今天給大家說說circRNA吧，就是環(huán)狀RNA，環(huán)狀RNA的定義是什么？circRNAs（Circular?RNAs，環(huán)形RNA分子）是一類不具有5'?末端帽子和3'?末端poly(A)尾巴、并以共價(jià)鍵形成環(huán)形結(jié)構(gòu)的非編碼RNA分子。它們通過pre-mRNA在細(xì)胞核內(nèi)，

與之相對的，就是具有5'?末端帽子和3'?末端poly(A)尾巴的RNA分子了？那是什么呢？就是mRNA、lncRNA這些兩端開放的RNA分子了。

circRNA在發(fā)表的高分文章中可大致分為三類機(jī)制：ceRNA（吸附miRNA，作為海綿）、可編碼翻譯成為短多肽、結(jié)合功能蛋白調(diào)控其胞內(nèi)功能。

而在國自然基金申請方面，項(xiàng)目也逐年增多，看看2018年申請到了多少個(gè)呢？如下

看的出來，8成以上的機(jī)制都是作為ceRNA機(jī)制調(diào)控miRNA的水平，參與調(diào)控下游靶基因的表達(dá)和功能。

那么我們?nèi)绻枰獎?chuàng)新的話，從已發(fā)表的文章中汲取好的思路，所以今天我們給大家?guī)?篇circRNA的高分文章，供大家學(xué)習(xí)和消化。

1.Exosomal circRNA derived from gastric tumor promotes white adipose browning by targeting the miR-133/PRDM16 pathway.

Int J Cancer7.361區(qū)4. 2019 May 15

分子機(jī)制亮點(diǎn)：不僅僅是ceRNA，還有熱點(diǎn)外泌體。本文通過對胃癌病人的血液外泌體進(jìn)行測序，結(jié)合統(tǒng)計(jì)學(xué)分析發(fā)現(xiàn)ciRS-133和白色脂肪組織變成褐色脂肪組織有相關(guān)性。通過進(jìn)一步的細(xì)胞培養(yǎng)和測序發(fā)現(xiàn)，胃癌細(xì)胞可分泌攜帶了ciRS-133的外泌體（exosome），在體外和體內(nèi)功能實(shí)驗(yàn)中發(fā)現(xiàn)，敲減掉ciRS-133的脂肪細(xì)胞前體細(xì)胞，可抑制其向褐色脂肪細(xì)胞分化。分子機(jī)制上，ciRS-133通過吸附抑制miR-133，促進(jìn)了靶基因PRDM16的表達(dá)，在這個(gè)代謝方向里，PRDM16水平升高可使白色脂肪轉(zhuǎn)為淺棕色脂肪是一個(gè)經(jīng)典知識點(diǎn)，所以這篇文章通過將上游創(chuàng)新點(diǎn)結(jié)合明星基因PRDM16，形成了完整的創(chuàng)新機(jī)制。

背景：惡病質(zhì)（cachexia）亦稱惡液質(zhì)。表現(xiàn)為極度消瘦，皮包骨頭，形如骷髏，貧血，無力，完全臥床，生活不能自理，極度痛苦，全身衰竭等綜合征。多由癌癥和其他嚴(yán)重慢性病引起。可看作是由于全身許多臟器發(fā)生障礙所致的一種中毒狀態(tài)。此癥的發(fā)生多指機(jī)體處于嚴(yán)重的機(jī)能失調(diào)狀態(tài)。

英文摘要：Cancer-related cachexia.The treatment options for cancer cachexia are limited, and the molecular mechanism remains poorly understood. Exosomes are small vesicles derived from cells.In our study, we showed that circRNAs in plasma exosomes have specific expression features in gastric cancer (GC), and ciRS-133 is linked with the browning of white adipose tissue (WAT) in GC patients. Exosomes derived from GC cells deliver ciRS-133 into preadipocytes, promoting the differentiation of preadipocytes into brown-like cells by activating PRDM16 and suppressing miR-133. Moreover, knockdown of ciRS-133 reduced cancer cachexia in tumor-implanted mice, decreasing oxygen consumption and heat production. Thus, exosome-delivered circRNAs are involved in WAT browning and play a key role in cancer-associated cachexia.

2.Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway.

