Progress of epithelial-mesenchymal transition occurred in residual tumor invasion and metastasis of hepatocellular carcinoma after non-surgical treatments

, ,

(Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China)

?

Progress of epithelial-mesenchymal transition occurred in residual tumor invasion and metastasis of hepatocellular carcinoma after non-surgical treatments

TONGYuyang,XUXiaolin,LUOBaoming*

(DepartmentofUltrasound,SunYat-senMemorialHospital,SunYat-senUniversity,Guangzhou510120,China)

The epithelial-mesenchymal transition (EMT) is featured by absence of epithelial phenotype and acquiring the mesenchymal characteristics. The phenomenon of epithelial-mesenchymal transition is closely related with the increase of the invasion and metastasis potential of residual cancer after non-surgical treatment for primary hepatic carcinoma. Progress of EMT in promoting invasion and metastasis of residual tumor in the non-surgical treatments of hepatocellular carcinoma were reviewed in this article.

Epithelial-mesenchymal transition; Liver neoplasms; Invasion; Neoplasm metastasis

原發(fā)性肝癌(primary hepatic carcinoma， PHC)已成為全球范圍內(nèi)第5大常見癌癥，并位居腫瘤相關(guān)死亡的第2位[1]。目前，外科治療，即手術(shù)切除或肝臟移植，仍然是肝癌的首選治療措施和最有效手段[2]。但多數(shù)患者確診時(shí)已屬中晚期，且國內(nèi)肝癌患者多合并肝炎、肝硬化，患者的肝功能分級(jí)較差，手術(shù)創(chuàng)傷大，增加了術(shù)后發(fā)生肝功能衰竭和死亡的風(fēng)險(xiǎn)[3]；此外，手術(shù)適應(yīng)證較嚴(yán)格，供肝短缺，目前僅不足30%的患者接受手術(shù)治療[4]。因此各種非手術(shù)療法在控制腫瘤、延長生存期、提高生存質(zhì)量方面?zhèn)涫荜P(guān)注，射頻消融(radiofrequency ablation， RFA)、肝動(dòng)脈栓塞(transcathether arterial embolization， TAE)、化療、靶向治療、放射治療、中醫(yī)中藥治療等成為肝癌非手術(shù)治療的重要選擇，但腫瘤的復(fù)發(fā)、轉(zhuǎn)移仍是制約療效的瓶頸[5]。近年來，研究[6]表明上皮-間質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transition， EMT)在腫瘤的侵襲、轉(zhuǎn)移過程中發(fā)揮重要作用。本文將對(duì)近年來關(guān)于EMT在提升肝癌非手術(shù)治療后殘癌侵襲、轉(zhuǎn)移潛能方面的研究進(jìn)展進(jìn)行綜述。

1　EMT簡述

EMT是上皮細(xì)胞在特定的生理、病理狀態(tài)下向間質(zhì)細(xì)胞轉(zhuǎn)分化的現(xiàn)象。該過程不僅是胚胎發(fā)育中的重要環(huán)節(jié)，還在許多病理過程中發(fā)揮重要作用，尤其與腫瘤的侵襲、轉(zhuǎn)移關(guān)系密切。EMT是由連接緊密、相對(duì)靜止的上皮細(xì)胞向連接疏松，具有遷移、活動(dòng)能力的間質(zhì)組織轉(zhuǎn)化的過程[7]。通過EMT，腫瘤細(xì)胞可獲得抗凋亡和衰老、腫瘤干細(xì)胞免疫耐受等特性[8]。EMT過程中，最重要的改變包括：E-鈣黏蛋白(E-cadherin， E-cad)的減少或丟失，以角蛋白為主的細(xì)胞骨架轉(zhuǎn)變?yōu)椴ㄐ蔚鞍?vimentin)為主的細(xì)胞骨架，引起細(xì)胞形態(tài)的改變[9]；出現(xiàn)間質(zhì)細(xì)胞來源蛋白標(biāo)記物的重新表達(dá)或表達(dá)水平增加，如vimentin、纖維連接蛋白(fibronectin， FN)、神經(jīng)鈣黏蛋白(N-cadherin， N-cad)等，其中N-cad表現(xiàn)出細(xì)胞間弱黏連性[10]。同時(shí)，基質(zhì)金屬蛋白酶(matrix metalloproteinases, MMPs)上調(diào)，細(xì)胞外基質(zhì)重構(gòu)(基膜金屬蛋白下調(diào)，Ⅰ型膠原、纖維連接蛋白上調(diào))，有利于癌細(xì)胞向鄰近組織侵襲或進(jìn)入血管、淋巴管向遠(yuǎn)處轉(zhuǎn)移。因此，EMT現(xiàn)象是腫瘤局部侵襲和遠(yuǎn)處轉(zhuǎn)移的始動(dòng)環(huán)節(jié)[11]。

