翟玉香，王莉莉，于新娟，宮大偉，張永菊，董全江

青島大學(xué)醫(yī)學(xué)院附屬青島市市立醫(yī)院中心實(shí)驗(yàn)室，山東 青島 266071

PRKAA1和PSCA基因多態(tài)性與胃癌相關(guān)性研究新進(jìn)展

翟玉香，王莉莉，于新娟，宮大偉，張永菊，董全江

青島大學(xué)醫(yī)學(xué)院附屬青島市市立醫(yī)院中心實(shí)驗(yàn)室，山東 青島 266071

胃癌是消化系統(tǒng)最常見惡性腫瘤之一，死亡率高。目前全基因組關(guān)聯(lián)研究(genome-wide association study, GWAS)發(fā)現(xiàn)多個(gè)基因的單核苷酸多態(tài)性(single nucleotide polymorphism, SNP)與胃癌相關(guān)，其中位于PRKAA1上的rs13361707、rs10074991、rs154268、rs3805486、rs6882903和rs10036575多態(tài)性與胃癌易感性相關(guān)，該基因在機(jī)體能量代謝，細(xì)胞生長(zhǎng)增殖、凋亡、自噬等方面具有重要作用。PSCA基因編碼產(chǎn)物可抑制腫瘤生長(zhǎng)，rs2294008、rs2976392等位點(diǎn)多態(tài)性與胃癌風(fēng)險(xiǎn)增加相關(guān)。本文就PRKAA1和PSCA基因多態(tài)性與胃癌相關(guān)性研究新進(jìn)展作一概述。

全基因組關(guān)聯(lián)研究；胃癌；PRKAA1；PSCA；單核苷酸多態(tài)性

胃癌是世界第5大常見癌癥,也是癌癥相關(guān)死亡的第3大原因[1]，雖然胃癌發(fā)生的分子級(jí)聯(lián)反應(yīng)很大程度上依然未知[2]，但已證實(shí)遺傳背景[3]、行為因素(飲酒、吸煙、飲食等)[4]和感染性因素(幽門螺桿菌)[5]與胃癌發(fā)生風(fēng)險(xiǎn)相關(guān)。全球幽門螺桿菌的感染率為40%～80%，但其中僅較小一部分(約1%)的感染者發(fā)展為胃癌，提示不同遺傳背景的個(gè)體在相同的環(huán)境暴露下其胃癌的易感性不同，這種易感性目前被認(rèn)為是由個(gè)體的遺傳因素所決定。單核苷酸多態(tài)性(single nucleotide polymorphism, SNP)是個(gè)體間遺傳差異的主要形式。因此，探索基因組中SNP與胃癌易感性的關(guān)系，闡明胃癌的遺傳易感機(jī)制，對(duì)胃癌的發(fā)病機(jī)制的進(jìn)一步研究及其預(yù)防和治療方面提供了新思路。近年來(lái)，全基因組關(guān)聯(lián)研究(genome-wide association study, GWAS)作為一種可在全基因組范圍篩查疾病相關(guān)序列變異的群體關(guān)聯(lián)研究方法，已發(fā)現(xiàn)多個(gè)與胃癌易感性相關(guān)的基因，本文就PRKAA1和PSCA與胃癌易感性的相關(guān)性研究新進(jìn)展作一概述。

