NPRL2基因與奧沙利鉑治療結(jié)直腸癌的研究進(jìn)展

付偉然 劉艾蕓 杜雅菊

哈爾濱醫(yī)科大學(xué)附屬第二醫(yī)院消化內(nèi)科(150001)

NPRL2基因與奧沙利鉑治療結(jié)直腸癌的研究進(jìn)展

付偉然 劉艾蕓 杜雅菊*

哈爾濱醫(yī)科大學(xué)附屬第二醫(yī)院消化內(nèi)科(150001)

結(jié)直腸癌(CRC)是全球三大惡性腫瘤之一，具有高發(fā)病率和高死亡率。研究發(fā)現(xiàn)，NPRL2基因與CRC發(fā)生、發(fā)展關(guān)系密切，CRC患者NPRL2基因表達(dá)顯著降低。奧沙利鉑是第三代鉑類抗腫瘤藥物，已廣泛應(yīng)用于胃腸道腫瘤化療，可提高CRC患者生存率，但部分患者存在耐藥。NPRL2基因可增加奧沙利鉑治療CRC的敏感性，是CRC潛在的治療靶點(diǎn)。本文就NPRL2基因與奧沙利鉑治療CRC的研究進(jìn)展作一綜述。

結(jié)直腸腫瘤； NPRL2基因； 奧沙利鉑； 治療

結(jié)直腸癌(colorectal cancer, CRC)是最常見的消化道惡性腫瘤之一，其發(fā)病率居全球癌癥第三位，死亡率居第二位，每年新發(fā)確診患者約120萬例[1]。隨著人們生活水平的提高和飲食習(xí)慣的改變，我國CRC發(fā)病率逐年增高，并已成為死亡率位居第三的惡性腫瘤[2-3]。手術(shù)切除和全身化療是CRC的主要治療方式，但因CRC起病隱匿，多數(shù)患者確診時已處于疾病晚期，喪失了外科手術(shù)切除病變組織的機(jī)會，因此以化療為主的綜合治療是晚期CRC的主要治療方案?；熆商岣逤RC患者生存率，目前常用藥物包括奧沙利鉑(oxaliplatin)、5-氟尿嘧啶(5-fluorouracil)和伊立替康等(irinotecan)。腫瘤化療相關(guān)不良反應(yīng)較多，臨床表現(xiàn)和作用機(jī)制極為復(fù)雜。長期化療患者易出現(xiàn)復(fù)發(fā)，復(fù)發(fā)后腫瘤惡性程度更高，且存在耐藥現(xiàn)象，長期治療效果不佳，其生存率通常不足6個月。腫瘤對化療藥物耐藥的可能機(jī)制包括藥物吸收減少、藥物外排增加、解毒系統(tǒng)激活、DNA修復(fù)激活、腫瘤細(xì)胞上皮-間質(zhì)轉(zhuǎn)化(EMT)或藥物誘導(dǎo)的細(xì)胞凋亡減弱等[4-5]。CRC相關(guān)基因的檢測可能有助于開展針對性治療，建立個體化治療方案，進(jìn)而減少耐藥和不良反應(yīng)的發(fā)生，改善CRC患者的預(yù)后[6-9]。本文就NPRL2(nitrogen permease regulator-like 2)基因與奧沙利鉑治療CRC的研究進(jìn)展作一綜述。

一、NPRL2基因結(jié)構(gòu)和生物學(xué)功能

1. NPRL2基因結(jié)構(gòu)：NPRL2是一種抑癌基因，又稱腫瘤抑制候選基因4(tumor suppressor candidate 4, TUSC4)，位于人染色體3p21.3區(qū)域，該區(qū)域的基因組表達(dá)異?；蚬δ苁д{(diào)已被證實(shí)與多種腫瘤發(fā)生、發(fā)展有關(guān)，其機(jī)制可能與NPRL2基因啟動子純合子缺失、微衛(wèi)星不穩(wěn)定性以及基因突變有關(guān)[10]。NPRL2基因由11個外顯子和10個內(nèi)含子組成，可利用多個起始密碼子和終止密碼子通過不同剪接方式編碼成多種剪接異構(gòu)體。NPRL2基因編碼的NPRL2蛋白由380個氨基酸組成，在人體多種組織和器官中均有表達(dá)。此外，NPRL2基因在生物物種間具有高度保守性。