參與誘導(dǎo)和調(diào)控EMT的因素眾多，涉及多條信號(hào)通路、多種轉(zhuǎn)錄因子。目前發(fā)現(xiàn)的主要通路有TGF-β通路、Wnt(Wingless-type)/β-catenin通路、Notch通路、Hedgehog通路。轉(zhuǎn)錄因子在信號(hào)轉(zhuǎn)導(dǎo)中位于蛋白激酶下游，目前發(fā)現(xiàn)Snail、Slug、Twist、ZEB1、ZEB2、核轉(zhuǎn)錄因子-κB(nuclear factor kappaB， NF-κB)等轉(zhuǎn)錄因子與EMT密切相關(guān)[12]。

2　EMT在肝癌非手術(shù)治療中的作用

肝癌的非手術(shù)治療，無論是局部RFA、TAE，還是放、化療，甚至是靶向治療多難以徹底消滅腫瘤細(xì)胞，治療后局部組織缺血缺氧，造成腫瘤微環(huán)境的變化，以及腫瘤細(xì)胞對(duì)藥物的耐受等促進(jìn)了殘癌細(xì)胞侵襲、轉(zhuǎn)移和惡性程度增加[13]。參與此過程的分子機(jī)制眾多且復(fù)雜，在臨床以及細(xì)胞、動(dòng)物模型中均可發(fā)現(xiàn)EMT現(xiàn)象，表明該現(xiàn)象在殘癌的侵襲、轉(zhuǎn)移過程中發(fā)揮著十分重要的作用。

2.1RFA因RFA治療費(fèi)用低、創(chuàng)傷小、可重復(fù)性好、并發(fā)癥少，在國內(nèi)外被公認(rèn)為是治療直徑<3 cm小肝癌的有效手段，其療效甚至可與手術(shù)治療相媲美[14]，但對(duì)于體積較大或鄰近大血管的病灶，由于存在消融不全，術(shù)后復(fù)發(fā)、轉(zhuǎn)移率高。為此，有學(xué)者[15]建立了裸鼠肝臟原位移植瘤模型，并隨機(jī)分為RFA不完全組和對(duì)照組。RFA不全組以5 W的功率射頻消融30 s，以保證殘癌的存在，而對(duì)照組中插入射頻針后不進(jìn)行消融，結(jié)果發(fā)現(xiàn)RFA不全組的肺和腹腔轉(zhuǎn)移率均明顯高于對(duì)照組；與對(duì)照組相比，RFA不全組E-cad表達(dá)水平下降，N-cad和vimentin上升，EMT相關(guān)轉(zhuǎn)錄因子Snail和Slug的mRNA水平也顯著高于對(duì)照組，可能因RFA不完全后激活了β-catenin信號(hào)通路進(jìn)而促進(jìn)肝癌細(xì)胞的EMT和侵襲、轉(zhuǎn)移。Dong等[16]在體外實(shí)驗(yàn)中模擬RFA中邊界消融不完全的殘癌細(xì)胞，發(fā)現(xiàn)熱處理后存活的殘癌細(xì)胞有較親代更強(qiáng)的侵襲和遷移能力；將殘癌細(xì)胞經(jīng)尾靜脈注入裸鼠體內(nèi)，發(fā)現(xiàn)該實(shí)驗(yàn)組裸鼠肺表面轉(zhuǎn)移瘤的大小范圍比對(duì)照組增加97.4%，小鼠肺組織連續(xù)切片HE染色同樣證明該結(jié)果，鏡下發(fā)現(xiàn)殘癌細(xì)胞間連接減少，呈紡錘樣，形成更多的偽足；組織免疫印跡證實(shí)實(shí)驗(yàn)組E-cad表達(dá)量顯著降低，N-cad、FN、vimentin、MMP2和MMP9表達(dá)上調(diào)，發(fā)現(xiàn)Akt和ERK1/2信號(hào)通路參與RFA后殘癌的EMT和侵襲、轉(zhuǎn)移，Yoshida等[17]的研究也得到了類似的結(jié)果，均發(fā)現(xiàn)RFA不完全后殘余的肝癌細(xì)胞會(huì)發(fā)生EMT現(xiàn)象，且侵襲、轉(zhuǎn)移能力增強(qiáng)。

