Publications by authors named "Rongxuan Zhu"

12 Publications

  • Page 1 of 1

Author Correction: METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N-methyladenosine-dependent YTHDF binding.

Nat Commun 2021 Jul 20;12(1):4529. Epub 2021 Jul 20.

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-24860-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292537PMC
July 2021

METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N-methyladenosine-dependent YTHDF binding.

Nat Commun 2021 06 21;12(1):3803. Epub 2021 Jun 21.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

The adenomatous polyposis coli (APC) is a frequently mutated tumour suppressor gene in cancers. However, whether APC is regulated at the epitranscriptomic level remains elusive. In this study, we analysed TCGA data and separated 200 paired oesophageal squamous cell carcinoma (ESCC) specimens and their adjacent normal tissues and demonstrated that methyltransferase-like 3 (METTL3) is highly expressed in tumour tissues. mA-RNA immunoprecipitation sequencing revealed that METTL3 upregulates the mA modification of APC, which recruits YTHDF for APC mRNA degradation. Reduced APC expression increases the expression of β-catenin and β-catenin-mediated cyclin D1, c-Myc, and PKM2 expression, thereby leading to enhanced aerobic glycolysis, ESCC cell proliferation, and tumour formation in mice. In addition, downregulated APC expression correlates with upregulated METTL3 expression in human ESCC specimens and poor prognosis in ESCC patients. Our findings reveal a mechanism by which the Wnt/β-catenin pathway is upregulated in ESCC via METTL3/YTHDF-coupled epitranscriptomal downregulation of APC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23501-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217513PMC
June 2021

Nuclear translocation of the 4-pass transmembrane protein Tspan8.

Cell Res 2021 Jun 7. Epub 2021 Jun 7.

State Key Laboratory of Oncogenes and Related Genes, Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41422-021-00522-9DOI Listing
June 2021

WNT/β-catenin-suppressed FTO expression increases mA of c-Myc mRNA to promote tumor cell glycolysis and tumorigenesis.

Cell Death Dis 2021 05 8;12(5):462. Epub 2021 May 8.

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China.

FTO removes the N6-methyladenosine (mA) modification from genes and plays a critical role in cancer development. However, the mechanisms underlying the regulation of FTO and its subsequent impact on the regulation of the epitranscriptome remain to be further elucidated. Here, we demonstrate that FTO expression is downregulated and inversely correlated with poor survival of lung adenocarcinoma patients. Mechanistically, Wnt signaling induces the binding of EZH2 to β-catenin. This protein complex binds to the LEF/TCF-binding elements at the promoter region of FTO, where EZH2 enhances H3K27me3 and inhibits FTO expression. Downregulated FTO expression substantially enhances the mA levels in the mRNAs of a large number of genes in critical pathways, particularly metabolic pathway genes, such as MYC. Enhanced mA levels on MYC mRNA recruit YTHDF1 binding, which promotes MYC mRNA translation and a subsequent increase in glycolysis and proliferation of tumor cells and tumorigenesis. Our findings uncovered a critical mechanism of epitranscriptome regulation by Wnt/β-catenin-mediated FTO downregulation and underscored the role of mA modifications of MYC mRNA in regulating tumor cell glycolysis and growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-021-03739-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106678PMC
May 2021

The cancer-testis gene, sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency.

Cancer Biol Med 2021 02;18(1):74-87

State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

Objective: The newly defined cancer-testis (CT) gene, was previously found to play key roles in DNA double-strand break (DSB) repair. In this study, we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers (TNBCs).

Methods: The Cancer Genome Atlas database was used to quantify the expression of . Cox regression analysis was used to evaluate the association between expression and the prognosis of human TNBC. The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed . Patient-derived xenograft (PDX) models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.

Results: We confirmed as a CT gene whose expression was restricted to the testes and breast tumors, especially TNBCs. Its activation was significantly associated with poor survival in breast cancer patients [overall, hazard ratio (HR) = 1.90 (1.16-2.06); TNBCs: HR = 7.05 (1.16-41.80)]. In addition, we found that was oncogenic and significantly promoted the proliferation of TNBC cells. Further analysis showed that participated in DSB repair in TNBCs. However, in contrast to its function in meiosis, it mediated homologous recombination deficiency (HRD) through the activation of polyADP-ribose polymerase (PARP)1 by interacting with YBX1. Furthermore, activated MEIOB was shown to confer sensitivity to PARP inhibitors, which was confirmed in PDX models.

