引用本文

李成偉, 李圣青. N-myc下游調(diào)控基因1在呼吸系統(tǒng)疾病中的研究進展[J]. 復旦學報醫(yī)學版, 2022, 49(2): 282-288.

LI Cheng-wei, LI Sheng-qing. Research progress on the role of N-myc downstream regulatory gene 1 in respiratory diseases[J]. Fudan University Journal of Medical Sciences, 2022, 49(2): 282-288.

N-myc下游調(diào)控基因1在呼吸系統(tǒng)疾病中的研究進展

復旦大學附屬華山醫(yī)院呼吸與危重癥醫(yī)學科 上海 200040

收稿日期：2021-02-25；網(wǎng)絡(luò)首發(fā)時間: 2022-03-08 13:52:04

基金項目：國家自然科學基金(81970048)

摘要：N-myc下游調(diào)控基因1（N-myc downstream regulated gene-1，NDRG1）是NDRG家族的第一個成員，與低氧和應激相關(guān)。NDRG1廣泛分布在全身多種組織器官中，具有特有的分子結(jié)構(gòu)和化學修飾。在肺中NDRG1主要表達在呼吸道組織內(nèi)，其表達水平和化學修飾與多種呼吸系統(tǒng)疾病的發(fā)生發(fā)展有密切關(guān)系，包括感染性疾病、慢性氣道炎性疾病、低氧相關(guān)疾?。ㄈ绶螕p傷、急性呼吸窘迫綜合征）等，同時在腫瘤低氧微環(huán)境、腫瘤進展及耐藥等方面也發(fā)揮重要作用。本文就NDRG1在呼吸系統(tǒng)疾病中的相關(guān)研究進展作一綜述。

關(guān)鍵詞：N-myc下游調(diào)控基因1（NDRG1）    呼吸系統(tǒng)疾病    信號通路    

Research progress on the role of N-myc downstream regulatory gene 1 in respiratory diseases

LI Cheng-wei , LI Sheng-qing     

Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China

Foundation item: This work was supported by the National Natural Science Foundation of China (81970048)

Abstract: N-myc downstream regulated gene-1 (NDRG1), the firstly identified member of NDRG family, is a hypoxia and stress related gene. NDRG1 is widely distributed and expressed in a variety of tissues and organs, with its unique molecular structure and chemical modification.NDRG1 is mainly expressed in the respiratory tract tissue in the lung.The expression level and chemical modification of NDRG1 is closely related to the occurrence and development of various respiratory diseases, including infectious diseases, chronic airway inflammatory diseases, hypoxia related diseases such as lung injury and acute respiratory distress syndrome, as well as hypoxic tumor microenvironment, tumor progression and therapeutic resistance.Therefore, this review summarizes the research progress on the role of NDRG1 in respiratory diseases.

Key words: N-myc downstream regulated gene-1 (NDRG1)    respiratory diseases    signaling pathway    

N-myc下游調(diào)控基因（N-myc downstream regulated gene，NDRG）家族是包括NDRG1~4在內(nèi)的新的基因家族，NDRG1是NDRG家族的第一個成員，最先被鑒定為由廣泛表達的NDRG1基因編碼的細胞質(zhì)蛋白[1-2]。呼吸系統(tǒng)疾病是常見疾病，死亡率高，疾病負擔重，已經(jīng)成為最突出的公共衛(wèi)生與醫(yī)療問題之一，對我國人民健康構(gòu)成嚴重威脅。隨著大氣污染、吸煙、老齡化及病原菌耐藥等問題的日益凸顯，呼吸系統(tǒng)疾病的防治形勢愈發(fā)嚴峻。呼吸系統(tǒng)疾病多存在缺氧或氧化應激，皆是誘導NDRG1表達的重要誘因。在肺中NDRG1主要表達在呼吸道組織的細胞內(nèi)[3-4]，參與多種生理活動和功能調(diào)節(jié)，包括腫瘤進展以及細胞應激反應，因此NDRG1在疾病發(fā)生發(fā)展過程中發(fā)揮重要作用。

