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Aziz Ghahary - One of the best experts on this subject based on the ideXlab platform.
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topical application of a film forming emulgel dressing that controls the release of Stratifin and acetylsalicylic acid and improves prevents hypertrophic scarring
Wound Repair and Regeneration, 2013Co-Authors: Elham Rahmanineishaboor, Ryan Hartwell, Reza Jallili, Victor C M Leung, Nicholas Carr, Aziz GhaharyAbstract:Here, we evaluate the efficacy of an emulgel dressing to control the release of an antifibrogenic factor, Stratifin (SFN), along with an anti-inflammatory drug, acetylsalicylic acid (ASA), to be used as a wound dressing with hypertrophic scar reducing features. Emulgel dressings were prepared by dispersing positively charged submicron vesicles in carboxymethyl cellulose gel. Release kinetics of SFN/ASA and toxicity for primary skin cells were assessed in vitro. Antifibrogenic efficacy of medicated emulgel dressings was tested on a rabbit ear fibrotic model. Following topical application on the wounds, emulgels formed an occlusive film and controlled the release of SFN and ASA for 7 and 24 hours, respectively. Wounds treated with SFN/ASA-containing emulgel dressings showed an 80% reduction in scar elevation compared with untreated controls. Topical formulations were nontoxic for cultured human keratinocytes and fibroblasts. Inflammation was significantly controlled in treated wounds, as shown by a reduced number of infiltrated CD3(+) T cells (p < 0.001) and macrophages. SFN/ASA-treated wounds showed a significantly higher (p < 0.001) expression of matrix metalloproteinase-1, resulting in reduced collagen deposition and less scarring. Film-forming emulgel dressings that control the release of antifibrogenic and anti-inflammatory factors provide an excellent treatment option for postburn hypertrophic scar management.
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localized controlled release of Stratifin reduces implantation induced dermal fibrosis
Acta Biomaterialia, 2012Co-Authors: Elham Rahmanineishaboor, John K Jackson, Ryan Hartwell, Reza B Jalili, Erin Brown, Aziz GhaharyAbstract:Localized controlled release of anti-fibrogenic factors can potentially prevent tissue fibrosis surrounding biomedical prostheses, such as vascular stents and breast implants. We have previously demonstrated that therapeutic intervention with topically applied Stratifin in a rabbit ear fibrotic model not only prevents dermal fibrosis but also promotes more normal tissue repair by regulating extracellular matrix deposition. In this work, the anti-fibrogenic effect of a controlled release form of Stratifin was investigated in the prevention of fibrosis induced by dermal poly(lactic-co-glycolic acid) (PLGA) microsphere/poly(vinyl alcohol) (PVA) hydrogel implants. Pharmacodynamic effects were evaluated by histopathological examination of subcutaneous tissue surrounding implanted composites. Controlled release of Stratifin from PLGA microsphere/PVA hydrogel implants significantly moderated dermal fibrosis and inflammation by reducing collagen deposition (30%), total tissue cellularity (48%) and infiltrated CD3+ immune cells (81%) in the surrounding tissue compared with the Stratifin-free implants. The controlled release of Stratifin from implants markedly increased the level of matrix metalloproteinase-1 expression in the surrounding tissue, which resulted in less collagen deposition. These Stratifin-eluting PLGA/PVA composites show promise as coatings to decrease the typical fibrosis exhibited around implanted biomedical prostheses, such as breast implants and vascular stents.
