HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia.
HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia.
复制标题
HIF-1 诱导的线粒体核糖体蛋白 L52：乳腺癌细胞响应缺氧而适应和转移起始的机制。
作者：
Li X;Wang M;Li S;Chen Y;Wang M;Wu Z;Sun X;Yao L;Dong H;Song Y;Xu Y
背景：缺氧是实体肿瘤物理微环境的标志。缺氧作为调控肿瘤发生发展的关键因素，可对多种基因的表达进行重编程，其在肿瘤中的生物学功能和分子机制尚不清楚。线粒体核糖体蛋白家族由核编码的线粒体蛋白组成，负责线粒体中的蛋白质合成。方法：采用高通量RNA测序方法，鉴定乳腺癌组织与邻近正常组织、乳腺癌转移瘤与非转移瘤之间mrna的差异表达。我们对临床样本和TCGA数据库进行分析，观察线粒体核糖体蛋白L52 （MRPL52）在人乳腺癌中的临床价值。MRPL52启动子区域的强效缺氧反应元件通过染色质免疫沉淀和荧光素酶报告基因检测被鉴定和验证。使用MRPL52异位表达和敲低的乳腺癌细胞系在20%或1% O2环境中培养进行功能实验。结果：MRPL52在人乳腺癌中表达上调，与乳腺癌患者侵袭性临床病理特征和更高的转移风险显著相关。我们发现MRPL52在乳腺癌中的过表达是由缺氧诱导因子-1诱导的，以应对缺氧暴露。我们的实验证明了MRPL52在抑制缺氧乳腺癌细胞凋亡、促进迁移和侵袭中的作用。在机制上，MRPL52促进pten诱导的假定的激酶1 /帕金森依赖的线粒体自噬，去除氧化损伤的线粒体，防止不受控制的活性氧（ROS）的产生，从而抑制线粒体凋亡级联的激活。此外，MRPL52通过激活ROS-Notch1-Snail信号通路，增强了缺氧乳腺癌细胞的上皮-间质转化、迁移和侵袭。得益于这种双向调节机制，MRPL52负责维持一个窗口内的ROS水平，该窗口可以诱导致瘤性信号转导，而不会引起缺氧乳腺癌细胞的细胞毒性。结论：本研究阐明了MRPL52介导缺氧诱导的乳腺癌凋亡抵抗和转移起始的分子机制，为癌症与肿瘤微环境的相互作用提供了新的认识。
Background: Hypoxia is a hallmark of the physical microenvironment of solid tumors. As a key factor that regulates tumor development and progression, hypoxia can reprogram the expression of multiple genes, whose biological function and molecular mechanism in cancer remain largely unclear. The mitochondrial ribosome protein family consists of nuclear-encoded mitochondrial proteins that are responsible for protein synthesis in the mitochondria. Methods: A high-throughput RNA sequencing assay was carried out to identify differentially expressed mRNAs between breast cancer tissues and adjacent normal tissues as well as breast tumors with metastasis and those without metastasis. Our clinical samples and TCGA database were analyzed to observe the clinical value of mitochondrial ribosome protein L52 (MRPL52) in human breast cancer. Potent hypoxia response elements in the promoter region of MRPL52 were identified and validated by chromatin immunoprecipitation and luciferase reporter assays. Functional experiments were performed using breast cancer cell lines with MRPL52 ectopic expression and knockdown cultured in a 20% or 1% O2 environment. Results: MRPL52 expression was upregulated in human breast cancer and was significantly associated with aggressive clinicopathological characteristics and a higher metastatic risk of breast cancer patients. We found that the overexpression of MRPL52 in breast cancer is induced by hypoxia-inducible factor-1 in response to hypoxic exposure. The role of MRPL52 in suppressing apoptosis and promoting migration and invasion of hypoxic breast cancer cells was demonstrated by our experimental evidence. Mechanistically, MRPL52 promoted PTEN-induced putative kinase 1 /Parkin-dependent mitophagy to remove oxidatively damaged mitochondria and prevent uncontrolled reactive oxygen species (ROS) generation, thus repressing activation of the mitochondrial apoptotic cascade. Additionally, MRPL52 augmented epithelial-mesenchymal transition, migration and invasion of hypoxic breast cancer cells by activating the ROS-Notch1-Snail signaling pathway. Benefited from this bidirectional regulatory mechanism, MRPL52 is responsible for maintaining ROS levels in a window that can induce tumorigenic signal transduction without causing cytotoxicity in hypoxic breast cancer cells. Conclusions: This work elucidates the molecular mechanism by which MRPL52 mediates hypoxia-induced apoptotic resistance and metastatic initiation of breast cancer, and provides new insights into the interplay between cancer and the tumor microenvironment.