近日,，國際胃腸病學(xué)權(quán)威期刊《Gastroenterology》在線發(fā)表了中科院上海生命科學(xué)研究院/上海交通大學(xué)醫(yī)學(xué)院健康科學(xué)研究所張笑人研究組的最新研究成果“A
microRNA 221- and 222-mediated feedback loop, via PDLIM2, maintains
constitutive activation of NFκB and STAT3 in colorectal cancer
cells”,，揭示miR-221/22介導(dǎo)的炎癥信號正反饋環(huán)路在結(jié)直腸癌發(fā)生和發(fā)展過程中的重要作用,。
結(jié)直腸癌是胃腸道系統(tǒng)中最常見的惡性腫瘤之一,，其發(fā)病率居惡性腫瘤第三位,，患者死亡率高居惡性腫瘤死因第二位,。近年來,，我國結(jié)直腸癌的發(fā)病率和死亡率呈明顯上升趨勢,。越來越多的證據(jù)表明,，慢性炎癥和結(jié)直腸癌的發(fā)生發(fā)展存在著密切的關(guān)系。其中,，轉(zhuǎn)錄因子NFκB和STAT3兩條通路的過度激活在慢性炎癥和結(jié)直腸癌的發(fā)生發(fā)展過程中扮演著關(guān)鍵的作用,。然而，目前導(dǎo)致這兩條通路激活的分子機制仍不是十分清楚,。
劉三宏副研究員和博士研究生孫小華在張笑人研究員的指導(dǎo)下與上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院的王明亮教授合作研究發(fā)現(xiàn),，miR-221/222介導(dǎo)的正反饋環(huán)路促進NFκB和STAT3通路的激活，并促進結(jié)直腸癌的發(fā)生和發(fā)展,。miR-221/222一方面通過穩(wěn)定NFκB通路中的核心轉(zhuǎn)錄因子RelA的mRNA穩(wěn)定性,，維持RelA的高表達；另一方面通過抑制RelA和STAT3共有的E3泛素化連接酶PDLIM2,，維持RelA和STAT3的蛋白穩(wěn)定性,，從而促進NFκB和STAT3通路的組成性激活。同時,，NFκB和STAT3可以誘導(dǎo)miR-221/222的表達,，由此形成正反饋環(huán)路，結(jié)果顯示該反饋環(huán)路也存在于臨床腫瘤樣本中,。在小鼠結(jié)腸癌AOM/DSS模型中,，通過尾靜脈注射能特異結(jié)合miR-221/222的“海綿”，可有效阻斷NFκB和STAT3通路的激活，并抑制小鼠結(jié)腸癌的發(fā)生和發(fā)展,。該研究發(fā)現(xiàn)了miR-221/222,、
NFκB和STAT3正反饋環(huán)在結(jié)腸癌中的重要作用，為結(jié)腸癌的診斷和治療提供了新的潛在靶點,。
該研究得到了國家科技部,、國家自然科學(xué)基金委和中國科學(xué)院等經(jīng)費資助以及復(fù)旦大學(xué)附屬中山醫(yī)院侯英勇教授的大力支持和幫助。
A new mechanism underlying the constitutive activation of NFκB and
STAT3 in human colorectal cancer
Recently, the work from Dr. Xiaoren Zhang‘s group (Institute of
Health Sciences, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences and Shanghai Jiao Tong University
School of Medicine), titled “A microRNA 221- and 222-mediated
feedback loop, via PDLIM2, maintains constitutive activation of
NFκB and STAT3 in colorectal cancer cells”, was published on line
in Gastroenterology. The study revealed that miR-221/222-mediated
positive feedback loop played an important role in the constitutive
activation of inflammatory signals and the development of
colorectal cancer.
Constitutive activation of NFκB and STAT3 pathways in human
colorectal cancers (CRCs) links inflammation to CRC development and
progression. However, the underlying mechanisms remain to be
elucidated. In collaboration with Prof. Mingliang Wang (Ruijin
Hospital Affiliated to Shanghai Jiao Tong University), Dr Sanhong
Liu and Ph. D candidate Xiaohua Sun, supervised by Dr. Xiaoren
Zhang, discovered that miR-221 and miR-222 positively regulated
both NFκB and STAT3 activities, which in return induced miR-221/222
expression, creating a positive feedback loop in human CRCs.
miR-221/222 directly bound to the coding region of RelA, leading to
increased RelA mRNA stability. In addition, miR-221/222 reduced
ubiquitination and degradation of RelA and STAT3 proteins by
directly targeting the 3’ UTR of PDLIM2 mRNA, an E3 ligase for both
RelA and STAT3, collectively upregulating RelA and STAT3 protein.
The study demonstrated that disruption of the positive feedback
loop suppressed human CRC cell growth in vitro and in vivo.
miR-221/222 expression correlated with the expression of RelA,
STAT3 and PDLIM2 in human CRCs. These findings defined a novel
mechanism underlying constitutive activation of NFκB and STAT3
pathways in human CRCs, revealing miR-221/222 served as novel
potential therapeutic targets for CRCs.
The project was supported by the Ministry of Science and
Technology of China, the National Natural Science Foundation of
China, China Academy of Sciences. Prof. Yingyong Hou (Zhongshan
Hospital Affiliated to Fudan University) also provided supports for
this project. (IHS)