1 PRKAA1

PRKAA1基因位于常染色體5p13，該基因編碼活化AMP蛋白激酶(adenosine monophosphate activated protein kinase, AMPK)。AMPK是維持細(xì)胞內(nèi)能量代謝的能量感受器，當(dāng)AMP/ATP比值升高時(shí)AMPK被激活。激活后，AMPK增加分解代謝以增加ATP的合成及抑制消耗ATP的合成代謝過程。AMPK下游與葡萄糖和脂肪分解代謝相關(guān)的基因變異，如PFK2、CPT-1β、HSL、MEF2A等都可影響機(jī)體的能量供應(yīng)。PFK2基因的rs1064891位點(diǎn)[6]及CPT-1β基因rs131759和rs470117位點(diǎn)[7]變異與肥胖表型相關(guān)?；诖耍梢宰鳛樵S多治療藥物的潛在靶點(diǎn)，對(duì)多種疾病的治療發(fā)揮一定作用。此外，AMPK在激活自噬和抑制能源消耗過程中也起了一定的作用，如細(xì)胞的生長(zhǎng)和增殖。目前研究證實(shí)，AMPK通過調(diào)節(jié)細(xì)胞極性在能量代謝中發(fā)揮作用[8]，新陳代謝對(duì)腫瘤的發(fā)展至關(guān)重要，并且是腫瘤相關(guān)死亡的重要原因。它還參與腫瘤細(xì)胞的轉(zhuǎn)移和擴(kuò)散。事實(shí)上，AMPK通過微導(dǎo)管作用刺激細(xì)胞運(yùn)動(dòng)，“沉默”AMPK導(dǎo)致細(xì)胞前后極性改變及定向遷移[9]。此外，LBK1可磷酸化AMPK，并對(duì)細(xì)胞極化起作用，參與腫瘤細(xì)胞定向遷移[10]。上皮細(xì)胞具有頂端和基底極性，通過緊密連接、橋粒、黏附彼此緊密相連。極性缺失導(dǎo)致上皮-間質(zhì)轉(zhuǎn)化及隨后腫瘤入侵。因此，深入研究PRKAA1多態(tài)性與胃癌易感性的關(guān)系不僅可以深入理解胃癌的發(fā)病機(jī)制，同時(shí)對(duì)胃癌的診斷和治療奠定理論基礎(chǔ)。

對(duì)亞洲人進(jìn)行GWAS顯示，活化的蛋白激酶催化亞基α1的遺傳多態(tài)性與胃癌的發(fā)生密切相關(guān)[11]。目前大多數(shù)研究針對(duì)rs13361707和rs10074991位點(diǎn)進(jìn)行分析。Kim等[12]發(fā)現(xiàn)，rs13361707多態(tài)性與胃癌相關(guān)(TCvsTT：OR=1.29；CCvsTT：OR=2.05)。Qiu等[13]對(duì)中國(guó)東部地區(qū)1 124例胃癌病例和1 194名對(duì)照者進(jìn)行研究發(fā)現(xiàn)，PRKAA1基因rs13361707位點(diǎn)C等位基因可增加胃癌風(fēng)險(xiǎn)(CTvsTT：OR=1.72，95%CI: 1.40～2.12；CCvsTT：OR=2.15，95%CI: 1.70～2.71；CTvsCC：OR=1.86，95%CI: 1.53～2.26；CCvsTT/CT：OR=1.49，95%CI: 1.24～1.79)。Eom等[14]和其他一些對(duì)東亞人群進(jìn)行的研究[12]及新近歐洲人群的GWAS[15]結(jié)果與此結(jié)論相一致。這些結(jié)果提示，rs13361707可能在胃癌發(fā)展中起重要作用。雖然rs13361707不是該基因中發(fā)現(xiàn)的唯一SNP位點(diǎn)，但它對(duì)檢測(cè)PRKAA1中其他位點(diǎn)SNP與胃癌發(fā)展的相關(guān)性具有重要作用。Hu等[16]發(fā)現(xiàn)，rs10074991能增加賁門和非賁門胃癌的發(fā)病風(fēng)險(xiǎn)。rs10074991位點(diǎn)GG基因型受試者患胃癌風(fēng)險(xiǎn)是不攜帶G等位基因受試者的2.15倍；rs13361707位點(diǎn)CC基因型受試者患胃癌風(fēng)險(xiǎn)是TT基因型受試者的2.20倍[14]。

Kim等[12]評(píng)估PRKAA1檢測(cè)了5個(gè)SNP位點(diǎn)(rs13361707、rs154268、rs3805486、rs6882903和rs10074991)，結(jié)果發(fā)現(xiàn)均能增加胃癌發(fā)病風(fēng)險(xiǎn)。而張永菊等[17]研究發(fā)現(xiàn)，PRKAA1基因rs10036575位點(diǎn)CT+CC基因型攜帶者胃癌發(fā)病風(fēng)險(xiǎn)降低。