NDRG1的結(jié)構(gòu)  NDRG1最先發(fā)現(xiàn)于N-myc敲除的小鼠胚胎中，受N-myc抑制性調(diào)控。根據(jù)鑒定的細胞及基因功能的差異，該分子具有多種不同的名稱，包括分化相關(guān)基因1（differentiation-related gene-1，DRG1）還原劑和衣霉素反應蛋白（reducing agent and tunicamycin-responsive protein，RTP）、鈣相關(guān)蛋白43（Ca2+-associated protein 43，Cap43）和氧調(diào)節(jié)蛋白（protein regulated by oxygen，PROXY-1），最后被人類基因組組織基因命名委員會（HUGO Gene Nomenclature Committee）正式命名為NDRG1[5]。NDRG1定位于染色體8q24.3[6]，全長60 085 bp，包含16個外顯子和15個內(nèi)含子，編碼2 997 bp的mRNA，其中1 182 bp為可編碼區(qū)[7]。NDRG1的mRNA被翻譯成相對分子質(zhì)量43 000、由394個氨基酸組成的蛋白質(zhì)[8]。人類NDRG1蛋白與NDRG其他家族成員的不同之處在于，包含3個十肽串聯(lián)重復序列，每個十肽串聯(lián)重復序列都由GTRSHTSE殘基組成[9]。此外，NDRG家族其他成員也缺乏C末端的兩個殘基Ser和Glu[10]。NDRG1的C端結(jié)構(gòu)域在NDRG蛋白質(zhì)中是獨特結(jié)構(gòu)，已證實血清和糖皮質(zhì)激素誘導激酶1（serum and glucocorticoid-inducible kinase-1，SGK-1）在Thr328、Ser330、Thr346、Thr356和Thr366處磷酸化NDRG1[11-12]，而糖原合成酶激酶3β（glycogen synthase kinase 3β，GSK-3β）在Ser342、Ser352和Ser362處磷酸化NDRG1[13]。SGK1和GSK3β是抑制NDRG1的兩種上游激酶，導致NDRG1水平降低[14]。同時，在C末端區(qū)域有一個磷酸泛乙烯連接位點（phosphopantetheine attachment site，PPAS）[15]，在缺氧條件下，NDRG1的PPAS區(qū)域全部或部分缺失可消除核易位，應對細胞DNA損傷的反應表明PPAS可能負責NDRG1的核定位[16]。在NDRG1蛋白質(zhì)N末端附近發(fā)現(xiàn)了另一種獨特的結(jié)構(gòu)，即蛋白質(zhì)N末端附近的螺旋-螺旋（helix-turn-helix，HTH）以及α/β水解酶折疊內(nèi)的帽狀結(jié)構(gòu)域（殘基169~235）[15]。目前這些結(jié)構(gòu)的確切功能還不清楚。

NDRG1的分布及表達  通過原位雜交分析，NDRG1在正常人體的大多數(shù)器官和系統(tǒng)中均有表達，包括消化道、免疫系統(tǒng)、生殖系統(tǒng)和泌尿系統(tǒng)，其中在腎臟、前列腺和卵巢的表達水平最高[3]。部分組織如大腦、心臟、卵巢、骨骼肌和血管等在mRNA水平表達NDRG1，但在蛋白水平無表達[4]。NDRG1可對多種生物刺激產(chǎn)生反應，包括NO、鈣離子水平及缺氧等[2]。雖然NDRG1在人體組織中廣泛表達，但似乎具有組織特異性功能。胎盤中發(fā)現(xiàn)的NDRG1表達可歸結(jié)為其在滋養(yǎng)層分化和缺氧誘導損傷保護中的作用[17]。NDRG1的普遍表達表明該分子可能在正常生理中發(fā)揮多效性作用。在肺組織中，免疫組織化學顯示NDRG1蛋白主要在皮脂腺、外分泌腺及呼吸道肺支氣管腺體表達，而在血管內(nèi)皮細胞、平滑肌細胞未檢測到[3]。檢索the Human Protein Atlas數(shù)據(jù)庫（https://www.proteinatlas.org/）同樣表明，NDRG1在呼吸道上皮中呈高表達，在肺泡細胞及巨噬細胞中呈中度表達，而在肺血管中未檢測到。

NDRG1與感染性疾病  煙曲霉（A. fumigatus）是一種常見真菌，當人體免疫功能受損時，就會發(fā)生嚴重的侵襲性曲霉病感染，煙曲霉分生孢子與Ⅱ型肺泡上皮細胞的相互作用在疾病進展中起重要作用[18]。Zhang等[19]用體外細胞模型比較了Ⅱ型肺上皮細胞在有無煙曲霉刺激下的蛋白質(zhì)組學，表明煙曲霉感染后NDRG1表達上調(diào)，NDRG1敲除后煙曲霉的內(nèi)化效率顯著降低。這些結(jié)果表明煙曲霉促進NDRG1表達，影響肺上皮細胞代謝。

