黃 昊，楊星九，李夢(mèng)媛，朱瑞敏，高 苒

(中國(guó)醫(yī)學(xué)科學(xué)院醫(yī)學(xué)實(shí)驗(yàn)動(dòng)物研究所，北京協(xié)和醫(yī)學(xué)院比較醫(yī)學(xué)中心，衛(wèi)計(jì)委人類疾病比較醫(yī)學(xué)重點(diǎn)實(shí)驗(yàn)室，北京 100021)

研究進(jìn)展

異質(zhì)性胞核核糖核蛋白K與腫瘤研究的最新進(jìn)展

黃 昊，楊星九，李夢(mèng)媛，朱瑞敏，高 苒*

(中國(guó)醫(yī)學(xué)科學(xué)院醫(yī)學(xué)實(shí)驗(yàn)動(dòng)物研究所，北京協(xié)和醫(yī)學(xué)院比較醫(yī)學(xué)中心，衛(wèi)計(jì)委人類疾病比較醫(yī)學(xué)重點(diǎn)實(shí)驗(yàn)室，北京 100021)

近幾十年來(lái)，癌基因和抑癌基因一直是腫瘤生物學(xué)中的一個(gè)重要分類，然而對(duì)于一些基因卻很難將其歸類。異質(zhì)性胞核核糖核蛋白K(heterogeneous nuclear ribonucleoprotein K，HNRNPK)是一個(gè)核酸結(jié)合蛋白，參與了基因表達(dá)調(diào)控、信號(hào)轉(zhuǎn)導(dǎo)等很多細(xì)胞進(jìn)程。近些年發(fā)現(xiàn)HNRNPK在多種腫瘤中過(guò)表達(dá)，且其過(guò)表達(dá)與患者的預(yù)后呈負(fù)相關(guān)，提示其可能在這些腫瘤中發(fā)揮癌基因的功能。然而，在急性髓系白血病(acute myeloid leukemia，AML)的研究報(bào)道中發(fā)現(xiàn)HNRNPK可能扮演抑癌基因的角色。因此，本文對(duì)HNRNPK在腫瘤發(fā)生發(fā)展中的分子功能及作用機(jī)制的最新進(jìn)展進(jìn)行綜述。

異質(zhì)性胞核核糖核蛋白K；腫瘤；分子功能

過(guò)去的幾十年里，臨床和基礎(chǔ)科學(xué)研究試圖確定直接影響腫瘤發(fā)生的關(guān)鍵的基因改變。在這一過(guò)程中，研究者們將這類基因分成致癌基因或抑癌基因，這使得研究者和臨床醫(yī)生可以描述多種基因改變可能導(dǎo)致的功能和臨床結(jié)果。然而，這種分類并不能如實(shí)反映異常的基因表達(dá)所導(dǎo)致的后果，如p53基因最初被定義為癌基因，但當(dāng)對(duì)p53的細(xì)胞功能深入研究后被證明其是一個(gè)潛在的抑癌基因[1]。

近期研究發(fā)現(xiàn)，異質(zhì)性胞核核糖核蛋白K(heterogeneous nuclear ribonucleoprotein K，HNRNPK)在腫瘤的發(fā)生發(fā)展過(guò)程中發(fā)揮重要作用，但仍很難將其分類為癌基因或抑癌基因。很多研究中均顯示HNRNPK具有調(diào)節(jié)腫瘤發(fā)生和腫瘤抑制通路的能力，過(guò)表達(dá)和低表達(dá)均有導(dǎo)致細(xì)胞增殖和抑制凋亡的報(bào)道。臨床報(bào)道中也有不同的見(jiàn)解，在結(jié)直腸癌、鼻咽癌、前列腺癌、黑色素瘤、口腔鱗狀細(xì)胞癌及胃癌的報(bào)道中，HNRNPK發(fā)揮著癌基因的角色，其過(guò)表達(dá)與腫瘤的發(fā)生及預(yù)后呈負(fù)相關(guān)[2-7]。在急性髓系白血病(acute myeloid leukemia，AML)的研究中，卻發(fā)揮抑癌基因角色，HNRNPK單倍劑量不足的小鼠易患AML及淋巴瘤[8]。因此結(jié)合目前的細(xì)胞學(xué)和臨床資料，HNRNPK并不能簡(jiǎn)單地分類為癌基因或抑癌基因。本文對(duì)HNRNPK的在腫瘤發(fā)生發(fā)展中的分子功能及作用機(jī)制進(jìn)行綜述，為全面了解HNRNPK的功能提供一定的線索。