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paracrine regulation of fibroblast aminopeptidase n cd13 expression by keratinocyte releasable Stratifin
Journal of Cellular Physiology, 2011Co-Authors: Amy Lai, Abdi Ghaffari, Aziz GhaharyAbstract:As wound healing proceeds into the tissue remodeling phase, cellular interactions become dominated by the interplay of keratinocytes with fibroblasts in the skin, which is largely mediated through paracrine signaling and greatly affects the molecular constitution of the extracellular matrix. We have recently identified aminopeptidase N (APN)/CD13 as a potential fibroblast receptor for 14-3-3 sigma (also known as Stratifin), a keratinocyte-releasable protein with potent matrix metalloproteinase 1 (MMP1) stimulatory activity. The present study demonstrates that the expression of APN on dermal fibroblasts is regulated through paracrine signaling by keratinocyte-derived soluble factors. By using an in vitro keratinocyte-fibroblast co-culture system, we showed that APN expression in dermal fibroblasts is induced in the presence of keratinocytes or in response to keratinocyte-conditioned medium. Conditioned medium collected from differentiated keratinocytes further increases APN protein production, suggesting an amplified stimulatory effect by keratinocyte differentiation. Recombinant Stratifin potently induces APN synthesis in a dose-dependent manner. A consistent correlation between the protein expression levels of APN and MMP1 was also observed. These results confirm paracrine regulation of APN expression in dermal fibroblasts by keratinocyte-derived stimuli, in particular Stratifin, and provide evidence that APN may serve as a target in the regulation of MMP1 expression in epidermal–mesenchymal communication. J. Cell. Physiol. 226: 3114–3120, 2011. © 2011 Wiley Periodicals, Inc.
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composite hydrogel formulations of Stratifin to control mmp 1 expression in dermal fibroblasts
Pharmaceutical Research, 2009Co-Authors: Elham Rahmanineishaboor, John K Jackson, Helen M Burt, Aziz GhaharyAbstract:Purpose Stratifin is a potent anti-fibrogenic factor that stimulates the expression of matrix metalloproteinase-1 (MMP-1) in dermal fibroblasts. The propose of this work was to develop a controlled release delivery system for Stratifin that can be applied at the time of wound closure to release Stratifin and stimulate the expression of MMP-1 in a sustained manner over the late stages of wound healing (after 3 days).
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primary human keratinocytes externalize Stratifin protein via exosomes
Journal of Cellular Biochemistry, 2008Co-Authors: Claudia Chavezmunoz, Ruhangiz T. Kilani, Jennifer Morse, Aziz GhaharyAbstract:Although, Stratifin (SFN) is externalized by keratinocytes and stimulates the expression of matrix metalloproteinase-1 (MMP-1) in fibroblasts, its mechanism of externalization is not known. Here, we hypothesize that keratinocytes have a capacity to release Stratifin through externalization of exosomes. To test this hypothesis, exosomes were purified from human keratinocyte conditioned medium (KCM) and analyzed for the presence of SFN by Western blot analysis using lysosomal-associated membrane protein 2 (LAMP-2) and heat shock cognate 70 (hsc70) as exosomal markers. The results showed the presence of SFN in keratinocyte lysate, concentrated KCM and exosomes, but not in concentrated unconditioned medium. Transmission electron microscopic examination revealed the presence of unique "saucer-like" structures characteristic of exosomes whose diameters were <100 nm. Similar to the recombinant SFN, the exosomes associated proteins stimulated MMP-1 expression in fibroblasts. Depletion of the exosomes markedly reduced this MMP-1 stimulatory effect. To further statistically confirm these findings, fibroblasts were treated with three different exosome preparations and the finding showed more than 7.4-fold increase in the level of MMP-1 in the treated cells. Furthermore, we found that approximately 1% of the total proteins contained in exosomes correspond to SFN. In conclusion, this study is the first report showing that keratinocytes have the capacity to produce exosomes through which some intracellular proteins such as SFN, with MMP-1 stimulating activity for fibroblasts, is externalized into keratinocyte microenvironment.
Masayuki Noguchi - One of the best experts on this subject based on the ideXlab platform.