對A549細胞感染不同宿主來源的A型流感病毒（包括人源性季節(jié)性流感A病毒H3N2、豬源性流感A病毒H1N1及禽源性流感A病毒H3N2）進行mRNA表達譜分析，并用RT-qPCR驗證，發(fā)現(xiàn)NDRG1具有差異表達[20]。A549細胞感染H5N1病毒后發(fā)現(xiàn)，病毒蛋白可上調(diào)NDRG1表達，NDRG1過表達釋放出約4倍的病毒粒子，而NDRG1敲除導致病毒表達下降。進一步研究表明，NDRG1下調(diào)IκB激酶β（inhibitor kappa B kinase β，IKKβ）誘導的干擾素β（interferon β，IFN-β）和IL-8，提示NDRG1下調(diào)核因子κB（nuclear factor kappa-B，NF-κB），進一步抑制固有免疫，促進了A型流感病毒復制[21]。

與上述研究結(jié)果相反，豬繁殖與呼吸綜合征病毒（porcine reproductive and respiratory syndrome virus，PRRSV）感染會下調(diào)NDRG1表達，NDRG1缺乏可減少細胞內(nèi)脂滴數(shù)量，并促進自噬，增加水解游離脂肪酸的產(chǎn)量，從而促進病毒RNA復制和子代病毒組裝。因此，NDRG1和脂質(zhì)吞噬對于了解PRRSV的發(fā)病機制和開發(fā)新的治療方法具有重要意義[22]。EB病毒（Epstein-Barr virus，EBV）可編碼自己的microRNAs，然而其生物學作用仍不詳，通過對病毒miRNA陽性和陰性的差異表達基因進行篩選，發(fā)現(xiàn)多種EBV編碼的miRNA協(xié)同下調(diào)NDRG1，同時免疫組化分析顯示EBV陽性鼻咽癌組織中NDRG1表達水平明顯下調(diào)，NDRG1在其中發(fā)揮的作用有助于進一步闡明EBV介導的上皮癌變機制[23]。

膿毒癥相關(guān)性器官損傷在膿毒癥患者中有較高的發(fā)病率和死亡率，吸入2%氫氣可有效改善膿毒癥及相關(guān)器官損傷[24]。Jiang等[25]采用液相色譜-串聯(lián)質(zhì)譜分析研究氫氣治療膿毒癥的相關(guān)蛋白質(zhì)組學，發(fā)現(xiàn)氫氣通過下調(diào)NDRG1及其他基因的表達減輕膿毒癥小鼠的腸道損傷，但具體機制有待進一步研究。

NDRG1與慢性氣道炎性疾病  慢性鼻-鼻竇炎是一種常見的上呼吸道疾病，盡管對其發(fā)病機制知之甚少，但越來越多的證據(jù)表明上皮物理屏障缺陷起著重要作用，而鼻上皮屏障功能受多種內(nèi)外因素的調(diào)控，可由吸入性過敏原、微生物或病毒感染、細胞因子、缺氧或缺鋅等原因引起[26]。利用Affimetrix人類全基因組基因芯片進行微陣列分析，鑒定出NDRG1在上皮細胞屏障發(fā)育過程中被誘導表達，慢性鼻-鼻竇炎患者鼻組織纖毛上皮細胞中NDRG1高表達，杯狀細胞或受損上皮細胞中NDRG1低表達；NDRG1敲除通過降低連接蛋白claudin-9的表達，破壞氣道上皮細胞的緊密連接，提示NDRG1對氣道上皮細胞屏障的完整性起重要作用[27]。

NDRG1與肺損傷/急性呼吸窘迫綜合征  危重患者對呼吸機誘導的肺損傷的敏感性不同，表明基因-環(huán)境相互作用可能促進個體的易感性。對小鼠進行大潮氣量通氣后肺泡毛細血管通透性的測定，發(fā)現(xiàn)NDRG1上調(diào)，但具體作用及機制尚不清楚[28]。脂毒素A4（lipoxina4，LXA4）通過促進肺上皮細胞上皮鈉通道（epithelial sodium channel，ENaC）的表達，減輕脂多糖（lipopolysaccharide，LPS）誘導的急性肺損傷和急性呼吸窘迫綜合征[29]。Zhang等[30]將A549細胞與LPS和LXA4共同孵育，對A549細胞進行轉(zhuǎn)錄組測序，發(fā)現(xiàn)NDRG1在LXA4中呈劑量依賴性升高，NDRG1敲除抑制LPS處理的A549細胞活力，而磷脂酰肌醇3激酶（phosphatidylinositol 3 kinase，PI3K）抑制劑LY294002可抑制NDRG1和ENaC-α的表達以及SGK 1的磷酸化，提示NDRG1通過介導PI3K信號通路恢復ENaC的表達，從而在LPS誘導的A549細胞損傷中發(fā)揮保護作用。

