程 利 何勇勇 綜述 唐 亮 審校

(安徽省宣城市人民醫(yī)院普外一科，宣城 242000)

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文獻(xiàn)綜述·

鞘氨醇激酶在腫瘤中的作用

程 利 何勇勇 綜述 唐 亮 審校

(安徽省宣城市人民醫(yī)院普外一科，宣城 242000)

鞘氨醇激酶是一種癌基因，能夠促進(jìn)惡性腫瘤細(xì)胞生長(zhǎng)和抑制其凋亡，抑制劑的使用能夠使腫瘤細(xì)胞加速凋亡。高表達(dá)鞘氨醇激酶的惡性腫瘤患者有較短的生存期和較高的復(fù)發(fā)率，而低表達(dá)者患者生存期較長(zhǎng)。鞘氨醇激酶抑制劑的使用可以提高患者生存率和降低復(fù)發(fā)率。鞘氨醇激酶是惡性腫瘤患者預(yù)后的有用指標(biāo)，可以作為治療惡性腫瘤患者的一個(gè)有效的靶點(diǎn)。本文對(duì)鞘氨醇激酶對(duì)惡性腫瘤患者預(yù)后的影響做一綜述。

鞘氨醇激酶； 惡性腫瘤

鞘磷脂代謝產(chǎn)物在腫瘤細(xì)胞的新陳代謝中扮演重要角色，其中磷酸鞘氨醇(sphingosine-1-phosphate，S1P)促進(jìn)細(xì)胞生存與增殖，與之相反，神經(jīng)酰胺(ceramide)和鞘氨醇(sphingosine,SP)促使細(xì)胞生長(zhǎng)停滯和凋亡。這些脂類代謝產(chǎn)物在細(xì)胞中可以相互轉(zhuǎn)換，它們之間的平衡調(diào)節(jié)著細(xì)胞的增殖、存活和凋亡。鞘氨醇激酶(sphingosine kinase，SPHK)是這個(gè)平衡的關(guān)鍵酶，能夠催化SP生成S1P。研究[1]表明SPHK在多種實(shí)體腫瘤中均高表達(dá)，其基因具有癌基因的特征，保護(hù)腫瘤細(xì)胞避免凋亡。高表達(dá)SPHK患者有較低的生存期和較高的復(fù)發(fā)率[2]。SPHK抑制劑的應(yīng)用實(shí)現(xiàn)其活性的下調(diào)，阻止其在惡性腫瘤中的作用[3]。因此，SPHK蛋白的檢測(cè)是判斷腫瘤患者預(yù)后的一個(gè)非常有意義的分子標(biāo)志物，SPHK分子靶向治療在微創(chuàng)介入領(lǐng)域?qū)?huì)有非常好的應(yīng)用前景。本文對(duì)SPHK在腫瘤預(yù)后中的作用做一綜述。

