expression was significantly higher in GC tissues(66.6%,18/27) compared with normal gastric mucosa tissues(26.3%,15/57;P<0.001).IHC data showed that the positive rate of HIF-1α was 64.8%(24/37) in chronic atrophic gastritis tissues,61.7%(21/34) in intestinal metaplasia tissues,and 56.8%(83/146) in GC tissues,all of which were significantly higher than that in normal tissues(26.3%,15/57).Expression of HIF-1α was positively associated with age in GC(P<0.05).Kaplan-Meier analysis showed that patients with a low level of HIF-1α had apparently better survival than those with a high level(P<0.0001).HIF-1αprotein(RR=3.229,95%CI:2.024-5.151) was identified to be an independent risk factor for the outcome of GC patients.CONCLUSION High HIF-1α expression is associated with gastric malignant transformation and poor prognosis in high altitude areas.
AIM To detect the expression of hypoxia indurible factor-1α(HIF-1α) in gastric malignant transformation in people from high altitude area of Qinghai,China.METHODS RT-PCR was used to detect the expression of HIF-1α gene in 7 cell lines and 27 pairs of GC and matched tumor adjacent normal gastric mucosa tissues.Using tissue microarray including 57 normal gastric mucosa tissues,37 chronic atrophic gastritis tissues,34 intestinal metaplasia tissues,and 146 gastric cancer(GC)tissues,immunohistochemistry(IHC) was performed to detect the level of HIF-1α protein expression.RESULTS The expression of HIF-1α at the mRNA level was different in GC cell lines.HIF-1αexpression in AGS,SGC7901,and N87 cells was higher than that in MGC803,BGC823,PAMC82 and MKN45 cells.The level of HIF-1α expression was significantly higher in GC tissues(66.6%,18/27) compared with normal gastric mucosa tissues(26.3%,15/57;P<0.001).IHC data showed that the positive rate of HIF-1α was 64.8%(24/37) in chronic atrophic gastritis tissues,61.7%(21/34) in intestinal metaplasia tissues,and 56.8%(83/146) in GC tissues,all of which were significantly higher than that in normal tissues(26.3%,15/57).Expression of HIF-1α was positively associated with age in GC(P<0.05).Kaplan-Meier analysis showed that patients with a low level of HIF-1α had apparently better survival than those with a high level(P<0.0001).HIF-1αprotein(RR=3.229,95%CI:2.024-5.151) was identified to be an independent risk factor for the outcome of GC patients.CONCLUSION High HIF-1α expression is associated with gastric malignant transformation and poor prognosis in high altitude areas.
引文
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6 Nam SY,Ko YS,Jung J,Yoon J,Kim YH,Choi YJ,Park JW,Chang MS,Kim WH,Lee BL.A hypoxia-dependent upregulation of hypoxiaindudble factor-1 by nuclear factor-κB promotes gastric tumour growth and angiogenesis.Br J Cancer 2011;104:166-174[PMID:21119667 DOI:10.1038/sj.bjc.6606020]