缺氧誘導信號通路參與高原環(huán)境適應性調(diào)節(jié)等多種病理過程，NDRG1具有較強的缺氧應激反應功能[31]，可能在缺氧相關(guān)疾病中發(fā)揮重要作用。Grigoryev等[32]將C57BL/6J小鼠置于缺氧室中10 h，通過與常氧對照組差異基因篩選發(fā)現(xiàn)NDRG1在缺氧小鼠中表達上調(diào)，提示NDRG1在小鼠低氧過程中可能具有一定功能。NDRG1在缺氧的原代人類滋養(yǎng)層中表達增加，NDRG1基因敲除的胚胎生長受限，隨著缺氧暴露，NDRG1缺乏導致載脂蛋白A2、A4、A5、C2和C4表達減少，表明NDRG1通過調(diào)節(jié)脂蛋白代謝參與缺氧損傷[33]。

NDRG1與肺部腫瘤  NDRG1是一種已知的多發(fā)性腫瘤轉(zhuǎn)移抑制因子，其在惡性腫瘤中的作用尚未完全闡明。既往研究發(fā)現(xiàn)NDRG在多種惡性腫瘤中呈高表達，促進腫瘤進展（包括肺癌）。Wang等[34]發(fā)現(xiàn)，肺癌患者血清NDRG1水平明顯高于健康對照組。在肺組織中，與癌旁正常組織相比，肺癌組織中NDRG1表達明顯增加[34-37]，肺腺癌的NDRG1水平明顯高于肺鱗癌[34]，且NDRG1基因表達水平不隨端粒狀態(tài)改變[38]。預后分析顯示NDRG1高表達預后差，提示NDRG1是非小細胞肺癌預后不良的預測指標[36, 39]。

缺氧誘導信號通路參與腫瘤發(fā)生的多種病理過程。雖然NDRG1對缺氧的反應研究較多，但是對于NDRG1的具體調(diào)控機制研究較少。Wang等[40]研究發(fā)現(xiàn)，低氧誘導因子1α（hypoxia inducible factor-1α，HIF-1α）可以結(jié)合NDRG1啟動子的-1202到-450區(qū)域，激活NDRG1表達，提示了NGRG1在缺氧應激反應中的作用機制。地高辛可通過抑制HIF-1α的合成，在轉(zhuǎn)錄水平下調(diào)缺氧誘導的NDRG1過表達[41]。Cangul等[42]發(fā)現(xiàn)，HIF-1非依賴性通路參與慢性低氧時該基因的調(diào)控。下調(diào)V-Ets骨髓成紅細胞增多癥病毒E26癌基因同源物1（recombinant V-Ets erythroblastosis virus E26 oncogene homolog 1，ETS1）抑制NDRG1的表達，表明ETS1與HIF-1共同參與調(diào)節(jié)低氧誘導基因[43]。職業(yè)性接觸鎳化合物與肺癌有關(guān)，Tchou-Wong等[44]研究表明，鎳暴露增加了A549細胞中NDRG1啟動子和編碼區(qū)H3K4的三甲基化水平，為鎳化合物致癌性的表觀遺傳機制提供了新的思路。轉(zhuǎn)移性肺癌在肺腺癌患者中很常見，但其分子機制尚未完全闡明，miRNA可促進腫瘤發(fā)生發(fā)展，其中miR-576-3p在晚期肺腺癌顯著降低，SGK1是miR-576-3p的直接靶點，對miR-576-3p水平的調(diào)節(jié)導致SGK1水平改變及其下游靶點NDRG1的活化改變，從而調(diào)控肺腺癌的遷移和侵襲[45]。長鏈非編碼RNA（long non-coding RNA，lncRNA）在小細胞肺癌中的研究很少。Zeng等[46]首次證明Linc00173與小細胞肺癌的進展相關(guān)，Linc00173通過miRNA-218作為競爭性內(nèi)源性RNA上調(diào)酪氨酸激酶，進而NDRG1上調(diào)，β-catenin易位，促進小細胞肺癌進展。染色質(zhì)重塑蛋白家族CW型鋅指結(jié)構(gòu)蛋白2（microrchidia family CW-type zinc finger 2，MORC2）是一種新發(fā)現(xiàn)的染色質(zhì)重塑蛋白，MORC2過表達抑制NDRG1啟動子的活性，介導體內(nèi)結(jié)直腸癌細胞的肺轉(zhuǎn)移[47]。