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Stratifin regulates stabilization of receptor tyrosine kinases via interaction with ubiquitin-specific protease 8 in lung adenocarcinoma
Oncogene, 2018Co-Authors: Aya Shiba-ishii, Tomoki Nakagawa, Shun-ichiro Iemura, Tohru Natsume, Noriyuki Nakano, Ryota Matsuoka, Shingo Sakashita, Atsushi Kawaguchi, Yukio Sato, Masayuki NoguchiAbstract:Previously we have reported that Stratifin (SFN, 14-3-3 sigma) acts as a novel oncogene, accelerating the tumor initiation and progression of lung adenocarcinoma. Here, pull-down assay and LC-MS/MS analysis revealed that ubiquitin-specific protease 8 (USP8) specifically bound to SFN in lung adenocarcinoma cells. Both USP8 and SFN showed higher expression in human lung adenocarcinoma than in normal lung tissue, and USP8 expression was significantly correlated with SFN expression. Expression of SFN, but not of USP8, was associated with histological subtype, pathological stage, and poor prognosis. USP8 stabilizes receptor tyrosine kinases (RTKs) such as EGFR and MET by deubiquitination, contributing to the proliferative activity of many human cancers including non-small cell lung cancer. In vitro, USP8 binds to SFN and they co-localize at the early endosomes in lung adenocarcinoma cells. Moreover, USP8 or SFN knockdown leads to downregulation of tumor cellular proliferation and upregulation of apoptosis, p-EGFR or p-MET, which are related to the degradation pathway, and accumulation of ubiquitinated RTKs, leading to lysosomal degradation. Additionally, mutant USP8, which is unable to bind to SFN, reduces the expression of RTKs and p-STAT3. We also found that interaction with SFN is critical for USP8 to exert its autodeubiquitination function and avoid dephosphorylation by PP1. Our findings demonstrate that SFN enhances RTK stabilization through abnormal USP8 regulation in lung adenocarcinoma, suggesting that SFN could be a more suitable therapeutic target for lung adenocarcinoma than USP8.
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immunocytochemical staining for Stratifin and ociad2 in bronchial washing specimens increases sensitivity for diagnosis of lung cancer
Cytopathology, 2015Co-Authors: N Itoguchi, Tomoki Nakagawa, Yoshihiko Murata, A Shibaishii, Yuko Minami, Masayuki NoguchiAbstract:Objective Brushing or washing cytology taken at bronchoscopy is a standard diagnostic procedure for lung cancer. The present study evaluated the sensitivity of immunocytochemical diagnosis of lung cancer using bronchial washing materials. Methods We collected bronchial washing samples taken at bronchoscopy between July 2012 and July 2013 at Tsukuba University Hospital and studied 106 cases that were finally diagnosed as lung cancer. We collected exfoliated cells using a thin-layer advanced cytology assay system (TACAS™) and performed cytological diagnosis using Papanicolaou staining. As controls, we randomly selected 30 tumour-negative cases from among samples collected during the same period. Using these materials, we also examined the expression of Stratifin (14-3-3 sigma) (n = 92) and OCIAD2 ovarian immunoreactive antigen domain 2) (n = 106) by immunocytochemistry, as these are considered to be broad spectrum immune markers for lung adenocarcinoma including early invasive lung adenocarcinoma. Results Using Papanicolaou staining, 52 out of 106 lung cancers (49.1%) were diagnosed as positive. However, positivity was increased to 63.0% by immunocytochemistry using anti-Stratifin or anti-OCIAD2 antibodies. Biopsies were taken in 103/106 cases and cancer was diagnosed in 60/103, (58.3%). The sensitivity of Stratifin or OCIAD2 was significantly higher than that of Papanicolaou staining (P = 0.027), but immunocytochemistry detected false-positive cells in 3/30 cases (10%) for Stratifin and 2/30 cases (7%) for OCIAD2. Conclusion Immunocytochemical staining for Stratifin and OCIAD2 improved diagnostic sensitivity for lung cancers but diagnostic specificity was lower than that for cytology alone. The immunostains carried up to a 10% risk of a false-positive result and therefore positive staining must be confirmed by morphological evidence of malignancy.
