姜濤, 李衛(wèi)海, 何作順, 谷仕艷
6-甲基腺苷結(jié)合蛋白YTHDC2在腫瘤中的研究進展*
姜濤, 李衛(wèi)海, 何作順, 谷仕艷△
(大理大學(xué)公共衛(wèi)生學(xué)院,云南 大理 671000)
含YTH結(jié)構(gòu)域蛋白2;6-甲基腺苷;腫瘤;生物學(xué)功能
6-甲基腺苷(6-methyladenosine, m6A)是真核生物RNA上最常見的可逆甲基化修飾,可影響相應(yīng)RNA的加工和降解過程,進而調(diào)控細胞的生長、發(fā)育、分化和死亡等多種病理生理過程[1]。研究已明確,m6A修飾是由甲基轉(zhuǎn)移酶、去甲基轉(zhuǎn)移酶和甲基結(jié)合蛋白(又稱“redear”)共同調(diào)控的可逆修飾,其中甲基結(jié)合蛋白是m6A修飾發(fā)揮生物學(xué)功能最重要的介導(dǎo)者[2]。當(dāng)前鑒定出的m6A結(jié)合蛋白種類較多,主要有YTH結(jié)構(gòu)域家族蛋白(YTH domain family protein, YTHDF)如YTHDF1、YTHDF2、YTHDF3等,含YTH結(jié)構(gòu)域蛋白(YTH domain containing protein, YTHDC)如YTHDC1和YTHDC2等[3],其中,YTHDC2的生物學(xué)功能被研究較多也較為明確。YTHDC2能通過識別長鏈非編碼RNA含鋅帶結(jié)構(gòu)域蛋白1反義RNA 1(zinc ribbon domain-containing 1 antisense RNA 1, ZNRD1-AS1)上的m6A修飾,增強ZNRD1-AS1的穩(wěn)定性,提升ZNRD1-AS1水平,從而抑制肺癌的惡性表型[4];YTHDC2識別Yes相關(guān)蛋白(Yes-associated protein, YAP)mRNA 5'-非翻譯區(qū)(untranslated region, UTR)上的m6A修飾,提高YAP mRNA的翻譯效率進而促進胃癌的惡性表型[5];YTHDC2也能識別細絲蛋白A(filamin A, FLNA)mRNA上的m6A修飾,削弱FLNAmRNA的穩(wěn)定性,進而下調(diào)FLNA蛋白表達[6]。近年,由于YTHDC2對RNA的上述調(diào)控機制,在腫瘤中的作用備受矚目,故本文對YTHDC2在多種腫瘤中的作用和機制進行總結(jié)歸納,并深入闡釋YTHDC2在m6A修飾介導(dǎo)下參與腫瘤發(fā)生發(fā)展的機制,為YTHDC2作為腫瘤防治靶點提供參考依據(jù)。
作為癌癥死因之首的腫瘤,肺癌又以非小細胞癌的比例最高,可分為肺腺癌和肺鱗狀細胞癌[7-8]。據(jù)報導(dǎo),是肺癌發(fā)生的抑癌基因,即在肺癌組織中,基因低表達基因過表達可有效抑制肺癌的惡性表型,且YTHDC2蛋白含量的高低與肺癌患者良好的預(yù)后呈正相關(guān)[7, 9]。Wang等[4]通過體內(nèi)和體外實驗發(fā)現(xiàn)肺癌細胞中ZNRD1-AS1上存在5個m6A修飾的位點,而YTHDC2可以識別ZNRD1-AS1上的m6A修飾并對其產(chǎn)生正向調(diào)控作用,可以增強ZNRD1-AS1的穩(wěn)定性而減少降解,進而抑制下游靶基因微小RNA-942蛋白的表達,抑制肺癌的惡性表型。另一項研究使用在線預(yù)測工具基于序列的RNA腺苷甲基化位點預(yù)測器,在腫瘤抑制因子CYLD (cylindromatosis protein)的mRNA上發(fā)現(xiàn)4個m6A甲基化修飾位點,研究者接著采用RNA甲基化免疫共沉淀技術(shù)結(jié)合甲基化抑制劑3-脫氮腺苷和脂肪量及肥胖相關(guān)蛋白(fat mass and obesity-associated protein, FTO)抑制劑富馬酸進一步證實YTHDC2可以識別并結(jié)合腫瘤抑制因子CYLD mRNA上的m6A修飾,增強CYLD mRNA的穩(wěn)定性,上調(diào)CYLD蛋白表達水平,進而抑制核因子NF-κB介導(dǎo)的信號通路,最終抑制肺癌的增殖和遷移[9]。