Dohee Kwon1, Jaemoon Koh2, Sehui Kim1, Heounjeong Go3, Hye Sook Min4, Young A Kim5, Deog Kyeom Kim6, Yoon Kyung Jeon7, Doo Hyun Chung8. 1. Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. 2. Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. 3. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea. 4. Graduate School of Public Health, Seoul National University, Seoul, 08826, Republic of Korea. 5. Department of Pathology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, 07061, Republic of Korea. 6. Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, 07061, Republic of Korea. 7. Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea; Seoul National University Cancer Research Institute, Seoul, 03080, Republic of Korea. Electronic address: ykjeon@snu.ac.kr. 8. Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. Electronic address: doohyun@snu.ac.kr.
Abstract
OBJECTIVES: Endoplasmic reticulum (ER) stress is associated with tumor development and progression via pro-tumorigenic and anti-tumorigenic effects. However, the clinicopathological implications of the ER stress pathway in non-small cell lung cancer remain unclear. Therefore, we sought to address these issues in this study. MATERIALS AND METHODS: Expression of two ER stress-related proteins, GRP78 and XBP1 spliced-form (XBP1s), was evaluated in pulmonary adenocarcinoma (pADC; n = 369) and squamous cell carcinoma (pSqCC; n = 246) using immunohistochemistry. RESULTS: Expression levels of GRP78 and XBP1s were significantly higher in pADCs and pSqCCs, respectively (both, P < 0.0001). In the pADC group, XBP1s expression was higher in patients with ALK translocation than in those with wild-type ALK, wild-type EGFR, or EGFR mutation (P < 0.005). No significant difference in GRP78 expression according to ALK or EGFR status was noted. pADC harboring high GRP78 expression exhibited an increased XBP1s expression (P = 0.0067). Higher XBP1s expression was associated with shorter disease-free survival (DFS) in patients with pADC (P = 0.026) and in those with ALK translocation (P = 0.001). Higher GRP78 expression was associated with shorter DFS in patients with pADC (P = 0.029) and those with EGFR mutation (P = 0.005). Multivariate survival analysis revealed that high XBP1s expression was an independent predictor of poor DFS in pADC (P = 0.004, hazard ratio [HR] = 3.115), and that high GRP78 expression was an independent predictor of poor DFS in EGFR-mutated pADC (P = 0.007, HR = 2.168). Taken together, high expression of XBP1s or GRP78 was an independent poor prognostic factor in pADC (P = 0.002, HR = 2.403). CONCLUSION: GRP78 and XBP1s are expressed variably in pADC, but their overexpression is associated with poor patient prognosis. The ER stress pathway may be a prognostic biomarker and potential therapeutic target for pADC.
OBJECTIVES: Endoplasmic reticulum (ER) stress is associated with tumor development and progression via pro-tumorigenic and anti-tumorigenic effects. However, the clinicopathological implications of the ER stress pathway in non-small cell lung cancer remain unclear. Therefore, we sought to address these issues in this study. MATERIALS AND METHODS: Expression of two ER stress-related proteins, GRP78 and XBP1 spliced-form (XBP1s), was evaluated in pulmonary adenocarcinoma (pADC; n = 369) and squamous cell carcinoma (pSqCC; n = 246) using immunohistochemistry. RESULTS: Expression levels of GRP78 and XBP1s were significantly higher in pADCs and pSqCCs, respectively (both, P < 0.0001). In the pADC group, XBP1s expression was higher in patients with ALK translocation than in those with wild-type ALK, wild-type EGFR, or EGFR mutation (P < 0.005). No significant difference in GRP78 expression according to ALK or EGFR status was noted. pADC harboring high GRP78 expression exhibited an increased XBP1s expression (P = 0.0067). Higher XBP1s expression was associated with shorter disease-free survival (DFS) in patients with pADC (P = 0.026) and in those with ALK translocation (P = 0.001). Higher GRP78 expression was associated with shorter DFS in patients with pADC (P = 0.029) and those with EGFR mutation (P = 0.005). Multivariate survival analysis revealed that high XBP1s expression was an independent predictor of poor DFS in pADC (P = 0.004, hazard ratio [HR] = 3.115), and that high GRP78 expression was an independent predictor of poor DFS in EGFR-mutated pADC (P = 0.007, HR = 2.168). Taken together, high expression of XBP1s or GRP78 was an independent poor prognostic factor in pADC (P = 0.002, HR = 2.403). CONCLUSION:GRP78 and XBP1s are expressed variably in pADC, but their overexpression is associated with poor patient prognosis. The ER stress pathway may be a prognostic biomarker and potential therapeutic target for pADC.
Authors: Sumedh S Shah; Gregor A Rodriguez; Alexis Musick; Winston M Walters; Nicolas de Cordoba; Eric Barbarite; Megan M Marlow; Brian Marples; Jeffrey S Prince; Ricardo J Komotar; Steven Vanni; Regina M Graham Journal: Cancers (Basel) Date: 2019-01-31 Impact factor: 6.639