針對NDRG1的下游信號通路，研究發(fā)現(xiàn)NDRG1基因沉默后凋亡前蛋白BAX增加，抗凋亡蛋白Bcl-2和Bclx減少，導致線粒體損傷，線粒體膜電位被破壞，通過有效降低葡萄糖攝取、乳酸輸出阻斷缺氧導致的有氧糖酵解[48]，這項研究為NDRG1在肺癌中的促增殖和抗凋亡機制帶來啟示。腫瘤起始細胞（tumor initiating cell，TIC）在多種腫瘤發(fā)生發(fā)展中起重要作用，但作用機制仍不清楚。研究發(fā)現(xiàn)NDRG1可促進非小細胞肺癌中TIC的干細胞樣特性，包括誘導多能干細胞因子、成球能力和致瘤性，其機制為NDRG1直接與細胞S期激酶相關(guān)蛋白2（sphase kinase associated protein 2，Skp2）相互作用，通過周期蛋白依賴性激酶2（cyclin-dependent kinases，CDK2）失活降低Skp2的磷酸化，阻止C-myc降解[49]。多種惡性腫瘤都與血管生成的調(diào)節(jié)受損有關(guān)，其中血管內(nèi)皮生長因子A（vascular endothelial growth factor A，VEGF-A）是一個關(guān)鍵的調(diào)節(jié)因子。Kosuke等[50]發(fā)現(xiàn)腫瘤血管內(nèi)皮細胞中NDRG1缺乏阻止了磷脂酶Cγ1和細胞外調(diào)節(jié)蛋白激酶（extracellular regulated protein kinases，ERK）1/2的激活，NDRG1通過其磷酸化位點與磷脂酶Cγ1形成復合物，從而降低VEGF-A誘導的血管生成，提示NDRG1在血管生成中的作用。

耐藥性是肺癌治療中一個嚴重的臨床問題，其中上皮細胞間質(zhì)轉(zhuǎn)化（epithelial-mesenchymal transition，EMT）過程在化療耐藥中起重要作用[51]。Hao等[52]利用蛋白質(zhì)組學方法鑒定出耐藥肺癌細胞中NDRG1顯著下調(diào)，NDRG1下調(diào)使腫瘤細胞獲得EMT表型，對順鉑的耐藥性增加。另一項研究表明，順鉑顯著上調(diào)肺癌細胞中轉(zhuǎn)錄激活因子3（activating transcription factor 3，ATF3）、磷酸化P53和切割半胱天冬酶3的表達，但在順鉑存在下NDRG1過表達降低了這些蛋白的水平，表明NDRG1參與肺癌對順鉑的耐藥[53]。He等[54]發(fā)現(xiàn)，與藥物敏感細胞相比，耐藥肺癌細胞中NDRG1水平較低，表明NDRG1是肺癌順鉑耐藥過程中DNA損傷反應和缺氧相關(guān)細胞應激反應的重要調(diào)節(jié)因子。同樣，下調(diào)NDRG1表達增加了H441細胞對足葉乙甙誘導的凋亡的敏感性，抑制NDRG1表達的策略可能有助于靶向治療[55]。具有激活表皮生長因子受體突變功能的非小細胞肺癌中，參與糖代謝的基因組在高表達p-NDRG1的患者中富集，總生存率與p-NDRG1呈負相關(guān)，揭示了p-NDRG1與EGFR耐藥細胞代謝重編程之間的聯(lián)系[56]。

結(jié)語  NDRG1是一種廣泛表達且功能多樣的基因，目前認為NDRG1在呼吸系統(tǒng)疾病中的作用主要集中在肺部感染、慢性氣道炎性疾病、低氧相關(guān)疾病及肺部腫瘤等，NDRG1可能成為這些肺部疾病的有效治療靶點。

作者貢獻聲明  李成偉  文獻復習，論文撰寫和修改。李圣青  論文構(gòu)思和修改。

利益沖突聲明  所有作者均聲明不存在利益沖突。

參考文獻

[1]

FANG BA, KOVA?EVI? ?, PARK KC, et al. Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy[J]. Biochim Biophys Acta, 2014, 1845(1): 1-19.