2. 生物學(xué)功能：NPRL2在人體多種正常組織(如心臟、肝臟、腎臟、腦和胰腺等)中均有顯著表達(dá)[11]，而在腫瘤(如肺癌、腎癌、肝癌、乳腺癌、鼻咽癌和卵巢癌等)中表達(dá)明顯減少，其具體機(jī)制尚未明確[12-13]。NPRL2基因可干擾多種腫瘤細(xì)胞生長，與腫瘤發(fā)生、發(fā)展和預(yù)后相關(guān)[10,14]。NPRL2基因可通過參與DNA錯配修復(fù)、調(diào)控細(xì)胞周期信號轉(zhuǎn)導(dǎo)、誘導(dǎo)細(xì)胞凋亡、抑制細(xì)胞增殖等途徑發(fā)揮抑癌作用[10-11,15]，并可增加抗癌藥物敏感性，促進(jìn)腫瘤細(xì)胞凋亡[16]。Ueda等[17]利用攜帶NPRL2基因的腺病毒對肺癌裸鼠進(jìn)行瘤內(nèi)注射，發(fā)現(xiàn)癌細(xì)胞增殖和腫瘤轉(zhuǎn)移均受到明顯抑制，并證實(shí)NPRL2是預(yù)測肺癌和其他類型癌癥中順鉑治療敏感性的潛在標(biāo)記物，可作為分子靶向藥物來增加順鉑治療的敏感性。Wang等[18]通過基因失活檢測(GIT)發(fā)現(xiàn)小細(xì)胞肺癌細(xì)胞株U2020和腎癌細(xì)胞株KRC/Y染色體3p21.3區(qū)域存在多個抑癌基因，其中NPRL2基因在體內(nèi)、外均被證實(shí)具有較強(qiáng)抑制腫瘤細(xì)胞增殖的作用。Senchenko等[19]發(fā)現(xiàn)NPRL2基因在原發(fā)性非小細(xì)胞肺癌中表達(dá)減少。NPRL2基因與順鉑聯(lián)合治療肺癌時，可通過激活DNA損傷檢查點(diǎn)通路，使細(xì)胞周期阻滯在G2/M期并誘導(dǎo)凋亡，有效克服腫瘤細(xì)胞對順鉑的耐藥性[20]。Otani等[13]發(fā)現(xiàn)肝癌患者NPRL2 mRNA表達(dá)異常，是影響患者預(yù)后的獨(dú)立危險(xiǎn)因素。Tang等[21]通過將NPRL2基因轉(zhuǎn)染至腎透明細(xì)胞癌細(xì)胞株786-0中，發(fā)現(xiàn)NPRL2可有效調(diào)節(jié)細(xì)胞周期檢查點(diǎn)，使腎癌細(xì)胞周期阻滯在G0/G1期，從而抑制腫瘤細(xì)胞增殖，誘導(dǎo)腫瘤細(xì)胞凋亡。Liu等[22]發(fā)現(xiàn)NPRL2表達(dá)與CRC發(fā)生、發(fā)展密切相關(guān)，外周血NPRL2 mRNA水平可作為早期腺瘤和CRC篩查的潛在標(biāo)記物。

NPRL2基因失活導(dǎo)致相關(guān)抑癌基因表達(dá)異常，進(jìn)而誘導(dǎo)腫瘤發(fā)生，該過程可能的發(fā)生機(jī)制如下：①DNA復(fù)制的錯配修復(fù)系統(tǒng)異常引起DNA復(fù)制保真度降低以及基因組不穩(wěn)定(如微衛(wèi)星不穩(wěn)定性)，進(jìn)而導(dǎo)致NPRL2基因發(fā)生突變失活，促進(jìn)腫瘤進(jìn)展[23-24]。②NPRL2基因可抑制3-磷酸肌醇依賴性蛋白激酶1(PDK1)激活。PDK1是細(xì)胞增殖及其信號轉(zhuǎn)導(dǎo)的關(guān)鍵調(diào)節(jié)因子，與NPRL2基因結(jié)合后導(dǎo)致PDK1下游信號分子Akt和核糖體蛋白S6K失活，進(jìn)而抑制細(xì)胞增殖。NPRL2基因失活可引起PDK1異常激活，增強(qiáng)PDK1下游細(xì)胞增殖信號轉(zhuǎn)導(dǎo)，從而導(dǎo)致腫瘤發(fā)生[25]。③NPRL2基因可提高Chk1和Chk2激酶活性。Chk1和Chk2是細(xì)胞周期檢查點(diǎn)激酶，可阻滯細(xì)胞周期，在乳腺癌、前列腺癌、肺癌和食管癌中異常表達(dá)[26-27]。NPRL2基因失活可下調(diào)Chk1和Chk2激酶活性，引起DNA損傷修復(fù)系統(tǒng)異常，從而抑制腫瘤細(xì)胞凋亡，導(dǎo)致細(xì)胞周期紊亂，促進(jìn)腫瘤發(fā)生[26]。