研究表明，PRKAA1基因多個(gè)位點(diǎn)多態(tài)性均與胃癌易感性相關(guān)，其中rs13361707位點(diǎn)CC基因型、rs10074991位點(diǎn)GG基因型能夠使胃癌發(fā)病風(fēng)險(xiǎn)增加，rs10036575位點(diǎn)CT+CC基因型可使胃癌患病風(fēng)險(xiǎn)降低。PRKAA1多態(tài)基因型的檢測(cè)對(duì)胃癌風(fēng)險(xiǎn)預(yù)測(cè)具有輔助作用，并且這些位點(diǎn)可作為未來(lái)基因篩查及藥物治療的靶點(diǎn)，為胃癌的預(yù)防和治療提供新方向。

2 PSCA

PSCA基因定位于常染色體8q24，編碼特異性PSCA，有研究[18]證實(shí)，PSCA在胃內(nèi)可抑制細(xì)胞增殖和/或誘導(dǎo)細(xì)胞凋亡。這與PSCA在胃癌中表達(dá)下調(diào)相一致。PSCA在胃峽部/頸部區(qū)域表達(dá)，但在胃癌組織中不能檢測(cè)到其表達(dá)[19]，提示在胃癌中，PSCA的腫瘤抑制效應(yīng)缺失。另外，有體內(nèi)功能研究[20]報(bào)道其在腫瘤進(jìn)展中的生物學(xué)作用。Saeki等[21]分析PSCA結(jié)構(gòu)認(rèn)為，PSCA發(fā)揮作用至少通過兩種不同的機(jī)制：(1)PSCA與其他具有跨膜和細(xì)胞內(nèi)結(jié)構(gòu)域的蛋白形成復(fù)合體，激活下游靶點(diǎn)。這種學(xué)說(shuō)認(rèn)為PSCA含有激活素Ⅰ、Ⅱ型細(xì)胞外受體結(jié)構(gòu)域，可與生長(zhǎng)轉(zhuǎn)化因子β(TGF-β)結(jié)合發(fā)揮作用；(2)PSCA是一種GPI-錨定的細(xì)胞表面蛋白，由磷脂酶C將GPI去除，將PSCA從細(xì)胞表面釋放出來(lái)，通過受體介導(dǎo)的信號(hào)通路發(fā)揮作用。研究[22]發(fā)現(xiàn)，PSCA參與細(xì)胞黏附、增殖，影響患者存活率。因此，研究PSCA基因多態(tài)性在胃癌病因?qū)W中的作用非常必要。

GWAS研究證明，PSCA多態(tài)性與胃癌易感性相關(guān)。目前的研究絕大多數(shù)針對(duì)rs2294008和rs2976392進(jìn)行單位點(diǎn)分析，對(duì)其他區(qū)域的SNP位點(diǎn)(rs2920295、rs138377917、rs2920297)及多位點(diǎn)聯(lián)合作用與胃癌易感性的關(guān)系研究較少?；蛑衦s2294008是可影響PSCA啟動(dòng)子轉(zhuǎn)錄活性的功能性SNP。rs2294008和rs2976392與胃癌的相關(guān)性在中國(guó)人、白種人、日本及韓國(guó)人群的研究中得到驗(yàn)證[23-25]。隨后，Qiu等[26]對(duì)中國(guó)東部地區(qū)人群研究得出相同結(jié)論，PSCA多態(tài)性與胃癌易感性相關(guān)，rs2294008位點(diǎn)T變異基因型與胃癌風(fēng)險(xiǎn)增加相關(guān)(CTvsCC：OR=1.59，95%CI: 1.33～1.89；CT+TTvsCC：OR=1.38，95%CI: 1.17～1.62)；另一SNP位點(diǎn)rs2976392，變異A基因型與胃癌風(fēng)險(xiǎn)增加相關(guān)(AGvsGG：OR=1.61，95%CI: 1.35～1.91；AG+GGvsGG：OR=1.47，95%CI: 1.25～1.74)。先前Meta分析[27]也證明，rs2976392可增加胃癌風(fēng)險(xiǎn)。Chandra等[28]對(duì)亞洲人進(jìn)行研究發(fā)現(xiàn)，rs2294008能增加胃癌及膀胱癌的風(fēng)險(xiǎn)，然而并未發(fā)現(xiàn)，rs2976392與癌癥風(fēng)險(xiǎn)具有相關(guān)性，其他研究[29]也未發(fā)現(xiàn)其相關(guān)性。研究結(jié)果的差異可能是因樣本量太小、研究方法不同或是不同人群的不同遺傳背景造成。rs2976392 G>A位于PSCA內(nèi)含子中，與rs2294008C >T存在連鎖不平衡[30]。因此，在不同病例對(duì)照研究中得到陽(yáng)性相關(guān)結(jié)果可能是由于rs2294008的連鎖效應(yīng)。

