Wei-Ming Fu

The Chinese University of Hong Kong, Hong Kong, Hong Kong

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Publications (18)79.09 Total impact

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    ABSTRACT: Recently, the long non-coding RNA (lncRNA) H19 has been identified as an oncogenic gene in multiple cancer types and elevated expression of H19 was tightly linked to tumorigenesis and cancer progression. However, the molecular basis for this observation has not been characterized in colorectal cancer (CRC) especially during epithelial to mesenchymal transition (EMT) progression. In our studies, H19 was characterized as a novel regulator of EMT in CRC. We found that H19 was highly expressed in mesenchymal-like cancer cells and primary CRC tissues. Stable expression of H19 significantly promotes EMT progression and accelerates in vivo and in vitro tumor growth. Furthermore, by using bioinformatics study and RNA immunoprecipitation combined with luciferase reporter assays, we demonstrated that H19 functioned as a competing endogenous RNA (ceRNA) for miR-138 and miR-200a, antagonized their functions and led to the de-repression of their endogenous targets Vimentin, ZEB1, and ZEB2, all of which were core marker genes for mesenchymal cells. Taken together, these observations imply that the lncRNA H19 modulated the expression of multiple genes involved in EMT by acting as a competing endogenous RNA, which may build up the missing link between the regulatory miRNA network and EMT progression.
    Oncotarget 06/2015; · 6.63 Impact Factor
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    ABSTRACT: Long noncoding RNA Hotair has been considered as a pro-oncogene in multiple cancers. Although there is a group of emerging evidence which reveals its biological function and the association with clinical prognosis, the precise mechanism remains largely elusive. We investigated the function and mechanism of Hotair in hepatocellular carcinoma (HCC) cell models and a xenograft mouse model. The regulatory network between miR-218 and Hotair was elucidated by RNA immunoprecipitation and luciferase reporter assays. Finally, the corrections between Hotair, miR-218 and the target gene Bmi-1 were evaluated in 52 paired HCC specimens. In this study, we reported that Hotair negatively regulated miR-218 expression in HCC, which might be mediated through an EZH2-targeting-miR-218-2 promoter regulatory axis. Further investigation revealed that Hotair knockdown dramatically inhibited cell viability and induced G1-phase arrest in vitro and suppressed tumorigenicity in vivo by promoting miR-218 expression. Oncogene Bmi-1 was demonstrated to be a functional target of miR-218 and the main downstream targets P16(Ink4a) and P14(ARF) signaling were activated in Hotair-suppressed tumorigenesis. In primary human HCC specimens, Hotair and Bmi-1 were concordantly upregulated whereas miR-218 was downregulated in these tissues. Furthermore, Hotair was inversely associated with miR-218 expression and positively correlated with Bmi-1 expression in these clinical tissues. Hotair silence activates P16(Ink4a) and P14(ARF) signaling by enhancing miR-218 expression and suppressing Bmi-1 expression, resulting in the suppression of tumorigenesis in HCC. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 05/2015; DOI:10.1016/j.jhep.2015.05.016 · 10.40 Impact Factor
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    ABSTRACT: In the past decade, miRNA emerges as a vital player in orchestrating gene regulation and maintaining cellular homeostasis. It is well documented that miRNA influences a variety of biological events, including embryogenesis, cell fate decision, and cellular differentiation. Adipogenesis is an organized process of cellular differentiation by which pre-adipocytes differentiate towards mature adipocytes. It has been shown that adipogenesis is tightly modulated by a number of transcription factors such as PPARγ, KLF4, and C/EBPα. However, the molecular mechanisms underlying the missing link between miRNA and adipogenesis-related transcription factors remain elusive. In this study, we unveiled that miR-25, a member of miR-106b-25 cluster, was remarkably downregulated during 3T3-L1 adipogenesis. Restored expression of miR-25 significantly impaired 3T3-L1 adipogenesis and downregulated the expression of serial adipogenesis-related genes. Further experiments presented that ectopic expression of miR-25 did not affect cell proliferation and cell cycle progression. Finally, KLF4 and C/EBPα, two key regulators of adipocyte differentiation, were experimentally identified as bona fide targets for miR-25. These data indicate that miR-25 is a novel negative regulator of adipocyte differentiation and it suppressed 3T3-L1 adipogenesis by targeting KLF4 and C/EBPα, which provides novel insights into the molecular mechanism of miRNA-mediated cellular differentiation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Biochemistry 04/2015; DOI:10.1002/jcb.25214 · 3.37 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. As a highly conserved miRNA across a variety of species, microRNA-218 (miR-218) was found to play pivotal roles in tumorigenesis and progression. A group of evidence has demonstrated that miR-218 acts as a tumor suppressor by targeting many oncogenes related to proliferation, apoptosis and invasion. In this review, we provide a complex overview of miR-218, including its regulatory mechanisms, known functions in cancer and future challenges as a potential therapeutic target in human cancers. Copyright © 2015. Published by Elsevier Inc.