二、奧沙利鉑的臨床應(yīng)用

奧沙利鉑是一類含有1, 2-二氨環(huán)己烷基團(tuán)的DNA損傷類化療藥物，是繼順鉑之后的第三代鉑類抗癌藥，目前已廣泛應(yīng)用于臨床，并具有較好療效[28]。DNA損傷類藥物是一類重要的化療藥物，可通過誘導(dǎo)DNA損傷來抑制腫瘤細(xì)胞生長并誘導(dǎo)凋亡，但易導(dǎo)致腫瘤細(xì)胞產(chǎn)生耐藥性[29]。奧沙利鉑在靜止期細(xì)胞中的反應(yīng)最為活躍，其以DNA為作用靶點(diǎn)，與DNA鏈上的G共價結(jié)合形成配位金屬鹽絡(luò)合物，從而破壞DNA結(jié)構(gòu)和功能，促進(jìn)腫瘤細(xì)胞凋亡。奧沙利鉑對晚期腫瘤的療效和安全性均較好[30-31]，已廣泛應(yīng)用于晚期惡性腫瘤治療，但由于腫瘤細(xì)胞DNA損傷修復(fù)蛋白表達(dá)上調(diào)，腫瘤細(xì)胞DNA損傷修復(fù)能力增強(qiáng)，導(dǎo)致腫瘤細(xì)胞對DNA損傷類化療藥物(如奧沙利鉑等)耐藥性產(chǎn)生[32-34]?；熁颊叱３霈F(xiàn)癌癥復(fù)發(fā)和耐藥，故奧沙利鉑長期療效不佳。因此，提高藥物敏感性以避免耐藥情況出現(xiàn)是提高奧沙利鉑化療效果的關(guān)鍵。

三、NPRL2可增加奧沙利鉑治療CRC的敏感性

NPRL2可有效抑制腫瘤細(xì)胞活性，通過參與DNA錯配修復(fù)、調(diào)控細(xì)胞周期信號轉(zhuǎn)導(dǎo)以及誘導(dǎo)細(xì)胞凋亡等方式發(fā)揮抑癌作用[10-11]。腫瘤細(xì)胞NPRL2過度表達(dá)可抑制細(xì)胞增殖并誘導(dǎo)細(xì)胞凋亡，從而提高奧沙利鉑對CRC的敏感性。研究[35]表明，轉(zhuǎn)染NPRL2的人結(jié)腸癌細(xì)胞株HCT116中奧沙利鉑的半數(shù)抑菌濃度顯著低于正常細(xì)胞，且NPRL2對奧沙利鉑敏感性的促進(jìn)作用具有時間依賴性。

1. NPRL2通過抑制細(xì)胞生長增加奧沙利鉑對結(jié)腸癌細(xì)胞的敏感性：NPRL2基因轉(zhuǎn)染結(jié)腸癌細(xì)胞后，使腫瘤細(xì)胞周期阻滯于G1期，從而導(dǎo)致S期結(jié)腸癌細(xì)胞減少。與未轉(zhuǎn)染NPRL2的腫瘤細(xì)胞相比，奧沙利鉑顯著抑制轉(zhuǎn)染NPRL2的結(jié)腸癌細(xì)胞生長。

2. NPRL2通過促進(jìn)細(xì)胞凋亡增加奧沙利鉑對結(jié)腸癌細(xì)胞的敏感性：CD24是一類以糖基磷脂酰肌醇(GPI)錨定于細(xì)胞表面的糖蛋白[36]，是存在于活化內(nèi)皮細(xì)胞和血小板上的黏附素受體，可促進(jìn)腫瘤淋巴結(jié)轉(zhuǎn)移[37]，胃癌組織CD24高表達(dá)與腫瘤淋巴結(jié)轉(zhuǎn)移的相關(guān)性已被證實(shí)[38]。NPRL2過表達(dá)可導(dǎo)致CD24+結(jié)腸癌細(xì)胞比例下調(diào)，與奧沙利鉑聯(lián)合用于治療時，可明顯促進(jìn)結(jié)腸癌細(xì)胞凋亡。NPRL2過表達(dá)和奧沙利鉑聯(lián)合誘導(dǎo)的結(jié)腸癌細(xì)胞凋亡較兩者單獨(dú)作用更為明顯[35]。