2.2TAETAE和TACE被廣泛用于無法手術(shù)切除的PHC患者的姑息治療[18]。其原理是基于PHC的血供主要來源于肝動(dòng)脈，選擇性阻斷肝動(dòng)脈可使腫瘤壞死，同時(shí)對(duì)肝功能的影響降到最小。但TAE很難使腫瘤完全壞死，不完全栓塞后殘癌生物學(xué)特性的改變一直是臨床研究的重點(diǎn)[19]。TACE后局部缺氧激活了低氧誘導(dǎo)因子-1(hypoxia inducible factor-1α， HIF-1α)，HIF-1α作為肝癌復(fù)發(fā)的預(yù)后因子，可加速EMT的過程。EMT可使殘余腫瘤細(xì)胞獲得運(yùn)動(dòng)、遷移能力，增加循環(huán)腫瘤細(xì)胞(circulating tumor cells， CTCs)的數(shù)量，進(jìn)而促進(jìn)腫瘤的侵襲和轉(zhuǎn)移。Wang等[20]使用McA-RH7777肝癌大鼠模擬不完全栓塞，觀察TAE后缺氧對(duì)殘余癌侵襲轉(zhuǎn)移潛能的影響，發(fā)現(xiàn)2周后TAE組腫瘤體積的增加程度比對(duì)照組小，但腫瘤的血管浸潤、肝內(nèi)微轉(zhuǎn)移和肺轉(zhuǎn)移卻均高于對(duì)照組；TAE后，TAE組HIF-1α上升，vimentin和N-cad的表達(dá)也上升，而E-cad的表達(dá)下降；體外無氧培養(yǎng)的細(xì)胞間連接減少，呈紡錘樣，偽足增多，侵襲和遷移的能力強(qiáng)于常氧培養(yǎng)的細(xì)胞；與體內(nèi)實(shí)驗(yàn)相一致，無氧培養(yǎng)的細(xì)胞上皮標(biāo)志物表達(dá)下降，間質(zhì)標(biāo)志物表達(dá)上調(diào)。該研究組[21]進(jìn)一步檢測TAE后CTCs的變化，發(fā)現(xiàn)TAE后7天，TAE組CTCs的平均水平較假手術(shù)組顯著上升，通過分析HIF-1α和EMT標(biāo)志蛋白的表達(dá)水平，結(jié)果表明獲得間質(zhì)特性的細(xì)胞增強(qiáng)了原發(fā)腫瘤的轉(zhuǎn)移潛能，而且間質(zhì)細(xì)胞可抵抗凋亡信號(hào)，有助于CTCs在循環(huán)系統(tǒng)中存活。有研究[22]報(bào)道肝動(dòng)脈斷流造成癌旁組織缺氧，可使正常肝細(xì)胞發(fā)生EMT，EMT亦是肝纖維化乃至肝硬化發(fā)生的重要病理學(xué)基礎(chǔ)，癌旁正常肝細(xì)胞的EMT改變同樣也是增加肝癌惡性表型的病理學(xué)基礎(chǔ)。因此，推測TAE與EMT、CTCs以及腫瘤的侵襲、轉(zhuǎn)移關(guān)系密切。