1 SPHK1

Olivera等[4]在1998年首次從大鼠腎臟細(xì)胞中提取出SPHK，相對(duì)分子質(zhì)量為49 000。目前，SPHK家族共有7個(gè)同工酶被克隆和鑒定。SPHK1和SPHK2源自人類和小鼠，其在酵母和植物中的同源基因也已得到鑒定。在人類中，SPHK1基因位于17號(hào)染色體(17q25.2)，相對(duì)分子質(zhì)量為42 400，在心臟、脾、肺和大腦大量表達(dá)；而SPHK2基因位于19號(hào)染色體(19q13.2)，相對(duì)分子質(zhì)量為65 000，在腦、腎和肝表達(dá)最高。SPHK1和SPHK2基因保守區(qū)高度同源，結(jié)構(gòu)也有相同的C1～C4區(qū)和羧基端，其中包括保守的甘油二酯激酶ATP結(jié)合域。雖然SPHK1和SPHK2顯示80%的氨基酸序列相似性，然而它們之間的區(qū)別在中部和N′末端，SPHK1缺乏跨膜結(jié)構(gòu)域及識(shí)別信號(hào)序列；SPHK2在N′末端比SPHK1多240個(gè)氨基酸殘基且包含幾個(gè)跨膜結(jié)構(gòu)域，在N′末端擁有核定位信號(hào)，一旦與配體結(jié)合，就可以阻止信號(hào)進(jìn)入核內(nèi)從而抑制DNA的合成[5，6]。SPHK1可以被很多的生長(zhǎng)4因子激活，包括：血小板衍生生長(zhǎng)因子、血管內(nèi)皮生長(zhǎng)因子、血磷脂酸、G蛋白耦聯(lián)變體(guanosine-binding protein couple receptor,GPCR)配體、磷酸鞘氨醇、類固醇激素、細(xì)胞因子、肝細(xì)胞生長(zhǎng)因子和表皮生長(zhǎng)因子等[7，8]。SPHK1的激活機(jī)制有3種：①酸性磷脂的相互作用；②與其他蛋白信號(hào)分子相偶聯(lián)；③磷酸化和易位到細(xì)胞膜。SPHK1主要存在于細(xì)胞液中，激活后易位到細(xì)胞膜上催化SP轉(zhuǎn)化為S1P，S1P和S1P受體結(jié)合后使細(xì)胞發(fā)生各種生物活性的改變。

2 S1P

S1P既是細(xì)胞內(nèi)信號(hào)傳導(dǎo)的第二信使分子，又可以分泌至細(xì)胞外，通過細(xì)胞表面受體發(fā)揮生物學(xué)效應(yīng)。S1P細(xì)胞膜受體是內(nèi)皮分化基因家族(EDG)，為GPCR。S1P和S1P受體結(jié)合后，可以激活絲裂原活化蛋白激酶、磷脂酰肌醇3激酶和絲氨酸/蘇氨酸蛋白激酶等信號(hào)途徑，從而調(diào)節(jié)細(xì)胞增殖、凋亡、遷移和侵襲等生物效應(yīng)，并介導(dǎo)血管生成、炎性反應(yīng)、腫瘤的轉(zhuǎn)移和復(fù)發(fā)等病理生理過程[9]。

外源性S1P可以促進(jìn)內(nèi)皮細(xì)胞及多種腫瘤細(xì)胞增殖和遷移。S1P對(duì)細(xì)胞生物活性的影響取決于細(xì)胞表面受體亞型。在很多細(xì)胞中，激活S1P受體1產(chǎn)生遷移效應(yīng)，而S1P受體2激活后則產(chǎn)生細(xì)胞遷移抑制效應(yīng)。纖維蛋白溶酶原激活劑和它的受體結(jié)合可以促進(jìn)多形性膠質(zhì)母細(xì)胞瘤細(xì)胞侵襲能力，而抑制SPHK1能夠減弱這種侵襲能力。S1P和S1P受體1結(jié)合可以誘導(dǎo)纖維蛋白溶酶原激活劑系統(tǒng)，這一現(xiàn)象表明S1P的信號(hào)轉(zhuǎn)導(dǎo)可以增強(qiáng)多形性膠質(zhì)母細(xì)胞瘤細(xì)胞侵襲性[10，11]。S1P與S1P受體2結(jié)合對(duì)膠質(zhì)母細(xì)胞瘤起到抗遷移效應(yīng)，RHOA/RHO激酶激活與這種遷移反應(yīng)有密切關(guān)系[12]。S1P受體3在腫瘤細(xì)胞遷移中扮演重要角色，S1P受體3激活后促進(jìn)甲狀腺癌細(xì)胞遷移。SPHK1過表達(dá)使S1P水平升高并且使其與S1P受體1和S1P受體3結(jié)合后增加細(xì)胞遷移效應(yīng)[13]。因此，S1P受體亞型的平衡是影響細(xì)胞生物學(xué)功能的一個(gè)重要因素。