1 HNRNPK的結(jié)構(gòu)特點(diǎn)

HNRNPK基因位于9號(hào)染色體q21.32～q21.33，序列相對(duì)保守，編碼蛋白是核不均一核糖核蛋白家族成員之一，含有3個(gè)參與RNA和單鏈DNA結(jié)合的K同源區(qū)，每個(gè)K同源區(qū)由65～70個(gè)氨基酸組成[9]。HNRNPK含有一個(gè)調(diào)節(jié)該蛋白胞漿胞核轉(zhuǎn)運(yùn)的核定位信號(hào)，且含有一個(gè)調(diào)節(jié)雙向穿梭核孔復(fù)合體的核穿梭結(jié)構(gòu)域[10]。K同源區(qū)之間含有一個(gè)非結(jié)構(gòu)化的區(qū)域，是HNRNPK與其它分子伴侶結(jié)合的主要區(qū)域，包括DNA、RNA以及相互作用蛋白。HNRNPK包括四個(gè)選擇性剪接體，剪接體1與剪接體2在蛋白的C端有5～6個(gè)氨基酸的差別，剪接體3、4在C端分別與剪接體1、2相對(duì)應(yīng)，但缺失第111～134位氨基酸，預(yù)測(cè)的分子量為48～51 × 103。然而在傳統(tǒng)的單向SDS-PAGE凝膠電泳中，胞漿HNRNPK呈現(xiàn)66 × 103大小單一條帶，胞核HNRNPK呈現(xiàn)66 × 103和64 × 103大小雙條帶，提示胞漿組分中不含HNRNPK的剪接體3與4[11]。

2 HNRNPK的分子功能

HNRNPK的特殊分子結(jié)構(gòu)賦予了其招募組成多分子信號(hào)復(fù)合體的能力，包括一些激酶及因子，參與了基因表達(dá)調(diào)控、信號(hào)轉(zhuǎn)導(dǎo)等很多細(xì)胞進(jìn)程，包括HNRNPK的轉(zhuǎn)錄調(diào)控、RNA的加工和翻譯，以及轉(zhuǎn)錄后修飾活化。

2.1HNRNPK參與轉(zhuǎn)錄調(diào)控

HNRNPK能夠與單鏈或雙鏈DNA結(jié)合，以DNA-蛋白復(fù)合體的形式調(diào)控基因的轉(zhuǎn)錄。HNRNPK可以作為轉(zhuǎn)錄激活因子或轉(zhuǎn)錄抑制因子參與轉(zhuǎn)錄調(diào)控[12]。如通過(guò)結(jié)合轉(zhuǎn)錄激活c-myc、BRCA1、eIF4E、c-Src、CHRNA4等，轉(zhuǎn)錄抑制人胸苷激酶啟動(dòng)子、CD43基因啟動(dòng)子[11]。HNRNPK對(duì)轉(zhuǎn)錄的調(diào)控方式一般分為兩類：通過(guò)嘧啶富集區(qū)(CT元件)的調(diào)控和不依賴CT元件的調(diào)控。c-myc的啟動(dòng)子上游150 bp處含有5個(gè)CT重復(fù)序列，HNRNPK則通過(guò)識(shí)別這一啟動(dòng)子區(qū)域的CT元件，以CT元件依賴的方式調(diào)控基因的表達(dá)[13]。HNRNPK也可以通過(guò)與富含CG片段結(jié)合，改變DNA的二級(jí)結(jié)構(gòu)來(lái)激活血管內(nèi)皮細(xì)胞生長(zhǎng)因子的表達(dá)[14]。HNRNPK作為p53的共激活因子，在調(diào)節(jié)DNA損傷修復(fù)過(guò)程中發(fā)揮著重要的作用。DNA損傷能使HNRNPK依賴性地被招募到p53下游基因的啟動(dòng)子上，進(jìn)而促進(jìn)如p21、HDM2、C/EBPα以及C/EBPβ的表達(dá)，HNRNPK下調(diào)表達(dá)減少p53的轉(zhuǎn)錄，從而導(dǎo)致DNA損傷誘導(dǎo)的細(xì)胞周期停滯[15]。HNRNPK缺失的細(xì)胞不能誘導(dǎo)p21的表達(dá)，抗癌藥物nutlin與MDM2結(jié)合后，可以競(jìng)爭(zhēng)抑制HNRNPK的降解，使p21轉(zhuǎn)錄正常進(jìn)行，調(diào)節(jié)細(xì)胞周期[16]。

2.2HNRNPK參與RNA的加工及翻譯

HNRNPK的K同源區(qū)能與RNA剪接相關(guān)的分子結(jié)合，參與調(diào)控RNA的選擇性剪接，如9G8、SRp20、Bcl-Xs、G6PD等[17-19]。HNRNPK作為轉(zhuǎn)錄因子參與多種蛋白的翻譯過(guò)程。HNRNPK可以直接與EF-1α以及eIF4E的啟動(dòng)子區(qū)域結(jié)合，增加翻譯起始、細(xì)胞分裂以及腫瘤形成[20,21]。在神經(jīng)元分化過(guò)程中，HNRNPK通過(guò)與p21 mRNA的3’端非翻譯區(qū)結(jié)合，抑制p21的翻譯[22]。HNRNPK的C端含有一段富含AT區(qū)域，能與Src家族的SH3結(jié)構(gòu)域相互作用，特異性的激活c-Src，同時(shí)HNRNPK的酪氨酸殘基被磷酸化，則影響了HNRNPK與RNA的結(jié)合活性，抑制15-脂氧化酶(15-lipoxygenase)基因(LOX)mRNA的3’端非翻譯區(qū)的分化調(diào)控元件(differentiation control element，DICE)結(jié)合，表現(xiàn)為DICE對(duì)mRNA的抑制作用消失，從而激活翻譯過(guò)程[23]。

