Xiao J Wang

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

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Publications (9)49.34 Total impact

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    ABSTRACT: Cathelicidin is a host defense peptide with multiple innate immunity-related functions. Recent findings indicate that cathelicidin is frequently dysregulated in human cancers where it plays a paradoxical yet dominant role in the regulation of tumor malignancy. In this review, the regulation of malignant phenotypes by cathelicidin in relation to the activation of its receptors and intracellular signaling is discussed.
    Current Medicinal Chemistry 02/2014; 21(21). DOI:10.2174/0929867321666140205135351 · 3.85 Impact Factor
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    ABSTRACT: Colorectal cancer is a leading cause of morbidity and mortality worldwide. Understanding its genetic mechanisms is key to improving risk prediction, prognostication and treatment. Results from genome-wide association studies have engendered a growing list of colorectal cancer susceptibility genes whereas the application of genome-wide mutational analysis has enabled the depiction of mutational landscape of colorectal cancer at high resolution. The development of novel technologies, such as metagenomic and single-cell sequencing, is expected to have positive impact on future genetic studies. However, challenges remain to address the changing epidemiology of colorectal cancer, issues on genetic testing, and clinical utilization of genomic data.
    Seminars in Cancer Biology 10/2013; 23(6). DOI:10.1016/j.semcancer.2013.09.005 · 9.33 Impact Factor
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    ABSTRACT: Eukaryotes have two major intracellular protein degradation pathways, namely the ubiquitin-proteasome system (UPS) and autophagy. Inhibition of proteasomal activities has been previously shown to induce autophagy, indicating a coordinated and complementary relationship between these two systems. However, little is known about the regulation of the UPS by autophagy. In this study, we showed for the first time that proteasomes were activated in response to pharmacological inhibition of autophagy as well as disruption of autophagy-related genes by RNA interference under nutrient-deficient conditions in cultured human colon cancer cells. The induction was evidenced by the increased proteasomal activities and the upregulation of proteasomal subunits, including the proteasome β5 subunit, PSMB5. Co-inhibition of the proteasome and autophagy also synergistically increased the accumulation of polyubiquitinated proteins. Collectively, our findings suggest that proteasomes are activated in a compensatory manner for protein degradation upon autophagy inhibition. Our studies unveiled a novel regulatory mechanism between the two protein degradation pathways.
    Autophagy 07/2013; 9(10). DOI:10.4161/auto.25573 · 11.75 Impact Factor
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    ABSTRACT: Host immune peptides, including cathelicidins, have been reported to possess anticancer properties. We previously reported that LL-37, the only cathelicidin in humans, suppresses the development of colon cancer. In this study, the potential anticancer effect of FK-16, a fragment of LL-37 corresponding to residues 17 to 32, on cultured colon cancer cells was evaluated. FK-16 induced a unique pattern of cell death, marked by concurrent activation of caspase-independent apoptosis and autophagy. The former was mediated by the nuclear translocation of AIF and EndoG whereas the latter was characterized by enhanced expression of LC3-I/II, Atg5 and Atg7 and increased formation of LC3-positive autophagosomes. Knockdown of Atg5 or Atg7 attenuated the cytotoxicity of FK-16, indicating FK-16-induced autophagy was pro-death in nature. Mechanistically, FK-16 activated nuclear p53 to upregulate Bax and downregulate Bcl-2. Knockdown of p53, genetic ablation of Bax, or overexpression of Bcl-2 reversed FK-16-induced apoptosis and autophagy. Importantly, abolition of AIF/EndoG-dependent apoptosis enhanced FK-16-induced autophagy while abolition of autophagy augmented FK-16-induced AIF-/EndoG-dependent apoptosis. Collectively, FK-16 induces caspase-independent apoptosis and autophagy through the common p53-Bcl-2/Bax cascade in colon cancer cells. Our study also uncovered previously unknown reciprocal regulation between these two cell death pathways.
    PLoS ONE 05/2013; 8(5):e63641. DOI:10.1371/journal.pone.0063641 · 3.23 Impact Factor
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    ABSTRACT: Multiple intracellular signaling pathways, such as Wnt/β-catenin signaling, epidermal growth factor receptor/Ras signaling, and p53 signaling are frequently dysregulated in colorectal cancer. Recent evidence also points to the involvement of signaling pathways in the developmental process, including Notch signaling, Hedgehog signaling, and Hippo signaling. Dysregulation of these signaling pathways contribute to the acquisition of malignant phenotypes, including unchecked cell cycle progression, evasion of apoptosis, induction of genetic instability, and enhanced invasiveness and metastasis. Understanding their relative importance and crosstalk will provide a rational basis for anticancer drug development.
    Critical reviews in oncology/hematology 12/2012; 86(3). DOI:10.1016/j.critrevonc.2012.11.009 · 4.03 Impact Factor
