Expression of the Hippo Pathway Core Components in Endometrial Cancer and Its Association with Clinicopathologic Features

Abstract

Background: The Hippo signaling pathway has a key role in tumorigenesis. This study aimed to evaluate the relationship between the expression of core components of the Hippo signaling pathway and its association with clinicopathological features in endometrial cancer.

Materials and methods: We retrospectively collected endometrioid endometrial cancer specimens from 60 patients between January 2002 and December 2009 at Gyeongsang National University Hospital. Relevant clinicopathological data were obtained through electronic medical records of patients. The expression patterns of six core components (YAP, p-YAP, LATS1/2, MST1/2, KIBRA, and Merlin) were identified by immunohistochemistry on tissue microarray sections.

Results: The positive expression ratio was 75.0% for YAP, 73.3% for p-YAP, 26.7% for MST1/2, 16.7% for KIBRA, 15.0% for Merlin, and 15.0% for LATS1/2. YAP expression was negatively correlated with MST 1/2 kinases (p = 0.045) and positively correlated with p-YAP (p = 0.012). Merlin, and MST 1/2 kinases (p = 0.043) showed a positive correlation. A subgroup of patients aged below 60 years (p = 0.004) and with myometrial invasion depth of less than 1/2 (p = 0.041) showed a positive association with YAP expression. p-YAP expression was negatively associated with a subset of patients with primary tumour size ≥4 cm (p = 0.03). Logistic regression analysis showed a significant association between age and YAP expression. The odds ratio of p-YAP expression was significantly lower in the group with tumour size ≥4 cm.

Conclusion: Two prognostic factors, age and tumour size, were significantly associated with the expression of YAP and p-YAP in endometrial cancer. Further research should focus on their expression as a marker for prediction of clinicopathological implications in endometrial cancer.

Keywords: Hippo pathway; KIBRA; LATS1/2; MST1/2; YAP; endometrial cancer; p-YAP; prognostic factors.

Figure 1

(A) Immunohistochemical staining: Cytoplasm of cancer cells shows diffuse expression of YAP (×400). (B) Cytoplasm of cancer cells shows diffuse expression of p-YAP (×400). (C) Diffuse expression of MST1/2 in the cytoplasm (×400). (D) Diffuse positive signal of KIBRA in the cytoplasm of cancer cells (×400). (E) Diffuse positive signal of Merlin in the cytoplasm of cancer cells (×400). (F) Diffuse positive signal of LATS1/2 in the cytoplasm of cancer cells (×400).

Figure 2

The Spearman correlation coefficient with the p-value. (A,F,H) showed an inverse correlation (Spearman correlation coefficient = −0.271, −0.375, −0.309 and p-value = 0.043, 0.004, 0.016, respectively). (B–E,G,I–L) showed no correlation between two variables.

Figure 3

Visualization of odds ratios of YAP expression (A) and p-YAP expression (B) in endometrial cancer model. * Showed statistical significance.