Human beta-defensin-3 (hBD-3) upregulated by LPS via epidermal growth factor receptor (EGFR) signaling pathways to enhance lymphatic invasion of oral squamous cell carcinoma

Yu, Shanshan; Wang, Feng; Tang, Jing; Huang, Hongzhang; Wang, Haiyan; Ma, Pingping; Zheng, Li Wu; Zwahlen, Roger A.; Yang, Hong-Chang

doi:10.1016/j.tripleo.2011.02.053

Cited by 48 publications

(49 citation statements)

References 21 publications

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“…Therefore, the loss of focal adhesions upon miR-491-5p overexpression or knockdown of GIT1 may not be attributed to the reduction of paxillin, but mainly to the reduction of GIT1. Among the potential upstream activation of ERK1/2 is EGFR, which has been previously implicated in oral cancer development and progression (47,48). Our data show that depletion of GIT1 significantly reduces EGF-induced ERK1/2 activation in OSCC cells (Fig.…”

Section: Discussionsupporting

confidence: 62%

miRNA-491-5p and GIT1 Serve as Modulators and Biomarkers for Oral Squamous Cell Carcinoma Invasion and Metastasis

et al. 2014

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MicroRNAs offer tools to identify and treat invasive cancers. Using highly invasive isogenic oral squamous cell carcinoma (OSCC) cells, established using in vitro and in vivo selection protocols from poorly invasive parental cell populations, we used microarray expression analysis to identify a relative and specific decrease in miR-491-5p in invasive cells. Lower expression of miR-491-5p correlated with poor overall survival of patients with OSCCs. miR-491-5p overexpression in invasive OSCC cells suppressed their migratory behavior in vitro and lung metastatic behavior in vivo. We defined the G-protein-coupled receptor kinase-interacting protein 1 (GIT1)-as a direct target gene for miR-491-5p control. GIT1 overexpression was sufficient to rescue miR-491-5p-mediated inhibition of migration/invasion and lung metastasis. Conversely, GIT1 silencing phenocopied the ability of miR-491-5p to inhibit migration/invasion and metastasis of OSCC cells. Mechanistic investigations indicated that miR-491-5p overexpression or GIT1 attenuation reduced focal adhesions, with a concurrent decrease in steady-state levels of paxillin, phospho-paxillin, phospho-FAK, EGF/EGFR-mediated extracellular signal-regulated kinase (ERK1/2) activation, and MMP2/9 levels and activities. In clinical specimens of OSCCs, GIT1 levels were elevated relative to paired normal tissues and were correlated with lymph node metastasis, with expression levels of miR-491-5p and GIT1 correlated inversely in OSCCs, where they informed tumor grade. Together, our findings identify a functional axis for OSCC invasion that suggests miR-491-5p and GIT1 as biomarkers for prognosis in this cancer. Cancer Res; 74(3); 751-64. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 62%

miRNA-491-5p and GIT1 Serve as Modulators and Biomarkers for Oral Squamous Cell Carcinoma Invasion and Metastasis

et al. 2014

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“…The inconsistency between our findings compared to those from previous investigations reporting that tumors overexpressing hBD3 or Defb14 showed enhanced solidtumor growth remains unclear (14,15,27). This may have occurred because of differences in the concentration of hBD3 and Defb14 used, although the concentration of 20 μg/ml defensin used in our study was not excessively higher than that at which antimicrobial activity was observed (10).…”

Section: Figure 3 Time Dependency Of Cellular Damage Induced By Humacontrasting

confidence: 97%

“…This may have occurred because of differences in the concentration of hBD3 and Defb14 used, although the concentration of 20 μg/ml defensin used in our study was not excessively higher than that at which antimicrobial activity was observed (10). Additionally, different pathways may function, if the tumors themselves overexpress defensin (15,27).…”

Section: Figure 3 Time Dependency Of Cellular Damage Induced By Humamentioning

confidence: 81%

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In Vitro and In Vivo Anticancer Activity of Human β-Defensin-3 and Its Mouse Homolog

Hanaoka

Yamaguchi

Yamamoto

et al. 2016

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Abstract. Background Antimicrobial peptides have emerged as a part of the host defense mechanism in both animals and plants (1, 2). Specifically, defensins and cathelicidins are antimicrobial peptides found in humans (3). In the defensin family, there are α-defensin and β-defensin subfamilies, which conserve three specific disulfide pairings. These are produced by leukocytes and various types of epithelial cells constitutively, or in response to microbial signals and inflammatory cytokines (4-6).Human β-defensin-3 (hBD3) was first isolated from human skin (7) and its expression was detected in many tissues, including airway epithelial cells (8,9). In contrast to other defensin isoforms, the prominent features of hBD3 antimicrobial activity are its salt-independency and its broad antimicrobial spectrum (7, 10, 11).While antimicrobial peptides have attracted attention as potential molecules to treat cancer (12), previous observations on the anticancer effects of hBD3 have not been consistent. Some studies hypothesized that hBD3 can be oncogenic because hBD3 is frequently overexpressed in oral squamous cell carcinomas (13-15). Winter et al. indicated that hBD3 inhibited colon cancer-cell migration, although not cell proliferation (16). Moreover, Phan et al. indicated that hBD3 exhibits anticancer effects on various tumor cells through cell permeabilization (17).Here, we investigated the anticancer activities of various isoforms of β-defensin on lung cancer cells, and confirmed that this anticancer activity is also seen in animal models of cancer. Materials and MethodsReagents. Synthetic hBD1, hBD2, hBD3 and human neutrophil peptide-1 (HNP1) peptides were purchased from the PEPTIDE institute (Minoh, Japan), and were dissolved in 0.001% acetic acid to give a final concentration of 2 mg/ml.We predicted the mature Defb14 peptide spanning 45 COOHterminal amino acids as a mouse homolog of hBD3, identical to the predicted mature peptide of Defb14 from a previous report (18). At the Peptide Institute (Minoh, Japan), we chemically synthesized mature Defb14 peptide (19,20). The synthetic peptide was airoxidized to form three disulfide bonds. The material was eluted as a 5999 *These Authors contributed equally to this study.Correspondence to: Yasuhiro Yamaguchi, Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Tel: +81 358008652, Fax: +81 358006530, e-mail: yamayasu-tky@umin.ac.jp Key Words: Antimicrobial peptide, cytotoxicity, membrane damage. ANTICANCER RESEARCH 36: 5999-6004 (2016) single peak on reverse-phase high-performance liquid chromatography and confirmed by mass spectroscopy. It was lyophilized and dissolved in 0.001% acetic acid to give a final concentration of 2 mg/ml.Cell culture. A549 human lung carcinoma cells were obtained from the Cell Resource Center for Biomedical Research, Tohoku University (Sendai-shi, Japan). Lewis lung carcinoma (LLC) cells were obtained from RIKEN BRC (Tsukuba-shi, Japan). The cells were routine...

