Mithalesh Kumar Singh1, Lata Singh2, Kunzang Chosdol3, Neelam Pushker4,5, Neeru Saini4,5, Rachna Meel4,5, Sameer Bakhshi6, Seema Sen1, Seema Kashyap7. 1. Department of Ocular Pathology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. 2. Department of Biosciences, JMI, New Delhi, India. 3. Department of Biochemistry, AIIMS, New Delhi, India. 4. Department of Ophthalmology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. 5. Functional Genomics Unit, Institute of Genomics and Integrative Biology, New Delhi, India. 6. Department of Medical Oncology, IRCH, AIIMS, New Delhi, India. 7. Department of Ocular Pathology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. dr_skashyap@hotmail.com.
Abstract
PURPOSE: Non-canonical NFκB (NC-NFκB) pathway plays an influential role in metastasis, which promotes cancer proliferation and progression. The aim of the study was to examine the expression of NC-NFκB proteins and their correlation with clinicopathological factors associated with metastatic cases of uveal melanoma (UM) and with the patient outcome. METHOD: Expression of NC-NFκB proteins (p52, RelB, and co-expression of p52/RelB) was evaluated in 75 formalin-fixed cases of uveal melanoma by immunohistochemistry. Validation of nuclear immunoreactivity was done by western blotting. Transcriptional status of NC-NFκB genes was assessed in 60 fresh tumor tissues by quantitative real-time PCR. Co-immunoprecipitation was performed to determine the presence of native p52/RelB heterodimer in UM. Prognostic relevance was determined using Cox proportional hazard and Kaplan-Meier methods. RESULTS: Immunohistochemical expression of p52, RelB, and their co-expression was observed in 81%, 68.7%, 56.2% of metastatic cases, respectively, while their expression was seen only in 38%, 33% and 30% of non-metastatic cases. Loss of BAP-1 was correlated with expression of p52 and RelB proteins. Co-immunoprecipitation assay confirmed the putative interaction of p52 with RelB protein in metastatic cases of uveal melanoma. Co-expression of p52/RelB and expression of p52 protein was significantly correlated with decreased metastasis-free survival (MFS) (p = 0.004; p = 0.002) and overall survival (OS) (p = 0.004; p = 0.032), while the RelB expression only correlated with reduced MFS (p = 0.003). CONCLUSION: Our data showed that non-canonical NFκB proteins were significantly higher in metastatic cases and associated with poor outcome of the patients. Furthermore, the p52 protein could be used as a potential therapeutic biomarker for metastatic cases in uveal melanoma.
PURPOSE: Non-canonical NFκB (NC-NFκB) pathway plays an influential role in metastasis, which promotes cancer proliferation and progression. The aim of the study was to examine the expression of NC-NFκB proteins and their correlation with clinicopathological factors associated with metastatic cases of uveal melanoma (UM) and with the patient outcome. METHOD: Expression of NC-NFκB proteins (p52, RelB, and co-expression of p52/RelB) was evaluated in 75 formalin-fixed cases of uveal melanoma by immunohistochemistry. Validation of nuclear immunoreactivity was done by western blotting. Transcriptional status of NC-NFκB genes was assessed in 60 fresh tumor tissues by quantitative real-time PCR. Co-immunoprecipitation was performed to determine the presence of native p52/RelB heterodimer in UM. Prognostic relevance was determined using Cox proportional hazard and Kaplan-Meier methods. RESULTS: Immunohistochemical expression of p52, RelB, and their co-expression was observed in 81%, 68.7%, 56.2% of metastatic cases, respectively, while their expression was seen only in 38%, 33% and 30% of non-metastatic cases. Loss of BAP-1 was correlated with expression of p52 and RelB proteins. Co-immunoprecipitation assay confirmed the putative interaction of p52 with RelB protein in metastatic cases of uveal melanoma. Co-expression of p52/RelB and expression of p52 protein was significantly correlated with decreased metastasis-free survival (MFS) (p = 0.004; p = 0.002) and overall survival (OS) (p = 0.004; p = 0.032), while the RelB expression only correlated with reduced MFS (p = 0.003). CONCLUSION: Our data showed that non-canonical NFκB proteins were significantly higher in metastatic cases and associated with poor outcome of the patients. Furthermore, the p52 protein could be used as a potential therapeutic biomarker for metastatic cases in uveal melanoma.
Authors: Brandon T Nguyen; Ryan S Kim; Maria E Bretana; Eric Kegley; Amy C Schefler Journal: Graefes Arch Clin Exp Ophthalmol Date: 2017-11-28 Impact factor: 3.117
Authors: Anna E Koopmans; Robert M Verdijk; Rutger W W Brouwer; Thierry P P van den Bosch; Mike M P van den Berg; Jolanda Vaarwater; Christel E M Kockx; Dion Paridaens; Nicole C Naus; Mark Nellist; Wilfred F J van IJcken; Emine Kiliç; Annelies de Klein Journal: Mod Pathol Date: 2014-03-14 Impact factor: 7.842
Authors: Lance D Miller; Johanna Smeds; Joshy George; Vinsensius B Vega; Liza Vergara; Alexander Ploner; Yudi Pawitan; Per Hall; Sigrid Klaar; Edison T Liu; Jonas Bergh Journal: Proc Natl Acad Sci U S A Date: 2005-09-02 Impact factor: 11.205
Authors: Gülçin Gezgin; Mehmet Dogrusöz; T Huibertus van Essen; Wilhelmina G M Kroes; Gregorius P M Luyten; Pieter A van der Velden; Vonn Walter; Robert M Verdijk; Thorbald van Hall; Sjoerd H van der Burg; Martine J Jager Journal: Cancer Immunol Immunother Date: 2017-04-08 Impact factor: 6.968