Constitutive hypophosphorylation of extracellular signal-regulated kinases-1/2 and down-regulation of c-Jun in human gastric adenocarcinoma

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Abstract

Hyperphosphorylation of extracellular signal-regulated protein kinases-1/2 (ERK1/2) is known to promote cancer cell proliferation. We therefore investigated the constitutive phosphorylation levels of ERK1/2 and the expression of its downstream targets c-Fos, c-Jun, and cyclooxygenase-2 (COX-2) in biopsied human gastric cancer tissues. Results showed that ERK1/2 phosphorylation and c-Jun expression were significantly lowered in gastric cancer compared with the non-cancer adjacent tissues. The expression of c-Fos, however, was not altered while COX-2 was significantly up-regulated. To conclude, we demonstrate that hypophosphorylation of ERK1/2 may occur in gastric cancer. Such discovery may have implication in the application of pathway-directed therapy for this malignant disease.

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Materials and methods

Clinical samples. Surgical specimens from 20 patients with gastric adenocarcinoma admitted to the Department of Surgery, Queen Mary Hospital, Hong Kong, for gastrectomy were obtained. Samples were collected before surgery, chemotherapy or any other form of treatment. There were 13 men and 7 women with a median age of 68. Eleven patients were diagnosed with intestinal-type adenocarcinoma, six with diffuse-type, and three with mixed-type. The study has been approved by the ethics committee, Queen

Constitutive phosphorylation levels of ERK1/2 was lowered in gastric cancer

As ERK1/2 phosphorylation is implicated in the progression of cancer [1], the constitutive phosphorylation levels of ERK1/2 in primary gastric cancer tissues and the non-cancer adjacent tissues were determined by Western blot. As shown in Fig. 1, the phosphorylation levels of ERK1/2 in gastric cancer tissues were significantly reduced by 90% when compared with the non-cancer adjacent tissues (p < 0.005). The down-regulation of ERK1/2 phosphorylation was irrespective of histological types.

Discussion

ERK signaling contributes to cell proliferation [1], angiogenesis [19], invasion and metastasis [20], and resistance to apoptosis [3] that are related to tumor progression. Constitutive hyperphosphorylation of ERK1/2 has also been documented in many hematological and epithelial malignancies [8], [9], [10], [11], [12]. The constitutive phosphorylation levels of ERK1/2 in gastric cancer, however, were unknown. In the present study, we demonstrate that, beyond our expectation, the constitutive

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