2.3化療與靶向治療以往PHC化療通過周圍靜脈進(jìn)行，達(dá)肝藥物濃度低，維持時(shí)間短，不良反應(yīng)大，療效差，復(fù)發(fā)率高。于是肝動(dòng)脈灌注化療、肝動(dòng)脈栓塞化療、經(jīng)皮瘤體注射化療及經(jīng)門靜脈化療泵化療等應(yīng)運(yùn)而生?；熥鳛橐环N綜合治療手段，與其他治療方案配合運(yùn)用多可在晚期肝癌治療中取得較好療效。但不論是以阿霉素、5氟尿嘧啶、奧沙利鉑為代表的傳統(tǒng)化療藥的聯(lián)合應(yīng)用，還是近年來推出的以索拉菲尼為代表的多激酶、多靶點(diǎn)的靶向治療藥物，均未從根本上大幅提高或改善患者的生存率[23]?；煹目傮w有效率低，可能與化療促進(jìn)殘癌惡性程度增加以及肝癌細(xì)胞對(duì)化療藥物耐藥有關(guān)。有學(xué)者[24]采用奧沙利鉑預(yù)處理人肝癌細(xì)胞株，發(fā)現(xiàn)存活的細(xì)胞呈明顯的間質(zhì)細(xì)胞形態(tài)，侵襲和遷移能力強(qiáng)于對(duì)照組細(xì)胞；免疫熒光和Western blot的結(jié)果顯示存活的細(xì)胞上皮標(biāo)志物表達(dá)減低，間質(zhì)標(biāo)志物表達(dá)增高，并且Snail的表達(dá)也上升；為區(qū)分化療對(duì)腫瘤的影響和對(duì)宿主機(jī)體、血管的影響，將接受和未接受過奧利沙伯處理的裸鼠移植瘤重新接種到新的受體小鼠肝臟，6周后發(fā)現(xiàn)化療預(yù)處理組表現(xiàn)出更加活躍和頻繁的EMT，且該組的裸鼠肺轉(zhuǎn)移能力顯著增強(qiáng)。表明抗腫瘤藥奧沙利鉑可以抑制腫瘤生長，但也可促進(jìn)腫瘤EMT和侵襲、轉(zhuǎn)移，其機(jī)制可能與Snail的激活有關(guān)。Chow等[25]誘導(dǎo)了索拉菲尼耐藥(sorafenib-resistant， SorR)細(xì)胞，并證實(shí)耐藥基因ABCC1、ABCC2、ABCC3在SorR細(xì)胞的高表達(dá)，SorR細(xì)胞上皮細(xì)胞標(biāo)志物顯著下調(diào)，而間質(zhì)細(xì)胞標(biāo)志物表達(dá)上調(diào)，β-catenin、Smad2、Smad3出現(xiàn)核聚集；將SorR和對(duì)照組細(xì)胞分別原位注射到小鼠肝臟，6周后觀察對(duì)照組小鼠的肺轉(zhuǎn)移率(1/8)明顯小于SorR組(8/8)。對(duì)阿霉素[26]、5氟尿嘧啶[27]、吉西他濱[28]耐藥的肝癌細(xì)胞也有上述類似改變，推測長期使用化療藥物可誘導(dǎo)產(chǎn)生耐藥，促進(jìn)腫瘤細(xì)胞的EMT和隨后的侵襲、轉(zhuǎn)移增強(qiáng)。