[2]

PARK KC, PALUNCIC J, KOVACEVIC Z, et al. Pharmacological targeting and the diverse functions of the metastasis suppressor, NDRG1, in cancer[J]. Free Radic Biol Med, 2020, 157: 154-175. [DOI]

[3]

LACHAT P, SHAW P, GEBHARD S, et al. Expression of NDRG1, a differentiation-related gene, in human tissues[J]. Histochem Cell Biol, 2002, 118(5): 399-408. [DOI]

[4]

UHLéN M, FAGERBERG L, HALLSTR?M BM, et al. Proteomics.Tissue-based map of the human proteome[J]. Science, 2015, 347(6220): 1260419. [DOI]

[5]

LI J, KRETZNER L. The growth-inhibitory Ndrg1 gene is a Myc negative target in human neuroblastomas and other cell types with overexpressed N- or C-myc[J]. Mol Cell Biochem, 2003, 250(1-2): 91-105.

[6]

THIERRY-MIEG D, THIERRY-MIEG J. AceView: a comprehensive cDNA-supported gene and transcripts annotation[J]. Genome Biol, 2006, 7 Suppl 1(Suppl 1): S12.11-14.

[7]

BELZEN NVAN, DINJENS WN, EUSSEN BH, et al. Expression of differentiation-related genes in colorectal cancer: possible implications for prognosis[J]. Histol Histopathol, 1998, 13(4): 1233-1242.

[8]

ZHOU RH, KOKAME K, TSUKAMOTO Y, et al. Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart[J]. Genomics, 2001, 73(1): 86-97. [DOI]

[9]

KOKAME K, KATO H, MIYATA T. Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis.GRP78/BiP and novel genes[J]. J Biol Chem, 1996, 271(47): 29659-29665. [DOI]

[10]

HWANG J, KIM Y, KANG HB, et al. Crystal structure of the human N-myc downstream-regulated gene 2 protein provides insight into its role as a tumor suppressor[J]. J Biol Chem, 2011, 286(14): 12450-12460. [DOI]

[11]

INGLIS SK, GALLACHER M, BROWN SG, et al. SGK1 activity in Na+ absorbing airway epithelial cells monitored by assaying NDRG1-Thr346/356/366 phosphorylation[J]. Pflugers Arch, 2009, 457(6): 1287-1301. [DOI]

[12]

HOANG B, FROST P, SHI Y, et al. Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor[J]. Blood, 2010, 116(22): 4560-4568. [DOI]

[13]

MURRAY JT, CAMPBELL DG, MORRICE N, et al. Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3[J]. Biochem J, 2004, 384(Pt 3): 477-488.

[14]

SAHNI S, PARK KC, KOVACEVIC Z, et al. Two mechanisms involving the autophagic and proteasomal pathways process the metastasis suppressor protein, N-myc downstream regulated gene 1[J]. Biochim Biophys Acta Mol Basis Dis, 2019, 1865(6): 1361-1378. [DOI]

[15]

SHI XH, LARKIN JC, CHEN B, et al. The expression and localization of N-myc downstream-regulated gene 1 in human trophoblasts[J]. PLoS One, 2013, 8(9): e75473. [DOI]

[16]

KURDISTANI SK, ARIZTI P, REIMER CL, et al. Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage[J]. Cancer Res, 1998, 58(19): 4439-4444.

[17]

CHEN B, NELSON DM, SADOVSKY Y. N-myc down-regulated gene 1 modulates the response of term human trophoblasts to hypoxic injury[J]. J Biol Chem, 2006, 281(5): 2764-2772. [DOI]

[18]

TOOR A, CULIBRK L, SINGHERA GK, et al. Transcriptomic and proteomic host response to Aspergillus fumigatus conidia in an air-liquid interface model of human bronchial epithelium[J]. PLoS One, 2018, 13(12): e0209652. [DOI]

[19]

ZHANG X, HE D, GAO S, et al. iTRAQ-based proteomic analysis of the interaction of A549 human lung epithelial cells with Aspergillus fumigatus conidia[J]. Mol Med Rep, 2020, 22(6): 4601-4610. [DOI]

[20]

GAO J, GAO L, LI R, et al. Integrated analysis of microRNA-mRNA expression in A549 cells infected with influenza A viruses (IAVs) from different host species[J]. Virus Res, 2019, 263: 34-46. [DOI]

[21]

CHEN L, XING C, MA G, et al. N-myc downstream-regulated gene 1 facilitates influenza A virus replication by suppressing canonical NF-κB signaling[J]. Virus Res, 2018, 252: 22-28. [DOI]

[22]

WANG J, LIU JY, SHAO KY, et al. Porcine reproductive and respiratory syndrome virus activates lipophagy to facilitate viral replication through downregulation of NDRG1 expression[J]. J Virol, 2019, 93(17): e00526-19.