    Experimental Cell Research 04/2015; 334(1). DOI:10.1016/j.yexcr.2015.03.027 · 3.37 Impact Factor
  • Zhi-Yuan Li · Jin-Yan Chen · Zhang Yan-Ling · Wei-Ming Fu
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    ABSTRACT: This updated systematic review and meta-analyses aims to systematically evaluate the cross-protection of seasonal influenza vaccines against the 2009 pandemic A (H1N1) influenza infection, and investigate the potential effect of the influenza strains circulating previous to the pandemic on the association between vaccine receipt and pandemic infection. In addition, subgroup analysis was performed based on the study locations and previous circulating influenza viruses. Relevant articles in English and Chinese from 2009 to October 2013 were systematically searched, and 21 eligible studies were included. For case-control studies, an insignificant 20% reduced risk for pandemic influenza infection based on combined national data (OR = 0.80; 95%CI: 0.60, 1.05) was calculated for people receiving seasonal influenza vaccination. However, for RCTs, an insignificant increase in the risk of seasonal influenza vaccines was observed (RR = 1.27; 95% CI: 0.46, 3.53). For the subgroup analysis, a significant 35% cross-protection was observed in the subgroup where influenza A outbreaks were detected before the 2009 pandemic. Moreover, the results indicated that seasonal influenza vaccination may reduce the risk of influenza-like illnesses (ILIs) (RR = 0.91; 95% CI: 0.84, 0.99). Our findings partially support the hypothesis that seasonal vaccines may offer moderate cross-protection for adults against laboratory-confirmed pandemic influenza A (H1N1) infection and ILIs. Further immunological studies are needed to understand the mechanism underlying these findings.
    Human Vaccines and Immunotherapeutics 02/2015; 11(6). DOI:10.4161/21645515.2014.985495 · 3.64 Impact Factor
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    ABSTRACT: Traditional Chinese medicine is recently emerged as anti-cancer therapy or adjuvant with reduced side-effects and improved quality of life. In the present study, an active ingredient, 1,6,7-trihydroxyxanthone (THA), derived from Goodyera oblongifolia was found to strongly suppress cell growth and induce apoptosis in liver cancer cells. MicroRNAs are a group of small non-coding RNAs that regulate gene expression at post-transcriptional levels. Our results demonstrated that miR-218 was up-regulated and oncogene Bmi-1 was down-regulated by THA treatment. Further investigation showed that THA-induced-miR-218 up-regulation could lead to activation of tumor suppressor P16(Ink4a) and P14(ARF), the main down-stream targets of Bmi-1. In conclusion, THA might be a potential anti-cancer drug candidate, at least in part, through the activation of miR-218 and suppression of Bmi-1 expression.