7 Rohwer N,Lobitz S,Daskalow K,Jons T,Vieth M,Schlag PM,Kemmner W,Wiedenmann B,Cramer T,Hocker M.HIF-1alpha determines the metastatic potential of gastric cancer cells.Br J Cancer 2009;100:772-781[PMID:19223895 DOI:10.1038/sj.bjc.6604919]
8 Mizokami K,Kakeji Y,Oda S,Me K,Yonemura T,Konishi F,Maehara Y.Clinicopathologic significance of hypoxia-inducible factor lalpha overexpression in gastric carcinomas.JSurg Oncol2006;94:149-154[PMID:16847924 DOI:10.1002/jso.20568]
9 Chen L,Shi Y,Yuan J,Han Y,Qin R,Wu Q,Jia B,Wei B,Wei L,Dai G,Jiao S.HIF-1 alpha overexpression correlates with poor overall survival and disease-free survival in gastric cancer patients post-gastrectomy.PLoS One 2014;9:e90678[PMID:24614305 DOI:10.1371/journal.pone.0090678]
10吴友亮,胡玲娜,郑成德,孙若川,张尚鑫,闫强,李永翔.缺氧诱导因子1α在胃癌组织中的表达及其临床意义.中华医学杂志2016;96:1418-1423
11 Folkman J.Proceedings:Tumor angiogenesis factor.Cancer Res 1974;34:2109-2113[PMID:4842257]
12 Wu TY,Ding SQ,Liu JL,Jia JH,Dai RC,Zhu DC,Liang BZ,Qi DT,Sun YF.High-altitude gastrointestinal bleeding:an observation in Qinghai-Tibetan railroad construction workers on Mountain Tanggula.World J Gastroenterol 2007;13:774-780[PMID:17278202 DOI:10.3748/wjg.vl3.i5.774]
13 Wang ZT,Yao YM,Xiao GX,Sheng ZY.Risk factors of development of gut-derived bacterial translocation in thermally injured rats.World J Gastroenterol 2004;10:1619-1624[PMID:15162536DOI:10.3748/wjg.v10.i11.1619]
14 Wei H,Li F,Fu P,Liu X.Effects of the silencing of hypoxia-inducible Factor-1 alpha on metastasis of pancreatic cancer.Eur Rev Med Pharmacol Sci 2013;17:436-446[PMID:23467940]
15 Choi KS,Bae MK,Jeong JW,Moon HE,Kim KW.Hypoxia-induced angiogenesis during carcinogenesis.J Biochem Mol Biol 2003;36:120-127[PMID:12542982 DOI:10.5483/bmbrep.2003.36.1.120]
16 Majmundar AJ,Wong WJ,Simon MC.Hypoxiainducible factors and the response to hypoxic stress.Mol Cell 2010;40:294-309[PMID:20965423DOI:10.1016/j.molcel.2010.09.022]
17 Shenberger JS,Zhang L,Powell RJ,Barchowsky A.Hyperoxia enhances VEGF release from A549cells via post-transcriptional processes.Free Radic Biol Med 2007;43:844-852[PMID:17664148 DOI:10.1016/j.freeradbiomed.2007.05.033]
18 Rigiracciolo DC,Scarpelli A,Lappano R,Pisano A,Santolla MF,De Marco P,Cirillo F,Cappello AR,Dolce V,Belfiore A,Maggiolini M,De Francesco EM.Copper activates HIF-1α/GPER/VEGF signalling in cancer cells.Oncotarget 2015;6:34158-34177[PMID:26415222 DOI:10.18632/oncotarget.5779]
19 Kim DH,Sung B,Kang YJ,Hwang SY,Kim MJ,Yoon JH,Im E,Kim ND.Sulforaphane inhibits hypoxia-induced HIF-1αand VEGF expression and migration of human colon cancer cells.Int J Oncol 2015;47:2226-2232[PMID:26498863 DOI:10.3892/ijo.2015.3200]
20 Guleng B,Han J,Yang JQ,Huang QW,Huang JK,Yang XN,Liu JJ,Ren JL.TFF3 mediated induction of VEGF via hypoxia in human gastric cancer SGC-7901 cells.Mol Biol Rep 2012;39:4127-4134[PMID:21769478 DOI:10.1007/s11033-011-1195-2]
