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Prognostic value of RKIP and p-ERK in gastric cancer.

Fujimori Y, Inokuchi M, Takagi Y, Kato K, Kojima K, Sugihara K - J. Exp. Clin. Cancer Res. (2012)

Bottom Line: Expression of RKIP, p-MEK, and p-ERK was found in 69 (66%), 54 (51%), and 64 (61%) of all tumours, respectively.RKIP expression was associated with significantly longer relapse-free survival (RFS) (p = 0.0033), whereas p-MEK was not (p = 0.79).Our results demonstrated that loss of RKIP was associated with tumour progression and poor survival.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgical Oncology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

ABSTRACT

Background: The mitogen-activated protein kinase (MAPK) signaling pathway participates in several steps of tumour development and is considered a prominent therapeutic target for the design of chemotherapeutic agents. We evaluated the expressions of extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MEK), an upstream regulator of ERK, and Raf kinase inhibitor protein (RKIP), and investigated correlations of these expressions with clinicopathological features and outcomes in gastric cancer.

Methods: Tumour samples were obtained from 105 patients with gastric adenocarcinomas who underwent radical gastrectomy. The expressions of phosphorylated ERK (p-ERK), phosphorylated MEK (p-MEK), and RKIP were analysed by immunohistochemical staining.

Results: Expression of RKIP, p-MEK, and p-ERK was found in 69 (66%), 54 (51%), and 64 (61%) of all tumours, respectively. RKIP expression negatively correlated with the depth of invasion (p < 0.001), lymph node involvement (p = 0.028), and Union for International Cancer Control (UICC) stage (p = 0.007). RKIP expression was associated with significantly longer relapse-free survival (RFS) (p = 0.0033), whereas p-MEK was not (p = 0.79). Patients with p-ERK expression had slightly, but not significantly shorter RFS than those without such expression (p = 0.054). Patients with positive p-ERK and negative RKIP expression had significantly shorter RFS than the other patients (p < 0.001). The combination of RKIP and p-ERK expression was an independent prognostic factor (hazard ratio, 2.4; 95% confidence interval, 1.3 - 4.6; p = 0.008).

Conclusions: Our results demonstrated that loss of RKIP was associated with tumour progression and poor survival. Negative RKIP expression combined with positive p-ERK expression was an independent predictor of poor outcomes in patients with gastric cancer.

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Representative gastric carcinomas showing immunostaining for RKIP predominantly in the cytoplasm, (a), immunostaining for p-MEK predominantly in the cytoplasm (b), and immunostaining for p-ERK in the nucleus and the cytoplasm (c); magnification, 2×. The upper inset shows a surface site of tumour and the lower inset shows a site of deep invasion (a - c); magnification, 40×. Metastatic lymph nodes showing immunostaining for RKIP in the cytoplasm (d), for p-MEK in the nucleus (e), and for p-ERK with strong intensity in the nucleus (f); magnification, 40×. Tumour cells associated with venous invasion showing immunostaining for RKIP with weak intensity (g), for p-MEK (h), and for p-ERK in the nucleus (i); magnification, 40×.
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Figure 1: Representative gastric carcinomas showing immunostaining for RKIP predominantly in the cytoplasm, (a), immunostaining for p-MEK predominantly in the cytoplasm (b), and immunostaining for p-ERK in the nucleus and the cytoplasm (c); magnification, 2×. The upper inset shows a surface site of tumour and the lower inset shows a site of deep invasion (a - c); magnification, 40×. Metastatic lymph nodes showing immunostaining for RKIP in the cytoplasm (d), for p-MEK in the nucleus (e), and for p-ERK with strong intensity in the nucleus (f); magnification, 40×. Tumour cells associated with venous invasion showing immunostaining for RKIP with weak intensity (g), for p-MEK (h), and for p-ERK in the nucleus (i); magnification, 40×.

Mentions: RKIP, p-MEK, and p-ERK were respectively expressed by 69 (66%), 54 (51%), and 64 (61%) of all tumours (Figure 1a-c). RKIP expression was mainly observed in the cytoplasm of tumour or non-tumour cells. Expressions of p-MEK and p-ERK were found in both the cytoplasm and nucleus. Expressions of RKIP, p-MEK, and p-ERK were respectively detected in 5 (19%), 9 (35%), and 21 (81%) of 26 metastatic lymph nodes obtained from patients with recurrent disease (Figure 1d-f). Expression of p-ERK was found mainly in the nuclei of metastatic tumour cells. These proteins were also detected in tumour cells associated with venous invasion (Figure 1g-i). No p-ERK or p-MEK staining was detected in normal gastric mucosa. The expression of p-MEK positively correlated with the expressions of RKIP (p = 0.042) and p-ERK (p = 0.007), whereas there was no relation between RKIP and p-ERK expressions (p = 0.98) (Table 1). RKIP expression negatively correlated with the depth of invasion (p < 0.001), lymph node involvement (p = 0.028), and UICC stage (p = 0.007). RKIP was more commonly found in differentiated type than in undifferentiated type tumours (p = 0.042). The expressions of p-ERK and p-MEK significantly correlated with gender (p = 0.027, p = 0.036, respectively), but were not related to any other clinicopathological factor (Table 2).