Conclusions: played an oncogenic role in TNBC through its involvement in HRD. In addition, dysregulation of sensitized TNBC cells to PARP inhibitors, so may be a therapeutic target of PARP1 inhibitors in TNBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877187PMC
February 2021

The discordance pattern of molecular sub-types between primary and metastatic sites in Chinese breast cancer patients.

Int J Clin Exp Pathol 2018 1;11(12):5938-5947. Epub 2018 Dec 1.

Department of Oncology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, P. R. China.

Objective: Based on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER-2), and proliferation cell nuclear antigen (Ki-67) status, breast cancer (BC) can be divided into several molecular sub-types. The patterns of these biological receptors may change during the course of progression and metastasis which could lead to new treatment strategies accordingly.

Method: The present multi-center-based clinical data investigated the discordance patterns of molecular features in Chinese BC patients between primary tumors and distant metastasis. 151 pathologically confirmed BC patients were enrolled. The comparison of the statuses of ER, PR, HER-2, and the Ki-67 index by the IHC and/or FISH method was performed.

Results: The discordance rate in one or more molecular markers was 52.4% and varied between primary and metastatic lesions. The most common transformation pattern was the loss of ER and PR. On the other hand, the ER-positive patients have the longest OS. Patients with ER changing from positive to negative have the shortest OS. The patients with PR changing from negative to positive have the longest OS, while PR-negative patients have the shortest OS. The median DFI (disease-free interval) was 54.93 months in this study. ER, PR, and HER-2 transformation rates are common in patients with DFI < 2 years than in patients with DFI ≥ 5 years. For patients with an ER-positive expression in metastatic lesions, a significantly prolonged PFS was observed (P < 0.05) in those receiving endocrine treatment.

Conclusion: The transformation of molecular subtyping status was identified between primary and corresponding relapse lesions and was used for determining the treatment strategies and prognosis prediction in advanced BC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963059PMC
December 2018

TSPAN8 promotes cancer cell stemness via activation of sonic Hedgehog signaling.

Nat Commun 2019 06 28;10(1):2863. Epub 2019 Jun 28.

Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.

Cancer stem cells (CSCs) represent a major source of treatment resistance and tumor progression. However, regulation of CSCs stemness is not entirely understood. Here, we report that TSPAN8 expression is upregulated in breast CSCs, promotes the expression of the stemness gene NANOG, OCT4, and ALDHA1, and correlates with therapeutic resistance. Mechanistically, TSPAN8 interacts with PTCH1 and inhibits the degradation of the SHH/PTCH1 complex through recruitment of deubiquitinating enzyme ATXN3. This results in the translocation of SMO to cilia, downstream gene expression, resistance of CSCs to chemotherapeutic agents, and enhances tumor formation in mice. Accordingly, expression levels of TSPAN8, PTCH1, SHH, and ATXN3 are positively correlated in human breast cancer specimens, and high TSPAN8 and ATXN3 expression levels correlate with poor prognosis. These findings reveal a molecular basis of TSPAN8-enhanced Sonic Hedgehog signaling and highlight a role for TSPAN8 in promoting cancer stemness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-10739-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599078PMC
June 2019

Sirtuin-mediated deacetylation of hnRNP A1 suppresses glycolysis and growth in hepatocellular carcinoma.

Oncogene 2019 06 11;38(25):4915-4931. Epub 2019 Mar 11.

Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China.

Tumor cells undergo a metabolic shift in order to adapt to the altered microenvironment, although the underlying mechanisms have not been fully explored. HnRNP A1 is involved in the alternative splicing of the pyruvate kinase (PK) mRNA, allowing tumor cells to specifically produce the PKM2 isoform. We found that the acetylation status of hnRNP A1 in hepatocellular carcinoma (HCC) cells was dependent on glucose availability, which affected the PKM2-dependent glycolytic pathway. In the glucose-starved HCC cells, SIRT1 and SIRT6, members of deacetylase sirtuin family, were highly expressed and deacetylated hnRNP A1 after direct binding. We identified four lysine residues in hnRNP A1 that were deacetylated by SIRT1 and SIRT6, resulting in significant inhibition of glycolysis in HCC cells. Deacetylated hnRNP A1 reduced PKM2 and increased PKM1 alternative splicing in HCC cells under normal glucose conditions, thereby reducing the metabolic activity of PK and the non-metabolic PKM2-β-catenin signaling pathway. However, under glucose starvation, the low levels of acetylated hnRNP A1 reduced HCC cell metabolism to adapt to the nutrient deficiency. Taken together, sirtuin-mediated hnRNP A1 deacetylation inhibits HCC cell proliferation and tumorigenesis in a PKM2-dependent manner. These findings point to the metabolic reprogramming induced by hnRNP A1 acetylation in order to adapt to the nutritional status of the tumor microenvironment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-019-0764-zDOI Listing
June 2019

An open-label extension study to evaluate the safety of ropinirole prolonged release in Chinese patients with advanced Parkinson's disease.

