Inhibition of Wnt-β-Catenin Signaling by ICRT14 Drug Depends of Post-Transcriptional Regulation by HOTAIR in Human Cervical Cancer HeLa Cells.

Samuel Trujano-Camacho,Oliver Millan-Catalan,Daniel Hernández-Sotelo,Jossimar Coronel-Hernández,David Cantú-De León,Carlos Pérez-Plasencia,Izamary Delgado-Waldo,César López-Camarillo,Alma D Campos-Parra

doi:10.3389/fonc.2021.729228

Abstract

BackgroundIn Cervical cancer (CC), in addition to HPV infection, the most relevant alteration during CC initiation and progression is the aberrant activation of Wnt/β-catenin pathway. Several inhibitory drugs of this pathway are undergoing preclinical and clinical studies. Long non-coding RNAs (lncRNAs) are associated with resistance to treatments. In this regard, understanding the efficiency of drugs that block the Wnt/β-catenin pathway in CC is of relevance to eventually propose successful target therapies in patients with this disease.MethodsWe analyzed the levels of expression of 249 components of the Wnt/β-catenin pathway in a group of 109 CC patients. Three drugs that blocking specific elements of Wnt/β-catenin pathway (C59, NSC668036 and ICRT14) by TOP FLASH assays and qRT-PCR were tested in vitro in CC cells.Results137 genes of the Wnt/β-catenin pathway were up-regulated and 112 down-regulated in CC patient’s samples, demonstrating that this pathway is dysregulated. C59 was an efficient drug to inhibit Wnt/β-catenin pathway in CC cells. NSC668036, was not able to inhibit the transcriptional activity of the Wnt/β-catenin pathway. Strikingly, ICRT14 was neither able to inhibit this pathway in HeLa cells, due to HOTAIR interaction with β-catenin, maintaining the Wnt/β-catenin pathway activated.ConclusionsThese results demonstrate a mechanism by which HOTAIR evades the effect of ICRT14, a Wnt/β-catenin pathway inhibitory drug, in HeLa cell line. The emergence of these mechanisms reveals new scenarios in the design of target therapies used in cancer.

Highlights

Cervical cancer (CC) constitutes a major health concern worldwide since it is the fourth most common cancer in women [1]
All patients were diagnosed with CC and the most common histologic subtype was squamous cell carcinoma (90.8%)
We found that HOX transcript antisense intergenic RNA (HOTAIR) was significantly upregulated in CC cells lines and CC biopsies samples compared to the non-tumor cell line HaCat and normal tissues samples patients, respectively (Figure 6 and Supplementary File 3B)

Summary

Introduction

Cervical cancer (CC) constitutes a major health concern worldwide since it is the fourth most common cancer in women [1]. Among the most relevant alterations during CC initiation and progression is the aberrant activation of Wnt/b-catenin pathway, which is essential in cervical oncogenesis [6, 7]. NSC668036, is an organic molecule that acts at the cytoplasmic level binding to DVL protein, that inhibits the Wnt3A induced signaling [11] Another drug is ICRT14, which acts at the nuclear level inhibiting direct interactions between b-catenin and TCF4, antagonizing the transcriptional function of nuclear b-catenin and shutting down the signaling pathway [12]. In Cervical cancer (CC), in addition to HPV infection, the most relevant alteration during CC initiation and progression is the aberrant activation of Wnt/b-catenin pathway. Long non-coding RNAs (lncRNAs) are associated with resistance to treatments In this regard, understanding the efficiency of drugs that block the Wnt/b-catenin pathway in CC is of relevance to eventually propose successful target therapies in patients with this disease

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