3 SPHK與腫瘤的復(fù)發(fā)和預(yù)后

大量研究表明SPHK是一種致癌酶類，其激活與抗凋亡、轉(zhuǎn)化、增殖和腫瘤細(xì)胞生存密切相關(guān)[14～17]。NIH3T3成纖維細(xì)胞中SPHK基因過度表達(dá)增強(qiáng)細(xì)胞增殖和錨定獨(dú)立增長(zhǎng)能力，以及增強(qiáng)NOD/SCID小鼠致瘤性[16]。神經(jīng)母細(xì)胞瘤細(xì)胞和乳腺癌細(xì)胞內(nèi)源性SPHK基因表達(dá)沉默導(dǎo)致細(xì)胞周期停滯[18]。SPHK基因表達(dá)下調(diào)能夠有效抑制裸鼠腫瘤形成[19]。Li等[20]報(bào)道SPHK1在胃癌組織和胃癌細(xì)胞系中mRNA和蛋白表達(dá)量高于正常胃組織和癌旁組織，175例胃癌中161例SPHK1 mRNA和蛋白呈高表達(dá)狀態(tài)，陽性率為92%，并且與早期胃癌預(yù)后有密切相關(guān)性，高表達(dá)SPHK1胃癌患者5年生存率為23.85%，低表達(dá)SPHK1患者5年生存率為49.66%(P=0.0019)。Liu等[21]對(duì)159例唾液腺癌研究顯示，高表達(dá)SPHK1的唾液腺癌患者5年生存率為46.3%，低表達(dá)SPHK1患者5年生存率為93.4%(P=0.001)。Ruckh?berle等[22]對(duì)750例乳腺癌研究表明，高表達(dá)SPHK1患者5年生存率為64.9%，低表達(dá)SPHK1患者5年生存率為75.8%(P<0.05)。最近的研究表明溶血磷脂酸(lysophosphatidic acid,LPA)在胃癌細(xì)胞遷移和侵襲中扮演著重要角色，能夠促進(jìn)SPHK1在胃癌中高表達(dá)，促進(jìn)胃癌細(xì)胞遷移和侵襲能力，多因素分析顯示SPHK1是胃癌預(yù)后的獨(dú)立危險(xiǎn)因子[23]。此外，Cho等[24]研究表明SPHK1參與調(diào)控前列腺癌細(xì)胞生長(zhǎng)、存活、侵入、血管生成和腫瘤發(fā)生，利用調(diào)節(jié)低氧誘導(dǎo)因子1α下調(diào)SPHK1活性使前列腺癌細(xì)胞生長(zhǎng)和浸潤(rùn)得到有效控制。Tan等[25]基礎(chǔ)和臨床試驗(yàn)表明，SPHK1在結(jié)腸癌中起著重要作用，他們的試驗(yàn)研究表明SPHK1抑制劑的使用降低了結(jié)腸癌細(xì)胞生存能力，也增加了化療藥物5-FU的敏感性，提示SPHK1抑制劑可以作為化療藥物輔助劑，隨后的臨床試驗(yàn)也證實(shí)SPHK1高表達(dá)的結(jié)腸癌患者5年復(fù)發(fā)率為71.28%，低表達(dá)的結(jié)腸癌患者5年復(fù)發(fā)率為24.66%(P=0.042)；高表達(dá)SPHK1的結(jié)腸癌患者5年生存率為37.1%，低表達(dá)SPHK1的結(jié)腸癌患者5年生存率為62.9%(P<0.05)。綜上所述，SPHK1是很多惡性腫瘤預(yù)后的獨(dú)立影響因子。

4 腫瘤治療新靶點(diǎn)

