Prognostic role of BiP/GRP78 expression as ER stress in patients with gastric adenocarcinoma

Article type: Research Article

Authors: Ogawa, Hiroomi^a | Kaira, Kyoichi^{b; *} | Takahashi, Kengo^a | Shimizu, Akira^c | Altan, Bolag^b | Yoshinari, Daisuke^a | Asao, Takayuki^a | Oyama, Tetsunari^d

Affiliations: [a] Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan | [b] Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan | [c] Department of Dermatology, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan | [d] Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan

Correspondence: [*] Corresponding author: Kyoichi Kaira, Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma 371-8511, Japan. Tel.: +81 27 220 8136; Fax: +81 27 220 8136; E-mail: [email protected].

Abstract: PURPOSE: The glucose-regulated protein 78 (GRP78), also referred to as immunoglobulin heavy chain binding protein (BiP) (BiP/GRP78), is a major molecular chaperone in the endoplasmic reticulum (ER) and is extensively expressed in human neoplasms. Although the enhanced expression of BiP/GRP78 has been described to be associated with poor prognosis in gastric cancer (GC), details regarding its prognostic significance remain unclear. The aim of this study was to elucidate the prognostic role of BiP/GRP78 in patients with GC. METHODS: Study subjects included 328 patients who underwent surgical resection. Tumor specimens of primary tumors underwent immunohistochemical staining for BiP/GRP78. RESULTS: BiP/GRP78 was highly expressed in 57% (188/328) of patients. High expression of BiP/GRP78 was significantly associated with older age, male, disease staging, T factor, lymph node metastases, differentiation, lymphatic permeation, and vascular invasion. According to univariate analysis, age, disease staging, T factor, N factor, lymphatic permeation, vascular invasion, and BiP/GRP78 expression were significant prognostic factors for OS. In particular, high BiP/GRP78 expression was proven to be a significant predictor of prognosis in patients with older age, female sex, early disease stage, T1-2 factor, well or moderately differentiated tumors, and negative vascular invasion. CONCLUSION: BiP/GRP78 is significantly associated with tumor aggressiveness and progression. The increased expression of BiP/GRP78 was identified as an independent factor for predicting poor OS in patients with early stage of disease, especially T1-2 factor.

Keywords: ER stress, BiP, GRP78, Gastric Cancer, prognosis, immunohistochemistry

DOI: 10.3233/CBM-170062

Journal: Cancer Biomarkers, vol. 20, no. 3, pp. 273-281, 2017