Ma等[10]指出,在肺腺癌中YTHDC2可識別并結(jié)合溶質(zhì)載體家族7成員11(solute carrier family 7 member 11, SLC7A11)3'-UTR上的m6A修飾,破壞SLC7A11 mRNA的穩(wěn)定性,加速SLC7A11 mRNA衰變,進而下調(diào)SLC7A11蛋白的表達水平,削弱了肺腺癌細胞對胱氨酸的攝取,引起細胞氧化損傷,最終抑制肺腺癌的發(fā)生發(fā)展。此外,有學(xué)者指出,YTHDC2可以識別肺腺癌細胞中同源框A13(homeobox A13, HOXA13)的3'-UTR上m6A修飾位點,破壞HOXA13的穩(wěn)定性,抑制HOXA13的表達,下游靶基因的表達水平也受到抑制,進而引起鐵死亡,抑制肺腺癌的發(fā)生發(fā)展[11]。翟東鳳等[12]指出,YTHDC2可以識別LIM結(jié)構(gòu)域結(jié)合蛋白2(LIM domain binding 2, LDB2)上的m6A修飾,從而正向調(diào)控LDB2的表達,抑制肺腺癌細胞的增殖和侵襲。Zhu等[13]的研究則表明,YTHDC2在N分期和病理分期高的肺腺癌患者的腫瘤組織中表達較低;此外,YTHDC2的表達水平與RNA結(jié)合蛋白15和甲基轉(zhuǎn)移酶樣4呈正相關(guān)而與AlkB同源蛋白5呈負(fù)相關(guān)。Wang等[9]使用LinkedOmics在線工具進一步分析發(fā)現(xiàn)與YTHDC2相關(guān)的基因主要富集在“RNA轉(zhuǎn)運”、“mTOR信號通路”、“細胞周期”和“RNA降解”方面,而肺鱗狀細胞癌中的YTHDC2相關(guān)基因在“RNA轉(zhuǎn)運”和“RNA降解”方面顯著富集。
與在肺癌中的抑癌作用相反,YTHDC2在鼻咽癌中則能促進其惡性表型,具體而言,YTHDC2可以與胰島素樣生長因子1受體(insulin-like growth factor-1 receptor, IGF-1R)的mRNA相結(jié)合,促進IGF-1R mRNA的翻譯,增強IGF-1R蛋白的表達水平,激活下游磷脂酰肌醇3-激酶/蛋白激酶B/S6信號通路,促進鼻咽癌的發(fā)生發(fā)展;但有趣的是,當(dāng)?shù)捅磉_YTHDC2時,IGF-1R mRNA的轉(zhuǎn)錄和穩(wěn)定性并沒有受到影響,但IGF-1R蛋白表達下降,抑制了下游磷脂酰肌醇3-激酶/蛋白激酶B/S6信號通路,進而抑制鼻咽癌的惡性表型;此外,研究者進一步使用DNA甲基轉(zhuǎn)移酶抑制劑5-氮雜胞苷和吉西他濱分別處理鼻咽癌細胞,發(fā)現(xiàn)吉西他濱能顯著降低鼻咽癌細胞中YTHDC2的蛋白和mRNA水平,而5-氮雜胞苷則明顯升高鼻咽癌細胞中YTHDC2的蛋白和mRNA水平[14]。遺憾的是,以上研究并未檢測mRNA上的m6A修飾水平,YTHDC2對相關(guān)mRNA的影響是否依賴m6A修飾尚需做進一步的研究和明確。
胃癌是常見的消化道腫瘤,發(fā)病率和死亡率較高,對人類的健康造成嚴(yán)重威脅[15]。Yuan等[5]發(fā)現(xiàn),YTHDC2在人類胃癌組織中是一種高表達的促癌基因,并與不良預(yù)后相關(guān),進一步的分析結(jié)果表明,YTHDC2可識別YAP mRNA 5'-UTR上的m6A修飾,在不影響mRNA水平的前提下,提高YAP mRNA的翻譯效率,促進胃癌的發(fā)生發(fā)展;反過來,YAP/轉(zhuǎn)錄增強關(guān)聯(lián)域蛋白(transcriptional enhanced associate domain, TEAD)直接與啟動子上啟動843~831區(qū)域結(jié)合并激活的轉(zhuǎn)錄,從而形成YTHDC2和YAP之間的正調(diào)控環(huán)。在人胃癌細胞SGC7901和MKN45中,非甾體抗炎藥布洛芬可以增加P53上的m6A修飾水平以及YTHDF1、YTHDF3和YTHDC2等m6A結(jié)合蛋白的水平,進而增強P53的蛋白表達;布洛芬還能抑制p75神經(jīng)營養(yǎng)因子受體啟動子甲基化水平,從而增加p75神經(jīng)營養(yǎng)因子受體的蛋白表達水平[16]。