SPHK1對(duì)腫瘤復(fù)發(fā)和預(yù)后有至關(guān)重要的作用，SPHK1抑制劑的使用可以有效抑制腫瘤生長(zhǎng)，例如SPHK1抑制劑SK1-I能夠抑制人白血病細(xì)胞復(fù)制，加速其凋亡[26]。Fuereder等[27]研究表明SPHK1抑制劑的使用能夠使胃癌細(xì)胞凋亡加快并且抑制胃癌細(xì)胞生長(zhǎng)(P<0.05)。Ruckh?berle等[28]臨床研究表明SPHK1抑制劑的使用可以下調(diào)乳腺癌中SPHK1表達(dá)，并且對(duì)乳腺癌的治療有良好作用，SPHK1抑制劑組5年生存率為26.7%，非SPHK1抑制劑組5年生存率5.8%(P=0.042)。Pchejetski等[29]研究表明SPHK1抑制劑FTY720能夠抑制前列腺腫瘤生長(zhǎng)，F(xiàn)TY720治療后患者5年生存率為40%，非治療組患者生存率為28%(P<0.05)。神經(jīng)酰胺、SP和S1P作為能夠相互轉(zhuǎn)化的脂類代謝產(chǎn)物現(xiàn)在已經(jīng)被公認(rèn)為是調(diào)節(jié)細(xì)胞生物活性的重要物質(zhì)，參與細(xì)胞的生理和病理過程[30]。這些年對(duì)鞘磷脂類物質(zhì)在細(xì)胞中作用研究越來越多，神經(jīng)酰胺和SP已被證明與細(xì)胞周期停滯和細(xì)胞凋亡有關(guān)，而S1P參與細(xì)胞增殖、存活、遷移、血管生成和分化[31]。神經(jīng)酰胺、SP和S1P在細(xì)胞中水平與SPHK激活有密切關(guān)聯(lián)。當(dāng)細(xì)胞受到相關(guān)刺激的時(shí)候，細(xì)胞中SPHK被激活，催化SP轉(zhuǎn)換成S1P，這樣細(xì)胞中的S1P水平升高；相反，當(dāng)SPHK活性受到抑制，細(xì)胞中神經(jīng)酰胺、SP水平升高，而S1P水平降低，這種動(dòng)態(tài)平衡被稱為“鞘類變阻器”[32],在細(xì)胞的生存和凋亡中起關(guān)鍵作用，在這個(gè)平衡中,SPHK是關(guān)鍵限速酶。很多證據(jù)表明SPHK是一個(gè)潛在治療靶點(diǎn)：①SPHK基因本身就是一個(gè)癌基因；②SPHK在很多腫瘤細(xì)胞中都是過表達(dá)；③很多生長(zhǎng)因子和有絲分裂原能夠雙向激活SPHK，使細(xì)胞內(nèi)S1P水平升高；④SPHK能夠刺激腫瘤血管的生成；⑤SPHK和S1P本身就可以刺激細(xì)胞的移動(dòng)，與腫瘤細(xì)胞的侵襲和轉(zhuǎn)移有密切關(guān)系；⑥腫瘤的放療和化療效果減弱與SPHK水平升高有關(guān)，抑制SPHK能夠使這些治療效果增加；⑦SPHK、S1P和受體酪氨酸蛋白激酶提供了一個(gè)復(fù)雜的串?dāng)_網(wǎng)絡(luò)，SPHK是這個(gè)網(wǎng)絡(luò)調(diào)節(jié)循環(huán)中一個(gè)重要因素，它可以將腫瘤信號(hào)放大；⑧SPHK是“鞘類變阻器”控制器，抑制SPHK不僅可以抑制S1P產(chǎn)生，還可以使細(xì)胞中神經(jīng)酰胺和SP增加，使腫瘤細(xì)胞走向死亡。由此可見，SPHK1可以作為治療惡性腫瘤的潛在靶點(diǎn)。

1 Zhang Y, Wang Y, Wan Z, et al. Sphingosine kinase 1 and cancer: a systematic review and meta-analysis. PLoS One, 2014, 9(2):e90362-e90373.

2 Shi J, He YY, Sun JX, et al. The impact of sphingosine kinase 1 on the prognosis of hepatocellular carcinoma patients with portal vein tumor thrombus. Ann Hepatol,2015, 14(2):198-206.