新近一項(xiàng)針對(duì)歐洲人的研究[31]發(fā)現(xiàn)，PSCA上rs2920295 (P=1.0×10-7，OR=1.21)和rs138377917(P=6.1×10-4，OR=0.65)也與胃癌易感性相關(guān)。Sakamoto等[18]研究發(fā)現(xiàn)，rs2920297(OR=1.18，95%CI: 1.05～1.32)與非賁門胃癌相關(guān)。

已證實(shí)PSCA基因rs22940C08、rs2976392、rs2920295、rs138377917及rs2920297位點(diǎn)的多態(tài)性與胃癌易感性相關(guān)，然而，位于內(nèi)含子區(qū)域的SNP如何影響基因功能尚需進(jìn)一步研究。

3 展望

通過對(duì)胃癌的全基因組的關(guān)聯(lián)分析，SNP與胃癌易感性關(guān)系的認(rèn)識(shí)逐漸深入。然而，有些相關(guān)性在后來(lái)的重復(fù)研究并不能得到相同結(jié)果?？赡苁怯捎谟行┭芯侩m然將年齡、性別、吸煙、飲酒等因素考慮在內(nèi)，卻忽視了對(duì)胃癌同樣起作用的飲食、幽門螺桿菌感染等因素。尋找預(yù)示疾病的相關(guān)SNP，對(duì)于胃癌的預(yù)防和治療是一大進(jìn)步。深入探討它們之間的相關(guān)性，早期發(fā)現(xiàn)與胃癌發(fā)展相關(guān)的基因和標(biāo)志物對(duì)于胃癌的預(yù)防和早期干預(yù)腫瘤的發(fā)生、預(yù)防惡性腫瘤的發(fā)生具有重要意義。

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(責(zé)任編輯：馬 軍)

New progress of the association of gene polymorphisms of PRKAA1and PSCA with gastric cancer

ZHAI Yuxiang, WANG Lili, YU Xinjuan, GONG Dawei, ZHANG Yongju, DONG Quanjiang

Department of Central Laboratories, the Affiliated Qingdao Municipal Hospital of Qingdao University Medical College, Qingdao 266071, China

Gastric cancer is one of the most common malignant cancers, with a high mortality rate. Genome-wide association study (GWAS) has identified multiple single nucleotide polymorphisms (SNP) in various genes which are related with gastric cancer. Among them, rs13361707, rs10074991, rs154268, rs3805486, rs6882903 and rs10036575 in PRKAA1 gene are associated with the susceptibility of gastric cancer. The encoding product of PRKAA1 plays an important role in energy metabolism, cellular growth, proliferation, apoptosis and autophagy. PSCA can inhibit proliferation of gastric cancer cells. The variation of rs2294008 and rs2976392 in PSCA can increase the gastric cancer risk. In this paper, we reviewed the recent progress of the association of gene polymorphisms of PRKAA1 and PSCA with gastric cancer.

Genome-wide association study; Gastric cancer; PRKAA1; PSCA; Single nucleotide polymorphism

10.3969/j.issn.1006-5709.2017.09.003

R735.2

：A

：1006-5709(2017)09-0970-03

：2017-02-10

翟玉香，在讀碩士研究生。E-mail: 1309152779@qq.com

董全江,主任醫(yī)師，碩士研究生導(dǎo)師，研究方向：胃癌發(fā)病機(jī)制研究。E-mail: jiangacer@126.com