2.3HNRNPK的轉(zhuǎn)錄后修飾

HNRNPK通過(guò)自身的轉(zhuǎn)錄后修飾調(diào)節(jié)與其它分子的相互作用及功能，包括甲基化、類泛素化和磷酸化。精氨酸甲基化調(diào)節(jié)HNRNPK細(xì)胞內(nèi)分布、抑制與c-Src的相互作用、增強(qiáng)p53的轉(zhuǎn)錄活性[24-26]。紫外線導(dǎo)致的DNA損傷誘導(dǎo)HNRNPK中422位賴氨酸的類泛素化，促進(jìn)了p53的轉(zhuǎn)錄活性增強(qiáng)[27,28]。白介素1、胰島素和氧化應(yīng)激等細(xì)胞外信號(hào)促進(jìn)HNRNPK的絲、蘇氨酸及酪氨酸殘基發(fā)生磷酸化，且一些激酶也參與其中[11]。MEK/ERK通路的活化導(dǎo)致HNRNPK的284位與353位絲氨酸的磷酸化，對(duì)HNRNPK的生物學(xué)功能的影響與c-Src途徑相似，調(diào)節(jié)其在細(xì)胞內(nèi)的定位及胞漿聚集[29]。

3 HNRNPK與腫瘤

HNRNP家族與目前威脅人類生命的腫瘤疾病密切相關(guān)，多種腫瘤的形成和發(fā)展都與該家族蛋白有關(guān)。大多關(guān)于HNRNPK與腫瘤的研究數(shù)據(jù)均來(lái)自于臨床患者組織標(biāo)本的病理及免疫組化分析結(jié)果，據(jù)報(bào)道HNRNPK與結(jié)直腸癌、鼻咽癌、前列腺癌、黑色素瘤、口腔鱗狀細(xì)胞癌及胃癌的預(yù)后呈負(fù)相關(guān)[2-7]。雖然HNRNPK在多數(shù)腫瘤中呈高表達(dá)，并其與腫瘤患者的預(yù)后相關(guān)，提示HNRNPK的過(guò)表達(dá)可能發(fā)揮著一個(gè)致癌基因的功能。然而，HNRNPK的單倍劑量不足卻在AML中扮演一個(gè)抑癌基因的角色。另外，近期癌癥基因組圖譜(The Cancer Genome Atlas，TCGA)揭示了HNRNPK的突變具有導(dǎo)致AML發(fā)生的能力，但仍不清楚HNRNPK突變后是導(dǎo)致其功能增加還是發(fā)揮單倍劑量不足表型的作用[8,30]。

3.1HNRNPK與腫瘤發(fā)生

HNRNPK參與多種癌基因及抑癌基因的表達(dá)調(diào)控，促進(jìn)細(xì)胞的增殖、分裂，與多種腫瘤發(fā)生發(fā)展有關(guān)。Ostareck-Lederer等[31]證明了HNRNPK能與c-Src相互作用并導(dǎo)致其激活，反過(guò)來(lái)c-Src磷酸化HNRNPK的KH3結(jié)構(gòu)域第458位酪氨酸，使胞漿HNRNPK蛋白組分失活，并抑制其與DICE結(jié)合，從而激活翻譯機(jī)制。HNRNPK在轉(zhuǎn)錄和翻譯水平上皆能影響c-myc的活性，在體內(nèi)、外實(shí)驗(yàn)中證明其通過(guò)與c-myc啟動(dòng)子的嘧啶富集區(qū)(CT元件)結(jié)合，促進(jìn)c-myc的轉(zhuǎn)錄[32]。乳腺癌、前列腺癌細(xì)胞及黑色素瘤組織的HNRNPK高表達(dá)通常伴隨c-myc水平升高[5,33,34]。在肝癌組織及細(xì)胞中，Tcl1以一種HNRNPK依賴性形式激活G6PD，并促進(jìn)G6PD的前體RNA加工及其蛋白的表達(dá)。而另一方面抑癌基因編碼蛋白PTEN與HNRNPK形成復(fù)合物，抑制HNRNPK對(duì)G6PD前體RNA的剪切作用，從而抑制肝癌的發(fā)生[35]。如前文所述，HNRNPK與p53以協(xié)同作用參與調(diào)節(jié)DNA損傷修復(fù)，且能通過(guò)自身的甲基化、賴氨酸類泛素化、以及絲/蘇氨酸磷酸化增強(qiáng)其與p53的親和力，調(diào)節(jié)下游信號(hào)通路[15]。HNRNPK作為轉(zhuǎn)錄因子，能與eIF4E啟動(dòng)子區(qū)域結(jié)合，也能通過(guò)與p21 mRNA的3’端非翻譯區(qū)結(jié)合，抑制p21的翻譯，增加翻譯起始、細(xì)胞分裂以及腫瘤形成[20,21]。因此，HNRNPK自身水平的變化或轉(zhuǎn)錄后的修飾能夠調(diào)節(jié)腫瘤發(fā)生的幾條關(guān)鍵通路。