3 Qin Z, Dai L, Trillo-Tinoco J, et al. Targeting sphingosine kinase induces apoptosis and tumor regression for KSHV-associated primary effusion lymphoma. Mol Cancer Ther,2014,13 (1):154-164.

4 Olivera A, Kohama T, Tu Z, et al. Purification and characterization of rat kidney sphingosine kinase. J Biol Chem,1998,273(20):12576-12583.

5 Hasan NM, Longacre MJ, Stoker SW, et al. Sphingosine kinase 1 knockdown reduces insulin synthesis and secretion in a rat insulinoma cell line. Arch Biochem Biophys,2012,518(1):23-30.

6 Murakami M, Ito H, Hagiwara K, et al. Sphingosine kinase 1/S1P pathway involvement in the GDNF-induced GAP43 transcription. J Cell Biochem,2011,112(11):3449-3458.

7 Berdyshev EV, Gorshkova I, Usatyuk P, et al. Intracellular S1P generation is essential for S1P-induced motility of human lung endothelial cells: role of sphingosine kinase 1 and S1P lyase. PLoS One,2011,6(1):e16571-e16579.

8 Ter Braak M, Claas RF, Hegen B, et al. Cis-4-methylsphingosine is a sphingosine-1-phosphate receptor modulator. Biochem Pharmacol,2011,81(5):617-625.

9 Al-Jarallah A, Chen X, González L, et al. High density lipoprotein stimulated migration of macrophages depends on the scavenger receptor class B, type Ⅰ, PDZK1 and Akt1 and is blocked by sphingosine 1 phosphate receptor antagonists. PLoS One,2014,4(9):e106487-e106496.

10 Paugh BS, Bryan L, Paugh SW, et al.Interleukin-1 regulates the expression of sphingosine kinase 1 in glioblastoma cells. J Biol Chem,2009,284(6):3408-3417.

11 Kapitonov D, Allegood JC, Mitchell C, et al. Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. Cancer Res,2009,69(17):6915-6923.

12 Aydin M, Downing K, Villegas G, et al. The sphingosine-1-phosphate pathway is upregulated in response to partial urethral obstruction in male rats and activates RhoA/Rho-kinase signalling. BJU Int,2010,106(4):562-571.

13 Van Brocklyn JR, Jackson CA, Pearl DK, et al. Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol,2005,64(8):695-705.

14 Marfe G, Di Stefano C, Gambacurta A, et al. Sphingosine kinase 1 overexpression is regulated by signaling through PI3K, AKT2, and mTOR in imatinib-resistant chronic myeloid leukemia cells. Exp Hematol,2011,39(6):653-665.

15 Zhang H, Li W, Sun S, et al. Inhibition of sphingosine kinase 1 suppresses proliferation of glioma cells under hypoxia by attenuating activity of extracellular signal-regulated kinase. Cell Prolif,2012,45(2):167-175.

16 Nunes J, Naymark M, Sauer L, et al. Circulating sphingosine-1-phosphate and erythrocyte sphingosine kinase-1 activity as novel biomarkers for early prostate cancer detection. Br J Cancer,2012,106(5):909-915.

17 Cho SY, Lee HJ, Jeong SJ, et al. Sphingosine kinase 1 pathway is involved in melatonin-induced HIF-1alpha inactivation in hypoxic PC-3 prostate cancer cells. J Pineal Res,2011(1),51:87-93.

18 Shirai K, Kaneshiro T, Wada M, et al. A role of sphingosine kinase 1 in head and neck carcinogenesis. Cancer Prev Res,2011,4(3):454-462.

19 Pan J, Tao YF, Zhou Z, et al. An novel role of sphingosine kinase-1 (SPHK1) in the invasion and metastasis of esophageal carcinoma. J Transl Med,2011,9(10):157-165.

20 Li W, Yu CP, Xia JT, et al. Sphingosine kinase 1 is associated with gastric cancer progression and poor survival of patients. Clin Cancer Res,2009,15(4):1393-1399.