Genome Biol13.2141區(qū)1. 2019 Apr 26

分子機(jī)制：首先檢測發(fā)現(xiàn)Circβ-catenin是一個(gè)更多分布在細(xì)胞質(zhì)中的一個(gè)circRNA，尤其在肝癌組織中高表達(dá)。敲減掉Circβ-catenin后，可在細(xì)胞內(nèi)和動物體內(nèi)抑制肝癌細(xì)胞的增殖以及腫瘤的大小，抑制其生物學(xué)惡性行為，而在信號通路的檢測上發(fā)現(xiàn)其和β-catenin的表達(dá)正相關(guān)，但是不改變其mRNA水平，只改變其蛋白水平。但發(fā)現(xiàn)Circβ-catenin可編碼多肽，命名為β-catenin-370aa多肽，這個(gè)多肽是β-catenin同型異構(gòu)體，也就是結(jié)構(gòu)上類似，經(jīng)過測序發(fā)現(xiàn)Circβ-catenin其實(shí)是β-catenin基因轉(zhuǎn)錄本環(huán)化形成的circRNA，那么這個(gè)多肽即可結(jié)合GSK3β，抑制其磷酸化β-catenin以及泛素化降解的經(jīng)典途徑，這是另類的犧牲自己，拯救兄弟的機(jī)制。

英文摘要：Circβ-catenin is predominantly localized in the cytoplasm and displays resistance to RNase-R treatment. We find that circβ-catenin is highly expressed in liver cancer tissues when compared to adjacent normal tissues. Silencing of circβ-catenin significantly suppresses malignant phenotypes in vitro and in vivo, and knockdown of this circRNA reduces the protein level of β-catenin without affecting its mRNA level. We show that circβ-catenin affects a wide spectrum of Wnt pathway-related genes, and furthermore, circβ-catenin produces a novel 370-amino acid β-catenin isoform that uses the start codon as the linear β-catenin mRNA transcript and translation is terminated at a new stop codon created by circularization. We find that this novel isoform can stabilize full-length β-catenin by antagonizing GSK3β-induced β-catenin phosphorylation and degradation, leading to activation of the Wnt pathway.

3.Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma.

J Hepatol14.9111區(qū)30. 2018 Jun

分子機(jī)制：這個(gè)分子機(jī)制還是ceRNA，但是是雙miRNA，也就是一個(gè)circRNA可吸附兩種miRNA的機(jī)制，在課題上也算是創(chuàng)新的一種。通過高通量測序，分析得到cSMARCA5在肝癌組織中呈現(xiàn)低表達(dá)，其被高表達(dá)的DExH-Box Helicase 9抑制，通過獨(dú)立的分享因子分析，低表達(dá)的cSMARCA5肝癌換著預(yù)后更差（OS、RFS都差），腫瘤的侵襲性更強(qiáng)，體內(nèi)體外實(shí)驗(yàn)發(fā)現(xiàn)高表達(dá)cSMARCA5之后肝癌細(xì)胞的增殖和侵襲能力變?nèi)?，機(jī)制上發(fā)現(xiàn)原來其可同時(shí)吸附miR-17-3p and miR-181b-5p兩個(gè)miRNA，阻止它們靶向降解TIMP3蛋白（百度一下該蛋白，會發(fā)現(xiàn)其屬于一個(gè)抑癌基因，明星基因）

英文摘要：The expression of cSMARCA5 was lower in HCC tissues, because of the regulation of DExH-Box Helicase 9, an abundant nuclear RNA helicase. The downregulation of cSMARCA5 in HCC was significantly correlated with aggressive characteristics and served as an independent risk factor for overall survival and recurrence-free survival in patients with HCC after hepatectomy. Our in vivo and in vitro data indicated that cSMARCA5 inhibits the proliferation and migration of HCC cells. Mechanistically, we found that cSMARCA5 could promote the expression of TIMP3, a well-known tumor suppressor, by sponging miR-17-3p and miR-181b-5p.

其他精彩的circRNA的文章我們后續(xù)給大家詳細(xì)講解。

總結(jié)，今天講解了circRNA被外泌體釋放、翻譯成多肽拯救兄弟蛋白以及通過吸附多個(gè)miRNA來靶向調(diào)控目的基因的機(jī)制，共3種。