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“…The B7-H3 and TLT-2 immunoreactivity of all samples was independently evaluated by two investigators in a blinded manner, based on the intensity of staining as follows: 0, no staining; 1+, weak diffuse cytoplasmic staining (<10% of the cancer cells may exhibit stronger intensity); 2+, moderate to strong granular cytoplasmic staining, present in 10-90% of the cancer cells; 3+, >90% of the tumor cells exhibited strong intensity. All specimens were evaluated by the two independent and blinded investigators using a multiheaded microscope (CX31; Olympus Corporation, Tokyo, Japan) and the consensus score was used for subsequent analyses (22).…”

Section: Methodsmentioning

confidence: 99%

Expression levels of B7-H3 and TLT-2 in human oral squamous cell carcinoma

Zhang

Tang

et al. 2015

Oncology Letters

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Abstract. The aim of the present study was to investigate the role of immune regulatory molecules B7-H3 [also known as cluster of differentiation 276] and triggering receptor expressed on myeloid cell-like transcript-2 (TLT-2) in patients with oral squamous cell carcinoma (OSCC). Human OSCC samples were obtained from 76 patients (female, 32; male, 44; age range, 23-81 years; median age, 50.9 years) that underwent resection for OSCC at Peking University Shenzhen Hospital (Shenzhen, China) between 2007 and 2010. In addition, control oral mucosal samples were obtained from 76 healthy individuals (female, 36; male, 40; age range, 21-62 years; median age, 45.3 years) during wisdom tooth extraction. Protein and gene expression levels of B7-H3 and TLT-2 were determined by immunohistochemical analysis and reverse transcription-polymerase chain reaction (RT-PCR). In the healthy oral mucosa samples, B7-H3 expression was identified to be weak, while the expression of TLT-2 was only detected sporadically in the cell membrane and cytoplasm. By contrast, the two regulatory molecules were widely expressed in the aforementioned localizations in human OSCC specimens upon immunohistochemical examination. Furthermore, quantitative RT-PCR confirmed the presence of significantly higher B7-H3 and TLT-2 expression levels in OSCC specimens compared with the oral mucosa of healthy individuals. The significantly higher expression levels of B7-H3 and TLT-2 in human OSCC specimens may indicate an inhibitory role of these molecules in the antitumoral immune response. To investigate interactions between these two molecules and individual antitumoral immune response in OSCC patients, prospective clinical studies with an adequate sample size are required. IntroductionThe antitumoral immune response is a complex physiological process involving a variety of immune cells and molecules, including membrane molecules and dissolubility factors (1). As well as the engagement of T cell receptors, costimulation with immune regulatory molecules is required for the optimal activation of T cells (2). The B7 family, a group of costimulatory and coinhibitory proteins, encompasses critical ligands that interact with known and unknown receptors on the surface of T lymphocytes, regulating stimulation or inhibition (3). The aberrant expression of members of the B7 family is considered to be a mechanism by which human malignancies may escape host immune surveillance (3-5).B7-H3 [also known as cluster of differentiation (CD) 276], a member of the B7 family, is expressed on the surface of lymphoid cells, including dendritic cells, monocytes/macrophages and activated T cells. In addition, it is expressed on the surface of non-lymphoid tissue cells, including epithelial, anterior pituitary progenitor and muscle cells, as well as fibroblast-like synoviocytes (3,4). At present, the regulatory role of B7-H3 in tumor immunity remains controversial. A number of studies considered B7-H3 to be a costimulatory molecule promoting T-cell activation and proliferation and, thus,...

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Human beta-defensin-3 (hBD-3) upregulated by LPS via epidermal growth factor receptor (EGFR) signaling pathways to enhance lymphatic invasion of oral squamous cell carcinoma

Cited by 48 publications

References 21 publications

miRNA-491-5p and GIT1 Serve as Modulators and Biomarkers for Oral Squamous Cell Carcinoma Invasion and Metastasis

miRNA-491-5p and GIT1 Serve as Modulators and Biomarkers for Oral Squamous Cell Carcinoma Invasion and Metastasis

In Vitro and In Vivo Anticancer Activity of Human β-Defensin-3 and Its Mouse Homolog

Expression levels of B7-H3 and TLT-2 in human oral squamous cell carcinoma

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