TRIM72 exerts antitumor effects in breast cancer and modulates lactate production and MCT4 promoter activity by interacting with PPP3CA.
TRIM72 exerts antitumor effects in breast cancer and modulates lactate production and MCT4 promoter activity by interacting with PPP3CA.
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DOI：
10.1097/cad.0000000000001304
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发表时间：
2022-06-01
影响因子：
2.3
通讯作者：
Qiu Y
中科院分区：
文献类型：
--
作者：
Wang Z;Li H;Wang H;Li X;Zhang Q;Wang H;Li K;Qiu Y
低氧肿瘤微环境（TME）促进癌症进展，但其作为治疗靶点的价值仍未得到充分利用。TRIM 72可以保护细胞免受包括缺氧在内的各种应激。最近，低TRIM 72表达与癌症进展有关。然而，TRIM 72在乳腺癌（BC）中的生物学作用和分子机制仍不清楚。在此，我们分析了TRIM 72在BC组织和细胞系中的表达，通过蛋白质印迹（WB）和定量逆转录PCR。我们建立了使用质粒和慢病毒介导的上调TRIM 72的过表达，以及通过siRNA下调蛋白磷酸酶3催化亚基α（PPP 3CA）。通过MTS、Transwell和流式细胞术测定法在体外和在体内异种移植肿瘤中对BT549和MDA-MB-231细胞评估TRIM 72的肿瘤抑制作用。通过荧光素酶报告基因和免疫共沉淀（Co-IP）分析研究TRIM 72的分子机制。通过ELISA测定CoCl 2诱导的低氧环境下的乳酸产生。此外，WB检测到BC细胞中PI 3 K/Akt/mTOR通路相关蛋白的表达。结果表明，TRIM 72在BC中下调。TRIM 72的过表达在体外和异种移植肿瘤模型中抑制肿瘤增殖和侵袭。PPP 3CA在机制上改变了TRIM 72对缺氧诱导的乳酸产生和单羧酸转运蛋白4启动子活性的抑制作用，以及PI 3 K/Akt/mTOR信号通路的作用。我们的研究表明，TRIM 72调节TME并在BC进展中发挥肿瘤抑制作用。因此，TRIM 72可能作为BC的潜在治疗靶点。
A hypoxic tumor microenvironment (TME) promotes cancer progression, yet its value as a therapeutic target remains underexploited. Tripartite motif-containing 72 (TRIM72) may protect cells against various stresses including hypoxia. Recently, low TRIM72 expression has been implicated in cancer progression. However, the biological role and molecular mechanism of TRIM72 in breast cancer (BC) remain unclear. Herein, we analyzed the TRIM72 expression in BC tissue and cell lines by western blot (WB) and quantitative reverse transcription-PCR. We established the overexpression of TRIM72 using plasmids and lentiviral-mediated upregulation, as well as downregulation of protein phosphatase 3 catalytic subunit alpha (PPP3CA) by siRNA. The tumor-suppressive roles of TRIM72 were assessed on BT549 and MDA-MB-231 cells by MTS, Transwell, and flow cytometry assays in vitro and in xenografted tumors in vivo. The molecular mechanism of TRIM72 was investigated by luciferase reporter and co-immunoprecipitation (Co-IP) assay. Lactate production was measured by ELISA under hypoxic environments induced by CoCl2. Moreover, the expression of PI3K/Akt/mTOR pathway-associated proteins was detected by WB in BC cells. Results showed that TRIM72 was downregulated in BC. Overexpression of TRIM72 inhibited tumor proliferation and invasion in vitro and in a xenograft tumor model. Mechanistically, PPP3CA altered the inhibitory effects of TRIM72 on hypoxia-induced lactate production and monocarboxylate transporter 4-promoter activity, as well as the effect of the PI3K/Akt/mTOR signaling pathway. Our study suggests that TRIM72 modulates the TME and plays tumor-suppressive roles in BC progression. Therefore, TRIM72 may serve as a potential therapeutic target in BC.