HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia

Abstract

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% O 2 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.

LncRNA LINC00152 promotes oral squamous cell carcinoma growth via enhancing Upstream Transcription Factor 1 mediated Mitochondrial Ribosomal Protein L52 transcription

“…In breast cancer, MRPL52 was identified as a cancer‐promoting oncogene via modulating mitophagy under hypoxia 30 . It suppresses tumor cell apoptosis and accelerates invasion and migration under hypoxic conditions by promoting the removal of oxidatively damaged mitochondria and preventing an excessive generation of reactive oxygen species (ROS) 30 . Bioinformatic analysis in the current study confirmed the upregulation of MRPL52 in OSCC tumor tissues and its correlation with poor prognosis.…”

“…MRPL52 is a component of the mitoribosome large subunit. In breast cancer, MRPL52 was identified as a cancer‐promoting oncogene via modulating mitophagy under hypoxia 30 . It suppresses tumor cell apoptosis and accelerates invasion and migration under hypoxic conditions by promoting the removal of oxidatively damaged mitochondria and preventing an excessive generation of reactive oxygen species (ROS) 30 .…”

Protective effect of HINT2 on mitochondrial function via repressing MCU complex activation attenuates cardiac microvascular ischemia–reperfusion injury

“…Mitochondria are dynamic organelles that perform selfrepair via mitochondrial fission and fusion, two distinctly opposite processes in which one separates the damaged fractions from the whole mitochondrial body and the other merges two fractions into a healthy mitochondrion [39]. The balance of fission and fusion is critical to maintain mitochondrial and endothelial function [7,28]. However, mitochondrial fission in the coronary microcirculation is excessively activated after reperfusion, which further accentuates mitochondrial reactive oxygen species (ROS) accumulation, mitochondrial permeability transition pore (mPTP) opening, and apoptosis activation, ultimately resulting in microvascular dysfunction [51].…”

Vitexin Inhibits Gastric Cancer Growth and Metastasis through HMGB1-mediated Inactivation of the PI3K/AKT/mTOR/HIF-1α Signaling Pathway

“…The rapid growth of tumor cells may result in hypoxia even with an abundant supply of oxygen, and the insufficient vascularization in solid tumors further amplifies the hypoxia response within tumor cells [ 39 ]. In response to hypoxia, cancer cells exhibit modified expression of many genes regulated by HIF-1α, which is the major component of hypoxia signaling pathways [ 40 ].…”