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| 1 | Upregulation of miR-489-3p and miR-630 inhibits oxaliplatin uptake in renal cell carcinoma by targeting OCT2显示文摘Renal cell carcinoma(RCC) is one of the most common malignant tumors affecting the urogenital system, accounting for 90% of renal malignancies. Traditional chemotherapy options are often the front-line choice of regimen in the treatment of patients with RCC, but responses may be modest or limited due to resistance of the tumor to anticarcinogen. Downregulated expression of organic cation transporter OCT2 is a possible mechanism underlying oxaliplatin resistance in RCC treatment. In this study, we observed that mi R-489-3 p and mi R-630 suppress OCT2 expression by directly binding to the OCT2 30-UTR. Meanwhile, via 786-O-OCT2-mi RNAs stable expression cell models, we found that mi RNAs could repress the classic substrate 1-methyl-4-phenylpyridinium(MPP+), fluorogenic substrate N,N-dimethyl-4-(2-pyridin-4-ylethenyl) aniline(ASP+), and oxaliplatin uptake by OCT2 both in vitro and in xenografts. In 33 clinical samples, mi R-489-3 p and mi R-630 were significantly upregulated in RCC, negatively correlating with the OCT2 expression level compared to that in adjacent normal tissues, using tissue microarray analysis and q PCR validation. The increased binding of c-Myc to the promoter of pri-mi R-630, responsible for the upregulation of mi R-630 in RCC, was further evidenced by chromatin immunoprecipitation and dual-luciferase reporter assay. Overall, this study indicated that mi R-489-3 p and mi R-630 function as oncotherapy-obstructing micro RNAs by directly targeting OCT2 in RCC. | Lu Chen Le Chen Zhiyuan Qin Jinxiu Lei Sheng Ye Kui Zeng Hua Wang Meidan Ying Jianqing Gao Su Zeng Lushan Yu | 2019 | Acta Pharmaceutica Sinica B2019，9，5： | 5 |
| 2 | Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells显示文摘Metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastaticassociated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin α V function, which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples. Intriguingly,c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both in vitro and in vivo. Additionally, IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis. | Linlin Chang Yan Hu Yingying Fu Tianyi Zhou Jun You Jiamin Du Lin Zheng Ji Cao Meidan Ying Xiaoyang Dai Dan Su Qiaojun He Hong Zhu Bo Yang | 2019 | Acta Pharmaceutica Sinica B2019，9，3： | 3 |
| 3 | DJ-1 as a human oncogene and potential therapeutic target显示文摘 | Ji Cao Siyue Lou Meidan Ying Bo Yang | 2014 | Biochemical Pharmacology2014，，： | 1 |
| 4 | Hyperoside, a flavonoid compound,inhibits proliferation and stimulates osteogenic differentiation of human osteosarcoma cells 显示文摘 | ZHANG Ning YING Meidan WU Yongping | 2014 | Plos One2014，9，7： | 1 |
| 5 | Blockade of deubiquitinase YOD1 degrades oncogenic PML/RARα and eradicates acute promyelocytic leukemia cells显示文摘In most acute promyelocytic leukemia(APL)cells,promyelocytic leukemia(PML)fuses to retinoic acid receptor α (RARα)due to chromosomal translocation,thus generating PML/RARαoncoprotein,which is a relatively stable oncoprotein for degradation in APL.Elucidating the mechanism regulating the stability of PML/RARαmay help to degrade PML/RARαand eradicate APL cells.Here,we describe a deubiquitinase(DUB)-involved regulatory mechanism for the maintenance of PML/RARαstability and develop a novel pharmacological approach to degrading PML/RARαby inhibiting DUB.We utilized a DUB siRNA library to identify the ovarian tumor protease(OTU)family member deubiquitinase YOD1 as a critical DUB of PML/RARα.Suppression of YOD1 promoted the degradation of PML/RARα,thus inhibiting APL cells and prolonging the survival time of APL cell-bearing mice.Subsequent phenotypic screening of small molecules allowed us to identify ubiquitin isopeptidase inhibitor I(G5)as the first YOD1 pharmacological inhibitor.As expected,G5 notably degraded PML/RARαprotein and eradicated APL,particularly drug-resistant APL cells.Importantly,G5 also showed a strong killing effect on primary patient-derived APL blasts.Overall,our study not only reveals the DUB-involved regulatory mechanism on PML/RARαstability and validates YOD1 as a potential therapeutic target for APL,but also identifies G5 as a YOD1 inhibitor and a promising candidate for APL,particularly drug-resistant APL treatment. | Xuejing Shao Yingqian Chen Wei Wang Wenxin Du Xingya Zhang Minyi Cai Shaowei Bing Ji Cao Xiaojun Xu Bo Yang Qiaojun He Meidan Ying | 2022 | Acta Pharmaceutica Sinica B2022，12，4： | 1 |