[23]

KANDA T, MIYATA M, KANO M, et al. Clustered microRNAs of the Epstein-Barr virus cooperatively downregulate an epithelial cell-specific metastasis suppressor[J]. J Virol, 2015, 89(5): 2684-2697. [DOI]

[24]

YANG T, WANG L, SUN R, et al. Hydrogen-rich medium ameliorates lipopolysaccharide-induced barrier dysfunction via rhoa-mdia1 signaling in caco-2 cells[J]. Shock, 2016, 45(2): 228-237. [DOI]

[25]

JIANG Y, BIAN Y, LIAN N, et al. iTRAQ-based quantitative proteomic analysis of intestines in murine polymicrobial sepsis with hydrogen gas treatment[J]. Drug Des Devel Ther, 2020, 14: 4885-4900. [DOI]

[26]

JIAO J, WANG C, ZHANG L. Epithelial physical barrier defects in chronic rhinosinusitis[J]. Expert Rev Clin Immunol, 2019, 15(6): 679-688. [DOI]

[27]

GON Y, MARUOKA S, KISHI H, et al. NDRG1 is important to maintain the integrity of airway epithelial barrier through claudin-9 expression[J]. Cell Biol Int, 2017, 41(7): 716-725. [DOI]

[28]

LI HH, LI Q, LIU P, et al. WNT1-inducible signaling pathway protein 1 contributes to ventilator-induced lung injury[J]. Am J Respir Cell Mol Biol, 2012, 47(4): 528-535. [DOI]

[29]

QI W, LI H, CAI XH, et al. Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury[J]. Lab Invest, 2015, 95(11): 1258-1268. [DOI]

[30]

ZHANG JZ, LIU ZL, ZHANG YX, et al. Lipoxin A4 ameliorates lipopolysaccharide-induced A549 cell injury through upregulation of N-myc downstream-regulated gene-1[J]. Chin Med J (Engl), 2018, 131(11): 1342-1348. [DOI]

[31]

LE N, HUFFORD TM, PARK JS, et al. Differential expression and hypoxia-mediated regulation of the N-myc downstream regulated gene family[J]. FASEB J, 2021, 35(11): e21961.

[32]

GRIGORYEV DN, MA SF, SHIMODA LA, et al. Exon-based mapping of microarray probes: recovering differential gene expression signal in underpowered hypoxia experiment[J]. Mol Cell Probes, 2007, 21(2): 134-139. [DOI]

[33]

LARKIN J, CHEN B, SHI XH, et al. NDRG1 deficiency attenuates fetal growth and the intrauterine response to hypoxic injury[J]. Endocrinology, 2014, 155(3): 1099-1106. [DOI]

[34]

WANG D, TIAN X, JIANG Y. NDRG1/Cap43 overexpression in tumor tissues and serum from lung cancer patients[J]. J Cancer Res Clin Oncol, 2012, 138(11): 1813-1820. [DOI]

[35]

FAN C, YU J, LIU Y, et al. Increased NDRG1 expression is associated with advanced T stages and poor vascularization in non-small cell lung cancer[J]. Pathol Oncol Res, 2012, 18(3): 549-556. [DOI]

[36]

AZUMA K, KAWAHARA A, HATTORI S, et al. NDRG1/Cap43/Drg-1 may predict tumor angiogenesis and poor outcome in patients with lung cancer[J]. J Thorac Oncol, 2012, 7(5): 779-789. [DOI]

[37]

LAZAR V, SUO C, OREAR C, et al. Integrated molecular portrait of non-small cell lung cancers[J]. BMC Med Genomics, 2013, 6: 53. [DOI]

[38]

FERNáNDEZ-MARCELO T, MORáN A, DE JUAN C, et al. Differential expression of senescence and cell death factors in non-small cell lung and colorectal tumors showing telomere attrition[J]. Oncology, 2012, 82(3): 153-164. [DOI]

[39]

DAI T, DAI Y, MURATA Y, et al. The prognostic significance of N-myc downregulated gene 1 in lung adenocarcinoma[J]. Pathol Int, 2018, 68(4): 224-231. [DOI]

[40]

WANG Q, LI LH, GAO GD, et al. HIF-1α up-regulates NDRG1 expression through binding to NDRG1 promoter, leading to proliferation of lung cancer A549 cells[J]. Mol Biol Rep, 2013, 40(5): 3723-3729. [DOI]

[41]

WEI D, PENG JJ, GAO H, et al. Digoxin downregulates NDRG1 and VEGF through the inhibition of HIF-1α under hypoxic conditions in human lung adenocarcinoma A549 cells[J]. Int J Mol Sci, 2013, 14(4): 7273-7285. [DOI]

[42]

CANGUL H. Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers[J]. BMC Genet, 2004, 5: 27.

