Abstract
Endometrial cancer is the most common gynecologic malignancy in developed countries. Estrogen-dependent tumors (type I, endometrioid) account for 80% of cases and non-estrogen-dependent (type II, non-endometrioid) account for the rest. Endometrial cancer type I is generally thought to develop via precursor lesions along with the increasing accumulation of molecular genetic alterations. Endometrial hyperplasia with atypia/Endometrial Intraepithelial Neoplasia is the least common type of hyperplasia but it is the type most likely to progress to type I cancer, whereas endometrial hyperplasia without atypia rarely progresses to carcinoma. MicroRNAs are a class of small, non-coding, single-stranded RNAs that negatively regulate gene expression mainly binding to 3′-untranslated region of target mRNAs. In the current study, we identified a microRNAs signature (miR-205, miR-146a, miR-1260b) able to discriminate between atypical and typical endometrial hyperplasia in two independent cohorts of patients. The identification of molecular markers that can distinguish between these two distinct pathological conditions is considered to be highly useful for the clinical management of patients because hyperplasia with an atypical change is associated with a higher risk of developing cancer. We show that the combination of miR-205, −146a, and −1260b has the best predictive power in discriminating these two conditions (>90%). With the aim to find a biological role for these three microRNAs, we focused our attention on a common putative target involved in endometrial carcinogenesis: the oncosuppressor gene SMAD4. We showed that miRs-146a,−205, and−1260b directly target SMAD4 and their enforced expression induced proliferation and migration of Endometrioid Cancer derived cell lines, Hec1a cells. These data suggest that microRNAs-mediated impairment of the TGF-β pathway, due to inhibition of its effector molecule SMAD4, is a relevant molecular alteration in endometrial carcinoma development. Our findings show a potential diagnostic role of this microRNAs signature for the accurate diagnosis of Endometrial hyperplasia with atypia/Endometrial Intraepithelial Neoplasia and improve the understanding of their pivotal role in SMAD4 regulation.
Highlights
Worldwide, endometrial cancer (EC) represents 4% of all cancers in women and is the most common malignant tumor of the female genital tract in industrialized countries [1]
We found that highly conserved binding sites for each of these miRs were present in the mRNA of the oncosuppressor gene SMAD4, which has been shown to be down-modulated in EC [23]
Identification of molecular markers that can differentiate between atypical hyperplasia/endometrioid intraepithelial neoplasia: (AH/EIN) and BH are considered to be highly useful for clinical management of patients because hyperplasia with atypical change and/or Endometrial Intraepithelial Neoplasia are associated with a higher risk to progress to cancer [4]
Summary
Endometrial cancer (EC) represents 4% of all cancers in women and is the most common malignant tumor of the female genital tract in industrialized countries [1]. The World Health Organization classification of tumors (WHO) [5] divided endometrial hyperplasias into two categories: hyperplasia without atypia (Benign Hyperplasia, BH) and atypical hyperplasia/endometrioid intraepithelial neoplasia: (AH/EIN) [5]. AH/EIN is most likely to progress to type I endometrial carcinoma (∼30%), and has been reported to be associated with invasive EC in 62% of endometrial biopsy [6], whereas BH rarely progresses to EC (
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