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Stratifin accelerates progression of lung adenocarcinoma at an early stage
Molecular Cancer, 2015Co-Authors: Aya Shibaishii, Shingo Sakashita, Yunjung Kim, Toshihiro Shiozawa, Shinji Iyama, Kaishi Satomi, Junko Kano, Yukio Morishita, Masayuki NoguchiAbstract:Adenocarcinoma in situ (AIS) of the lung has an extremely favorable prognosis. However, early but invasive adenocarcinoma (eIA) sometimes has a fatal outcome. We had previously compared the expression profiles of AIS with those of eIA showing lymph node metastasis or a fatal outcome, and found that Stratifin (SFN, 14-3-3 sigma) was a differentially expressed gene related to cell proliferation. Here, we performed an in vivo study to clarify the role of SFN in initiation and progression of lung adenocarcinoma. Suppression of SFN expression in A549 (a human lung adenocarcinoma cell line) by siSFN significantly reduced cell proliferation activity and the S-phase subpopulation. In vivo, tumor development or metastasis to the lung was reduced in shSFN-transfected A549 cells. Moreover, we generated SFN-transgenic mice (Tg-SPC-SFN+/−) showing lung-specific expression of human SFN under the control of a tissue-specific enhancer, the SPC promoter. We found that Tg-SPC-SFN+/− mice developed lung tumors at a significantly higher rate than control mice after administration of chemical carcinogen, NNK. Interestingly, several Tg-SPC-SFN+/− mice developed tumors without NNK. These tumor cells showed high hSFN expression. These results suggest that SFN facilitates lung tumor development and progression. SFN appears to be a novel oncogene with potential as a therapeutic target.
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aberrant Stratifin overexpression is regulated by tumor associated cpg demethylation in lung adenocarcinoma
American Journal of Pathology, 2012Co-Authors: Aya Shibaishii, Masayuki NoguchiAbstract:We previously have shown the aberrant overexpression of Stratifin (SFN, 14-3-3 ς) in lung adenocarcinoma. Although SFN is known to facilitate tumor cell proliferation, the mechanism that underlies its aberrant expression has remained unclear. SFN, the downstream target of p53, often has been reported to be hypermethylated and subsequently silenced in certain cancers; however, its hypomethylation-linked reactivation has not yet been validated. In this study, we investigated the DNA methylation status of the SFN promoter region using 8 lung cancer cell lines and 32 specimens of adenocarcinoma tissue. Real-time methylation-specific PCR analysis showed that although both normal lung tissue and adenocarcinoma in situ bore a completely methylated SFN promoter, the promoter region in almost all invasive adenocarcinomas was at least partially methylated. The expression of SFN and its level of methylation were correlated strongly. Furthermore, statistical analysis revealed that the level of methylation became reduced with progression of the pathologic stage, although no clear relationship between methylation level and p53 abnormality was found. These results suggest that methylation-related silencing of SFN occurs in both normal lung tissues and adenocarcinoma in situ, and that demethylation of the SFN promoter participates in the aberrant expression of SFN in invasive adenocarcinoma cells, independently of p53 alteration. This novel finding might be informative for clarifying the mechanism that underlies the progression of early lung adenocarcinoma.
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high expression of Stratifin is a universal abnormality during the course of malignant progression of early stage lung adenocarcinoma
International Journal of Cancer, 2011Co-Authors: Aya Shibaishii, Yukio Sato, Yuko Minami, Junko Kano, Yukio Morishita, Masayuki NoguchiAbstract:Adenocarcinoma in situ (AIS) of the lung has an extremely favorable prognosis, with a 5-year survival rate of 100%. However, early invasive adenocarcinoma (EIA) often has a fatal outcome. In this study, we compared the expression profiles of AIS with those of EIA showing lymph node metastasis or a fatal outcome, and screened the differentially expressed genes by cDNA microarray. From the genes selected, we focused on Stratifin (SFN, 14-3-3 σ), which showed significantly higher expression in EIA than in AIS. Immunohistochemistry for SFN revealed that more than 95% of EIAs were immunopositive for SFN, in comparison to only 13% of AISs (p <0.05). Interestingly, positivity was detected not only in the invasive region but also in the in situ spreading component of EIA. Functionally, SFN facilitates the cell proliferation capacity of lung adenocarcinoma. These results indicate that SFN overexpression is a universal abnormality during the stepwise progression from in situ to invasive adenocarcinoma of the lung.
Murugesan Vanathi - One of the best experts on this subject based on the ideXlab platform.
