Aberrant Expression of Hypoxia-inducible Factor 1 , TWIST and E-cadherin is Associated with Aggressive Tumor Phenotypes in Endometrioid Endometrial Carcinoma

Abstract

Intratumoral hypoxia promotes angiogenesis, invasion and epithelial-mesenchymal transition, a pivotal event in tumor metastasis. TWIST is a master regulator of multiple developmental processes and has recently been shown to be the key factor responsible for cancer metastasis via the inhibition of E-cadherin expression, a hallmark of epithelial-mesenchymal transition. This study aimed to determine the expression of hypoxia-inducible factor 1α, TWIST and E-cadherin in patients with endometrioid endometrial carcinoma and to examine their clinical significance in endometrioid endometrial carcinoma progression. Using immunohistochemical and tissue microarray approaches, we evaluated the expression of hypoxia-inducible factor 1α, TWIST and E-cadherin in normal endometrial (n = 35), atypical hyperplasia (n = 28) and endometrioid endometrial carcinoma samples (n = 124). Furthermore, we statistically analyzed the association between these markers, as well as their correlation with clinicopathologic variables. The expression of hypoxia-inducible factor 1α and TWIST were markedly increased, whereas E-cadherin was decreased, as lesions progressed from normal endometrium to atypical hyperplasia to carcinoma (P < 0.01). Among various clinical parameters, the expression of hypoxia-inducible factor 1α and TWIST was strikingly elevated with aggressive tumor characteristics, including higher pathologic grade, deep myometrial invasion and lymph node involvement (P < 0.05). More importantly, overexpression of hypoxia-inducible factor 1α positively correlated with enhanced TWIST expression in endometrioid endometrial carcinoma samples (r = 0.249, P < 0.01); however, statistical analysis showed a negative relationship between TWIST upregulation and E-cadherin downregulation (r = -0.183, P = 0.042). These results demonstrated for the first time that the hypoxia-inducible factor 1α/TWIST/E-cadherin pathway may play a critical role in invasion and metastasis of endometrioid endometrial carcinoma. The combined evaluation of these markers may be useful in predicting aggressive phenotypes and thus prognosis in patients with endometrioid endometrial carcinoma.