The miR–181a–SFRP4 Axis Regulates Wnt Activation to Drive Stemness and Platinum Resistance in Ovarian Cancer

Nagaraj, Anil Belur; Knarr, Matthew; Sekhar, Sreeja; Connor, R. Shae; Joseph, Peronne; Kovalenko, Olga; Fleming, Alexis; Surti, Arshia; Nurmemmedov, Elmar; Beltrame, Luca; Marchini, Sergio; Kahn, Michaël; DiFeo, Analisa

doi:10.1158/0008-5472.can-20-2041

Cited by 35 publications

(17 citation statements)

References 31 publications

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“…miR-181a has been shown to target PTEN , a gene responsible for apoptosis regulation [ 25 ]. It has also been shown to play a role in the regulation of the Wnt, STAT3 and RAS/MAPK pathways, which have been implicated in leukemia development [ 26 , 27 , 28 ]. miR-181a has been shown to increase cell sensitivity to chemotherapeutic drugs by targeting several antiapoptotic genes [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

MicroRNAs in Leukemias: A Clinically Annotated Compendium

Turk

Calin

Kunej

2022

IJMS

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Leukemias are a group of malignancies of the blood and bone marrow. Multiple types of leukemia are known, however reliable treatments have not been developed for most leukemia types. Furthermore, even relatively reliable treatments can result in relapses. MicroRNAs (miRNAs) are a class of short, noncoding RNAs responsible for epigenetic regulation of gene expression and have been proposed as a source of potential novel therapeutic targets for leukemias. In order to identify central miRNAs for leukemia, we conducted data synthesis using two databases: miRTarBase and DISNOR. A total of 137 unique miRNAs associated with 16 types of leukemia were retrieved from miRTarBase and 86 protein-coding genes associated with leukemia were retrieved from the DISNOR database. Based on these data, we formed a visual network of 248 miRNA-target interactions (MTI) between leukemia-associated genes and miRNAs associated with ≥4 leukemia types. We then manually reviewed the literature describing these 248 MTIs for interactions identified in leukemia studies. This manually curated data was then used to visualize a network of 64 MTIs identified in leukemia patients, cell lines and animal models. We also formed a visual network of miRNA-leukemia associations. Finally, we compiled leukemia clinical trials from the ClinicalTrials database. miRNAs with the highest number of MTIs were miR-125b-5p, miR-155-5p, miR-181a-5p and miR-19a-3p, while target genes with the highest number of MTIs were TP53, BCL2, KIT, ATM, RUNX1 and ABL1. The analysis of 248 MTIs revealed a large, highly interconnected network. Additionally, a large MTI subnetwork was present in the network visualized from manually reviewed data. The interconnectedness of the MTI subnetwork suggests that certain miRNAs represent central disease molecules for multiple leukemia types. Additional studies on miRNAs, their target genes and associated biological pathways are required to elucidate the therapeutic potential of miRNAs in leukemia.

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Section: Discussionmentioning

confidence: 99%

MicroRNAs in Leukemias: A Clinically Annotated Compendium

Turk

Calin

Kunej

2022

IJMS

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“…In cancer such as pancreatic cancer, lung adenocarcinomas, colorectal cancer, and liver cancer, the small subpopulation of cancer cells expressing high Wnt/β-catenin signaling showed CSCs phenotype and were resistant to drug. The inhibition of Wnt signaling in these cells suppressed the stem cells phenotype, thereby affecting the chemoresistance (Taelman et al, 2010;Ilmer et al, 2015;Belur Nagaraj et al, 2021).…”

Section: Enrichment/induction Of Cancer Stem Cell Like Phenotypementioning

confidence: 99%

The Role of Notch, Hedgehog, and Wnt Signaling Pathways in the Resistance of Tumors to Anticancer Therapies

Kumar

Vashishta

Kong

et al. 2021

Front. Cell Dev. Biol.

128

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Resistance to therapy is the major hurdle in the current cancer management. Cancer cells often rewire their cellular process to alternate mechanisms to resist the deleterious effect mounted by different therapeutic approaches. The major signaling pathways involved in the developmental process, such as Notch, Hedgehog, and Wnt, play a vital role in development, tumorigenesis, and also in the resistance to the various anticancer therapies. Understanding how cancer utilizes these developmental pathways in acquiring the resistance to the multi-therapeutic approach cancer can give rise to a new insight of the anti-therapy resistance mechanisms, which can be explored for the development of a novel therapeutic approach. We present a brief overview of Notch, Hedgehog, and Wnt signaling pathways in cancer and its role in providing resistance to various cancer treatment modalities such as chemotherapy, radiotherapy, molecular targeted therapy, and immunotherapy. Understanding the importance of these molecular networks will provide a rational basis for novel and safer combined anticancer therapeutic approaches for the improvement of cancer treatment by overcoming drug resistance.

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“…Multiple ncRNAs, including miRNAs and lncRNAs, are increasingly implicated in the treatment resistance in OC ( 194 , 195 ). Therefore, targeting tumor-specific miRNAs and lncRNAs is expected to overcome drug resistance of OC.…”

Section: Therapeutic Targeting Of the Oc Epigenomementioning

confidence: 99%

“…Recently, miRNAs have received increasing attention as biomarkers and therapeutic targets for OC. For instance, Belur Nagaraj and colleagues found that miR-181a is an activator of Wnt/β-catenin signaling, driving stemness and chemotherapy resistance in high-grade serous ovarian cancer (HGSOC), thus being a potential target for treating recurrent OC ( 194 ). Using next-generation sequencing (NGS) techniques, Au Yeung et al.…”

Section: Therapeutic Targeting Of the Oc Epigenomementioning

confidence: 99%

The Emerging Roles and Therapeutic Implications of Epigenetic Modifications in Ovarian Cancer

Wang

Huang

et al. 2022

Front. Endocrinol.

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Ovarian cancer (OC) is one of the most lethal gynecologic malignancies globally. In spite of positive responses to initial therapy, the overall survival rates of OC patients remain poor due to the development of drug resistance and consequent cancer recurrence. Indeed, intensive studies have been conducted to unravel the molecular mechanisms underlying OC therapeutic resistance. Besides, emerging evidence suggests a crucial role for epigenetic modifications, namely, DNA methylation, histone modifications, and non-coding RNA regulation, in the drug resistance of OC. These epigenetic modifications contribute to chemoresistance through various mechanisms, namely, upregulating the expression of multidrug resistance proteins (MRPs), remodeling of the tumor microenvironment, and deregulated immune response. Therefore, an in-depth understanding of the role of epigenetic mechanisms in clinical therapeutic resistance may improve the outcome of OC patients. In this review, we will discuss the epigenetic regulation of OC drug resistance and propose the potential clinical implications of epigenetic therapies to prevent or reverse OC drug resistance, which may inspire novel treatment options by targeting resistance mechanisms for drug-resistant OC patients.

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The miR–181a–SFRP4 Axis Regulates Wnt Activation to Drive Stemness and Platinum Resistance in Ovarian Cancer

Cited by 35 publications

References 31 publications

MicroRNAs in Leukemias: A Clinically Annotated Compendium

MicroRNAs in Leukemias: A Clinically Annotated Compendium

The Role of Notch, Hedgehog, and Wnt Signaling Pathways in the Resistance of Tumors to Anticancer Therapies

The Emerging Roles and Therapeutic Implications of Epigenetic Modifications in Ovarian Cancer

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