[43]

SALNIKOW K, APRELIKOVA O, IVANOV S, et al. Regulation of hypoxia-inducible genes by ETS1 transcription factor[J]. Carcinogenesis, 2008, 29(8): 1493-1499. [DOI]

[44]

TCHOU-WONG KM, KIOK K, TANG Z, et al. Effects of nickel treatment on H3K4 trimethylation and gene expression[J]. PLoS One, 2011, 6(3): e17728. [DOI]

[45]

GREENAWALT EJ, EDMONDS MD, JAIN N, et al. Targeting of SGK1 by miR-576-3p inhibits lung adenocarcinoma migration and invasion[J]. Mol Cancer Res, 2019, 17(1): 289-298. [DOI]

[46]

ZENG F, WANG Q, WANG S, et al. Linc00173 promotes chemoresistance and progression of small cell lung cancer by sponging miR-218 to regulate Etk expression[J]. Oncogene, 2020, 39(2): 293-307. [DOI]

[47]

LIU J, SHAO Y, HE Y, et al. MORC2 promotes development of an aggressive colorectal cancer phenotype through inhibition of NDRG1[J]. Cancer Sci, 2019, 110(1): 135-146. [DOI]

[48]

GUO DD, XIE KF, LUO XJ. Hypoxia-induced elevated NDRG1 mediates apoptosis through reprograming mitochondrial fission in HCC[J]. Gene, 2020, 741: 144552. [DOI]

[49]

WANG Y, ZHOU Y, TAO F, et al. N-myc downstream regulated gene 1(NDRG1) promotes the stem-like properties of lung cancer cells through stabilized c-Myc[J]. Cancer Lett, 2017, 401: 53-62. [DOI]

[50]

WATARI K, SHIBATA T, FUJITA H, et al. NDRG1 activates VEGF-A-induced angiogenesis through PLCγ1/ERK signaling in mouse vascular endothelial cells[J]. Commun Biol, 2020, 3(1): 107. [DOI]

[51]

BEDI U, MISHRA VK, WASILEWSKI D, et al. Epigenetic plasticity: a central regulator of epithelial-to-mesenchymal transition in cancer[J]. Oncotarget, 2014, 5(8): 2016-2029. [DOI]

[52]

LIU H, GU Y, YIN J, et al. SET-mediated NDRG1 inhibition is involved in acquisition of epithelial-to-mesenchymal transition phenotype and cisplatin resistance in human lung cancer cell[J]. Cell Signal, 2014, 26(12): 2710-2720. [DOI]

[53]

DU A, JIANG Y, FAN C. NDRG1 Downregulates ATF3 and inhibits cisplatin-induced cytotoxicity in lung cancer A549 cells[J]. Int J Med Sci, 2018, 15(13): 1502-1507. [DOI]

[54]

HE L, LIU K, WANG X, et al. NDRG1 disruption alleviates cisplatin/sodium glycididazole-induced DNA damage response and apoptosis in ERCC1-defective lung cancer cells[J]. Int J Biochem Cell Biol, 2018, 100: 54-60. [DOI]

[55]

WU F, ROM WN, KOSHIJI M, et al. Role of GLI1 and NDRG1 in increased resistance to apoptosis induction[J]. J Environ Pathol Toxicol Oncol, 2015, 34(3): 213-225. [DOI]

[56]

CHIANG CT, DEMETRIOU AN, UNG N, et al. mTORC2 contributes to the metabolic reprogramming in EGFR tyrosine-kinase inhibitor resistant cells in non-small cell lung cancer[J]. Cancer Lett, 2018, 434: 152-159. [DOI]

相關(guān)知識

The Role of Hydration in Maintaining Health
The impact of comprehensive healthy lifestyles on obstructive sleep apnea and the mediating role of BMI: insights from NHANES 2005
Research progress on the relationship between dietary patterns and common noninfectious chronic diseases
Progress on the antimicrobial properties of essential oils
Benefits of Sexual Activity on Psychological, Relational, and Sexual Health During the COVID
Research progress on the illumination requirements for the elderly's vision health
The effects of Ramadan intermittent fasting on athletic performance: recommendations for the maintenance of physical fitness
The Health Benefits of Dietary Fibre
The Promise of Sleep
Tsinghua Vanke School of Public Health Holds 'Five Years of Growth, Building the Future of Public Health Conference on Quality

網(wǎng)址: Research progress on the role of N http://www.u1s5d6.cn/newsview1236899.html