3.2HNRNPK與腫瘤轉(zhuǎn)移

HNRNPK和腫瘤的轉(zhuǎn)移也有密切聯(lián)系。Inoue等[36]利用轉(zhuǎn)移功能缺失篩選體系，篩選出HNRNPK可能作為一種癌癥轉(zhuǎn)移相關(guān)的蛋白，其在胞漿內(nèi)的聚集效應(yīng)在細(xì)胞轉(zhuǎn)移過(guò)程中發(fā)揮重要作用。Gao等[37]證明了HNRNPK能夠激活Ras-Raf-MAPK信號(hào)通路，并且上調(diào)在腫瘤侵襲轉(zhuǎn)移中起關(guān)鍵性作用的基質(zhì)金屬蛋白酶家族成員MMP3和MMP10，促進(jìn)腫瘤的發(fā)生及發(fā)展。Strozynski等[38]通過(guò)雙向電泳聯(lián)合質(zhì)譜技術(shù)發(fā)現(xiàn)HNRNPK在放射線處理后的細(xì)胞中高表達(dá)，靶向抑制HNRNPK的表達(dá)能夠抑制頭頸鱗狀細(xì)胞癌細(xì)胞的轉(zhuǎn)移能力，提示其可能參與了頭頸鱗狀細(xì)胞癌的轉(zhuǎn)移過(guò)程。HNRNPK的胞漿聚集顯著促進(jìn)腎小細(xì)胞癌細(xì)胞的侵襲能力[39]。國(guó)內(nèi)有研究表明，HNRNPK在肺癌原發(fā)灶及支氣管切緣(+)組肺癌組織中均呈現(xiàn)較高水平的表達(dá)(65%)；正常組織及炎性對(duì)照組中HNRNPK的陽(yáng)性表達(dá)率則較低(33.3%)，該研究提示HNRNPK在肺癌的發(fā)生中起重要作用。同時(shí)該研究還發(fā)現(xiàn)HNRNPK在肺癌轉(zhuǎn)移及浸潤(rùn)組織(轉(zhuǎn)移淋巴結(jié)+支氣管切緣)中有高的陽(yáng)性表達(dá)率，而且在肺癌轉(zhuǎn)移淋巴結(jié)組有最高的表達(dá)強(qiáng)度，提示其高表達(dá)可能與肺癌轉(zhuǎn)移相關(guān)[40]。

Moumen等[15]通過(guò)蛋白質(zhì)組學(xué)研究發(fā)現(xiàn)HNRNPK以DNA損傷信號(hào)激酶ATM或ATR激活的方式，在DNA損傷時(shí)能被快速誘導(dǎo)表達(dá)；HNRNPK缺失能導(dǎo)致p53靶基因的轉(zhuǎn)錄失活，并引發(fā)DNA損傷導(dǎo)致的細(xì)胞周期阻滯缺陷。DNA損傷誘導(dǎo)的HNRNPK的小泛素相關(guān)修飾(small ubiquitin-like modifier，SUMO)作用，能夠調(diào)節(jié)p53的轉(zhuǎn)錄激活[27]。另外有研究表明HNRNPK蛋白第296位和第299位精氨酸的甲基化，抑制了促凋亡激酶PKCδ介導(dǎo)的第302位絲氨酸磷酸化，從而使DNA損傷導(dǎo)致的細(xì)胞凋亡減少，提示HNRNPK可能在抗凋亡及腫瘤細(xì)胞中避免凋亡的過(guò)程中發(fā)揮重要作用[41]。Chen等[3]在鼻咽癌的研究中發(fā)現(xiàn)HNRNPK通過(guò)調(diào)節(jié)下游的抗凋亡基因發(fā)揮抗凋亡活性，證明了HNRNPK能與抗凋亡基因FLIP的啟動(dòng)子結(jié)合并導(dǎo)致其轉(zhuǎn)錄激活。結(jié)直腸癌的研究中發(fā)現(xiàn)長(zhǎng)鏈非編碼RNA CASC11通過(guò)與HNRNPK相互作用，激活WNT/β-catenin通路，從而促進(jìn)結(jié)直腸癌細(xì)胞的生長(zhǎng)及轉(zhuǎn)移[42]。