    APOPTOSIS 11/2014; 20(1):1-8. DOI:10.1007/s10495-014-1047-3 · 3.61 Impact Factor
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    ABSTRACT: Fascia‑derived stem cells (FDSCs) were previously isolated from the fascia of the gluteus maximus of the rat. However, the use of FDSCs as a cell source for musculoskeletal tissue engineering has not been compared with that of adipose‑derived stem cells (ADSCs) and bone marrow‑derived mesenchymal stem cells (BMSCs). Therefore, the present study aimed to compare the mesenchymal stem cell (MSC) and self‑renewal stem cell markers, proliferative capacity and multilineage differentiation potential of these stem cells in vitro. The MSC and embryonic stem cell (ESC) marker profiles were compared using flow cytometry and quantitative polymerase chain reaction (qPCR). Their proliferative capacities were compared using 5‑bromo‑2'‑deoxyuridine and MTT assays. Their osteogenic, adipogenic and chondrogenic differentiation potentials were compared using standard staining assays and qPCR. The FDSCs possessed similar cell morphology and immunophenotypic profiles with BMSCs and ADSCs. FDSCs demonstrated a similar expression pattern of ESC markers with ADSCs, which has higher expression of sex determining region Y‑box (Sox)2 and octamer‑binding transcription factor 4, and lower expression of Krüppel‑like factor 4, when compared with BMSCs. FDSCs exhibited higher proliferation under serum‑deprived conditions (0.5% FBS growth medium), and attained higher expression levels of collagen type I, α 2 and type II, α 1 as well as Sox9 mRNA than ADSCs and BMSCs upon chondrogenic induction. An increased amount of proteoglycan deposition was also observed in the FDSC group. However, lower levels of adipogenic and osteogenic marker expression in FDSCs were detected compared with ADSCs and BMSCs upon adipogenic and osteogenic induction, respectively. FDSCs possessed high chondrogenic potential, low osteogenic and adipogenic differentiation potential and were responsive to the induction signals for collagen‑rich fascial structure regeneration. Therefore, FDSCs may represent an improved alternative cell source to conventional ADSCs and BMSCs for musculoskeletal tissue repair and tissue engineering, particularly for collagen‑rich structures with poor vasculature.
    Molecular Medicine Reports 11/2014; 11(3). DOI:10.3892/mmr.2014.2967 · 1.48 Impact Factor
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    Jing-Yu He · Na Ma · Shu Zhu · Katsuko Komatsu · Zhi-Yuan Li · Wei-Ming Fu
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    ABSTRACT: Codonopsis, in the family Campanulaceae, is a genus containing 42 species of dicotyledonous herbaceous perennial plants, predominantly found in Central, East and South Asia. Several Codonopsis species are widely used in traditional medicine and are considered to have multiple medicinal properties. Among the Codonopsis species, Codonopsis pilosula (Franch.) Nannf. and C. lanceolata (Sieb. et Zucc.) Benth. & Hook. f. ex Trautv. are more popular than others according to the findings, especially phytochemical and bioactive studies. Phytochemical research shows that Codonopsis species contain mainly polyacetylenes, phenylpropanoids, alkaloids, triterpenoids and polysaccharides, which contribute to multiple bioactivities. However, the mechanisms of their bioactivities need to be further elucidated. The less popular Codonopsis species remain to be studied and exploited. In addition, although a series of methods for the quality evaluation of Codonopsis species have been developed, a feasible and reliable approach to the efficacious and safe use of various Codonopsis species is still needed, with considering botanical origin, chemical constituents and bioactive effects. This review aims to provide up-to-date and comprehensive information on the phytochemistry, bioactivity and quality control of medicinal plants in the genus Codonopsis and to highlight current gaps in knowledge, which is useful for the wider development of the Codonopsis genus.
