UBASH3B-mediated MRPL12 Y60 dephosphorylation inhibits LUAD development by driving mitochondrial metabolism reprogramming.

BACKGROUND: Metabolic reprogramming plays a pivotal role in tumorigenesis and development of lung adenocarcinoma (LUAD). However, the precise mechanisms and potential targets for metabolic reprogramming in LUAD remain elusive. Our prior investigations revealed that the mitochondrial ribosomal protein MRPL12, identified as a novel mitochondrial transcriptional regulatory gene, exerts a critical influence on mitochondrial metabolism. Despite this, the role and regulatory mechanisms underlying MRPL12's transcriptional activity in cancers remain unexplored. METHODS: Human LUAD tissues, Tp53fl/fl;KrasG12D-driven LUAD mouse models, LUAD patient-derived organoids (PDO), and LUAD cell lines were used to explored the expression and function of MRPL12. The posttranslational modification of MRPL12 was analyzed by mass spectrometry, and the oncogenic role of key phosphorylation sites of MRPL12 in LUAD development was verified in vivo and in vitro. RESULTS: MRPL12 was upregulated in human LUAD tissues, Tp53fl/fl;KrasG12D-driven LUAD tissues in mice, LUAD PDO, and LUAD cell lines, correlating with poor patient survival. Overexpression of MRPL12 significantly promoted LUAD tumorigenesis, metastasis, and PDO formation, while MRPL12 knockdown elicited the opposite phenotype. Additionally, MRPL12 deletion in a Tp53fl/fl;KrasG12D-driven mouse LUAD model conferred a notable survival advantage, delaying tumor onset and reducing malignant progression. Mechanistically, we discovered that MRPL12 promotes tumor progression by upregulating mitochondrial oxidative phosphorylation. Furthermore, we identified UBASH3B as a specific binder of MRPL12, dephosphorylating tyrosine 60 in MRPL12 (MRPL12 Y60) and inhibiting its oncogenic functions. The decrease in MRPL12 Y60 phosphorylation impeded the binding of MRPL12 to POLRMT, downregulating mitochondrial metabolism in LUAD cells. In-depth in vivo, in vitro, and organoid models validated the inhibitory effect of MRPL12 Y60 mutation on LUAD. CONCLUSION: This study establishes MRPL12 as a novel oncogene in LUAD, contributing to LUAD pathogenesis by orchestrating mitochondrial metabolism reprogramming towards oxidative phosphorylation (OXPHOS). Furthermore, it confirms Y60 as a specific phosphorylation modification site regulating MRPL12's oncogenic functions, offering insights for the development of LUAD-specific targeted drugs and clinical interventions.

Circular RNA hsa_circ_0102231 sponges miR-145 to promote non-small cell lung cancer cell proliferation by up-regulating the expression of RBBP4.

Circular RNAs (circRNAs) are important regulators in various cancers. Previous studies have found that hsa_circ_0102231 is an oncogene in lung adenocarcinoma. Here, we investigated its mechanism in the development of non-small cell lung cancer (NSCLC). We detected the levels of hsa_circ_0102231 in five NSCLC cell lines and one normal bronchial epithelium cell line. The interaction between hsa_circ_0102231 and miR-145 was predicted and confirmed by pull-down and luciferase assays. The nuclear mass separation assay and fluorescence in situ hybridization were used to detect the distribution of hsa_circ_0102231. Cell Counting Kit-8 and Transwell assays were used to assess the cell proliferative and invasive ability. Western blot and RT-qPCR, respectively, detected the protein and mRNA levels of RBBP4. The RBBP4 promoter activity was detected with a luciferase assay. We found that hsa_circ_0102231 level was higher in NSCLC cells. hsa_circ_0102231 is mainly localized to the cytoplasm. hsa_circ_0102231 promotes NSCLC cell proliferation and invasion by sponge for miR-145. miR-145 significantly decreases the RBBP4 promoter activity, and its mRNA and protein levels. RBBP4 is an oncogene to promote proliferation and invasion ability. Our findings suggest that hsa_circ_0102231 promotes proliferation and invasion by mediating the miR-145/RBBP4 axis in NSCLC, indicating that it might be a potential target for NSCLC treatment.