3.3HNRNPK與腫瘤耐藥

近些年發(fā)現(xiàn)HNRNPK可能與腫瘤細(xì)胞的耐藥性具有相關(guān)性。Eder等[43,44]在惡性黑色素瘤細(xì)胞中發(fā)現(xiàn)，MAPK通路的活性與HNRNPK的表達(dá)具有相關(guān)性，射線處理NRAS突變的黑色素瘤細(xì)胞后HNRNPK呈劑量依賴性升高并向胞漿聚集，從而導(dǎo)致細(xì)胞對(duì)放射治療耐受，靶向抑制HNRNPK的表達(dá)與絲裂原活化的細(xì)胞外信號(hào)調(diào)節(jié)激酶(mitogen-activated extracellular signal-regulated kinase，MEK)抑制劑對(duì)細(xì)胞的凋亡促進(jìn)作用相符，MEK抑制劑能下調(diào)HNRNPK的表達(dá)，從而與射線聯(lián)用可以顯著增加細(xì)胞凋亡及促進(jìn)放療敏感性；其在結(jié)直腸癌細(xì)胞的研究中發(fā)現(xiàn)類似的結(jié)果，KRAS突變的結(jié)直腸癌細(xì)胞，射線處理后HNRNPK快速上調(diào)，從而導(dǎo)致細(xì)胞放療耐受，MEK抑制劑處理后能下調(diào)HNRNPK的表達(dá)，從而增強(qiáng)放療敏感性。HNRNPK在AML耐藥的患者骨髓中以及耐藥的細(xì)胞系中均高表達(dá)，靶向抑制HNRNPK的表達(dá)能夠逆轉(zhuǎn)耐藥的細(xì)胞對(duì)阿霉素的化療耐受性，另外還發(fā)現(xiàn)HNRNPK可能通過(guò)調(diào)節(jié)細(xì)胞自噬參與了阿霉素耐受的過(guò)程[45]。肺癌細(xì)胞系H1299經(jīng)過(guò)腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體(tumor necrosis factor-related apoptosis-inducing ligand，TRAIL)處理后，HNRNPK從胞核向胞漿轉(zhuǎn)移，并在胞漿中與GSK3β相互作用，并抑制其第9位絲氨酸的磷酸化，從而穩(wěn)定c-FLIP蛋白，導(dǎo)致細(xì)胞對(duì)TRAIL產(chǎn)生耐受[46]。

3.4HNRNPK與腫瘤治療

近些年也有研究者發(fā)現(xiàn)一些藥物成分能夠靶向HNRNPK發(fā)揮抑瘤效果。印度人參的乙醇提取物能夠選擇性的殺傷腫瘤細(xì)胞活性，且能在體內(nèi)、外發(fā)揮抗腫瘤轉(zhuǎn)移、侵襲及抗腫瘤血管生成的作用；進(jìn)一步通過(guò)生物信息學(xué)和生物化學(xué)系列研究方法發(fā)現(xiàn)印度人參乙醇提取物通過(guò)下調(diào)轉(zhuǎn)移相關(guān)蛋白HNRNPK、VEGF及基質(zhì)金屬蛋白酶發(fā)揮抗腫瘤轉(zhuǎn)移及血管生成的作用[47]。國(guó)內(nèi)學(xué)者也有研究發(fā)現(xiàn)一種怒江藤黃提取物中的化合物，通過(guò)促進(jìn)泛素化蛋白酶體依賴的HNRNPK降解下調(diào)HNRNPK的水平，進(jìn)而誘導(dǎo)細(xì)胞周期阻滯，從而發(fā)揮抗腫瘤的作用[48]。

4 總結(jié)和展望

HNRNPK在腫瘤的發(fā)生發(fā)展過(guò)程中發(fā)揮多種細(xì)胞學(xué)功能，鑒于目前的研究成果，仍然很難確定HNRNPK是否可以作為一個(gè)腫瘤發(fā)生發(fā)展過(guò)程中的驅(qū)動(dòng)基因。HNRNPK在腫瘤的發(fā)生發(fā)展過(guò)程中的作用很有可能依賴于組織類型或微環(huán)境，包括其募集結(jié)合的RNA、DNA和蛋白。HNRNPK在大部分腫瘤中高表達(dá)，且與患者的預(yù)后呈負(fù)相關(guān)，但因其缺乏組織特異性限制了其作為腫瘤診斷標(biāo)記物的可能，另外缺少可以檢測(cè)其表達(dá)豐度的檢測(cè)方法；因此仍需要進(jìn)一步的研究HNRNPK作為潛在腫瘤標(biāo)記物的可能性。HNRNPK敲除小鼠模型提示HNRNPK缺失與小鼠的生長(zhǎng)發(fā)育相關(guān)，完全缺失導(dǎo)致小鼠胚胎致死，HNRNPK的單倍劑量不足也能導(dǎo)致小鼠的生長(zhǎng)發(fā)育缺陷，同時(shí)易發(fā)血液惡性腫瘤及淋巴瘤，說(shuō)明HNRNPK可能在血液系統(tǒng)惡性腫瘤或淋巴瘤中扮演抑癌基因的角色。因此很有必要開(kāi)發(fā)系統(tǒng)過(guò)表達(dá)HNRNPK的轉(zhuǎn)基因小鼠模型，以觀察HNRNPK過(guò)表達(dá)對(duì)腫瘤發(fā)生發(fā)展的作用，同時(shí)也能開(kāi)發(fā)HNRNPK過(guò)表達(dá)依賴的靶向藥物。綜上所述，雖然關(guān)于HNRNPK的研究報(bào)道很多，但若想全面了解其在腫瘤發(fā)生發(fā)展中的作用，仍有很多的工作需要開(kāi)展。