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Stratifin in ocular surface squamous neoplasia and its association with p53
Acta Ophthalmologica, 2021Co-Authors: Sheetal Chauhan, Seema Sen, Shyam S Chauhan, Neelam Pushker, Radhika Tandon, Seema Kashyap, Murugesan Vanathi, Mandeep S BajajAbstract:Purpose Sunlight-induced p53 mutations are known to contribute towards increased risk of ocular surface squamous neoplasia (OSSN). Stratifin (14-3-3σ)/HEM (human epithelial marker) is a p53-mediated inhibitor of cell cycle progression and has been shown to be a target of epigenetic deregulation in various carcinomas. In the present study, Stratifin expression, its promoter methylation status as well as expression of mutant p53 in early and advanced AJCC stages (8th edition) of OSSN, was evaluated. Methods Sixty-four OSSN [20 conjunctival intraepithelial neoplasia (CIN) and 44 squamous cell carcinoma (SCC)] patients were registered for this study, and they were followed up for 36-58 months (mean 48 ± 3.6). Immunoexpression of Stratifin and mutant p53 protein, mRNA expression of Stratifin by reverse transcription polymerase chain reaction (PCR) and methylation status of Stratifin by methylation-specific PCR, was undertaken. Results Hypermethylation of Stratifin promoter in 63% (40/64), loss of Stratifin expression in 75% (48/64) and downregulation of Stratifin mRNA in 61% (39/64) were observed. Stratifin hypermethylation was significantly associated with reduced disease-free survival in both early and advanced T stage SCC cases. Expression of mutant p53 expression was seen in 48% (31/64) OSSN cases. Of the 31 patients with mutant p53 expression, 87% (27/31) also demonstrated loss of Stratifin immunoexpression. A significant association was seen between mutant p53 expression and Stratifin loss (p = 0.01) in advanced T stage SCC cases. Conclusions Hypermethylation of Stratifin gene and its reduced mRNA expression both are potential biomarkers for identifying high-risk OSSN patients. Aberrant methylation of Stratifin and simultaneous mutant p53 expression implicates involvement of p53-Stratifin mediated signalling pathway in the pathogenesis of OSSN.
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abstract a03 epigenetic alterations of Stratifin in ocular surface squamous neoplasia pathogenesis and prognosis
Cancer Research, 2013Co-Authors: Sheetal Chauhan, Seema Sen, Shyam S Chauhan, Neelam Pushker, Radhika Tandon, Seema Kashyap, Anjana Sharma, Murugesan VanathiAbstract:Purpose: Ocular Surface Squamous neoplasia (OSSN) is the most common tumor of conjunctival epithelium associated with risk of permanent visual impairment. It includes conjunctival intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC).Of the multifactorial etiopathogenesis of OSSN, ultraviolet irradiation has been reported as a major risk factor in the pathogenesis of OSSN. Sunlight induced p53 mutations are known to contribute towards increased risk of OSSN. Stratifin (14-3-3σ)/HEM (human epithelial marker) is a p53 mediated inhibitor of cell cycle progression and has been shown to be a target of epigenetic deregulation in various carcinomas. In the present study, Stratifin expression, its promoter methylation status and expression of mutant p53 in OSSN was studied. The significance of Stratifin and p53 in the pathogenesis and prognosis of ocular surface squamous neoplasia (OSSN) patients was also evaluated. Methods: Sixty-four histopathologically confirmed OSSN cases (44 SCC and 20 CIN) were included in this study. AJCC TNM staging was performed and patients were followed up for 32 months. Immunohistochemical expression of Stratifin (clone-ab14123) and mutant p53 (clone-DO7) protein was evaluated; methylation status of Stratifin was determined by methylation specific PCR using specific primers. Kaplan–Meier survival and Cox regression analysis was done to assess the prognostic significance of Stratifin and p53. Results: Loss of Stratifin immunoexpression was observed in 75% (48/64) and 48% (31/64) cases showed mutant p53 expression. Hypermethylation of Stratifin promoter was seen in 63% (40/64) OSSN cases. Of the 48 cases with loss of Stratifin expression, promoter hypermethylation was seen in 35% (17/48), mutant p53 expression in 10% (5/48) and both promoter hypermethylation and mutant p53 expression in 58% (23/48) cases. These results indicate that both hypermethylation of Stratifin and mutant p53 expression are associated with loss of Stratifin in OSSN cases. On statistical analysis, Stratifin loss was significantly associated with tumor size >2cm, T3 and T4 category, poor histopathological differentiation of SCC and reduced disease free survival (P 0.05). Cox analysis showed Stratifin to be an independent prognostic marker for OSSN (p =0.03) patients. Mutant p53 expression was associated with history of longer sunlight exposure in 56% cases. No significant correlation was observed between mutant p53 expression and other clinicopathological feature or clinical outcome. Conclusions: Our results indicate that loss of Stratifin is a key event in the pathogenesis of OSSN. Presence of both aberrant methylation of Stratifin and mutant p53 expression implicates involvement of p53-Stratifin mediated signalling pathway in the pathogenesis of OSSN. Stratifin loss may also prove to be a useful biomarker for identifying high risk OSSN patients. Citation Format: Sheetal Chauhan, Seema Sen, Anjana Sharma, Shyam S. Chauhan, Seema Kashyap, Radhika Tandon, Neelam Pushker, M Vanathi. Epigenetic alterations of Stratifin in ocular surface squamous neoplasia: Pathogenesis and prognosis. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A03.