在結(jié)腸癌中,YTHDC2可以通過增強缺氧誘導(dǎo)因子1α(hypoxia-inducible factor-1α,)基因的翻譯效率,進而促進結(jié)腸癌的轉(zhuǎn)移和侵襲;具體而言,HIF-1α作為作為結(jié)腸癌的啟動因子可以通過轉(zhuǎn)錄因子Twist相關(guān)蛋白1促進上皮-間充質(zhì)轉(zhuǎn)化從而促進結(jié)腸癌的轉(zhuǎn)移和侵襲[17]。YTHDC2在結(jié)腸癌中上調(diào)并與腫瘤分期呈明顯正相關(guān),表明YTHDC2可能是結(jié)腸癌患者的診斷標(biāo)志物[18]。Xu等[19]指出,YTHDC2在結(jié)腸腺癌中呈現(xiàn)低表達且男女表達有顯著差異;進一步分析表明,YTHDC2的表達水平與臨床分期有顯著相關(guān)性且YTHDC2過表達的患者有更好的預(yù)后。兩項研究表明,YTHDC2在結(jié)直腸癌中低表達并且YTHDC2低表達的患者預(yù)后較差[20-21];劉寧等[23]的研究指出,YTHDC2為結(jié)直腸癌生存預(yù)后的關(guān)鍵調(diào)節(jié)因子并且為保護因子[22];也有研究表明YTHDC2在直腸癌中低表達且與不良預(yù)后成負(fù)相關(guān)。
食管癌是最具侵襲性的消化道腫瘤,嚴(yán)重危害群眾健康[24-25]。既往研究顯示,在食管癌中是一種低表達的抑癌基因;具體而言,研究者通過體外實驗發(fā)現(xiàn)上的單核苷酸多態(tài)性rs2416282可抑制YTHDC2的表達而促進食管癌的惡性表型[26]。然而Zhao等[27]的研究與上述結(jié)果存在差異,他們指出YTHDC2在食管癌呈現(xiàn)過表達,且YTHDC2的表達水平與食管癌的不良預(yù)后呈顯著正相關(guān)。
研究揭示,YTHDC2蛋白在肝癌中過表達[28-31]:胡寬等[28]表示,YTHDC2的表達水平與臨床TNM分期及腫瘤分級密切相關(guān);另一研究表明的2個單核苷酸多態(tài)性rs6594732和rs10071816與接受動脈化療栓塞治療后的肝癌患者死亡風(fēng)險增加有很強的正相關(guān)[29];此外,Li等[30]和Liu等[31]指出可作為肝細胞癌患者的獨立預(yù)后預(yù)測基因。
以上這些研究明確了YTHDC2在結(jié)腸癌、食管癌及肝癌等發(fā)生發(fā)展中的作用,但均未檢測m6A修飾水平,故YTHDC2是否通過介導(dǎo)m6A修飾的生物學(xué)功能發(fā)揮促癌或抑癌作用還需進一步的探討。
卵巢癌是女性第七大常見癌癥,其5年生存率低于45%[32]。王鑫鑫等[6]指出,上存在多個m6A修飾的位點,YTHDC2可以識別并結(jié)合這些位點,以m6A修飾依賴的方式下調(diào)的表達,從而抑制卵巢癌的惡性表型。該研究還指出,YTHDC2在卵巢癌中呈現(xiàn)低表達并與不良預(yù)后呈負(fù)相關(guān)。相反的是,Zhu等[33]指出,YTHDC2在卵巢癌中高表達并且與不良預(yù)后呈正相關(guān)。我們猜測,造成上述結(jié)果原因可能是YTHDC2在卵巢癌不同組織中分布不同以及與研究者采取的研究方法有關(guān)。
前列腺癌作為最常見的男性惡性腫瘤之一,嚴(yán)重威脅男性健康[34]。當(dāng)前研究顯示,YTHDC2在前列腺癌組織中過表達[35-36],并且能促進前列腺癌的惡性表型[36-37]。在具體機制方面,YTHDC2可以正向調(diào)控IGF-1R mRNA,激活I(lǐng)GF-1R/蛋白激酶B軸,從而促進前列腺癌的增殖、遷移和侵襲;過表達YTHDC2可以逆轉(zhuǎn)因低表達環(huán)狀RNA midline-1 (circMID1)對前列腺癌的抑制;此外,YTHDC2的表達受微小RNA-330-3p抑制[37]。
有兩項研究指出,在頭頸部鱗狀細胞癌中,YTHDC2過表達的患者有更好的預(yù)后[38-39]。其中,Li等[38]指出YTHDC2高表達伴CD4+T細胞高免疫浸潤的患者較YTHDC2低表達伴CD4+T細胞低免疫浸潤的患者預(yù)后更好;而Zhou等[39]指出YTHDC2過表達的患者有更長的總體生存期,并且YTHDC2的高表達與細胞凋亡的激活和泛素介導(dǎo)的蛋白降解密切相關(guān)。
