Increased expression of mitogen-activated protein kinase and its upstream regulating signal in human gastric cancer

AIM: To investigate the expression of mitogen-activated protein kinases (MAPKs) and its upstream protein kinase in human gastric cancer and to evaluate the relationship between protein levels and clinicopathological parameters.METHODS: Westem blot was used to measure the expression of extracellular signal-regulated kinase (ERK)-1, ERK-2, ERK-3,p38 and mitogen or ERK activated protein kinaseMEK-1proteins in surgically resected gastric carcinoma, adjacent normal mucosa and metastatic lymph nodes from 42 patients.Immunohistochemistry was employed for their localization.RESULTS: Compared with normal tissues, the protein levels of ERK-1 (integral optical density value 159 526±65 760 vs122 807±65 515, P = 0.001), ERK-2 (168 471±95 051 vs120 469±72 874, P＜0.001), ERK-3 (118 651±71 513 vs70 934±68 058, P＜0.001), P38 (104 776±51 650 vs82 930±40 392, P= 0.048) and MEK-1(116 486±45 725 vs101 434±49 387, P = 0.027) were increased in gastric cancer tissues. Overexpression of ERK-3 was correlated to TNM staging [average ratio of integral optic density (IOD)tumor:IODnormal in TNM Ⅰ, Ⅱ, Ⅲ, Ⅳ tumors was 1.43±0.34,5.08±3.74, 4.99±1.08, 1.44±1.02, n = 42, P = 0.023] and serosa invasion (4.31±4.34 vs 2.00±2.03, P = 0.037). In poorly differentiated cancers (n = 33), the protein levels of ERK-1 and ERK-2 in stage Ⅲ and Ⅳ tumors were higher than those in stage Ⅰ and Ⅱ tumors (2.64±3.01 vs 1.01±0.33,P = 0.022; 2.05±1.54 vs 1.24±0.40, P = 0.030). Gastric cancer tissues with either lymph node involvement (2.49±2.91vs 1.03±0.36, P= 0.023; 1.98±1.49 vs 1.24±0.44, P= 0.036)or serosa invasion (2.39±2.82 vs 1.01±0.35, P = 0.022;1.95±1.44 vs 1.14±0.36, P = 0.015) expressed higher protein levels of ERK-1 and ERK-2. In Borrmann Ⅱ tumors,expression of ERK-2 and ERK-3 was increased compared with Borrmann Ⅲ tumors (2.57±1.86 vs 1.23±0.60, P = 0.022;5.50±5.05 vs 1.83±1.21, P = 0.014). Borrmann Ⅳ tumors expressed higher p38 protein levels. No statistically significant difference in expression of MAPKs was found when stratified to tumor size or histological grade (P＞0.05).Protein levels of ERK-2, ERK-3 and MEK-1 in metastatic lymph nodes were 2-7 folds higher than those in adjacent normal mucosa. The immunohistochemistry demonstrated that ERK-1, ERK-2, ERK-3, p38 and MEK-1 proteins were mainly localized in cytoplasm. The expression of MEK-1 in gastric cancer cells metastasized to lymph nodes was higher than that of the primary site.CONCLUSION: MAPKs, particularly ERK subclass are overexpressed in the majority of gastric cancers.Overexpression of ERKs is correlated to TNM staging, serosa invasion, and lymph node involvement. The overexpression of p38 most likely plays a prominent role in certain morphological subtypes of gastric cancers. MEK-1 is also overexpressed in gastric cancer, particularly in metastatic lymph nodes. Upregulation of MAPK signal transduction pathways may play an important role in tumorigenesis and metastatic potential of gastric cancer.