21 Griffiths EA,Pritchard SA,McGrath SM,Valentine HR,Price PM,Welch IM,West CM.Hypoxiaassociated markers in gastric carcinogenesis and HIF-2alpha in gastric and gastro-oesophageal cancer prognosis.Br J Cancer 2008;98:965-973[PMID:18283323 DOI:10.1038/sj.bjc.6604210]
22 Wong PP,Bodrug N,Hodivala-Dilke KM.Exploring Novel Methods for Modulating Tumor Blood Vessels in Cancer Treatment.Curr Biol2016;26:R1161-R1166[PMID:27825457 DOI:10.1016/j.cub.2016.09.043]
23 Li B,Takeda K,Yokoyama S,Shibahara S.A prolyl-hydroxylase inhibitor,ethyl-3,4-dihydroxybenzoate,induces haem oxygenase-1expression in human cells through a mechanism independent of hypoxia-indudble factor-lalpha.J Biochem 2008;144:643-654[PMID:18799519 DOI:10.1093/jb/mvn115]
24 Fitzpatrick B,Mehibel M,Cowen RL,Stratford IJ.iNOS as a therapeutic target for treatment of human tumors.Nitric Oxide 2008;19:217-224[PMID:18515106 DOI:10.1016/j.niox.2008.05.001]
25 Chen T,Ren Z,Ye LC,Zhou PH,Xu JM,Shi Q,Yao LQ,Zhong YS.Factor inhibiting HIF1α(FIH-1)functions as a tumor suppressor in human colorectal cancer by repressing HIF1αpathway.Cancer Biol Ther 2015;16:244-252[PMID:25602156DOI:10.1080/15384047.2014.1002346]
26 Mancini M,Gariboldi MB,Taiana E,Bonzi MC,Craparotta I,Pagin M,Monti E.Co-targeting the IGF system and HIF-1 inhibits migration and invasion by(triple-negative)breast cancer cells.Br J Cancer 2014;110:2865-2873[PMID:24853185DOI:10.1038/bjc.2014.269]
27 Muz B,de la Puente P,Azab F,Azab AK.The role of hypoxia in cancer progression,angiogenesis,metastasis,and resistance to therapy.Hypoxia(Auckl)2015;3:83-92[PMID:27774485 DOI:10.2147/HP.S93413]
28 Allen M,Louise Jones J.Jekyll and Hyde:the role of the microenvironment on the progression of cancer.J Pathol 2011;223:162-176[PMID:21125673 DOI:10.1002/path.2803]
29 Abdel-Rahman O.Targeting vascular endothelial growth factor(VEGF)pathway in gastric cancer:preclinical and clinical aspects.Crit Rev Oncol Hematol 2015;93:18-27[PMID:24970311 DOI:10.1016/j.critrevonc.2014.05.012]
30 Griffiths EA,Pritchard SA,Valentine HR,Whitchelo N,Bishop PW,Ebert MP,Price PM,Welch IM,West CM.Hypoxia-inducible factorlalpha expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas.Br J Cancer2007;96:95-103[PMID:17179985 DOI:10.1038/sj.bjc.6603524]
2 Qi YJ,Cui S,Yang YZ,Han JQ,Cai BJ,Sheng CF,Ma Y,Wuren T,Ge RL.Excision repair cross-complementation group 1 codon 118polymorphism,micro ribonucleic acid and protein expression,clinical outcome of the advanced gastric cancer response to first-line FOLFOX-4in Qinghai-Tibetan plateau population.JCancer Res Ther 2013;9:410-415[PMID:24125975 DOI:10.4103/0973-1482.119319]
3 Jing JJ,Liu HY,Hao JK,Wang LN,Wang YP,Sun LH,Yuan Y.Gastric cancer incidence and mortality in Zhuanghe,China,between 2005 and2010.World J Gastroenterol 2012;18:1262-1269[PMID:22468091 DOI:10.3748/wjg.vl8.ill.l262]