此外,有學(xué)者指出YTHDC2表達水平的異常與軟組織肉瘤的不良預(yù)后相關(guān),即在獲得RNA結(jié)合基元蛋白15和YTHDC2且失去胰島素樣生長因子2 mRNA結(jié)合蛋白1的情況下,患者無病生存率較低;YHDC2高表達的患者Janus激酶2致癌特征相關(guān)基因表達水平較高[40]。
另有研究指出,YTHDC2的表達水平與腦低級別膠質(zhì)瘤的預(yù)后呈負(fù)相關(guān),與皮膚黑色素瘤的預(yù)后呈正相關(guān)[41]。朱瀟鵬等[42]指出YTHDC2與膠質(zhì)母細胞瘤抑制性基因生長停滯特異性轉(zhuǎn)錄本5成負(fù)相關(guān)。Fanale等[43]指出YTHDC2可能是胰腺癌易感性的潛在分子靶標(biāo),也是早期有價值的檢測標(biāo)記。
綜上所述,YTHDC2作為YTHDC家族成員之一可以依賴或不依賴m6A修飾的方式參與多種腫瘤的發(fā)生發(fā)展。隨著研究的進展,我們對YTHDC2在癌癥中的生物學(xué)功能以及調(diào)控作用有了更深的了解,然而,在不同腫瘤組織中YTHDC2發(fā)揮的作用不盡相同,其參與腫瘤發(fā)生發(fā)展的機制也未被完全闡明。鑒于YTHDC2可影響多種RNA的穩(wěn)定性和翻譯過程,研究YTHDC2在腫瘤發(fā)生發(fā)展中的作用和機制有非常關(guān)鍵的意義,可為腫瘤診斷和防治靶標(biāo)的開發(fā)利用提供重要參考。
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Progress in role of6-methyladenosine binding protein YTHDC2 in tumors
JIANG Tao, LI Weihai, HE Zuoshun, GU Shiyan△
(,,671000,)
The YTH domain containing 2 (YTHDC2) protein, a methyl-binding protein of6-methyladenosine (m6A), recognizes and binds m6A modifications to mediate the biological functions of m6A modifications. As m6A modifications are widely found on various RNAs, the biological functions of YTHDC2 in combination with distinct kinds of RNAs are also different. Emerging studies have shown that YTHDC2 is involved in the occurrence and development of lung, gastric, ovarian and other carcinomas through binding to m6A modifications. Binding can then yield a pro- or anti-cancer effect, which is significantly associated with the prognosis of various tumors. This paper summarizes the role and specific mechanisms of YTHDC2 in tumors to provide a reference basis for exploring the prevention, diagnosis and treatment of different tumors from the perspective of YTHDC2.
YTH domain containing 2;6-methyladenosine; tumor; biological function
R730.23; R363
A
10.3969/j.issn.1000-4718.2023.09.020
1000-4718(2023)09-1697-05
2023-01-09
2023-04-18
國家自然科學(xué)基金資助項目(No. 82065585; No. 82260631)
Tel: 18887297129; E-mail: ygsy727@163.com
(責(zé)任編輯:宋延君,羅森)