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      Potential Use of 1-25-dihydroxyvitamin D in the Diagnosis and Treatment of Papillary Thyroid Cancer

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          Abstract

          Background

          Low levels of 1-25-dihydroxyvitamin D3 [1,25(OH)2D3] in serum may be a risk factor for several tumor types. Also, high cathelicidin antimicrobial peptide (CAMP) expression is regarded to be important against tumor progression. We evaluated the potential importance of 1,25(OH)2D3 in the diagnosis and treatment of papillary thyroid cancer (PTC).

          Material/Methods

          The preoperative serum level of 1,25(OH)2D3 was measured using a double-antibody sandwich enzyme-linked immunosorbent assay. Vitamin D3 receptor (VDR) expression was detected by streptavidin-peroxidase immunohistochemical staining in PTC specimens. Receiver operating characteristic (ROC) curves were created to assess the diagnostic value of 1,25(OH)2D3. The effect of 1,25(OH)2D3 on the proliferation and apoptosis of PTC cell lines were studied by Cell Counting Kit (CCK)-8 assay and Annexin V/propidium iodide staining, respectively. CAMP expression was measured by qRT-PCR and western blotting. Short interfering RNAs were used to reduce CAMP expression in PTC cell lines.

          Results

          The preoperative serum level of 1,25(OH)2D3 in PTC was obviously lower than that in nodular goiter (NG) ( P<0.05). The ROC curve suggested that 1,25(OH)2D3 might serve as a potential diagnostic value at a cutoff of 20.13 pg/mL, The VDR showed higher expression in PTC than in paired adjacent non-cancerous tissue. 1,25(OH)2D3 inhibited the proliferation and induced the apoptosis of PTC cells, and increased CAMP expression significantly, whereas CAMP knockdown demonstrated opposite effects.

          Conclusions

          1,25(OH)2D3 may be a new, potential biomarker for the identification of PTC and NG. It may also become 1,25(OH)2D3 may a potential target for drug action to treat PTC through CAMP.

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          Most cited references36

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          Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: past, present and future.

          Vitamin D was discovered as the preventive agent of nutritional rickets, a defect in bone development due to inadequate uptake of dietary calcium. However, a variety of studies over the last several years has revealed that vitamin D controls much more than calcium homeostasis. For example, recent research has underlined the key role of vitamin D signaling in regulation of innate immunity in humans. Vitamin D is converted to 25-hydroxyvitamin D (25D), its major circulating form, and then to hormonal 1,25-dihydroxyvitamin D (1,25D) in target cells. We now know that when cells of the immune system such a macrophages sense a bacterial infection they acquire the capacity to convert circulating 25D into 1,25D. Moreover, 1,25D thus produced is a direct inducer of expression of genes encoding antimicrobial peptides, in particular cathelicidin antimicrobial peptide (CAMP). Antimicrobial peptides such as CAMP are vanguards of innate immune responses to bacterial infection and can act as signaling molecules to regulate immune system function. This review covers what we have learned in the past few years about the expression and function of CAMP under physiological and pathophysiological conditions, and addresses the potential future applications of vitamin D analogues to therapeutic regulation of CAMP expression. Copyright (c) 2010 Elsevier Ltd. All rights reserved.
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            Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer.

            Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). 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 terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-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 proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin-sensitive G-protein-coupled receptor (GPCR) 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 pathophysiologic 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.
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              The associations between RAS mutations and clinical characteristics in follicular thyroid tumors: new insights from a single center and a large patient cohort.

              Many studies on thyroid follicular tumors have reported the presence of somatic mutations to three forms of RAS: HRAS, KRAS, and NRAS. However, the frequency and clinical significance of these RAS mutations remain unclear, in large part due to the different methodologies being used for mutation analysis and the limited number of cases featured in studies. To clarify the significance of RAS mutations, we examined a large number of follicular adenomas and carcinomas obtained from a single institute using established methods for the analysis of RAS. Tumor samples from 40 follicular adenoma and 58 follicular carcinoma patients treated at the Kanagawa Cancer Center Hospital were analyzed. The three RAS mutations at codons 12 and 61 were assessed with a polymerase chain reaction-based loop-hybrid mobility shift assay followed by confirmation with direct sequencing. The relationships between mutation status and clinicopathological features at the time of the initial operation and the prognosis of the patients were also analyzed. Twelve out of 40 (30%) adenomas harbored RAS mutations. In contrast, 33 out of 58 (57%) follicular carcinomas harbored RAS mutations, and the mutation was predominantly found in the NRAS codon 61 (22/33, 67%, p<0.01). The rate of gene mutations was significantly higher in the carcinomas than in the adenomas (p<0.01). The NRAS codon 61 mutation in follicular carcinomas was positively associated with distant metastases through the entire clinical course of the patients (p<0.05), and RAS mutations were associated with poor overall patient survival (p<0.05). We investigated the frequency of RAS mutations in follicular thyroid tumors from a large number of cases obtained from a single institute. The predominance of NRAS codon 61 mutations as a feature of carcinomas indicates that the diagnosis of adenoma alongside the presence of this mutation should be made cautiously. Our study raises the possibility that follicular adenomas with the RAS mutations have an inherent malignant potential; however, the clinical significance of this finding should be further investigated in more patients and over a longer follow-up period.
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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2018
                19 March 2018
                : 24
                : 1614-1623
                Affiliations
                Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
                Author notes
                Corresponding Author: Hao Zhang, e-mail: haozhang@ 123456mail.cmu.edu.cn
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                Article
                909544
                10.12659/MSM.909544
                5872905
                29553126
                bba87b2d-fc11-4761-8bb0-79b67e0eb0dd
                © Med Sci Monit, 2018

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

                History
                : 18 February 2018
                : 02 March 2018
                Categories
                Lab/In Vitro Research

                biological markers,calcitriol,cathelicidins,receptors, calcitriol,thyroid neoplasms

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