3. NPRL2通過抑制PI3K/Akt/mTOR信號通路增加奧沙利鉑對結(jié)腸癌細(xì)胞的敏感性：PI3K/Akt/mTOR信號通路在消化道腫瘤中過度活化，是CRC發(fā)生、發(fā)展的核心環(huán)節(jié)[39]，在腫瘤細(xì)胞增殖、凋亡、血管生成和腫瘤轉(zhuǎn)移中發(fā)揮重要作用，是潛在的多分子治療靶點(diǎn)[40-41]。外界刺激因子(如生長因子等)與細(xì)胞膜表面受體結(jié)合后，可激活PI3K并磷酸化Akt，Akt活化后可激活下游靶蛋白mTOR，mTOR與受體結(jié)合后進(jìn)一步激活蛋白激酶p70S6K和蛋白翻譯調(diào)控因子4E-BP1，從而促進(jìn)細(xì)胞增殖。NPRL2可通過下調(diào)PI3K/Akt/mTOR信號通路活化水平，使腫瘤細(xì)胞周期阻滯于G1期，抑制腫瘤細(xì)胞增殖，進(jìn)而提高奧沙利鉑的治療敏感性[42]。此外，對于NPRL2基因高表達(dá)的結(jié)腸癌細(xì)胞，奧沙利鉑可通過上調(diào)細(xì)胞凋亡蛋白酶caspase-3和caspase-9表達(dá)，促進(jìn)結(jié)腸癌細(xì)胞凋亡。

四、結(jié)語

綜上所述，NPRL2基因與CRC發(fā)生、發(fā)展密切相關(guān)。目前研究已證實(shí)NPRL2可通過抑制腫瘤細(xì)胞增殖、促進(jìn)腫瘤細(xì)胞凋亡、調(diào)節(jié)PI3K/Akt/mTOR信號通路活化等途徑來增加奧沙利鉑的治療敏感性，逆轉(zhuǎn)腫瘤細(xì)胞對奧沙利鉑的耐藥性。NPRL2與奧沙利鉑聯(lián)用的治療方案可在分子水平為腫瘤的基因治療提供新思路，有望成為CRC治療的新手段。但NPRL2基因增加奧沙利鉑敏感性的具體作用機(jī)制仍有待進(jìn)一步研究來證實(shí)。

1 Perazzo F, Piaggio F, Krupitzki H, et al. Clinical-pathological features and gene profile in colorectal cancer [Article in Spanish] [J]. Medicina (B Aires), 2013, 73 (5): 417-422.

2 陳龍, 韓盛璽. BRAF基因與結(jié)腸癌的關(guān)系及臨床意義[J]. 實(shí)用醫(yī)院臨床雜志, 2009, 6 (3): 123-125.

3 周琴, 林國楨, 李科. 廣州市2004-2009年惡性腫瘤住院患者流行特征分析[J]. 中華腫瘤防治雜志, 2013, 20 (13): 972-976.

4 Kajiyama H, Shibata K, Terauchi M, et al. Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells[J]. Int J Oncol, 2007, 31 (2): 277-283.

5 Xiong W, Ren ZG, Qiu SJ, et al. Residual hepatocellular carcinoma after oxaliplatin treatment has increased metastatic potential in a nude mouse model and is attenuated by Songyou Yin[J]. BMC Cancer, 2010, 10: 219.

6 Luo Y, Wang L, Wang J. Developing proteomics-based biomarkers for colorectal neoplasms for clinical practice: opportunities and challenges[J]. Proteomics Clin Appl, 2013, 7 (1-2): 30-41.

7 Andersen V, Holst R, Vogel U. Systematic review: diet-gene interactions and the risk of colorectal cancer[J]. Aliment Pharmacol Ther, 2013, 37 (4): 383-391.

8 Bretthauer M, Kalager M. Principles, effectiveness and caveats in screening for cancer[J]. Br J Surg, 2013, 100 (1): 55-65.

