The lncRNA ‘UCA1’ modulates the response to chemotherapy of ovarian cancer through direct binding to miR‐27a‐5p and control of UBE2N levels

Abstract

Ovarian cancer (OC) is the leading cause of death in patients with gynecologic cancers. Due to late diagnosis and resistance to chemotherapy, the 5-year survival rate in patients with OC is below 40%. We observed that UCA1 a lncRNA previously reported to play an oncogenic role in several malignancies, is overexpressed in the chemoresistant OC cell line OAW42-R compared to their chemotherapy sensitive counterpart OAW42. Additionally, UCA1 overexpression was related to poor prognosis in two independent patient cohorts. Currently, the molecular mechanisms though which UCA1 acts in OC are poorly understood. We demonstrated that downregulation of the short isoform of UCA1 sensitized OC cells to cisplatin, and that UCA1 acted as competing endogenous RNA to miR-27a-5p. Upon UCA1 downregulation, miR-27a-5p downregulated its direct target UBE2N leading to the upregulation of BIM, a proapoptotic protein of the Bcl-2 family. The upregulation of BIM is the event responsible for the sensitization of OC cells to cisplatin. In order to model response to therapy in patients with OC, we used several patient-derived organoid cultures, a model faithfully mimicking patient's response to therapy.Inhibition of UBE2N sensitized patient-derived organoids to platinum salts. In conclusion, response to treatment in patients with OC is regulated by the UCA1/ miR-27a-5p/ UBE2N axis, where UBE2N inhibition could potentially represent a novel therapeutic strategy to counter chemoresistance in OC.

Long noncoding RNAs as therapeutic targets to overcome chemoresistance in ovarian cancer

“…LncRNA UCA1 reduced cisplatin response of OAW42 ovarian cancer cells via direct sponging to miR-27a-5p and decreasing the expression of UBE2N levels, resulting in the inhibition of BIM expression, a member of the Bcl-2 family to induce apoptotic death ( Wambecke et al, 2021 ). UCA1 accelerated cisplatin resistance via miR-27a-5p/UBE2N/BIM axis in ovarian cancer cells ( Wambecke et al, 2021 ).…”

“…A ferroptosis and iron-metabolism-related lncRNA profile has been reported for prediction of therapeutic responses by analysis of integrated clinical data and omics data in ovarian cancer ( Feng et al, 2022 ). LncRNAs have been emerged in regulating drug sensitivity in ovarian cancer ( Tripathi et al, 2018 ; Abildgaard et al, 2019 ; Wambecke et al, 2020 ; Wambecke et al, 2021 ). In the following sections, we will describe the role of various lncRNAs in regulation of cisplatin, paclitaxel, 5-FU, rapamycin and carboplatin resistance.…”

Les tumoroïdes, modèles précliniques en plein essor pour l’oncologie

“…Notre équipe a uti-lisé des tumoroïdes ovariens pour évaluer l'effet antitumoral d'une combinaison d'un inhibiteur de Bcl-x L et d'un inhibiteur de l'EGFR [44], ou d'un antagoniste des récepteurs α 1 -adrénergiques [45]. Nous avons par ailleurs pu identifier la protéine UBE2N (ubiquitin-conjugating enzyme E2 N) comme une cible thérapeutique potentielle dans les cancers de l'ovaire, son inhibition sensibilisant plusieurs tumoroïdes à l'action du carboplatine [46]. En étant au plus proche de ses caractéristiques et en présentant une hétérogénéité similaire à celle de la tumeur d'origine, le modèle des tumoroïdes permet donc de cribler à haut débit les nombreuses options thérapeutiques émergentes, et potentiellement d'identifier les sous-types tumoraux qui pourraient préférentiellement en bénéficier.…”

PCAT6 May Be a Whistler and Checkpoint Target for Precision Therapy in Human Cancers

“…Exploring new mechanisms of chemotherapeutic drugs to overcome chemoresistance is urgently needed. Recently, lncRNA dysregulation has been associated with drug resistance, including UCA1 [ 127 ], CYTOR [ 128 ], and TINCR [ 129 ]. Furthermore, the aberrant expression of PCAT6 was also verified to be related to chemoresistance in cancers.…”