2.4放射治療隨著放射生物學(xué)理念的更新及對(duì)放射技術(shù)的不斷深入研究，現(xiàn)代放射治療主要包括三維適形放療、調(diào)強(qiáng)放療、立體定向和質(zhì)子放療等，高精度、高效率放療為其在肝癌治療中的應(yīng)用提供了新的機(jī)會(huì)[29]。雖然在放療后早期會(huì)得到對(duì)腫瘤較好的控制甚至縮小消失，但很快即會(huì)出現(xiàn)復(fù)發(fā)轉(zhuǎn)移，且進(jìn)展快，預(yù)后差。因此，有必要闡明放療對(duì)癌細(xì)胞侵襲和轉(zhuǎn)移潛能的影響，及其相關(guān)分子機(jī)制。Li等[30]對(duì)具有轉(zhuǎn)移潛能的MHCC97L人肝癌細(xì)胞進(jìn)行X線照射，發(fā)現(xiàn)接受照射處理的細(xì)胞較對(duì)照組細(xì)胞侵襲性強(qiáng)，且隨著時(shí)間和放射劑量的增加而增強(qiáng)；為排除腫瘤負(fù)荷和免疫系統(tǒng)對(duì)腫瘤轉(zhuǎn)移的影響，將接受照射處理和未接受照射的對(duì)照組腫瘤分別原位移植入新的裸鼠肝內(nèi)，發(fā)現(xiàn)6周后對(duì)照組腫瘤呈外生性生長，與正常肝組織邊界清晰；而預(yù)處理組腫瘤呈浸潤性生長，與周邊肝實(shí)質(zhì)邊界不清；且預(yù)處理組的裸鼠肝內(nèi)轉(zhuǎn)移和肺轉(zhuǎn)移明顯多于對(duì)照組；對(duì)EMT相關(guān)基因的表達(dá)進(jìn)行檢測，結(jié)果顯示預(yù)處理組E-cad顯著下降，vimentin和N-cad明顯上升，且TMPRSS4的表達(dá)也上升，TMPRSS4可通過激活ERK1/2和MAPK通路從而促進(jìn)EMT；使用siRNA干擾TMPRSS4的表達(dá)后可逆轉(zhuǎn)EMT，減少肝內(nèi)轉(zhuǎn)移灶的數(shù)目。表明放射治療可以誘導(dǎo)殘余癌細(xì)胞EMT，增強(qiáng)其侵襲和轉(zhuǎn)移的能力，其機(jī)制可能與放療后TMPRSS4表達(dá)升高有關(guān)，而逆轉(zhuǎn)EMT能夠抑制殘癌的侵襲、轉(zhuǎn)移。Jia等[31]進(jìn)行了與上述相似的實(shí)驗(yàn)，發(fā)現(xiàn)放射治療可以抑制腫瘤生長，但可能通過增加瘤內(nèi)缺氧，誘導(dǎo)EMT，進(jìn)而促進(jìn)腫瘤的侵襲和轉(zhuǎn)移。

3　展望

EMT在肝癌非手術(shù)治療后殘癌的侵襲、轉(zhuǎn)移過程中扮演著重要角色，如果能夠阻止或抑制治療誘導(dǎo)的EMT，可能會(huì)阻斷治療后肝癌惡性表型的發(fā)展以及腫瘤侵襲、轉(zhuǎn)移。因此，探索參與EMT過程的分子機(jī)制，發(fā)現(xiàn)其中的關(guān)鍵分子，對(duì)于發(fā)現(xiàn)新治療靶點(diǎn)，開發(fā)新靶向治療藥物和手段，并且通過聯(lián)合各種治療方案提高各種抗癌療法的總體療效，具有重要的臨床意義和應(yīng)用價(jià)值。

[1]Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: Clinical frontiers and perspectives. Gut, 2014,63(5):844-855.

[2]Shi XJ, Jin X, Wang MQ, et al. Effect of resection following downstaging of unresectable hepatocelluar carcinoma by transcatheter arterial chemoembolization. Chin Med J (Engl), 2012,125(2):197-202.

[3]Yamada S, Utsunomiya T, Morine Y, et al. Expressions of hypoxia-inducible factor-1 and epithelial cell adhesion molecule are linked with aggressive local recurrence of hepatocellular carcinoma after radiofrequency ablation therapy. Ann Surg Oncol, 2014,21(S3):436-442.