4 Hicks TP,Stark CA,Fletcher WA.Origins of afferents to visual suprageniculate nucleus of the cat.J Comp Neurol 1986;246:544-554[PMID:2422232 DOI:10.1007/s11605-013-2407-y]
5 Medina Villaamil V,Aparicio Gallego G,Santamarina Cainzos I,Valladares-Ayerbes M,Anton Aparicio LM.Searching for Hif1-αinteracting proteins in renal cell carcinoma.Clin Transl Oncol 2012;14:698-708[PMID:22926943DOI:10.1007/s12094-012-0857-4]
6 Nam SY,Ko YS,Jung J,Yoon J,Kim YH,Choi YJ,Park JW,Chang MS,Kim WH,Lee BL.A hypoxia-dependent upregulation of hypoxiaindudble factor-1 by nuclear factor-κB promotes gastric tumour growth and angiogenesis.Br J Cancer 2011;104:166-174[PMID:21119667 DOI:10.1038/sj.bjc.6606020]
7 Rohwer N,Lobitz S,Daskalow K,Jons T,Vieth M,Schlag PM,Kemmner W,Wiedenmann B,Cramer T,Hocker M.HIF-1alpha determines the metastatic potential of gastric cancer cells.Br J Cancer 2009;100:772-781[PMID:19223895 DOI:10.1038/sj.bjc.6604919]
8 Mizokami K,Kakeji Y,Oda S,Me K,Yonemura T,Konishi F,Maehara Y.Clinicopathologic significance of hypoxia-inducible factor lalpha overexpression in gastric carcinomas.JSurg Oncol2006;94:149-154[PMID:16847924 DOI:10.1002/jso.20568]
9 Chen L,Shi Y,Yuan J,Han Y,Qin R,Wu Q,Jia B,Wei B,Wei L,Dai G,Jiao S.HIF-1 alpha overexpression correlates with poor overall survival and disease-free survival in gastric cancer patients post-gastrectomy.PLoS One 2014;9:e90678[PMID:24614305 DOI:10.1371/journal.pone.0090678]
10吴友亮,胡玲娜,郑成德,孙若川,张尚鑫,闫强,李永翔.缺氧诱导因子1α在胃癌组织中的表达及其临床意义.中华医学杂志2016;96:1418-1423
11 Folkman J.Proceedings:Tumor angiogenesis factor.Cancer Res 1974;34:2109-2113[PMID:4842257]
12 Wu TY,Ding SQ,Liu JL,Jia JH,Dai RC,Zhu DC,Liang BZ,Qi DT,Sun YF.High-altitude gastrointestinal bleeding:an observation in Qinghai-Tibetan railroad construction workers on Mountain Tanggula.World J Gastroenterol 2007;13:774-780[PMID:17278202 DOI:10.3748/wjg.vl3.i5.774]
13 Wang ZT,Yao YM,Xiao GX,Sheng ZY.Risk factors of development of gut-derived bacterial translocation in thermally injured rats.World J Gastroenterol 2004;10:1619-1624[PMID:15162536DOI:10.3748/wjg.v10.i11.1619]
14 Wei H,Li F,Fu P,Liu X.Effects of the silencing of hypoxia-inducible Factor-1 alpha on metastasis of pancreatic cancer.Eur Rev Med Pharmacol Sci 2013;17:436-446[PMID:23467940]
15 Choi KS,Bae MK,Jeong JW,Moon HE,Kim KW.Hypoxia-induced angiogenesis during carcinogenesis.J Biochem Mol Biol 2003;36:120-127[PMID:12542982 DOI:10.5483/bmbrep.2003.36.1.120]
16 Majmundar AJ,Wong WJ,Simon MC.Hypoxiainducible factors and the response to hypoxic stress.Mol Cell 2010;40:294-309[PMID:20965423DOI:10.1016/j.molcel.2010.09.022]
17 Shenberger JS,Zhang L,Powell RJ,Barchowsky A.Hyperoxia enhances VEGF release from A549cells via post-transcriptional processes.Free Radic Biol Med 2007;43:844-852[PMID:17664148 DOI:10.1016/j.freeradbiomed.2007.05.033]
