Adam S Johnson1, Oluwole Fadare2. 1. Department of Pathology, Vanderbilt University Medical Center Nashville, TN, USA. 2. Department of Pathology, University of California San Diego San Diego, CA, USA.
Abstract
BACKGROUND: The balance of pro- and anti-apoptotic proteins plays a critical role in the regulation of cell death, and a disruption of this delicate balance may eventuate in carcinogenesis through a net reduction in apoptosis. Numerous chemotherapeutic strategies directly or indirectly target apoptotic pathways. However, a thorough assessment of apoptosis-related proteins has not previously been performed in endometrial clear cell carcinoma (CCC). This study aims to determine the significance of 9 apoptosis-related proteins in the pathogenesis of CCC as compared to non-neoplastic endometrium (NNE), low- and high-grade endometrial endometrioid carcinomas (LG-EEC, HG-EEC), and endometrial serous carcinoma (ESC). MATERIALS AND METHODS: Expression of 6 anti-apoptotic proteins (Bcl-2, Bcl-xL, cFLIPL, MCL-1, survivin, NFκB/p65) and three pro-apoptotic proteins (Bax, caspase-3, caspase-8) was assessed by immunohistochemistry on 49 CCC, 37 LG-EEC, 12 HG-ECC, 16 ESC, and 25 NNE in a tissue microarray. Objective IHC scores were assigned by an automated image capture system. Scores were then correlated with clinicopathologic values and each other. RESULTS: Most notably, CCC showed significantly reduced expression of cFLIPL relative to ESC, LG-EEC, HG-EEC, and NNE. CCC also showed significantly reduced expression of both Caspase 8 and NF-κB/p65 relative to ESC, HG-EEC, and NNE, but not LG-EEC. Bcl-2 and Bcl-xL showed reduced expression in CCC relative to all groups except ESC for Bcl-2 and NNE for Bcl-xL. There was no significant correlation between the proteins regarding expression levels. Within the CCC group, none of the proteins showed any significant association with patient age, myometrial invasion, final stage, lymphovascular invasion, disease-free or overall survival. CONCLUSION: Our analysis of the expression and correlation patterns of a panel of apoptosis-related proteins suggests that the downregulation of cFLIPL in CCC is significant relative to almost all other tissues, NNE, HG-EEC, and ESC. Other proteins, including Caspase 8, NF-κB/p65, Bcl-2 and Bcl-xL may also be significant. The regulation of apoptosis-related proteins in CCC may be important and may provide insight into chemoresistance in this enigmatic histotype. However, the paradoxical downregulation of both pro- and anti-apoptotic mediators suggests that additional study is needed to clarify the role of apoptotic mechanisms in CCC. IJCEP
BACKGROUND: The balance of pro- and anti-apoptotic proteins plays a critical role in the regulation of cell death, and a disruption of this delicate balance may eventuate in carcinogenesis through a net reduction in apoptosis. Numerous chemotherapeutic strategies directly or indirectly target apoptotic pathways. However, a thorough assessment of apoptosis-related proteins has not previously been performed in endometrial clear cell carcinoma (CCC). This study aims to determine the significance of 9 apoptosis-related proteins in the pathogenesis of CCC as compared to non-neoplastic endometrium (NNE), low- and high-grade endometrial endometrioid carcinomas (LG-EEC, HG-EEC), and endometrial serous carcinoma (ESC). MATERIALS AND METHODS: Expression of 6 anti-apoptotic proteins (Bcl-2, Bcl-xL, cFLIPL, MCL-1, survivin, NFκB/p65) and three pro-apoptotic proteins (Bax, caspase-3, caspase-8) was assessed by immunohistochemistry on 49 CCC, 37 LG-EEC, 12 HG-ECC, 16 ESC, and 25 NNE in a tissue microarray. Objective IHC scores were assigned by an automated image capture system. Scores were then correlated with clinicopathologic values and each other. RESULTS: Most notably, CCC showed significantly reduced expression of cFLIPL relative to ESC, LG-EEC, HG-EEC, and NNE. CCC also showed significantly reduced expression of both Caspase 8 and NF-κB/p65 relative to ESC, HG-EEC, and NNE, but not LG-EEC. Bcl-2 and Bcl-xL showed reduced expression in CCC relative to all groups except ESC for Bcl-2 and NNE for Bcl-xL. There was no significant correlation between the proteins regarding expression levels. Within the CCC group, none of the proteins showed any significant association with patient age, myometrial invasion, final stage, lymphovascular invasion, disease-free or overall survival. CONCLUSION: Our analysis of the expression and correlation patterns of a panel of apoptosis-related proteins suggests that the downregulation of cFLIPL in CCC is significant relative to almost all other tissues, NNE, HG-EEC, and ESC. Other proteins, including Caspase 8, NF-κB/p65, Bcl-2 and Bcl-xL may also be significant. The regulation of apoptosis-related proteins in CCC may be important and may provide insight into chemoresistance in this enigmatic histotype. However, the paradoxical downregulation of both pro- and anti-apoptotic mediators suggests that additional study is needed to clarify the role of apoptotic mechanisms in CCC. IJCEP
Authors: Oluwole Fadare; Vinita Parkash; Katja Gwin; Krisztina Z Hanley; Elke A Jarboe; Sharon X Liang; Charles M Quick; Wenxin Zheng; Kojo R Rawish; Jonathan L Hecht; Mohamed M Desouki Journal: Hum Pathol Date: 2013-10-10 Impact factor: 3.466
Authors: Caterina Ierano; Arup R Chakraborty; Alina Nicolae; Julian C Bahr; Zhirong Zhan; Stefania Pittaluga; Susan E Bates; Robert W Robey Journal: Cell Cycle Date: 2013-08-07 Impact factor: 4.534