9 Sillars-Hardebol AH, Carvalho B, van Engeland M, et al. The adenoma hunt in colorectal cancer screening: defining the target[J]. J Pathol, 2012, 226 (1): 1-6.

10 Lerman MI, Minna JD. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium[J]. Cancer Res, 2000, 60 (21): 6116-6133.

11 Li J, Wang F, Haraldson K, et al. Functional characterization of the candidate tumor suppressor gene NPRL2/G21 located in 3p21.3C[J]. Cancer Res, 2004, 64 (18): 6438-6443.

12 Anedchenko EA, Dmitriev AA, Krasnov GS, et al. Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer [Article in Russian] [J]. Mol Biol (Mosk), 2008, 42 (6): 965-976.

13 Otani S, Takeda S, Yamada S, et al. The tumor suppressor NPRL2 in hepatocellular carcinoma plays an important role in progression and can be served as an independent prognostic factor[J]. J Surg Oncol, 2009, 100 (5): 358-363.

14 Chow LS, Lo KW, Kwong J, et al. RASSF1A is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma[J]. Int J Cancer, 2004, 109 (6): 839-847.

15 Wistuba II, Behrens C, Virmani AK, et al. High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints[J]. Cancer Res, 2000, 60 (7): 1949-1960.

16 Wei Y, Lilly MA. The TORC1 inhibitors Nprl2 and Nprl3 mediate an adaptive response to amino-acid starvation in Drosophila[J]. Cell Death Differ, 2014, 21 (9): 1460-1468.

17 Ueda K, Kawashima H, Ohtani S, et al. The 3p21.3 tumor suppressor NPRL2 plays an important role in cisplatin-induced resistance in human non-small-cell lung cancer cells[J]. Cancer Res, 2006, 66 (19): 9682-9690.

18 Wang F, Grigorieva EV, Li J, et al. HYAL1 and HYAL2 inhibit tumour growthinvivobut notinvitro[J]. PLoS One, 2008, 3 (8): e3031.

19 Senchenko VN, Anedchenko EA, Kondratieva TT, et al. Simultaneous down-regulation of tumor suppressor genes RBSP3/CTDSPL, NPRL2/G21 and RASSF1A in primary non-small cell lung cancer[J]. BMC Cancer, 2010, 10: 75.

20 Jayachandran G, Ueda K, Wang B, et al. NPRL2 sensitizes human non-small cell lung cancer (NSCLC) cells to cisplatin treatment by regulating key components in the DNA repair pathway[J]. PLoS One, 2010, 5 (8): e11994.

21 Tang Y, Jiang L, Tang W. Decreased expression of NPRL2 in renal cancer cells is associated with unfavourable pathological, proliferation and apoptotic features[J]. Pathol Oncol Res, 2014, 20 (4): 829-837.

22 Liu AY, Liu DG, Du YJ, et al. Relationship between tumor and peripheral blood NPRL2 mRNA levels in patients with colorectal adenoma and colorectal cancer[J]. Cancer Biol Ther, 2014, 15 (5): 489-495.

23 Economidou F, Tzortzaki EG, Schiza S, et al. Microsatellite DNA analysis does not distinguish malignant from benign pleural effusions[J]. Oncol Rep, 2007, 18 (6): 1507-1512.

24 Castagnaro A, Marangio E, Verduri A, et al. Microsatellite analysis of induced sputum DNA in patients with lung cancer in heavy smokers and in healthy subjects[J]. Exp Lung Res, 2007, 33 (6): 289-301.

25 Kurata A, Katayama R, Watanabe T, et al. TUSC4/NPRL2, a novel PDK1-interacting protein, inhibits PDK1 tyrosine phosphorylation and its downstream signaling[J]. Cancer Sci, 2008, 99 (9): 1827-1834.

26 Kim JH, Kim H, Lee KY, et al. Genetic polymorphisms of ataxia telangiectasia mutated affect lung cancer risk[J]. Hum Mol Genet, 2006, 15 (7): 1181-1186.

27 王玉祥, 祝淑釵, 封巍, 等. CHK1和CHK2 shRNA轉(zhuǎn)染對食管癌細(xì)胞照射后G2期阻滯的影響[J]. 中華腫瘤雜志, 2006, 28 (8): 572-577.

28 Song N, Pogue-Geile KL, Gavin PG, et al. Clinical Outcome From Oxaliplatin Treatment in Stage Ⅱ/Ⅲ Colon Cancer According to Intrinsic Subtypes: Secondary Analysis of NSABP C-07/NRG Oncology Randomized Clinical Trial[J]. JAMA Oncol, 2016, 2 (9): 1162-1169.