21 Liu G, Zheng H, Zhang Z, et al. Overexpression of sphingosine kinase 1 is associated with salivary gland carcinoma progression and might be a novel predictive marker for adjuvant therapy. BMC Cancer,2010,10(16):495-505.

22 Ruckh?berle E, Rody A, Engels K, et al. Microarray analysis of altered sphingolipid metabolism reveals prognostic significance ofsphingosine kinase 1 in breast cancer. Breast Cancer Res Treat, 2008,112(1):41-52.

23 Shida D, Fang X, Kordula T, et al. Cross-talk between LPA1 and epidermal growth factor receptors mediates up-regulation of sphingosine kinase 1 to promote gastric cancer cell motility and invasion. Cancer Res,2008,15(16):6569-6577.

24 Cho SY, Cho S, Park E, et al. Coumestrol suppresses hypoxia inducible factor 1α by inhibiting ROS mediated sphingosine kinase 1 in hypoxic PC-3 prostate cancer cells. Bioorg Med Chem Lett,2014,24(11):2560-2564.

25 Tan SS, Khin LW, Wong L, et al. Sphingosine kinase 1 promotes malignant progression in colon cancer and independently predicts survival of patients with colon cancer by competing risk approach in South asian population. Clin Transl Gastroenterol,2014,5(10):e51-e57.

26 Paugh SW, Paugh BS, Rahmani M, et al. A selective sphingosine kinase 1 inhibitor intergrates multiple molecular therapeutic targets in human leukemia. Blood, 2008, 112(4):1382-1391.

27 Fuereder T, Hoeflmayer D, Jaeger-Lansky A, et al. Sphingosine kinase 1 is a relevant molecular target in gastric cancer. Anticancer Drugs,2011,22(3):245-252.

28 Ruckh?berle E, Karn T, Denkert C, et al. Predictive value of sphingosine kinase 1 expression in neoadjuvant treatment of breast cancer.J Cancer Res Clin Oncol, 2013, 139(10):1681-1689.

29 Pchejetski D, Bohler T, Brizuela L, et al. FTY(fingolimod) sensitizes prostate cancer cells to radiothera hy by inhibition of sphingosine kinase-1. Cancer Res, 2010,70(21):8651-8661.

30 Kharel Y, Mathews TP, Gellett AM, et al. Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate. Biochem J,2011,440(3):345-353.

31 Xiao M, Liu Y, Zou F, et al. Sensitization of human colon cancer cells to sodium butyrate-induced apoptosis by modulation of sphingosine kinase 2 and protein kinase D. Exp Cell Res,2012,318(1):43-52.

32 Kariya Y, Kihara A, Ikeda M, et al. Products by the sphingosine kinase/sphingosine 1-phosphate (S1P) lyase pathway but not S1P stimulate mitogenesis. Genes Cells,2005,10(6):605-615.

(修回日期：2015-02-09)

(責(zé)任編輯：李賀瓊)

Role of Sphingosine Kinase on Tumors

ChenLi,HeYongyong,TangLiang.

DepartmentofGeneralSurgeryWardⅠ,XuanchengPeople’sHospitalofAnhui,Xuancheng242000,China

Correspondingauthor:HeYongyong,E-mail:heyongyong84@sina.com

【Summary】 Sphingosine kinase (SPHK) is an oncogene promoting tumor cell growth and inhibiting apoptosis. Inhibitors of SPHK promote tumor cell apoptosis. Patients with higher SPHK expression have shorter overall survival time and higher recurrence rates, whereas those with lower SPHK expression survives longer. Inhibitors of SPHK can improve survival and reduce recurrence rates. SPHK is a useful marker for the prognosis of malignant tumors, and it could be an effective target for treating malignant tumors. This article is to investigate effects of SPHK on the prognosis in patients with malignant tumors.

Sphingosine kinase; Malignant tumor

，E-mail：heyongyong84@sina.com

R730.53

A

1009-6604(2015)09-0840-04

10.3969/j.issn.1009-6604.2015.09.021

2014-05-21)