[1] Mishra A, Brat DJ, Verma M. P53 tumor suppression network in cancer epigenetics [J]. Methods Mol Biol, 2015, 1238: 597-605.

[2] Carpenter B, McKay M, Dundas SR, et al. Heterogeneous nuclear ribonucleoprotein K is over expressed, aberrantly localised and is associated with poor prognosis in colorectal cancer [J]. Br J Cancer, 2006, 95(7): 921-927.

[3] Chen LC, Chung IC, Hsueh C, et al. The antiapoptotic protein, FLIP, is regulated by heterogeneous nuclear ribonucleoprotein K and correlates with poor overall survival of nasopharyngeal carcinoma patients [J]. Cell Death Differ, 2010, 17(9): 1463-1473.

[4] Ciarlo M, Benelli R, Barbieri O, et al. Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β-catenin signaling in prostate cancer cells [J]. Int J Cancer, 2012, 131(3): 582-590.

[5] Wen F, Shen A, Shanas R, et al. Higher expression of the heterogeneous nuclear ribonucleoprotein K in melanoma [J]. Ann Surg Oncol, 2010, 17(10): 2619-2627.

[6] Wu CS, Chang KP, Chen LC, et al. Heterogeneous ribonucleoprotein K and thymidine phosphorylase are independent prognostic and therapeutic markers for oral squamous cell carcinoma [J]. Oral Oncol, 2012, 48(6): 516-522.

[7] Yang R, Zeng Y, Xu H, et al. Heterogeneous nuclear ribonucleoprotein K is overexpressed and associated with poor prognosis in gastric cancer [J]. Oncol Rep, 2016, 36(2): 929-935.

[8] Gallardo M, Lee HJ, Zhang X, et al. hnRNP K is a haploinsufficient tumor suppressor that regulates proliferation and differentiation programs in hematologic malignancies [J]. Cancer Cell, 2015, 28(4): 486-499.

[9] Siomi H, Matunis MJ, Michael WM, et al. The pre-mRNA binding K protein contains a novel evolutionarily conserved motif [J]. Nucleic Acids Res, 1993, 21(5): 1193-1198.

[10] Chkheidze AN, Liebhaber SA. A novel set of nuclear localization signals determine distributions of the αCP RNA-binding proteins [J]. Mol Cell Biol, 2003, 23(23): 8405-8415.

[11] Barboro P, Ferrari N, Balbi C. Emerging roles of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in cancer progression [J]. Cancer Lett, 2014, 352(2): 152-159.

[12] Choi HS, Hwang CK, Song KY, et al. Poly(C)-binding proteins as transcriptional regulators of gene expression [J]. Biochem Biophys Res Commun, 2009, 380(3): 431-436.

[13] Tomonaga T, Levens D. Heterogeneous nuclear ribonucleoprotein K is a DNA-binding transactivator [J]. J Biol Chem, 1995, 270(9): 4875-4881.

[14] Uribe DJ, Guo K, Shin YJ, et al. Heterogeneous nuclear ribonucleoprotein K and nucleolin as transcriptional activators of the vascular endothelial growth factor promoter through interaction with secondary DNA structures [J]. Biochemistry, 2011, 50(18): 3796-3806.

[15] Moumen A, Masterson P, O’Connor MJ, et al. hnRNP K: an HDM2 target and transcriptional coactivator of p53 in response to DNA damage [J]. Cell, 2005, 123(6): 1065-1078.

[16] Enge M, Bao W, Hedstr?m E, et al. MDM2-dependent downregulation of p21 and hnRNP K provides a switch between apoptosis and growth arrest induced by pharmacologically activated p53 [J]. Cancer Cell, 2009, 15(3): 171-183.

[17] Shnyreva M, Schullery DS, Suzuki H, et al. Interaction of two multifunctional proteins. Heterogeneous nuclear ribonucleoprotein K and Y-box-binding protein [J]. J Biol Chem, 2000, 275(20): 15498-15503.