18 Rigiracciolo DC,Scarpelli A,Lappano R,Pisano A,Santolla MF,De Marco P,Cirillo F,Cappello AR,Dolce V,Belfiore A,Maggiolini M,De Francesco EM.Copper activates HIF-1α/GPER/VEGF signalling in cancer cells.Oncotarget 2015;6:34158-34177[PMID:26415222 DOI:10.18632/oncotarget.5779]
19 Kim DH,Sung B,Kang YJ,Hwang SY,Kim MJ,Yoon JH,Im E,Kim ND.Sulforaphane inhibits hypoxia-induced HIF-1αand VEGF expression and migration of human colon cancer cells.Int J Oncol 2015;47:2226-2232[PMID:26498863 DOI:10.3892/ijo.2015.3200]
20 Guleng B,Han J,Yang JQ,Huang QW,Huang JK,Yang XN,Liu JJ,Ren JL.TFF3 mediated induction of VEGF via hypoxia in human gastric cancer SGC-7901 cells.Mol Biol Rep 2012;39:4127-4134[PMID:21769478 DOI:10.1007/s11033-011-1195-2]
21 Griffiths EA,Pritchard SA,McGrath SM,Valentine HR,Price PM,Welch IM,West CM.Hypoxiaassociated markers in gastric carcinogenesis and HIF-2alpha in gastric and gastro-oesophageal cancer prognosis.Br J Cancer 2008;98:965-973[PMID:18283323 DOI:10.1038/sj.bjc.6604210]
22 Wong PP,Bodrug N,Hodivala-Dilke KM.Exploring Novel Methods for Modulating Tumor Blood Vessels in Cancer Treatment.Curr Biol2016;26:R1161-R1166[PMID:27825457 DOI:10.1016/j.cub.2016.09.043]
23 Li B,Takeda K,Yokoyama S,Shibahara S.A prolyl-hydroxylase inhibitor,ethyl-3,4-dihydroxybenzoate,induces haem oxygenase-1expression in human cells through a mechanism independent of hypoxia-indudble factor-lalpha.J Biochem 2008;144:643-654[PMID:18799519 DOI:10.1093/jb/mvn115]
24 Fitzpatrick B,Mehibel M,Cowen RL,Stratford IJ.iNOS as a therapeutic target for treatment of human tumors.Nitric Oxide 2008;19:217-224[PMID:18515106 DOI:10.1016/j.niox.2008.05.001]
25 Chen T,Ren Z,Ye LC,Zhou PH,Xu JM,Shi Q,Yao LQ,Zhong YS.Factor inhibiting HIF1α(FIH-1)functions as a tumor suppressor in human colorectal cancer by repressing HIF1αpathway.Cancer Biol Ther 2015;16:244-252[PMID:25602156DOI:10.1080/15384047.2014.1002346]
26 Mancini M,Gariboldi MB,Taiana E,Bonzi MC,Craparotta I,Pagin M,Monti E.Co-targeting the IGF system and HIF-1 inhibits migration and invasion by(triple-negative)breast cancer cells.Br J Cancer 2014;110:2865-2873[PMID:24853185DOI:10.1038/bjc.2014.269]
27 Muz B,de la Puente P,Azab F,Azab AK.The role of hypoxia in cancer progression,angiogenesis,metastasis,and resistance to therapy.Hypoxia(Auckl)2015;3:83-92[PMID:27774485 DOI:10.2147/HP.S93413]
28 Allen M,Louise Jones J.Jekyll and Hyde:the role of the microenvironment on the progression of cancer.J Pathol 2011;223:162-176[PMID:21125673 DOI:10.1002/path.2803]
29 Abdel-Rahman O.Targeting vascular endothelial growth factor(VEGF)pathway in gastric cancer:preclinical and clinical aspects.Crit Rev Oncol Hematol 2015;93:18-27[PMID:24970311 DOI:10.1016/j.critrevonc.2014.05.012]
30 Griffiths EA,Pritchard SA,Valentine HR,Whitchelo N,Bishop PW,Ebert MP,Price PM,Welch IM,West CM.Hypoxia-inducible factorlalpha expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas.Br J Cancer2007;96:95-103[PMID:17179985 DOI:10.1038/sj.bjc.6603524]