Sheetal Chauhan - One of the best experts on this subject based on the ideXlab platform.
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Stratifin in ocular surface squamous neoplasia and its association with p53
Acta Ophthalmologica, 2021Co-Authors: Sheetal Chauhan, Seema Sen, Shyam S Chauhan, Neelam Pushker, Radhika Tandon, Seema Kashyap, Murugesan Vanathi, Mandeep S BajajAbstract:Purpose Sunlight-induced p53 mutations are known to contribute towards increased risk of ocular surface squamous neoplasia (OSSN). Stratifin (14-3-3σ)/HEM (human epithelial marker) is a p53-mediated inhibitor of cell cycle progression and has been shown to be a target of epigenetic deregulation in various carcinomas. In the present study, Stratifin expression, its promoter methylation status as well as expression of mutant p53 in early and advanced AJCC stages (8th edition) of OSSN, was evaluated. Methods Sixty-four OSSN [20 conjunctival intraepithelial neoplasia (CIN) and 44 squamous cell carcinoma (SCC)] patients were registered for this study, and they were followed up for 36-58 months (mean 48 ± 3.6). Immunoexpression of Stratifin and mutant p53 protein, mRNA expression of Stratifin by reverse transcription polymerase chain reaction (PCR) and methylation status of Stratifin by methylation-specific PCR, was undertaken. Results Hypermethylation of Stratifin promoter in 63% (40/64), loss of Stratifin expression in 75% (48/64) and downregulation of Stratifin mRNA in 61% (39/64) were observed. Stratifin hypermethylation was significantly associated with reduced disease-free survival in both early and advanced T stage SCC cases. Expression of mutant p53 expression was seen in 48% (31/64) OSSN cases. Of the 31 patients with mutant p53 expression, 87% (27/31) also demonstrated loss of Stratifin immunoexpression. A significant association was seen between mutant p53 expression and Stratifin loss (p = 0.01) in advanced T stage SCC cases. Conclusions Hypermethylation of Stratifin gene and its reduced mRNA expression both are potential biomarkers for identifying high-risk OSSN patients. Aberrant methylation of Stratifin and simultaneous mutant p53 expression implicates involvement of p53-Stratifin mediated signalling pathway in the pathogenesis of OSSN.