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    ABSTRACT: Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMNs). LL-37, the only human cathelicidin, has been implicated in tumorigenesis but there has been limited investigation of its expression and function in cancer. Here we report that LL-37 activates a p53-mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with TUNEL-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the pro-apoptotic factors AIF and EndoG, through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin-sensitive G-protein-coupled receptor pathway. Correspondingly, colonic mucosa of cathelicidin-deficient mice exhibited reduced expression of p53, Bax and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin-deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiological relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG-mediated apoptosis in colon cancer cells.
    Cancer Research 10/2012; 72(24). DOI:10.1158/0008-5472.CAN-12-2359 · 9.33 Impact Factor
  • Chang G Dong · William K K Wu · Su Y Feng · Xiao J Wang · Jun F Shao · Jian Qiao ·
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    ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs that function as negative gene regulators. Alterations in the expression of miRNAs have been implicated in the pathogenesis and development of most human malignancies. Recent data indicate that microRNA-21 and microRNA-10b are significantly elevated in glioblastoma multiforme (GBM) suggesting their role in the regulation of multiple genes associated with cancer. In this study, U87MG human glioblastoma cells were treated with miRNA inhibitors targeting miR-10b and miR-21, alone or in combination. The results showed that the miR-21 inhibitor additively interacted with miR-10b inhibitor on U87MG cells. The 50% inhibitory concentration values were dramatically decreased in cells treated with the combination of miR-10b and miR-21 inhibitors. Furthermore, inhibitors synergistically combined, enhanced apoptosis significantly and reduced invasion ability assessed by flow cytometry and Transwell migration assay. Thus, the miR-21 inhibitor may interrupt the activity of EGFR pathways, increasing PDCD4 and TPM1 expression and reducing MMP activities, independently of PTEN status. Meanwhile, miR-10b inhibitor reduced by Twist proceeds to inhibit translation of the mRNA encoding HOXD10 leading to the increase of the expression of the well-characterized pro-metastatic gene RHOC. Taken together, these data strongly suggest that a combination of miR-21 inhibitor and miR-10b inhibitor could be an effective therapeutic strategy for controlling the growth of GBM by inhibiting oncogene expression and overexpressing tumor suppressor genes. Moreover, a regulatory strategy based on the combination of miRNA inhibitors may provide insights into the mechanisms of the modulation of signaling genes involved in tumor cell apoptosis and invasiveness.
    International Journal of Oncology 07/2012; 41(3):1005-12. DOI:10.3892/ijo.2012.1542 · 3.03 Impact Factor
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    ABSTRACT: Hydrogen sulfide (H(2)S) is a gaseous bacterial metabolite that reaches high levels in the large intestine. In the present study, the effect of H(2)S on the proliferation of normal and cancerous colon epithelial cells was investigated. An immortalized colon epithelial cell line (YAMC) and a panel of colon cancer cell lines (HT-29, SW1116, HCT116) were exposed to H(2)S at concentrations similar to those found in the human colon. H(2)S inhibited normal and cancerous colon epithelial cell proliferation as measured by MTT assay. The anti-mitogenic effect of H(2)S was accompanied by G(1)-phase cell cycle arrest and the induction of the cyclin-dependent kinase inhibitor p21(Cip). Moreover, exposure to H(2)S led to features characteristic of autophagy, including increased formation of LC3B(+) autophagic vacuoles and acidic vesicular organelles as determined by immunofluorescence and acridine orange staining, respectively. Abolition of autophagy by RNA interference targeting Vps34 or Atg7 enhanced the anti-proliferative effect of H(2)S. Further mechanistic investigation revealed that H(2)S stimulated the phosphorylation of AMP-activated protein kinase (AMPK) and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and S6 kinase. Inhibition of AMPK significantly reversed H(2)S-induced autophagy and inhibition of cell proliferation. Collectively, we demonstrate that H(2)S inhibits colon epithelial cell proliferation and induces protective autophagy via the AMPK pathway.
    PLoS ONE 05/2012; 7(5):e37572. DOI:10.1371/journal.pone.0037572 · 3.23 Impact Factor
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    Su Y Feng · Chang G Dong · William K K Wu · Xiao J Wang · Jian Qiao · Jun F Shao ·
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    ABSTRACT: Glioma is a highly fatal malignant disease and its treatment options are limited. microRNAs represent a novel target for the treatment of cancer. In the present study, we used a lentiviral vector to stably express anti-microRNAs targeting the oncogenic miR-27a in U87 glioma cells. The stable expression of anti-miR-27a significantly reduced the proliferation and increased the accumulation of U87 cells in the sub-G1 phase as determined by Cell Counting kit-8 (CCK-8) assays and flow cytometry, respectively. Results from the Matrigel transwell assay also indicated that the inhibition of miR-27a substantially impaired the invasiveness of U87 cells. By combining bioinformatic and proteomic approaches, we identified the mRNAs of 8 proteins upregulated in anti-miR-27a-expressing U87 cells as putative direct targets of miR-27a. Collectively, these data suggest that the lentiviral expression of anti-miR-27a is a feasible approach for the suppression of malignant phenotypes of glioma cells.
    Molecular Medicine Reports 05/2012; 6(2):275-81. DOI:10.3892/mmr.2012.915 · 1.55 Impact Factor

Publication Stats

148 Citations
49.34 Total Impact Points


  • 2012-2013
    • The Chinese University of Hong Kong
      • • Institute of Digestive Disease
      • • Department of Medicine and Therapeutics
      Hong Kong, Hong Kong