    Journal of Natural Medicines 08/2014; 69(1). DOI:10.1007/s11418-014-0861-9 · 1.45 Impact Factor
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    ABSTRACT: The Krüppel like factor 6 (KLF6) gene encodes multiple protein isoforms derived from alternative mRNA splicing, most of which are intimately involved in hepatocarcinogenesis and tumor progression. Recent bioinformatics analysis shows that alternative mRNA splicing of the KLF6 gene produces around 16 alternatively spliced variants with divergent or even opposing functions. Intriguingly, the full-length KLF6 (KLF6-FL) is a tumor suppressor gene frequently inactivated in liver cancer, whereas KLF6 splice variant 1 (KLF6-SV1) is an oncogenic isoform with antagonistic function against KLF6-FL. Compelling evidences indicate that miRNA, the small endogenous non-coding RNA (ncRNA), acts as a vital player in modulating a variety of cellular biological processes through targeting different mRNA regions of protein-coding genes. To identify the potential miRNAs specifically targeting KLF6-FL, we utilized bioinformatics analysis in combination with the luciferase reporter assays and screened out two miRNAs, namely miR-210 and miR-1301, specifically targeted the tumor suppressive KLF6-FL rather than the oncogenic KLF6-SV1. Our in vitro experiments demonstrated that stable expression of KLF6-FL inhibited cell proliferation, migration and angiogenesis while overexpression of miR-1301 promoted cell migration and angiogenesis. Further experiments demonstrated that miR-1301 was highly expressed in liver cancer cell lines as well as clinical specimens and we also identified the potential methylation and histone acetylation for miR-1301 gene. To sum up, our findings unveiled a novel molecular mechanism that specific miRNAs promoted tumorigenesis by targeting the tumor suppressive isoform KLF6-FL rather than its oncogenic isoform KLF6-SV1.
    RNA Biology 06/2014; 11(7). DOI:10.4161/rna.29356 · 5.38 Impact Factor
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    ABSTRACT: Vaccination is an effective strategy to prevent and control the transmission of hepatitis A. Hepatitis A immunization program has been taken into effect since 2001 in Tianjin, China. This study evaluated the effectiveness of strategies in the prevention and control of hepatitis A. Data of serological survey, annual hepatitis A incidence, immunization coverage and the positive rate of hepatitis A IgG before and after the immunization program in residents under 15 years old were used to do the analysis. The results indicated that hepatitis A vaccine induced a striking decrease of hepatitis A incidence and a significant increase in the positive rate of anti-HAV IgG among the children younger than 15 years old. Hepatitis A vaccination in children was proved to be effective in the prevention and control of hepatitis A in Tianjin, China.
    Human Vaccines & Immunotherapeutics 02/2014; 10(4). DOI:10.4161/hv.27775 · 3.64 Impact Factor
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    ABSTRACT: Our previous study showed that the small molecule 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran [7,6-b] xanthone (TDP) played an apoptosis-inducing role in hepatocellular carcinoma (HCC) through suppressing Hsp27 expression. However, the interaction between TDP and Hsp27 remains unclear. To investigate the functional association between TDP and Hsp27 protein in HCC, the recombinant Hsp27 protein was incubated with TDP at room temperature, and assayed by mass spectrum (MS) and natural electrophoresis. The results showed that TDP effectively stimulated Hsp27 to form aggregates ex vitro, thereby leading to suppressing its chaperone activity. Furthermore, we observed that these aggregates would be degraded through the ubiquitin-proteasome (UPS) pathway. Moreover, TDP could directly interact with Asp17 and Phe55 in chain C of Hsp27 by the bioinformatics prediction. In conclusion, our study showed that Hsp27 was a direct target of TDP in anti-cancer activity, which provided strong support for the clinical potential of TDP.
    Cell Biology International 02/2014; 38(2). DOI:10.1002/cbin.10193 · 1.64 Impact Factor
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    ABSTRACT: As a super-antigen, staphylococcal enterotoxin C2 (SEC2) stimulates the release of massive inflammatory cytokines such as interferon-gamma (IFN-γ), interleukin-1 (IL-1) and interleukin-2 (IL-2) which are documented to implicate osteoblast differentiation. In the present study, SEC2 was found to significantly improve the osteoblast differentiation by up-regulating BMP2 and Runx2/Cbfa1 expression. Interferon (IFN)-inducible gene IFI16, a co-activator of Runx2/Cbfa1, was also activated by SEC2 in the osteoblast differentiation. In addition, exogenous introduction of SEC2 stimulated OPG expression and suppressed RANKL, suggesting suppression of osteoclastogenesis in hMSCs. Therefore, our results displayed that SEC2 plays an important role in the commitment of MSC to the osteoblast and it might be a potential new therapeutic candidate for bone regeneration.