29 Cheung-Ong K, Giaever G, Nislow C. DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology[J]. Chem Biol, 2013, 20 (5): 648-659.

30 Xu X, Wang L, Xu HQ, et al. Clinical comparison between paclitaxel liposome (Lipusu?) and paclitaxel for treatment of patients with metastatic gastric cancer[J]. Asian Pac J Cancer Prev, 2013, 14 (4): 2591-2594.

31 李朝陽, 曲顏麗, 唐勇. 奧沙利鉑聯(lián)合替吉奧或紫杉醇脂質(zhì)體治療晚期胃癌的臨床觀察[J]. 腫瘤, 2015, 35 (1): 92-98.

32 Salehan MR, Morse HR. DNA damage repair and tolerance: a role in chemotherapeutic drug resistance[J]. Br J Biomed Sci, 2013, 70 (1): 31-40.

33 Gentile F, Tuszynski JA, Barakat KH. Modelling DNA Repair Pathways: Recent Advances and Future Directions[J]. Curr Pharm Des, 2016, 22 (23): 3527-3546.

34 Herath NI, Devun F, Lienafa MC, et al. The DNA Repair Inhibitor DT01 as a Novel Therapeutic Strategy for Chemosensitization of Colorectal Liver Metastasis[J]. Mol Cancer Ther, 2016, 15 (1): 15-22.

35 Liu MN, Liu AY, Du YJ, et al. Nitrogen permease regulator-like 2 enhances sensitivity to oxaliplatin in colon cancer cells[J]. Mol Med Rep, 2015, 12 (1): 1189-1196.

36 Lim SC, Oh SH. The role of CD24 in various human epithelial neoplasias[J]. Pathol Res Pract, 2005, 201 (7): 479-486.

37 Sammar M, Aigner S, Hubbe M, et al. Heat-stable antigen (CD24) as ligand for mouse P-selectin[J]. Int Immunol, 1994, 6 (7): 1027-1036.

38 Yong CS, Ou Yang CM, Chou YH, et al. CD44/CD24 expression in recurrent gastric cancer: a retrospective analysis[J]. BMC Gastroenterol, 2012, 12: 95.

39 Johnson SM, Gulhati P, Rampy BA, et al. Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer[J]. J Am Coll Surg, 2010, 210 (5): 767-778.

40 Maira SM, Voliva C, Garcia-Echeverria C. Class IA phosphatidylinositol 3-kinase: from their biologic implication in human cancers to drug discovery[J]. Expert Opin Ther Targets, 2008, 12 (2): 223-238.

41 Ekstrand AI, J?nsson M, Lindblom A, et al. Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer[J]. Fam Cancer, 2010, 9 (2): 125-129.

42 Glienke W, Maute L, Wicht J, et al. The dual PI3K/mTOR inhibitor NVP-BGT226 induces cell cycle arrest and regulates Survivin gene expression in human pancreatic cancer cell lines[J]. Tumour Biol, 2012, 33 (3): 757-765.

AdvancesinStudyonNPRL2GeneandOxaliplatininTreatmentofColorectalCancer

FUWeiran,LIUAiyun,DUYaju.

DepartmentofGastroenterology,the2ndAffiliatedHospitalofHarbinMedicalUniversity,Harbin(150001)

DU Yaju, Email: duyaju1964@163.com

Colorectal cancer (CRC) is one of the three major malignant tumors in the world with high morbidity and mortality. It is found that NPRL2 gene is closely related to the occurrence and development of CRC, and the expression of NPRL2 gene in CRC patients is significantly reduced. Oxaliplatin is the third generation of platinum anticancer drugs, and has been widely used in the chemotherapy of gastrointestinal tumors. Oxaliplatin can improve the survival rate of CRC patients, but some patients have drug resistance. NPRL2 gene can increase the sensitivity of oxaliplatin in the treatment of CRC, and is a potential target for treatment of CRC. This article reviewed the advances in study on NPRL2 gene and oxaliplatin in the treatment of CRC.

Colorectal Neoplasms; NPRL2 Gene; Oxaliplatin; Therapy

10.3969/j.issn.1008-7125.2017.12.012

*本文通信作者，Email: duyaju1964@163.com

(2017-05-17收稿；2017-06-11修回)