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abstract a03 epigenetic alterations of Stratifin in ocular surface squamous neoplasia pathogenesis and prognosis
Cancer Research, 2013Co-Authors: Sheetal Chauhan, Seema Sen, Shyam S Chauhan, Neelam Pushker, Radhika Tandon, Seema Kashyap, Anjana Sharma, Murugesan VanathiAbstract:Purpose: Ocular Surface Squamous neoplasia (OSSN) is the most common tumor of conjunctival epithelium associated with risk of permanent visual impairment. It includes conjunctival intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC).Of the multifactorial etiopathogenesis of OSSN, ultraviolet irradiation has been reported as a major risk factor in the pathogenesis of OSSN. Sunlight induced p53 mutations are known to contribute towards increased risk of OSSN. Stratifin (14-3-3σ)/HEM (human epithelial marker) is a p53 mediated inhibitor of cell cycle progression and has been shown to be a target of epigenetic deregulation in various carcinomas. In the present study, Stratifin expression, its promoter methylation status and expression of mutant p53 in OSSN was studied. The significance of Stratifin and p53 in the pathogenesis and prognosis of ocular surface squamous neoplasia (OSSN) patients was also evaluated. Methods: Sixty-four histopathologically confirmed OSSN cases (44 SCC and 20 CIN) were included in this study. AJCC TNM staging was performed and patients were followed up for 32 months. Immunohistochemical expression of Stratifin (clone-ab14123) and mutant p53 (clone-DO7) protein was evaluated; methylation status of Stratifin was determined by methylation specific PCR using specific primers. Kaplan–Meier survival and Cox regression analysis was done to assess the prognostic significance of Stratifin and p53. Results: Loss of Stratifin immunoexpression was observed in 75% (48/64) and 48% (31/64) cases showed mutant p53 expression. Hypermethylation of Stratifin promoter was seen in 63% (40/64) OSSN cases. Of the 48 cases with loss of Stratifin expression, promoter hypermethylation was seen in 35% (17/48), mutant p53 expression in 10% (5/48) and both promoter hypermethylation and mutant p53 expression in 58% (23/48) cases. These results indicate that both hypermethylation of Stratifin and mutant p53 expression are associated with loss of Stratifin in OSSN cases. On statistical analysis, Stratifin loss was significantly associated with tumor size >2cm, T3 and T4 category, poor histopathological differentiation of SCC and reduced disease free survival (P 0.05). Cox analysis showed Stratifin to be an independent prognostic marker for OSSN (p =0.03) patients. Mutant p53 expression was associated with history of longer sunlight exposure in 56% cases. No significant correlation was observed between mutant p53 expression and other clinicopathological feature or clinical outcome. Conclusions: Our results indicate that loss of Stratifin is a key event in the pathogenesis of OSSN. Presence of both aberrant methylation of Stratifin and mutant p53 expression implicates involvement of p53-Stratifin mediated signalling pathway in the pathogenesis of OSSN. Stratifin loss may also prove to be a useful biomarker for identifying high risk OSSN patients. Citation Format: Sheetal Chauhan, Seema Sen, Anjana Sharma, Shyam S. Chauhan, Seema Kashyap, Radhika Tandon, Neelam Pushker, M Vanathi. Epigenetic alterations of Stratifin in ocular surface squamous neoplasia: Pathogenesis and prognosis. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A03.
Luciano Serpa Hammes - One of the best experts on this subject based on the ideXlab platform.
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up regulation of 14 3 3σ Stratifin is associated with high grade cin and high risk human papillomavirus hpv at baseline but does not predict outcomes of hr hpv infections or incident cin in the lams study
American Journal of Clinical Pathology, 2010Co-Authors: Stina Syrjanen, Paulo Naud, Luis Otavio Sarian, Sophie Francoise Mauricette Derchain, Cecilia Rotelimartins, Adhernar Longattofilho, Silvio Tatti, Margerita Branca, Mojca Eržen, Luciano Serpa HammesAbstract:To assess whether the potentially high-risk (HR) human papillomavirus (HPV)-related up-regulation of 14-3-3σ (Stratifin) has implications in the outcome of HPV infections or cervical intraepithelial neoplasia (CIN) lesions, cervical biopsy specimens from 225 women in the Latin American Screening Study were analyzed for 14-3-3σ expression using immunohistochemical analysis. We assessed its associations with CIN grade and HR HPV at baseline and value in predicting outcomes of HR-HPV infections and the development of incident CIN 1+ and CIN 2+. Expression of 14-3-3σ increased in parallel with the lesion grade. Up-regulation was also significantly related to HR-HPV detection (P = .004; odds ratio, 2.71; 95% confidence interval, 1.37-5.35) and showed a linear relationship to HR-HPV loads (P = .003). 14-3-3σ expression was of no value in predicting the outcomes (incident, persistent, clearance) of HR-HPV infections or incident CIN 1+ and CIN 2+. 14-3-3σ is not inactivated in cervical carcinoma and CIN but is up-regulated on transition from CIN 2 to CIN 3. Its normal functions in controlling G 1 /S and G 2 /M checkpoints are being bypassed by HR HPV.