中科院上海藥物研究所耿美玉課題組,、丁健課題組與復(fù)旦大學(xué)附屬中山醫(yī)院樊嘉課題組合作,，在肝炎-肝癌惡性轉(zhuǎn)化與肝癌復(fù)發(fā)轉(zhuǎn)移生物標(biāo)志物研究方面取得了重要進(jìn)展,。
肝癌是影響人類健康最常見的惡性腫瘤之一,，肝炎和肝癌的發(fā)生密切相關(guān),，約3/4的肝癌與肝炎病毒HBV/HCV感染相關(guān),。目前,，手術(shù)切除仍是肝癌首選的治療方式,，但術(shù)后的高復(fù)發(fā)率和轉(zhuǎn)移率是制約肝癌病人生存率的瓶頸。近年來,，越來越多的研究表明,，上皮細(xì)胞間充質(zhì)轉(zhuǎn)化（EMT）作為鏈接“炎癌轉(zhuǎn)化”的重要紐帶，在促進(jìn)腫瘤轉(zhuǎn)移,、腫瘤耐藥以及腫瘤干性維持中發(fā)揮關(guān)鍵作用,。
多聚免疫球蛋白受體pIgR是I型跨膜糖蛋白受體，通過感受炎性微環(huán)境介導(dǎo)細(xì)胞內(nèi)多聚免疫球蛋白A和多聚免疫球蛋白M的極性轉(zhuǎn)運(yùn),，在先天與后天免疫中均發(fā)揮重要作用,。
上海藥物研究所研究團(tuán)隊(duì)經(jīng)過多年潛心研究，首次發(fā)現(xiàn)高表達(dá)pIgR在體內(nèi)外均顯著誘導(dǎo)肝癌細(xì)胞的上皮細(xì)胞間充質(zhì)轉(zhuǎn)化,，促進(jìn)肝癌的早期復(fù)發(fā)與轉(zhuǎn)移,。深入機(jī)制探討表明，pIgR通過在早期內(nèi)涵體以Smad2為橋梁募集活化Smad復(fù)合物,，誘發(fā)EMT的發(fā)生,；功能區(qū)域剖析結(jié)果顯示，pIgR胞內(nèi)段的Ser682與Ser734兩個殘基在EMT轉(zhuǎn)化事件中發(fā)揮關(guān)鍵作用,，特別值得指出的是,，與pIgR轉(zhuǎn)運(yùn)功能密切相關(guān)的胞外段以及胞內(nèi)段的Tyr677,、Tyr743、Ser673和Ser735四個氨基酸殘基均不參與pIgR的EMT惡性轉(zhuǎn)化過程,。為了探究pIgR表達(dá)與肝癌預(yù)后的關(guān)聯(lián)性，通過與中山醫(yī)院樊嘉課題組合作,，發(fā)現(xiàn)pIgR高表達(dá)與肝癌預(yù)后密切相關(guān),，在HBV陽性肝癌病人中意義尤為顯著。進(jìn)一步分析表明,，pIgR是肝癌早期復(fù)發(fā)轉(zhuǎn)移的獨(dú)立預(yù)測標(biāo)志物,。
腫瘤研究領(lǐng)域權(quán)威學(xué)術(shù)期刊美國《國立癌癥研究所雜志》（J Natl Cancer Inst，影響因子14.697）于10月24日在線刊登了該項(xiàng)研究成果,。同期,，美國M.D.安德森癌癥中心Sendurai A Mani博士以pIgR: Frenemy of inflammation, EMT, and HCC progression為題，對該研究進(jìn)行了述評,，認(rèn)為不同于pIgR傳統(tǒng)的免疫防御功能,，該研究報道了首個免疫球蛋白受體pIgR作為關(guān)鍵的炎癥介導(dǎo)者，通過誘導(dǎo)EMT促進(jìn)了肝炎向肝癌的轉(zhuǎn)移轉(zhuǎn)化,，在肝癌耐藥及肝癌干性維持方面可能發(fā)揮著重要的調(diào)控作用,；pIgR作為肝癌早期復(fù)發(fā)轉(zhuǎn)移的獨(dú)立預(yù)測標(biāo)志物，為肝癌的早期診斷和治療提供了分子標(biāo)志物與靶標(biāo),，對規(guī)避治療風(fēng)險具有重要的指導(dǎo)意義,；同時，pIgR介導(dǎo)免疫球蛋白轉(zhuǎn)運(yùn)與EMT惡性轉(zhuǎn)化功能域的不同,，為特異性靶向pIgR介導(dǎo)EMT提供了重要的干預(yù)策略,，這種選擇性作用模式可能是賦予其發(fā)揮抗腫瘤復(fù)發(fā)轉(zhuǎn)移、克服非特異性靶向免疫轉(zhuǎn)運(yùn)功能所致毒副作用的關(guān)鍵,。
該研究工作挑戰(zhàn)了對pIgR傳統(tǒng)功能認(rèn)識的局限,，為重新定義免疫球蛋白受體家族的“非經(jīng)典功能”奠定了重要的理論基礎(chǔ)，為“炎癌轉(zhuǎn)化”提供了一個全新的研究視角,，為免疫球蛋白受體的免疫防御與免疫背叛的兩面性研究提供了重要范例,。(生物谷 Bioon.com)
doi:10.1093/jnci/djr421
PMC:
PMID:
pIgR: Frenemy of Inflammation, EMT, and HCC Progression
Nathalie Sphyris and Sendurai A. Mani
Hepatocellular carcinoma (HCC) is the fifth most common neoplasm worldwide and a major cause of cancer-related death. The development of HCC has long been associated with inflammation-causing agents such as chronic viral infection with hepatitis B or C, alcoholic cirrhosis, or dietary exposure to fungal aflatoxins ( 1– 3). Consequently, HCC progression unravels against a backdrop of persistent inflammation, extensive tissue remodeling, and excessive deposition of extracellular matrix components ( 2– 4). Moreover, recently gained insights have linked inflammation to the aberrant activation of a latent embryonic program—termed the epithelial–mesenchymal transition (EMT)—that endows tumor cells with metastatic competence ( 5– 7) and resistance to therapy ( 8). EMT is a complex process that enables the reprogramming of polarized epithelial cells toward a mesenchymal phenotype accompanied by shedding of epithelial characteristics, loss of apico-basal polarity, dissolution of intercellular contacts, and gain of intrinsic migratory and invasive capabilities ( 7). Both persistent inflammation and EMT have been independently implicated in wound healing and regeneration following tissue injury and in pathological conditions such as organ fibrosis and metastasis ( 7, 9, 10). Indeed, the induction of an inflammatory response plays dual and opposing roles in the context of tumor development. Initially, inflammation and immune surveillance serve to eliminate rogue premalignant or malignant cells, thus suppressing tumor formation. However, as tumors evolve, they not only evade immune surveillance but—somewhat paradoxically—provoke an inflammatory response, resulting in the recruitment of multiple immune cell types that secrete a diverse set of signaling molecules that promote cell proliferation and survival of resident cells and remodel the extracellular matrix to favor EMT.
