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      Circular RNA Protein Tyrosine Kinase 2 Promotes Cell Proliferation, Migration and Suppresses Apoptosis via Activating MicroRNA-638 Mediated MEK/ERK, WNT/β-Catenin Signaling Pathways in Multiple Myeloma

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          Abstract

          Our previous study observed that circular RNA protein tyrosine kinase 2 (circ-PTK2) was upregulated and correlated with worse clinical features and unfavorable prognosis in multiple myeloma (MM) patients. Thus, this study aimed to further characterize the regulatory function of circ-PTK2 on cell malignant activities and its target microRNA-638 (miR-638) as well as downstream MEK/ERK, WNT/β-catenin signaling pathways in MM. The effect of circ-PTK2 on MM cell proliferation, apoptosis, migration, invasion and its potential target miRNAs was assessed by transfecting circ-PTK2 overexpression plasmids into U226 cells and circ-PTK2 knock-down plasmids into LP-1 cells. Furthermore, the interaction between circ-PTK2 and miR-638 mediated MEK/ERK and WNT/β-catenin signaling pathways was validated by rescue experiments. Circ-PTK2 was overexpressed in most MM cell lines compared to normal plasma cells. Overexpressing circ-PTK2 promoted proliferation and migration, inhibited apoptosis in U266 cells, but did not affect cell invasion; knocking down circ-PTK2 achieved opposite effect in LP-1 cells. Besides, circ-PTK2 reversely regulated miR-638 expression but not miR-4690, miR-6724, miR-6749 or miR-6775. The following luciferase reporter assay illustrated the direct bind of circ-PTK2 towards miR-638. In rescue experiments, overexpressing miR-638 suppressed proliferation, migration, while promoted apoptosis in both wild U266 cells and circ-PTK2-overexpressed U266 cells; meanwhile, overexpressing miR-638 also suppressed MEK/ERK and WNT/β-catenin pathways in both wild U266 cells and circ-PTK2-overexpressed U266 cells. Knocking down miR-638 achieved opposite effect in both wild LP-1 cells and circ-PTK2-knocked-down LP-1 cells. In conclusion, circ-PTK2 promotes cell proliferation, migration, suppresses cell apoptosis via miR-638 mediated MEK&ERK and WNT&β-catenin signaling pathways in MM.

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          Most cited references31

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          Multiple myeloma: Every year a new standard?

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            Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options

            Aberrant activation of Wnt/β-catenin signaling plays a central role in the pathogenesis of a wide variety of malignancies and is typically caused by mutations in core Wnt pathway components driving constitutive, ligand-independent signaling. In multiple myelomas (MMs), however, these pathway intrinsic mutations are rare despite the fact that most tumors display aberrant Wnt pathway activity. Recent studies indicate that this activation is caused by genetic and epigenetic lesions of Wnt regulatory components, sensitizing MM cells to autocrine Wnt ligands and paracrine Wnts emanating from the bone marrow niche. These include deletion of the tumor suppressor CYLD, promotor methylation of the Wnt antagonists WIF1, DKK1, DKK3, and sFRP1, sFRP2, sFRP4, sFRP5, as well as overexpression of the co-transcriptional activator BCL9 and the R-spondin receptor LGR4. Furthermore, Wnt activity in MM is strongly promoted by interaction of both Wnts and R-spondins with syndecan-1 (CD138) on the MM cell-surface. Functionally, aberrant canonical Wnt signaling plays a dual role in the pathogenesis of MM: (I) it mediates proliferation, migration, and drug resistance of MM cells; (II) MM cells secrete Wnt antagonists that contribute to the development of osteolytic lesions by impairing osteoblast differentiation. As discussed in this review, these insights into the causes and consequences of aberrant Wnt signaling in MM will help to guide the development of targeting strategies. Importantly, since Wnt signaling in MM cells is largely ligand dependent, it can be targeted by drugs/antibodies that act upstream in the pathway, interfering with Wnt secretion, sequestering Wnts, or blocking Wnt (co)receptors.
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              Circular RNA Profiling Reveals Exosomal circ_0006156 as a Novel Biomarker in Papillary Thyroid Cancer

              Circular RNAs (circRNAs) are a class of noncoding RNAs that are broadly expressed in various biological cells and function in regulating gene expression. However, the molecular mechanisms that link circRNAs with progression of papillary thyroid carcinoma (PTC) are not well understood. In the present study, the function of circ_0006156 (circFNDC3B) was investigated in human PTC cells. First, we detected the expression of circFNDC3B in PTC tissues and PTC cell lines by RT-PCR. A luciferase reporter assay and AGO2-RNA immunoprecipitation (RIP) was used to confirm the relationship between circFNDC3B and microRNA (miR)-1178. PTC cells were stably transfected with small interfering RNA (siRNA) against circFNDC3B, and cell proliferation, migration, and invasion were detected to evaluate the effect of circFNDC3B in PTC, while tumorigenesis was assayed in nude mice. In this study, circFNDC3B was observed to be upregulated in PTC tissues and cell lines. Knockdown of circFNDC3B inhibited cell proliferation and promoted cell apoptosis in PTC cells. Bioinformatics analysis predicted that there is a circFNDC3B/miR-1178/Toll-like receptor 4 (TLR4) axis in PTC. The dual-luciferase reporter system validated the direct interaction of circFNDC3B, miR-1178, and TLR4. Furthermore, circFNDC3B facilitates PTC progression in vivo. Importantly, we demonstrated that circFNDC3B was upregulated in serum exosomes from PTC patients. In summary, our study demonstrated that circFNDC3B modulates PTC progression through the miR-1178/TLR4 pathway. Our findings indicated that circFNDC3B may serve as a promising therapeutic target for the treatment of PTC patients.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                28 July 2021
                2021
                : 11
                : 648189
                Affiliations
                [1]Department of Hematology and Oncology, Shanghai Jing’an District Zhabei Central Hospital , Shanghai, China
                Author notes

                Edited by: Anjali Mishra, Sidney Kimmel Cancer Center, United States

                Reviewed by: Kate Vandyke, University of Adelaide, Australia; Teresa Sadras, Beckman Research Institute, City of Hope, United States

                *Correspondence: Fan Zhou, zfsh257@ 123456163.com

                This article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2021.648189
                8355695
                34395238
                9c4315e3-440d-4bc1-9296-61e6b889219c
                Copyright © 2021 Zhou, Wang, Zhou, Chen, Shi, Peng, Wei and Wu

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 31 December 2020
                : 28 May 2021
                Page count
                Figures: 8, Tables: 2, Equations: 0, References: 31, Pages: 13, Words: 6232
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                circ-ptk2,mir-638,multiple myeloma,mek&erk,wnt&β-catenin
                Oncology & Radiotherapy
                circ-ptk2, mir-638, multiple myeloma, mek&erk, wnt&β-catenin

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