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AMOT suppresses tumor progression via regulating DNA damage response signaling in diffuse large B-cell lymphoma

Abstract

Angiomotin (AMOT) is a membrane protein that is aberrantly expressed in a variety of solid tumors. Accumulating evidence support that AMOT is involved in the pathological processes of tumor proliferation, apoptosis, and invasion. However, the potential role of AMOT in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) remains elusive. In the present study, we investigated the expression level and biological function of AMOT in DLBCL. AMOT expression was significantly reduced in DLBCL biopsy section, and low AMOT expression was associated with poor clinical prognosis. Overexpression of AMOT by lentivirus in human DLBCL cells induced cell viability inhibition concomitant with an increased percentage of cells in G1 phase and decreased percentage in S phase. Moreover, AMOT upregulation increased the sensitivity of DLBCL cells to doxorubicin. Furthermore, overexpression of AMOT led to reduced activation of key kinases for the DNA damage response (DDR). The above results indicated that AMOT acts as a tumor suppressor via inhibition of the DDR, thus reducing the viability while increasing the chemosensitivity in DLBCL. In summary, AMOT may be a novel potential target for DLBCL therapeutic intervention.

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Fig. 1: AMOT was downregulated in DLBCL and related to poor prognosis.
Fig. 2: Role of AMOT in DLBCL cell proliferation.
Fig. 3: AMOT induced cell cycle arrest and attenuated DDR checkpoint protein activation.
Fig. 4: AMOT increases chemosensitivity to doxorubicin in DLBCL cell lines.
Fig. 5: AMOT attenuated the key checkpoint kinase activity in doxorubicin-induced DNA damage response.

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All data generated and analyzed during this study are included in this article and its supplementary information files.

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Funding

This study was funded by Translational Research Grant of National Clinical Research Center for Hematologic Diseases (NCRCH) (No. 2020ZKMB01); National Natural Science Foundation (No. 81800194, No. 82070203, No. 81770210, No. 81270598, and No. 81473486); Key Research and Development Program of Shandong Province (No. 2018CXGC1213); Technology Development Projects of Shandong Province (No. 2017GSF18189); Shandong Provincial Natural Science Foundation (No. ZR2018BH011); China Postdoctoral Science Foundation (No. 2020M672103); Development Project of Youth Innovation Teams in Colleges and Universities of Shandong Province (No. 2020KJL006); Technology Development Project of Jinan City (No. 201805065); Taishan Scholars Program of Shandong Province; Academic promotion programme of Shandong First Medical University; Shandong Provincial Engineering Research Center of Lymphoma.

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Sang, T., Yang, J., Liu, J. et al. AMOT suppresses tumor progression via regulating DNA damage response signaling in diffuse large B-cell lymphoma. Cancer Gene Ther 28, 1125–1135 (2021). https://doi.org/10.1038/s41417-020-00258-5

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