[18] Revil T, Pelletier J, Toutant J, et al. Heterogeneous nuclear ribonucleoprotein K represses the production of pro-apoptotic Bcl-xS splice isoform [J]. J Biol Chem, 2009, 284(32): 21458-21467.

[19] Cyphert TJ, Suchanek AL, Griffith BN, et al. Starvation actively inhibits splicing of glucose-6-phosphate dehydrogenase mRNA via a bifunctional ESE/ESS element bound by hnRNP K [J]. Biochim Biophys Acta, 2013, 1829(9): 905-915.

[20] Bomsztyk K, Van Seuningen I, Suzuki H, et al. Diverse molecular interactions of the hnRNP K protein [J]. FEBS Lett, 1997, 403(2): 113-115.

[21] Lynch M, Chen L, Ravitz MJ, et al. hnRNP K binds a core polypyrimidine element in the eukaryotic translation initiation factor 4E (eIF4E) promoter, and its regulation of eIF4E contributes to neoplastic transformation [J]. Mol Cell Biol, 2005, 25(15): 6436-6453.

[22] Yano M, Okano HJ,Okano H. Involvement of Hu and heterogeneous nuclear ribonucleoprotein K in neuronal differentiation through p21 mRNA post-transcriptional regulation [J]. J Biol Chem, 2005, 280(13): 12690-12699.

[23] Naarmann IS, Harnisch C, Flach N, et al. mRNA silencing in human erythroid cell maturation: heterogeneous nuclear ribonucleoprotein K controls the expression of its regulator c-Src [J]. J Biol Chem, 2008, 283(26): 18461-18472.

[24] Chang YI, Hsu SC, Chau GY, et al. Identification of the methylation preference region in heterogeneous nuclear ribonucleoprotein K by protein arginine methyltransferase 1 and its implication in regulating nuclear/cytoplasmic distribution [J]. Biochem Biophys Res Commun, 2011, 404(3): 865-869.

[25] Ostareck-Lederer A, Ostareck DH, Rucknagel KP, et al. Asymmetric arginine dimethylation of heterogeneous nuclear ribonucleoprotein K by protein-arginine methyltransferase 1 inhibits its interaction with c-Src [J]. J Biol Chem, 2006, 281(16): 11115-11125.

[26] Chen Y, Zhou X, Liu N, et al. Arginine methylation of hnRNP K enhances p53 transcriptional activity [J]. FEBS Lett, 2008, 582(12): 1761-1765.

[27] Pelisch F, Pozzi B, Risso G, et al. DNA damage-induced heterogeneous nuclear ribonucleoprotein K SUMOylation regulates p53 transcriptional activation [J]. J Biol Chem, 2012, 287(36): 30789-30799.

[28] Lee SW, Lee MH, Park JH, et al. SUMOylation of hnRNP-K is required for p53-mediated cell-cycle arrest in response to DNA damage [J]. EMBO J, 2012, 31(23): 4441-4452.

[29] Habelhah H, Shah K, Huang L, et al. Identification of new JNK substrate using ATP pocket mutant JNK and a corresponding ATP analogue [J]. J Biol Chem, 2001, 276(21): 18090-18095.

[30] The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia [J]. N Engl J Med, 2013, 368(22): 2059-2074.

[31] Ostareck-Lederer A, Ostareck DH, Cans C, et al. c-Src-mediated phosphorylation of hnRNP K drives translational activation of specifically silenced mRNAs [J]. Mol Cell Biol, 2002, 22(13): 4535-4543.

[32] Takimoto M, Tomonaga T, Matunis M, et al. Specific binding of heterogeneous ribonucleoprotein particle protein K to the human c-myc promoter,invitro[J]. J Biol Chem, 1993, 268(24): 18249-18258.

[33] Mandal M, Vadlamudi R, Nguyen D, et al. Growth factors regulate heterogeneous nuclear ribonucleoprotein K expression and function [J]. J Biol Chem, 2001, 276(13): 9699-9704.

[34] Nagano K, Masters JR, Akpan A, et al. Differential protein synthesis and expression levels in normal and neoplastic human prostate cells and their regulation by type I and II interferons [J]. Oncogene, 2004, 23(9): 1693-1703.

[35] Hong X, Song R, Song H, et al. PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis [J]. Gut, 2014, 63(10): 1635-1647.

[36] Inoue A, Sawata SY, Taira K, et al. Loss-of-function screening by randomized intracellular antibodies: identification of hnRNP-K as a potential target for metastasis [J]. Proc Natl Acad Sci U S A, 2007, 104(21): 8983-8988.

[37] Gao R, Yu Y, Inoue A, et al. Heterogeneous nuclear ribonucleoprotein K (hnRNP-K) promotes tumor metastasis by induction of genes involved in extracellular matrix, cell movement, and angiogenesis [J]. J Biol Chem, 2013, 288(21): 15046-15056.

