The functions and clinical significance of circRNAs in hematological malignancies

Zhou, Xiangxiang; Zhan, Linquan; Huang, Kai; Wang, Xin

doi:10.1186/s13045-020-00976-1

Cited by 54 publications

(36 citation statements)

References 132 publications

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“…Hematological malignancies display high proliferative rates and therefore most novel anti-mitotics have shown better efficacy when compared to solid tumors [26][27][28]. However, the efficacy of PLK4 inhibition with CFI-400945 in hematological malignancies is still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma

et al. 2021

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Polo-like kinase 4 (PLK4), a key regulator of centriole biogenesis, has recently been shown to play key roles in tumorigenesis. Blocking PLK4 expression by interference or targeted drugs exhibits attractive potential in improving the efficacy of chemotherapy. Nevertheless, the role of PLK4 in diffuse large B-cell lymphoma (DLBCL) is still undefined. In this study, we discover that PLK4 is a potential target for the treatment of DLBCL, and demonstrate the efficacy of a PLK4 inhibitor when used in combination with doxorubicin. Pharmaceutical inhibition of PLK4 with CFI-400945 inhibited DLBCL cell proliferation and induced apoptotic cell death. The anti-tumor effects were accompanied by mitotic defects, including polyploidy and cytokinesis failure. Activation of p53 and Hippo/YAP tumor suppressor signaling pathway was identified as the potential mechanisms driving CFI-400945 activity. Moreover, CFI-400945 treatment resulted in activation of DNA damage response. Combining CFI-400945 with doxorubicin markedly delayed tumor progression in DLBCL xenografts. Finally, PLK4 was increased in primary DLBCL tissues and cell lines. High levels of PLK4 expression were associated with poor survival in the patients receiving CHOP-based treatment, implicating PLK4 as a predictive biomarker of DLBCL chemosensitivity. These results provide the therapeutic potential of CFI-400945 both as monotherapy or in combination with doxorubicin for the treatment of DLBCL.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma

et al. 2021

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“…CircRNAs are a type of abundant, highly conserved, stable, and tissue-specific regulatory RNAs, which have been revealed to play significant effects on a variety of biological processes; moreover, circRNAs dysregulation is closely associated with the tumorigenesis and treatment response of hematological malignancies [ 19 ]. In MM, some circRNAs have also been reported to participate in this malignancy progression.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of circ_0058058 suppresses proliferation, angiogenesis and metastasis in multiple myeloma through miR-338-3p/ATG14 pathway

et al. 2021

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Background Multiple myeloma (MM) is one of the most frequently diagnosed hematological malignancy. Dysregulation of circular RNAs (circRNAs) has important impacts on MM process. Herein, this work aimed to investigate the role and mechanism of circ_0058058 in MM progression. Methods Levels of genes and proteins were detected by real-time reverse transcription PCR (RT-qPCR) and Western blot. CCK-8 assay, colony formation assay, EdU assay, flow cytometry, tube formation assay, transwell assay and Western blot were utilized to detect the proliferation, apoptosis, angiogenesis and metastasis of MM cells. The target relationship between miR-338-3p and circ_0058058 or ATG14 (autophagy related 14) was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. In vivo experiments were performed using Xenograft assay. Results Circ_0058058 was up-regulated in MM bone marrow aspirates and cells, knockdown of circ_0058058 reduced MM cell proliferation, angiogenesis and metastasis, but induced apoptosis in vitro. In a MM xenograft mouse model, circ_0058058 silencing reduced MM tumor growth and cell proliferation. Mechanistically, circ_0058058 acted as a sponge for miR-338-3p to up-regulate ATG14 expression, which was validated to be a target of miR-338-3p. Rescue assay showed that miR-338-3p inhibition reversed the antitumor effects of circ_0058058 knockdown on MM cell. Moreover, forced expression of miR-338-3p suppressed MM cell malignant phenotype, which was abolished by ATG14 up-regulation. Conclusion Circ_0058058 functions as a sponge for miR-338-3p to elevate ATG14 expression to promote MM cell proliferation, metastasis and angiogenesis, affording a potential therapeutic target for MM prevention.

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“…AML is an aggressive hematological malignancy (HM) characterized by various genetic abnormalities and epigenetic dysregulation [ 117 , 118 ]. Compared with normal progenitor cells, METTL3 was more abundant in AML cells, coupled with declined cell differentiation and apoptosis both in vitro and in vivo [ 119 , 120 ].…”

Section: Mettl3 Mediates Tumorigenesis Via Rna Methylationmentioning

confidence: 99%

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

et al. 2021

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N6-methyladenosine (m6A) is a prevalent internal RNA modification in higher eukaryotic cells. As the pivotal m6A regulator, RNA methyltransferase-like 3 (METTL3) is responsible for methyl group transfer in the progression of m6A modification. This epigenetic regulation contributes to the structure and functional regulation of RNA and further promotes tumorigenesis and tumor progression. Accumulating evidence has illustrated the pivotal roles of METTL3 in a variety of human cancers. Here, we systemically summarize the interaction between METTL3 and RNAs, and illustrate the multiple functions of METTL3 in human cancer. METLL3 is aberrantly expressed in a variety of tumors. Elevation of METTL3 is usually associated with rapid progression and poor prognosis of tumors. On the other hand, METTL3 may also function as a tumor suppressor in several cancers. Based on the tumor-promoting effect of METTL3, the possibility of applying METTL3 inhibitors is further discussed, which is expected to provide novel insights into antitumor therapy.

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The functions and clinical significance of circRNAs in hematological malignancies

Cited by 54 publications

References 132 publications

Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma

Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma

Down-regulation of circ_0058058 suppresses proliferation, angiogenesis and metastasis in multiple myeloma through miR-338-3p/ATG14 pathway

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

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