title: Expression of GRP78 predicts taxane-based therapeutic resistance and recurrence of human gastric cancer.
abstract: Cancer cells adapt to chronic stress in the tumor microenvironment by inducing the expression of glucose-regulated protein 78 (GRP78), a major endoplasmic reticulum chaperone with Ca(2+)-binding and antiapoptotic properties. The effect in and potential role of its expression in progression of and prognosis for gastric cancer (GC) are unclear. In the present study, we investigated the clinical value of GRP78 expression in judgment of the severity of and prognosis for GC in a retrospective cohort study of 160 patients who underwent D2 radical gastrectomy and adjuvant chemotherapy. GRP78 expression was detected using immunohistochemistry. The relationships of GRP78 expression with age, sex, differentiation, invasion depth, disease stage, lymph node metastasis, and time to recurrence (TTR) were analyzed. The GRP78 expression was higher in tumors from patients with deep tumor infiltration, with poor differentiation, at late disease stages, and with lymph node metastasis than that in tumors from patients without. Also, GRP78 positivity was associated with short TTR (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.07-4.85; P=0.041). Subgroup analysis revealed that the HR in the GRP78-high group increased significantly in patients who did not receive taxane-containing regimens (HR, 2.21; 95% CI, 1.23-7.36; P=0.038). In contrast, in the patients who received taxane-based chemotherapy, the association between GRP78 positivity and increased risk of recurrence was not statistically significant (HR, 1.16; 95% CI, 0.81-2.98; P=0.111). In the patients with GRP78 expression, those who underwent taxane-containing chemotherapy had longer median TTRs than did those who did not undergo this treatment (P=0.017). Downregulation of GRP78 expression markedly inhibited proliferation of the GC cells at the G1 phase, whereas GRP78 overexpression promoted cell-cycle progression. These findings suggest that GRP78 overexpression promotes GC cells proliferation and is an independent indicator of poor prognosis for GC.
authors.affiliation: Department of Oncology and Tumor Institute, Shanghai East Hospital Affiliated to Tongji University School of Medicine, Shanghai 200120, People's Republic of China; Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Jiangsu, Nantong 226361, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pathology, Nantong University Affiliated Tumor Hospital, Jiangsu, Nantong 226001, People's Republic of China.
authors.forename: Shuyun
authors.initials: S
authors.lastname: Yang
authors.affiliation: Biological Center, Nantong University Affiliated Tumor Hospital, Jiangsu, Nantong 226001, People's Republic of China.
authors.forename: Jibin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Nantong University Affiliated Tumor Hospital, Jiangsu, Nantong 226361, People's Republic of China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Jiangsu, Nantong 226361, People's Republic of China.
authors.forename: Jianmei
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Jiangsu, Nantong 226361, People's Republic of China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Cao
authors.affiliation: The Department of Endocrinology, Tongji University School of Medicine, Shanghai Tenth People's Hospital, Shanghai 200072, People's Republic of China.
authors.forename: Kun
authors.initials: K
authors.lastname: Lu
authors.affiliation: Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Jiangsu, Nantong 226361, People's Republic of China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Oncology and Tumor Institute, Shanghai East Hospital Affiliated to Tongji University School of Medicine, Shanghai 200120, People's Republic of China. Electronic address: yonggao.53@gmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor; D001952:Bridged-Ring Compounds / Q000008:administration & dosage*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage*
chemical_list: D014408:Biomarkers, Tumor; D001952:Bridged-Ring Compounds; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D043823:Taxoids; C080625:taxane
keywords: Gastric cancer; Glucose-regulated protein 78; Prognosis; Proliferation