[38] Strozynski J, Heim J, Bunbanjerdsuk S, et al. Proteomic identification of the heterogeneous nuclear ribonucleoprotein K as irradiation responsive protein related to migration [J]. J Proteomics, 2015, 113: 154-161.

[39] Otoshi T, Tanaka T, Morimoto K, et al. Cytoplasmic accumulation of heterogeneous nuclear ribonucleoprotein K strongly promotes tumor invasion in renal cell carcinoma cells [J]. PLoS One, 2015, 10(12): e0145769.

[40] 陳艷, 李為民, 張尚福. hnRNP K在肺癌組織中的表達(dá) [J]. 中國(guó)肺癌雜志, 2008, 11(2): 241-245.

[41] Yang JH, Chiou YY, Fu SL, et al. Arginine methylation of hnRNPK negatively modulates apoptosis upon DNA damage through local regulation of phosphorylation [J]. Nucleic Acids Res, 2014, 42(15): 9908-9924.

[42] Zhang Z, Zhou C, Chang Y, et al. Long non-coding RNA CASC11 interacts with hnRNP-K and activates the WNT/β-catenin pathway to promote growth and metastasis in colorectal cancer [J]. Cancer Lett, 2016, 376(1): 62-73.

[43] Eder S, Lamkowski A, Priller M, et al. Radiosensitization and downregulation of heterogeneous nuclear ribonucleoprotein K (hnRNP K) upon inhibition of mitogen/extracellular signal-regulated kinase (MEK) in malignant melanoma cells [J]. Oncotarget, 2015, 6(19): 17178-17191.

[44] Eder S, Arndt A, Lamkowski A, et al. Baseline MAPK signaling activity confers intrinsic radioresistance toKRAS-mutantcolorectal carcinoma cells by rapid upregulation of heterogeneous nuclear ribonucleoprotein K (hnRNP K) [J]. Cancer Lett, 2017, 385: 160-167.

[45] Zhang J, Liu X, Lin Y, et al. HnRNP K contributes to drug resistance in acute myeloid leukemia through the regulation of autophagy [J]. Exp Hematol, 2016, 44(9): 850-856.

[46] Gao X, Feng J, He Y, et al. hnRNPK inhibits GSK3β Ser9 phosphorylation, thereby stabilizing c-FLIP and contributes to TRAIL resistance in H1299 lung adenocarcinoma cells [J]. Sci Rep, 2016, 6: 22999.

[47] Gao R, Shah N, Lee JS, et al. Withanone-rich combination of Ashwagandha withanolides restricts metastasis and angiogenesis through hnRNP-K [J]. Mol Cancer Ther, 2014, 13(12): 2930-2940.

[48] Zhang L, Feng J, Kong S, et al. Nujiangexathone A, a novel compound fromGarcinianujiangensis, suppresses cervical cancer growth by targeting hnRNPK [J]. Cancer Lett, 2016, 380(2): 447-456.

RecentprogressinresearchofheterogeneousnuclearribonucleoproteinKrelatedwithtumorpathogenesisandprogression

HUANG Hao， YANG Xing-jiu， Li Meng-yuan， ZHU Rui-min， GAO Ran*

(Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical College (PUMC); Key Laboratory of Human Diseases Comparative Medicine, National Health and Family Planning Commission of P.R.C, Beijing 100021, China)

Over the past few decades, the classification of oncogenes or tumor suppressor genes has been an important topic in cancer biology. However, it is difficult to classify some genes. Heterogeneous nuclear ribonucleoprotein K (HNRNPK) is a nucleic acid-binding protein, which is involved in the regulation of gene expression, signal transduction and many other cellular processes. In recent years, it has been found that HNRNPK is overexpressed in many types of tumors, and its overexpression is negatively correlated with the prognosis of patients, suggesting that HNRNPK may play a role as an oncogene in tumorigenesis. In contrast, however, HNRNPK has also been considered as a tumor suppressor gene in acute myeloid leukemia (AML). Therefore, in this article we summarize and discuss the recent progress in the molecular functions and regulatory mechanisms of HNRNPK in tumorigenesis and progression.

Heterogeneous nuclear ribonucleoprotein K, HNRNPK; Tumors; Molecular functions

協(xié)和青年科研基金(編號(hào)：3332016078)；中央級(jí)公益性科研院所基本業(yè)務(wù)費(fèi)(編號(hào)：2016RC310012)。

黃昊(1986 -)，男，助理研究員，研究方向：實(shí)驗(yàn)動(dòng)物腫瘤模型。E-mail: huanghao@cnilas.org

高苒(1980 -)，女，副研究員，研究方向：比較醫(yī)學(xué)、實(shí)驗(yàn)動(dòng)物模型的開(kāi)發(fā)及應(yīng)用。E-mail: gaoran@cnilas.org

R-33

A

1671-7856(2017) 11-0100-06

10.3969.j.issn.1671-7856. 2017.11.021

2017-01-09