Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer - PubMed (original) (raw)

Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer

Jae Yun Lim et al. World J Gastroenterol. 2012.

Abstract

Aim: To investigate M2 isoform of pyruvate kinase (PKM2) expression in gastric cancers and evaluate its potential as a prognostic biomarker and an anticancer target.

Methods: All tissue samples were derived from gastric cancer patients underwent curative gastrectomy as a primary treatment. Clinical and pathological information were obtained from the medical records. Gene expression microarray data from 60 cancer and 19 non-cancer gastric tissues were analyzed to evaluate the expression level of PKM2 mRNA. Tissue microarrays were constructed from 368 gastric cancer patients. Immunohistochemistry was used to measure PKM2 expression and PKM2 positivity of cancer was determined by proportion of PKM2-positive tumor cells and staining intensity. Association between PKM2 expression and the clinicopathological factors was evaluated and the correlation between PKM2 and cancer prognosis was evaluated.

Results: PKM2 mRNA levels were increased more than 2-fold in primary gastric cancers compared to adjacent normal tissues from the same patients (log transformed expression level: 7.6 ± 0.65 vs 6.3 ± 0.51, P < 0.001). Moreover, differentiated type cancers had significantly higher PKM2 mRNA compared to undifferentiated type cancers (log transformed expression level: 7.8 ± 0.70 vs 6.7 ± 0.71, P < 0.001). PKM2 protein was mainly localized in the cytoplasm of primary cancer cells and detected in 144 of 368 (39.1%) human gastric cancer cases. PKM2 expression was not related with stage (P = 0.811), but strongly correlated with gastric cancer differentiation (P < 0.001). Differentiated type cancers expressed more PKM2 protein than did the undifferentiated ones. Well differentiated adenocarcinoma showed 63.6% PKM2-positive cells; in contrast, signet-ring cell cancers showed only 17.7% PKM2-positive cells. Importantly, PKM2 expression was correlated with shorter overall survival (P < 0.05) independent of stage only in signet-ring cell cancers.

Conclusion: PKM2 expression might be an adverse prognostic factor for signet-ring cell carcinomas. Its function and potential as a prognostic marker should be further verified in gastric cancer.

Keywords: Biomarker; Gastric cancer; M2 isoform of pyruvate kinase; Prognosis; Signet ring cell carcinoma.

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Figures

Figure 1

Figure 1

Expression level of the M2 isoform of pyruvate kinase mRNA by gene expression microarray. A: The M2 isoform of pyruvate kinase (PKM2) up-regulation in the 18 primary gastric cancers compared to gastric adjacent noncancerous tissues paired from the same patient (P < 0.001); B: PKM2 up-regulation in the 22 differentiated type (D) gastric cancers compared to 27 undifferentiated type (UD) gastric cancers (P < 0.001). The column and bar represent mean and standard deviation, respectively.

Figure 2

Figure 2

Representative images from immunohistochemistry assays of 368 archived gastric cancer cases at 20 × 10 magnification. A: Moderately differentiated adenocarcinoma and negative for the M2 isoform of pyruvate kinase (PKM2) expression; B: Signet ring cell carcinoma and negative for PKM2 expression; C: Moderately differentiated adenocarcinoma and positive for PKM2 expression; D: Signet ring cell carcinoma and positive for PKM2 expression.

Figure 3

Figure 3

Recurrence-free survival (A) and overall survival (B) curves according to the M2 isoform of pyruvate kinase expression in signet ring cell gastric cancer after curative resection (n = 79). Positive M2 isoform of pyruvate kinase (PKM2) expression, real line; Negative PKM2 expression, dotted line.

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