Prognostic value of RKIP and p-ERK in gastric cancer.

Fujimori Y, Inokuchi M, Takagi Y, Kato K, Kojima K, Sugihara K - J. Exp. Clin. Cancer Res. (2012)

Representative gastric carcinomas showing immunostaining for RKIP predominantly in the cytoplasm, (a), immunostaining for p-MEK predominantly in the cytoplasm (b), and immunostaining for p-ERK in the nucleus and the cytoplasm (c); magnification, 2×. The upper inset shows a surface site of tumour and the lower inset shows a site of deep invasion (a - c); magnification, 40×. Metastatic lymph nodes showing immunostaining for RKIP in the cytoplasm (d), for p-MEK in the nucleus (e), and for p-ERK with strong intensity in the nucleus (f); magnification, 40×. Tumour cells associated with venous invasion showing immunostaining for RKIP with weak intensity (g), for p-MEK (h), and for p-ERK in the nucleus (i); magnification, 40×.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351370&req=5

Figure 1: Representative gastric carcinomas showing immunostaining for RKIP predominantly in the cytoplasm, (a), immunostaining for p-MEK predominantly in the cytoplasm (b), and immunostaining for p-ERK in the nucleus and the cytoplasm (c); magnification, 2×. The upper inset shows a surface site of tumour and the lower inset shows a site of deep invasion (a - c); magnification, 40×. Metastatic lymph nodes showing immunostaining for RKIP in the cytoplasm (d), for p-MEK in the nucleus (e), and for p-ERK with strong intensity in the nucleus (f); magnification, 40×. Tumour cells associated with venous invasion showing immunostaining for RKIP with weak intensity (g), for p-MEK (h), and for p-ERK in the nucleus (i); magnification, 40×.
Mentions: RKIP, p-MEK, and p-ERK were respectively expressed by 69 (66%), 54 (51%), and 64 (61%) of all tumours (Figure 1a-c). RKIP expression was mainly observed in the cytoplasm of tumour or non-tumour cells. Expressions of p-MEK and p-ERK were found in both the cytoplasm and nucleus. Expressions of RKIP, p-MEK, and p-ERK were respectively detected in 5 (19%), 9 (35%), and 21 (81%) of 26 metastatic lymph nodes obtained from patients with recurrent disease (Figure 1d-f). Expression of p-ERK was found mainly in the nuclei of metastatic tumour cells. These proteins were also detected in tumour cells associated with venous invasion (Figure 1g-i). No p-ERK or p-MEK staining was detected in normal gastric mucosa. The expression of p-MEK positively correlated with the expressions of RKIP (p = 0.042) and p-ERK (p = 0.007), whereas there was no relation between RKIP and p-ERK expressions (p = 0.98) (Table 1). RKIP expression negatively correlated with the depth of invasion (p < 0.001), lymph node involvement (p = 0.028), and UICC stage (p = 0.007). RKIP was more commonly found in differentiated type than in undifferentiated type tumours (p = 0.042). The expressions of p-ERK and p-MEK significantly correlated with gender (p = 0.027, p = 0.036, respectively), but were not related to any other clinicopathological factor (Table 2).

Bottom Line: Expression of RKIP, p-MEK, and p-ERK was found in 69 (66%), 54 (51%), and 64 (61%) of all tumours, respectively.RKIP expression was associated with significantly longer relapse-free survival (RFS) (p = 0.0033), whereas p-MEK was not (p = 0.79).Our results demonstrated that loss of RKIP was associated with tumour progression and poor survival.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgical Oncology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

ABSTRACT

Background: The mitogen-activated protein kinase (MAPK) signaling pathway participates in several steps of tumour development and is considered a prominent therapeutic target for the design of chemotherapeutic agents. We evaluated the expressions of extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MEK), an upstream regulator of ERK, and Raf kinase inhibitor protein (RKIP), and investigated correlations of these expressions with clinicopathological features and outcomes in gastric cancer.

Methods: Tumour samples were obtained from 105 patients with gastric adenocarcinomas who underwent radical gastrectomy. The expressions of phosphorylated ERK (p-ERK), phosphorylated MEK (p-MEK), and RKIP were analysed by immunohistochemical staining.

Results: Expression of RKIP, p-MEK, and p-ERK was found in 69 (66%), 54 (51%), and 64 (61%) of all tumours, respectively. RKIP expression negatively correlated with the depth of invasion (p < 0.001), lymph node involvement (p = 0.028), and Union for International Cancer Control (UICC) stage (p = 0.007). RKIP expression was associated with significantly longer relapse-free survival (RFS) (p = 0.0033), whereas p-MEK was not (p = 0.79). Patients with p-ERK expression had slightly, but not significantly shorter RFS than those without such expression (p = 0.054). Patients with positive p-ERK and negative RKIP expression had significantly shorter RFS than the other patients (p < 0.001). The combination of RKIP and p-ERK expression was an independent prognostic factor (hazard ratio, 2.4; 95% confidence interval, 1.3 - 4.6; p = 0.008).

Conclusions: Our results demonstrated that loss of RKIP was associated with tumour progression and poor survival. Negative RKIP expression combined with positive p-ERK expression was an independent predictor of poor outcomes in patients with gastric cancer.

Show MeSH
Related in: MedlinePlus