Curr Med Res Opin 2015 Apr 12;31(4):723-30. Epub 2015 Mar 12.

Department of Neurology, Peking Union Medical College Hospital , Beijing , China.

Objective: This open-label extension (OLE) study evaluated the safety profile of ropinirole prolonged release (PR) administered for 24 weeks as adjunctive to levodopa in Chinese patients with advanced Parkinson's disease (PD).

Methods: This was a 24 week, flexible-dose, OLE study in Chinese patients with advanced PD who received 24 week treatment with ropinirole PR in the preceding double-blind (DB), phase III study (NCT01154166) and had no break in receiving study treatment while switching from the DB study to the OLE study. In the OLE study, patients received ropinirole PR once daily, starting with 2 mg/d and increasing up to 8 mg/d at week 4 (2 mg increment/week); if tolerable, the dose could be further increased in 4 mg increments up to 24 mg/d according to clinical judgment. There were no efficacy assessments. Safety assessments included monitoring adverse events (AEs), neurological examination, Gambling Symptom Assessment Scale questionnaire, liver chemistry, and laboratory tests.

Results: Of the 295 enrolled patients, 282 completed the study. The most common reason for withdrawal was AEs (n = 9, 3.1%). The mean duration to ropinirole PR treatment was 173.1 days and an overall median daily dose of ropinirole was 8 mg (range: 2-24 mg). Overall, 114 (38.6%) patients experienced on-treatment AEs; the most frequent reported AEs ( ≥ 2%) were dyskinesia (6.1%), dizziness (4.1%), nausea (3.4%), hallucinations (3.4%), somnolence (2.7%) and decreased weight (2.4%). Sixty-eight patients (23.1%) experienced treatment-related AEs. Six patients experienced serious AEs (SAEs), of which hallucination was determined to be a treatment-related SAE. There were no other significant safety findings. No new safety signals for ropinirole were identified.

Conclusion: The safety profile of ropinirole was consistent with the preceding DB study and also with the established safety profile for ropinirole. Results support the long-term use of ropinirole PR as an adjunctive to levodopa in Chinese patients with advanced PD. ClinicalTrials.gov identifier: NCT 1536574.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1185/03007995.2015.1005835DOI Listing
April 2015

Integrative analysis of differential miRNA and functional study of miR-21 by seed-targeting inhibition in multiple myeloma cells in response to berberine.

BMC Syst Biol 2014 Jul 7;8:82. Epub 2014 Jul 7.

Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China.

Background: Berberine is a natural alkaloid derived from a traditional Chinese herbal medicine. It is known to modulate microRNA (miRNA) levels, although the mechanism for this action is unknown. Here, we previously demonstrate that the expression of 87 miRNAs is differentially affected by berberine in multiple myeloma cells. Among 49 miRNAs that are down-regulated, nine act as oncomirs, including miR-21. Integrative analysis showed that 28 of the down-regulated miRNAs participate in tumor protein p53 (TP53) signaling and other cancer pathways. miR-21 is involved in all these pathways, and is one of the most important oncomirs to be affected by berberine in multiple myeloma cells.

Results: We confirmed that berberine down-regulated miRNA-21 expression and significantly up-regulated the expression of programmed cell death 4 (PDCD4), a predicted miR-21 target. Luciferase reporter assays confirmed that PDCD4 was directly regulated by miR-21. Bioinformatic analysis revealed that the miR-21 promoter can be targeted by signal transducer and activator of transcription 3 (STAT3). Down-regulation of interleukin 6 (IL6) by berberine might lead to inhibition of miR-21 transcription through STAT3 down-regulation in multiple myeloma. Furthermore, both berberine and seed-targeting anti-miR-21 oligonucleotide induced apoptosis, G2-phase cell cycle arrest and colony inhibition in multiple myeloma cell lines. Depletion of PDCD4 by short interfering RNA could rescue berberine-induced cytotoxicity in multiple myeloma cells.