    Experimental Cell Research 12/2013; 322(1). DOI:10.1016/j.yexcr.2013.12.008 · 3.37 Impact Factor
  • Chinese medical journal 01/2013; 126(2):393-4. · 1.02 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is a global public health problem which causes approximately 500,000 deaths annually. Considering that the limited therapeutic options for HCC, novel therapeutic targets and drugs are urgently needed. In this study, we discovered that 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran [7,6-b] xanthone (TDP), isolated from the traditional Chinese medicinal herb, Garcinia oblongifolia, effectively inhibited cell growth and induced the caspase-dependent mitochondrial apoptosis in HCC. A two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomics were performed to find the molecular targets of TDP in HCC cells. Eighteen proteins were identified as differently expressed, with Hsp27 protein being one of the most significantly down-regulated proteins induced by TDP. In addition, the following gain- and loss-of-function studies indicated that Hsp27 mediates mitochondrial apoptosis induced by TDP. Furthermore, a nude mice model also demonstrated the suppressive effect of TDP on HCC. Our study suggests that TDP plays apoptosis-inducing roles by strongly suppressing the Hsp27 expression that is specifically associated with the mitochondrial death of the caspase-dependent pathway. In conclusion, TDP may be a potential anti-cancer drug candidate, especially to cancers with an abnormally high expression of Hsp27.
    Journal of proteomics 06/2012; 75(15):4833-43. DOI:10.1016/j.jprot.2012.05.032 · 3.93 Impact Factor
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    ABSTRACT: Gamboge is a traditional Chinese medicine and our previous study showed that gambogic acid and gambogenic acid suppress the proliferation of HCC cells. In the present study, another active component, 1,3,6,7-tetrahydroxyxanthone (TTA), was identified to effectively suppress HCC cell growth. In addition, our Hoechst-PI staining and flow cytometry analyses indicated that TTA induced apoptosis in HCC cells. In order to identify the targets of TTA in HCC cells, a two-dimensional gel electrophoresis was performed, and proteins in different expressions were identified by MALDA-TOF MS and MS/MS analyses. In summary, eighteen proteins with different expressions were identified in which twelve were up-regulated and six were down-regulated. Among them, the four most distinctively expressed proteins were further studied and validated by western blotting. The β-tubulin and translationally controlled tumor protein were decreased while the 14-3-3σ and P16 protein expressions were up-regulated. In addition, TTA suppressed tumorigenesis partially through P16-pRb signaling. 14-3-3σ silence reversed the suppressive effect of cell growth and apoptosis induced by introducing TTA. In conclusion, TTA effectively suppressed cell growth through, at least partially, up-regulation of P16 and 14-3-3σ.
    Apoptosis 05/2012; 17(8):842-51. DOI:10.1007/s10495-012-0729-y · 3.61 Impact Factor
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    ABSTRACT: MiR-637 (microRNA-637) is a primate-specific miRNA belonging to the small noncoding RNA family, which represses gene regulation at the post-transcriptional expression level. Although it was discovered approximately 5 years ago, its biomedical significance and regulatory mechanism remain obscure. Our preliminary data showed that miR-637 was significantly suppressed in four HCC cell lines and, also, in most of the hepatocellular carcinoma (HCC) specimens, thereby suggesting that miR-637 would be a tumor suppressor in HCC. Simultaneously, the enforced overexpression of miR-637 dramatically inhibited cell growth and induced the apoptosis of HCC cells. The transcription factor, signal transducer and activator of transcription 3 (Stat3), is constitutively activated in multiple tumors, and aberrant Stat3 activation is linked to the promotion of growth and desensitization of apoptosis. Our study showed that Stat3 tyrosine 705 phosphorylation and several Stat3-regulated antiapoptotic genes were down-regulated in miR-637 mimics-transfected and Lv-miR637-infected HCC cells. In addition, miR-637 overexpression negatively regulated Stat3 phosphorylation by suppressing autocrine leukemia inhibitory factor (LIF) expression and exogenous LIF-triggered Stat3 activation and rescued cell growth in these cells. A nude mice model also demonstrated the above-described results, which were obtained from the cell model. Furthermore, we found that LIF was highly expressed in a large proportion of HCC specimens, and its expression was inversely associated with miR-637 expression. Conclusion: Our data indicate that miR-637 acted as a tumor suppressor in HCC, and the suppressive effect was mediated, at least in part, by the disruption of Stat3 activation. (HEPATOLOGY 2011)
