PAQR3 facilitates the ferroptosis of diffuse large B-cell lymphoma via the regulation of LDLR-mediated PI3K/AKT pathway

IF 3.3 4区 医学 Q2 HEMATOLOGY
Xiangxiang Song, Weiming Zhang, Nasha Yu, Xing Zhong
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Abstract

Progesterone and adiponectin receptor 3 (PAQR3) has been found to regulate tumor progression by mediating cell ferroptosis. However, whether PAQR3 mediates ferroptosis in diffuse large B-cell lymphoma (DLBCL) needs further investigation. The mRNA and protein levels of PAQR3 and low-density lipoprotein receptor (LDLR) were assessed by qRT-PCR and WB assays. Cell proliferation was detected by MTT assay and EdU assay. Shrunken mitochondria was counted under transmission electron microscope. Cell ferroptosis was evaluated by measuring the levels of malondialdehyde, reactive oxygen species, glutathione, Fe2+, and the protein expression of ferroptosis-related markers. PAQR3 and LDLR interaction was confirmed by RIP assay and pull-down assay. Our study showed that PAQR3 was underexpressed, while LDLR was overexpressed in DLBCL tissues and cells. Functionally, PAQR3 overexpression or LDLR knockdown restrained DLBCL cell proliferation and enhanced ferroptosis. Mechanistically, PAQR3 reduced LDLR expression by inhibiting its mRNA stability. Meanwhile, LDLR overexpression reversed PAQR3-mediated the promoting on DLBCL cell ferroptosis, and LY294002 (PI3K/AKT inhibitor) eliminated the inhibiting effects of LDLR overexpression on DLBCL cell ferroptosis. Additionally, excessive PAQR3 reduced DLBCL tumor growth by enhancing tumor cell ferroptosis through LDLR-mediated PI3K/AKT pathway. In conclusion, our data suggested that PAQR3 restrained DLBCL progression by aggravating ferroptosis, which was achieved by inhibiting LDLR expression to repress PI3K/AKT pathway.

PAQR3通过调控LDLR介导的PI3K/AKT通路促进弥漫大B细胞淋巴瘤的铁变态反应。
研究发现,孕酮和脂肪连接素受体3(PAQR3)可通过介导细胞铁凋亡来调节肿瘤的进展。然而,PAQR3是否在弥漫大B细胞淋巴瘤(DLBCL)中介导铁凋亡还需要进一步研究。通过qRT-PCR和WB检测评估了PAQR3和低密度脂蛋白受体(LDLR)的mRNA和蛋白水平。细胞增殖通过 MTT 试验和 EdU 试验进行检测。在透射电子显微镜下对萎缩的线粒体进行计数。通过测量丙二醛、活性氧、谷胱甘肽、Fe2+ 的水平以及铁变态反应相关标记物的蛋白表达来评估细胞铁变态反应。PAQR3 和 LDLR 的相互作用通过 RIP 试验和牵引试验得到了证实。我们的研究表明,在DLBCL组织和细胞中,PAQR3表达不足,而LDLR表达过高。从功能上讲,PAQR3 的过表达或 LDLR 的敲除抑制了 DLBCL 细胞的增殖并增强了铁变态反应。从机理上讲,PAQR3通过抑制LDLR的mRNA稳定性来减少其表达。同时,LDLR的过表达逆转了PAQR3介导的对DLBCL细胞铁凋亡的促进作用,而LY294002(PI3K/AKT抑制剂)消除了LDLR过表达对DLBCL细胞铁凋亡的抑制作用。此外,过量的PAQR3可通过LDLR介导的PI3K/AKT通路增强肿瘤细胞的铁凋亡,从而减少DLBCL肿瘤的生长。总之,我们的数据表明,PAQR3通过抑制LDLR的表达来抑制PI3K/AKT通路,从而通过加重铁凋亡抑制DLBCL的进展。
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来源期刊
Hematological Oncology
Hematological Oncology 医学-血液学
CiteScore
4.20
自引率
6.10%
发文量
147
审稿时长
>12 weeks
期刊介绍: Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.
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