MAL gene overexpression as a marker of high-grade serous ovarian carcinoma stem-like cells that predicts chemoresistance and poor prognosis

BMC Cancer

Research Article

Stefano Calza¹  Franco Odicino²  Enrico Sartori²  Maurizio D’Incalci³  Giovanna Damia³  Sergio Marchini³  Luca Beltrame³  Francesca Ricci³  Laura Ardighieri⁴  Germana Tognon⁵  Eliana Bignotti⁵  Paola Todeschini⁶  Sergio Pecorelli⁶  Laura Tassone⁶  Laura Zanotti⁶  Elisabetta Bandiera⁶  Antonella Ravaggi⁶  Chiara Romani⁶  Renata Alessandra Tassi⁶ 

[1] Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy;Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden;Department of Obstetrics and Gynecology, University of Brescia, Brescia, Italy;Department of Oncology, IRCCS, “Mario Negri” Institute for Pharmacological Research, Milan, Italy;Department of Pathology, ASST Spedali Civili di Brescia, Brescia, Italy;Division of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy;“Angelo Nocivelli” Institute of Molecular Medicine, Division of Obstetrics and Gynecology, University of Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy;

关键词: Cancer stem cells;    Epithelial ovarian cancer;    Chemoresistance;    MAL;   

DOI  :  10.1186/s12885-017-3334-1

 received in 2016-09-29, accepted in 2017-05-09,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundThe existence of cancer stem cells (CSCs) within a tumor bulk has been demonstrated for many solid tumors including epithelial ovarian carcinoma (EOC). CSCs have been associated to tumor invasion, metastasis and development of chemoresistant recurrences. In this context, we aim to characterize EOC CSCs from the molecular point of view in order to identify potential biomarkers associated with chemoresistance.MethodsWe isolated a population of cells with stem-like characteristics (OVA-BS4 spheroids) from a primary human EOC cell line under selective conditions. OVA-BS4 spheroids were characterized for drug response by cytotoxicity assays and their molecular profile was investigated by microarray and RT-qPCR. Finally, we performed a gene expression study in a cohort of 74 high-grade serous EOC (HGSOC) patients by RT-qPCR.ResultsSpheroids exhibited properties of self-renewal and a pronounced expression of well-known stem cell genes. Moreover, they demonstrated greater resistance towards several anticancer drugs compared to parent cell line, consistent with their higher ABCG2 gene expression. From microarray studies MAL (T-cell differentiation protein) emerged as the most up-regulated gene in spheroids, compared to parent cell line. In HGSOC patients, MAL was significantly overexpressed in platinum-resistant compared to platinum-sensitive patients and resulted as an independent prognostic marker of survival.ConclusionsThis investigation provides an important contribution to the identification of molecular markers of ovarian CSCs and chemoresistance. Successful translation of molecular findings would lead to a better comprehension of the mechanisms triggering chemoresistant recurrences, to the individuation of novel therapeutic targets and to the personalization of treatment regimens.

【 授权许可】

CC BY   
© The Author(s). 2017