    Hepatology 12/2011; 54(6):2137 - 2148. DOI:10.1002/hep.24595 · 11.19 Impact Factor
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    ABSTRACT: Osteogenic differentiation of mesenchymal stem cells (MSCs) is a complex process, which is regulated by various factors including microRNAs. Our preliminary data showed that the expression of endogenous miR-20a was increased during the course of osteogenic differentiation. Simultaneously, the expression of osteoblast markers and regulators BMP2, BMP4, Runx2, Osx, OCN and OPN was also elevated whereas adipocyte markers PPARγ and osteoblast antagonist, Bambi and Crim1, were downregulated, thereby suggesting that miR-20a plays an important role in regulating osteoblast differentiation. To validate this hypothesis, we tested its effects on osteogenic differentiation by introducing miR-20a mimics and lentiviral-miR20a-expression vectors into hMSCs. We showed that miR-20a promoted osteogenic differentiation by the upregulation of BMP/Runx2 signaling. We performed bioinformatics analysis and predicted that PPARγ, Bambi and Crim1 would be potential targets of miR-20a. PPARγ is a negative regulator of BMP/Runx2 signaling whereas Bambi or Crim1 are antagonists of the BMP pathway. Furthermore, we confirmed that all these molecules were indeed the targets of miR-20a by luciferase reporter, quantitative RT-PCR and western blot assays. Similarly to miR-20a overexpression, the osteogenesis was enhanced by the silence of PPARγ, Bambi or Crim1 by specific siRNAs. Taken together, for the first time, we demonstrated that miR-20a promoted the osteogenesis of hMSCs in a co-regulatory pattern by targeting PPARγ, Bambi and Crim1, the negative regulators of BMP signaling.
    RNA biology 09/2011; 8(5):829-38. DOI:10.4161/rna.8.5.16043 · 5.38 Impact Factor
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    ABSTRACT: Bone development is dynamically regulated by homeostasis, in which a balance between adipocytes and osteoblasts is maintained. Disruption of this differentiation balance leads to various bone-related metabolic diseases, including osteoporosis. In the present study, a primate-specific microRNA (miR-637) was found to be involved in the differentiation of human mesenchymal stem cells (hMSCs). Our preliminary data indicated that miR-637 suppressed the growth of hMSCs and induced S-phase arrest. Expression of miR-637 was increased during adipocyte differentiation (AD), whereas it was decreased during osteoblast differentiation (OS), which suggests miR-637 could act as a mediator of adipoosteogenic differentiation. Osterix (Osx), a significant transcription factor of osteoblasts, was shown to be a direct target of miR-637, which significantly enhanced AD and suppressed OS in hMSCs through direct suppression of Osx expression. Furthermore, miR-637 also significantly enhanced de novo adipogenesis in nude mice. In conclusion, our data indicated that the expression of miR-637 was indispensable for maintaining the balance of adipocytes and osteoblasts. Disruption of miR-637 expression patterns leads to irreversible damage to the balance of differentiation in bone marrow.
    Molecular biology of the cell 08/2011; 22(21):3955-61. DOI:10.1091/mbc.E11-04-0356 · 5.98 Impact Factor

Publication Stats

156 Citations
79.09 Total Impact Points

Institutions

  • 2011–2015
    • The Chinese University of Hong Kong
      • • School of Biomedical Sciences
      • • Stanley Ho Center for Emerging Infectious Diseases
      Hong Kong, Hong Kong
    • Third Military Medical University
      Ch’ung-ch’ing-shih, Chongqing Shi, China
  • 2014
    • Chinese Academy of Sciences
      Peping, Beijing, China