[4]Yamada S, Okumura N, Wei L, et al. Epithelial to mesenchymal transition is associated with shorter disease-free survival in hepatocellular carcinoma. Ann Surg Oncol, 2014,21(12):3882-3890.

[5]Xiong W, Tang ZY, Ren ZG, et al. Changes of metastatic potential of residual hepatocellular carcinoma in nude mice after in vivo chemotherapy and the corresponding mechanisms. Zhonghua Zhong Liu Za Zhi, 2012,34(11):805-809.

[6]Huang JY, Zhang K, Chen DQ, et al. MicroRNA-451: Epithelial-mesenchymal transition inhibitor and prognostic biomarker of hepatocelluar carcinoma. Oncotarget, 2015,6(21):18613-18630.

[7]Zubeldia IG, Bleau AM, Redrado M, et al. Epithelial to mesenchymal transition and cancer stem cell phenotypes leading to liver metastasis are abrogated by the novel TGFbeta1-targeting peptides P17 and P144. Exp Cell Res, 2013,319(3):12-22.

[8]Warrier S, Bhuvanalakshmi G, Arfuso F, et al. Cancer stem-like cells from head and neck cancers are chemosensitized by the Wnt antagonist, sFRP4, by inducing apoptosis, decreasing stemness, drug resistance and epithelial to mesenchymal transition. Cancer Gene Ther, 2014,21(9):381-388.

[9]Zhai X, Zhu H, Wang W, et al. Abnormal expression of EMT-related proteins, S100A4, vimentin and E-cadherin, is correlated with clinicopathological features and prognosis in HCC. Med Oncol, 2014,31(6):970.

[10]Kong D, Zhang F, Shao J, et al. Curcumin inhibits cobalt chloride-induced epithelial-to-mesenchymal transition associated with interference with TGF-beta/Smad signaling in hepatocytes. Lab Invest, 2015,95(11):1234-1245.

[11]Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science, 2011,331(6024):1559-1564.

[12]Song FN, Duan M, Liu LZ, et al. RANKL promotes migration and invasion of hepatocellular carcinoma cells via NF-kappaB-mediated epithelial-mesenchymal transition. PLoS One, 2014,9(9):e108507.

[13]Zhong JH, Ma L, Li LQ. Postoperative therapy options for hepatocellular carcinoma. Scand J Gastroenterol, 2014,49(6):649-661.

[14]劉昕.影像學(xué)評(píng)價(jià)射頻消融治療肝癌的療效.中國介入影像與治療學(xué),2012,9(2):136-138.

[15]Zhang N, Wang L, Chai ZT, et al. Incomplete radiofrequency ablation enhances invasiveness and metastasis of residual cancer of hepatocellular carcinoma cell HCCLM3 via activating beta-catenin signaling. PLoS One, 2014,9(12):e115949.

[16]Dong S, Kong J, Kong F, et al. Insufficient radiofrequency ablation promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through Akt and ERK signaling pathways. J Transl Med, 2013,11:273.

[17]Yoshida S, Kornek M, Ikenaga N, et al. Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma. Hepatology, 2013,58(5):1667-1680.

[18]申太忠，宋莉，楊敏，等.TACE聯(lián)合RFA治療原發(fā)性肝細(xì)胞癌預(yù)后多因素分析.中國介入影像與治療學(xué),2012,9(5):322-326.

[19]Sacco R, Mismas V, Marceglia S, et al. Transarterial radioembolization for hepatocellular carcinoma: An update and perspectives. World J Gastroenterol, 2015,21(21):6518-6525.

[20]Wang GZ, Fang ZT, Zhang W, et al. Increased metastatic potential of residual carcinoma after transarterial embolization in rat with McA-RH7777 hepatoma. Oncol Rep, 2014,31(1):95-102.

[21]Fang ZT, Wang G Z, Zhang W, et al. Transcatheter arterial embolization promotes liver tumor metastasis by increasing the population of circulating tumor cells. Onco Targets Ther, 2013,6(5):1563-1572.