| 6 | WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit显示文摘The dysregulation of transcription factors is widely associated with tumorigenesis.As the most well-defined transcription factor in multiple types of cancer,c-Myc can transform cells by transactivating various downstream genes.Given that there is no effective way to directly inhibit c-Myc,c-Myc targeting strategies hold great potential for cancer therapy.In this study,we found that WSB1,which has a highly positive correlation with c-Myc in 10 cancer cell lines and clinical samples,is a direct target gene of c-Myc,and can positively regulate c-Myc expression,which forms a feedforward circuit promoting cancer development.RNA sequencing results from Bel-7402 cells confirmed that WSB1 promoted cMyc expression through theβ-catenin pathway.Mechanistically,WSB1 affectedβ-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptorβ-TRCP recruitment,which inhibited the ubiquitination ofβ-catenin and transactivated c-Myc.Of interest,the effect of WSB1 on c-Myc was independent of its E3 ligase activity.Moreover,overexpressing WSB1 in the Bel-7402 xenograft model could further strengthen the tumor-driven effect of c-Myc overexpression.Thus,our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role,highlighting a potential c-Myc intervention strategy in cancer treatment. | Xiaomeng Gao Jieqiong You Yanling Gong Meng Yuan Haiying Zhu Liang Fang Hong Zhu Meidan Ying Qiaojun He Bo Yang Ji Cao | 2022 | Acta Pharmaceutica Sinica B2022，12，3： | 0 |
| 7 | AKT inhibitor Hu7691 induces differentiation of neuroblastoma cells显示文摘While neuroblastoma accounts for 15%of childhood tumor-related deaths,treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs.Currently,maintenance therapy of differentiation induction is the standard of care for neuroblastoma patients in clinical,especially high-risk patients.However,differentiation therapy is not used as a first-line treatment for neuroblastoma due to low efficacy,unclear mechanism,and few drug options.Through compound library screening,we accidently found the potential differentiation-inducing effect of AKT inhibitor Hu7691.The protein kinase B(AKT)pathway is an important signaling pathway for regulating tumorigenesis and neural differentiation,yet the relation between the AKT pathway and neuroblastoma differentiation remains unclear.Here,we reveal the anti-proliferation and neurogenesis effect of Hu7691 on multiple neuroblastoma cell lines.Further evidence including neurites outgrowth,cell cycle arrest,and differentiation mRNA marker clarified the differentiation-inducing effect of Hu7691.Meanwhile,with the introduction of other AKT inhibitors,it is now clear that multiple AKT inhibitors can induce neuroblastoma differentiation.Furthermore,silencing AKT was found to have the effect of inducing neuroblastoma differentiation.Finally,confirmation of the therapeutic effects of Hu7691 is dependent on inducing differentiation in vivo,suggesting that Hu7691 is a potential molecule against neuroblastoma.Through this study,we not only define the key role of AKT in the progression of neuroblastoma differentiation but also provide potential drugs and key targets for the application of differentiation therapies for neuroblastoma clinically. | Shaowei Bing Senfeng Xiang Zhimei Xia Yilong Wang Zhonghai Guan Jinxin Che Aixiao Xu Xiaowu Dong Ji Cao Bo Yang Jinhu Wang Qiaojun He Meidan Ying | 2023 | Acta Pharmaceutica Sinica B2023，13，4： | 0 |
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