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| 1 | NF-κB and STAT3 signaling pathways collaboratively link infl ammation to cancer显示文摘Although links between cancer and inflammation were fi rstly proposed in the nineteenth century,the molecular mechanism has not yet been clearly understood.Epidemiological studies have identified chronic infections and infl ammation as major risk factors for various types of cancer.NF-κB transcription factors and the signaling pathways are central coordinators in innate and adaptive immune responses.STAT3 regulates the expression of a variety of genes in response to cellular stimuli,and thus plays a key role in cell growth and apoptosis.Recently,roles of NF-κB and STAT3 in colon,gastric and liver cancers have been extensively investigated.The activation and interaction between STAT3 and NF-κB play vital roles in control of the communication between cancer cells and infl ammatory cells.NF-κB and STAT3 are two major factors controlling the ability of pre-neoplastic and malignant cells to resist apoptosis-based tumor-surveillance and regulating tumor angiogenesis and invasiveness.Understanding the molecular mechanisms of NF-κB and STAT3 cooperation in cancer will offer opportunities for the design of new chemo-preventive and chemotherapeutic approaches. | Yihui Fan Renfang Mao Jianhua Yang | 2013 | Protein & Cell2013，4，3： | 52 |
| 2 | The generation of PD-L1 and PD-L2 in cancer cells: From nuclear chromatin reorganization to extracellular presentation显示文摘The immune checkpoint blockade(ICB)targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers.However,the low response rate and frequently observed severe side effects limit its broad benefits.It is partially due to less understanding of the biological regulation of PD-L1.Here,we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation.In PD-L1 and PD-L2 highly expressed cancer cells,a new TAD(topologically associating domain)(chr9:5,400,000-5,600,000)around CD274 and CD273 was discovered,which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2.The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1.After transcription,the PD-L1 is tightly regulated by mi RNAs and RNA-binding proteins via the long 3’UTR.At translational level,PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination.In addition,PD-L1 can be secreted via exosome to systematically inhibit immune response.Therefore,fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy. | Zhiwei Fan Changyue Wu Miaomiao Chen Yongying Jiang Yuanyuan Wu Renfang Mao Yihui Fan | 2022 | Acta Pharmaceutica Sinica B2022，12，3： | 4 |
| 3 | Regnase-1, a rapid response ribonuclease regulating nflammation and stress responses显示文摘 | Renfang Mao Riyun Yang Xia Chen Edward W Harhaj Xiaoying Wang Yihui Fan | 2017 | Cellular & Molecular Immunology2017，14，5： | 3 |
| 4 | Enhancer RNAs: A missing regulatory layer in gene transcription显示文摘Enhancers and super-enhancers exert indispensable roles in maintaining cell identity through spatiotemporally regulating gene transcription.Meanwhile,active enhancers and super-enhancers also produce transcripts termed enhancer RNAs(eRNAs) from their DNA elements.Although enhancers have been identified for more than 30 years,widespread transcription from enhancers are just discovered by genome-wide sequencing and considered as the key to understand longstanding questions in gene transcription.RNA-transcribed enhancers are marked by histone modifications such as H3K4m1/2 and H3K27Ac,and enriched with transcription regulatory factors such as LDTFs,P300,CBP,BRD4 and MED1.Those regulatory factors might constitute a Mega-Trans-like complex to potently activate enhancers.Compared to mRNAs,eRNAs are quite unstable and play roles at local.Functionally,it has been shown that e RNAs promote formation of enhancer-promoter loops.Several studies also demonstrated that eRNAs help the binding of RNA polymerase II(RNAPII) or transition of paused RNAPII by de-association of the negative elongation factor(NELF) complex.Nevertheless,these proposed mechanisms are not universally accepted and still under controversy.Here,we comprehensively summarize the reported findings and make perspectives for future exploration.We also believe that super-enhancer derived RNAs(seRNAs) might be informative to understand the nature of super-enhancers. | Renfang Mao Yuanyuan Wu Yue Ming Yuanpei Xu Shouyan Wang Xia Chen Xiaoying Wang Yihui Fan | 2019 | Science China(Life Sciences)2019，62，7： | 1 |
| 5 | Super-enhancer receives signals from the extracellular matrix to induce PD-L1-mediated immune evasion via integrin/ BRAF/TAK1/ERK/ETV4 signaling显示文摘Objective:PD-L1 and PD-L2 expression levels determine immune evasion and the therapeutic efficacy of immune checkpoint blockade.The factors that drive inducible PD-L1 expression have been extensively studied,but mechanisms that result in constitutive PD-L1 expression in cancer cells are largely unknown.Methods:DNA elements were deleted in cells by CRISPR/Cas9-mediated knockout.Protein function was inhibited by chemical inhibitors.Protein levels were examined by Western blot,mRNA levels were examined by real-time RT-PCR,and surface protein expression was determined by cellular immunofluorescence and flow cytometry.Immune evasion was examined by in vitro T cell-mediated killing.Results:We determined the core regions(chr9:5,496,378–5,499,663)of a previously identified PD-L1L2-super-enhancer(SE).Through systematic analysis,we found that the E26 transformation-specific(ETS)variant transcription factor(ETV4)bound to this core DNA region but not to DNA surrounding PD-L1L2SE.Genetic knockout of ETV4 dramatically reduced the expressions of both PD-L1 and PD-L2.ETV4 transcription was dependent on ERK activation,and BRAF/TAK1-induced ERK activation was dependent on extracellular signaling fromαvβ3 integrin,which profoundly affected ETV4 transcription and PD-L1/L2 expression.Genetic silencing or pharmacological inhibition of components of the PD-L1L2-SE-associated pathway rendered cancer cells susceptible to T cell-mediated killing.Conclusions:We identified a pathway originating from the extracellular matrix that signaled via integrin/BRAF/TAK1/ERK/ETV4 to PD-L1L2-SE to induce PD-L1-mediated immune evasion.These results provided new insights into PD-L1L2-SE activation and pathways associated with immune checkpoint regulation in cancer. | Panpan Ma Xinxin Jin Zhiwei Fan Zhou Wang Suhui Yue Changyue Wu Shiyin Chen Yuanyuan Wu Miaomiao Chen Donghua Gu Siliang Zhang Renfang Mao Yihui Fan | 2022 | Cancer Biology & Medicine2022，19，5： | 0 |
| 6 | The C-terminal low-complexity domain involved in liquid-liquid phase separation is required for BRD4 function in vivo显示文摘Dear Editor,Recently,liquid-liquid phase separation(LLPS)attracts great interest for its ability to achieve spatial separation and effective organization of macromolecules(Gomes and Shorter,2018).It is believed to be the driving force to form membraneless organelles and thus plays fundamental roles in a large number of biological processes(Shin and Brangwynne,2017).A list of proteins have been identified that could undergo LLPS in vitro and in vivo(Du and Chen,2018).However,the physiological role of LLPS in animals remains largely unknown. | Chenlu Wang Erhao Zhang Fan Wu Yufeng Sun Yingcheng Wu Baorui Tao Yue Ming Yuanpei Xu Renfang Mao Yihui Fan | 2019 | Journal of Molecular Cell Biology2019，11，9： | 0 |
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