[22]劉亮，徐華祥，王文權(quán)，等.肝動(dòng)脈斷流促進(jìn)癌旁正常肝細(xì)胞上皮-間質(zhì)轉(zhuǎn)化.中華實(shí)驗(yàn)外科雜志,2011,28(10):1643-1645.

[23]Jiao M, Nan KJ. Activation of PI3 kinase/Akt/HIF-1alpha pathway contributes to hypoxia-induced epithelial-mesenchymal transition and chemoresistance in hepatocellular carcinoma. Int J Oncol, 2012,40(2):461-468.

[24]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. BMC Cancer, 2010,10:219.

[25]Chow AK, Ng L, Lam CS, et al. The Enhanced metastatic potential of hepatocellular carcinoma (HCC) cells with sorafenib resistance. PLoS One, 2013,8(11):e78675.

[26]Lou B, Fan J, Wang K, et al. N1-guanyl-1,7-diaminoheptane (GC7) enhances the therapeutic efficacy of doxorubicin by inhibiting activation of eukaryotic translation initiation factor 5A2 (eIF5A2) and preventing the epithelial-mesenchymal transition in hepatocellular carcinoma cells. Exp Cell Res, 2013,319(17):2708-2717.

[27]Uchibori K, Kasamatsu A, Sunaga M, et al. Establishment and characterization of two 5-fluorouracil-resistant hepatocellular carcinoma cell lines. Int J Oncol, 2012,40(4):1005-1010.

[28]Wu Q, Wang R, Yang Q, et al. Chemoresistance to gemcitabine in hepatoma cells induces epithelial-mesenchymal transition and involves activation of PDGF-D pathway. Oncotarget, 2013,4(11):1999-2009.

[29]Yim HJ, Suh SJ, Um SH. Current management of hepatocellular carcinoma: An Eastern perspective. World J Gastroenterol, 2015,21(13):3826-3842.

[30]Li T, Zeng ZC, Wang L, et al. Radiation enhances long-term metastasis potential of residual hepatocellular carcinoma in nude mice through TMPRSS4-induced epithelial-mesenchymal transition. Cancer Gene Ther, 2011,18(9):617-626.

[31]Jia JB, Wang WQ, Sun HC, et al. A novel tripeptide, tyroserleutide, inhibits irradiation-induced invasiveness and metastasis of hepatocellular carcinoma in nude mice. Invest New Drugs, 2011,29(5):861-872.

童宇洋(1991—)，男，安徽合肥人，在讀碩士。研究方向：腹部與淺表器官的超聲診斷。E-mail： tongyy2014@163.com

羅葆明，中山大學(xué)孫逸仙紀(jì)念醫(yī)院超聲科，510120。

2016-03-11

2016-05-12

10.13929/j.1672-8475.2016.07.015

上皮-間質(zhì)轉(zhuǎn)化在肝癌非手術(shù)治療后促進(jìn)殘癌侵襲、轉(zhuǎn)移的研究進(jìn)展

童宇洋，許曉琳，羅葆明*

(中山大學(xué)孫逸仙紀(jì)念醫(yī)院超聲科，廣東 廣州510120)

上皮-間質(zhì)轉(zhuǎn)化(EMT)以上皮表型的缺失伴隨上皮間質(zhì)特性的獲得為主要特征。上皮-間質(zhì)轉(zhuǎn)化現(xiàn)象與肝癌非手術(shù)治療后殘癌的侵襲、轉(zhuǎn)移能力增加關(guān)系密切。本文對(duì)近年來有關(guān)EMT在各種肝癌非手術(shù)治療后，促進(jìn)殘癌侵襲、轉(zhuǎn)移的研究進(jìn)展進(jìn)行綜述。

上皮-間質(zhì)轉(zhuǎn)化；肝腫瘤；侵襲；腫瘤轉(zhuǎn)移

R735.7; R815

A

1672-8475(2016)07-0449-04

E-mail： bmluo2005@126.com