Conclusions: Our results suggest that berberine suppresses multiple myeloma cell growth, at least in part, by down-regulating miR-21 levels possibly through IL6/STAT3. This led to increased PDCD4 expression, which is likely to result in suppression of the p53 signaling pathway. These findings may also provide new mechanistic insight into the anti-cancer effects of certain compounds in traditional Chinese herbal medicines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1752-0509-8-82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096730PMC
July 2014

Seed-targeting anti-miR-21 inhibiting malignant progression of retinoblastoma and analysis of their phosphorylation signaling pathways.

Exp Eye Res 2014 May 7;122:1-8. Epub 2014 Mar 7.

Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, Guangzhou 510632, China. Electronic address:

MiR-21 acts as a ubiquitous oncogene in major classes of human cancers and is a potential target for therapeutic intervention. However, the relative expression of miR-21 in retinoblastoma is poorly understood. Here we detected miR-21 expression in HXO-RB44 cell line human normal retinal tissues and retinoblastoma (Rb) tissue specimens, and studied its function using an 8-mer tiny seed-targeting anti-miR-21 (t-anti-miR-21). RT-PCR revealed that miR-21 was highly overexpressed in HXO-RB44 cells and Rb tissue specimens compared with normal human retinal tissues. The localization and transfection efficiency of t-anti-miR-21 and the cell cycle distribution were detected by confocal microscopy and flow cytometry. In addition, we found that t-anti-miR-21 led to a significant inhibition of retinoblastoma cell proliferation, migration and colony formation in vitro, with a similar effect to anti-miR-21. Anti-miR-21 down-regulated the miR-21 level, whereas both 8-mer t-anti-miR-21 and 15-mer m-anti-miR-21 had no impact on miR-21 expression levels. Finally, the phosphorylation signaling pathway, down-regulated by t-anti-miR-21, was integrated by KEGG assay, which elucidated the potential mechanisms of inhibition of miR-21 in retinoblastoma. Taken together, knockdown of miR-21 in the HXO-RB44 cell is capable of inhibiting cancer progression in retinoblastoma. Seed-targeting t-anti-miR-21 was a novel strategy for mir-21-based therapeutics and drug discovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exer.2014.02.017DOI Listing
May 2014

The efficacy and safety of ropinirole prolonged release tablets as adjunctive therapy in Chinese subjects with advanced Parkinson's disease: a multicenter, double-blind, randomized, placebo-controlled study.

Parkinsonism Relat Disord 2013 Nov 6;19(11):1022-6. Epub 2013 Aug 6.

Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China. Electronic address:

Aim: The first evaluation of the efficacy and safety of ropinirole prolonged release (PR) as an adjunct to L-dopa in Chinese patients with advanced Parkinson's disease (PD) not optimally controlled with L-dopa.

Methods: In a 24-week, double-blind, placebo-controlled, parallel-group study, subjects with advanced PD were randomized 1:1 to ropinirole PR (N = 175) or placebo (N = 170) as add-on therapy to L-dopa. Primary outcome measure was change from baseline in awake time spent "off". Starting dose of ropinirole PR was 2 mg/day, titrated based on clinical response (maximum 24 mg/day).

Results: At week 24, the mean dose of ropinirole PR was 11.4 mg/day with a mean reduction of L-dopa from 506.6 to 411.6 mg/day. Subjects receiving ropinirole PR experienced a significant reduction of "off" time (2.1 h) compared with placebo (0.4 h). Secondary outcome measures including hours of "on" time without troublesome dyskinesis were significantly increased in the ropinirole PR group (1.7 h) compared with placebo (0.3 h). Subjects classified as responders were significantly more frequent in the ropinirole PR (22.8%) than placebo group (2.5%). Efficacy outcomes including Unified Parkinson's disease Rating Scale and PDQ-39 subscales of mobility were significantly improved in the ropinirole PR versus placebo group. The most frequent adverse event experienced in the ropinirole PR group was dyskinesia.

Conclusions: This study demonstrated for the first time in Chinese subjects that ropinirole PR improved Parkinson's disease symptoms, permitting a reduction in L-dopa dose. The adverse events observed were consistent with the established safety profile of ropinirole, with no new safety signal identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2013.07.009DOI Listing
November 2013
-->