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Circular RNA TMEM87A promotes cell proliferation and metastasis of gastric cancer by elevating ULK1 via sponging miR-142-5p (circRNA)

ABSTRACT: Background:Circular RNAs (circRNAs) act as vital regulators of gene expression in a variety of cancers. However, the role of circRNAs in gastric cancer (GC) remains largely unexplored. Herein, we identified that circTMEM87A sponges miR-142-5p to promote GC progression through up-regulating ULK1 expression. Methods:The expression of circTMEM87A in GC was determined by RNA sequencing and quantitative real-time PCR (qRT-PCR). The effects of knockdown or exogenous expression of circTMEM87A on GC cell phenotypes were evaluated both in vitro and in vivo. The interacting miRNA of circTMEM87A was predicted by bioinformatics and confirmed by RNA pull-down, dual-luciferase reporter assay and fluorescence in situ hybridization (FISH). The mechanism by which circTMEM87A/miR-142-5p/ULK1 axis promotes GC was determined by western blot, GFP/mRFP-LC3 puncta analysis, transmission electron microscope (TEM). Results:CircTMEM87A was dramatically elevated in GC tissues and cell lines, and high circTMEM87A expression was closely correlated with poor prognosis of GC patients. Knockdown of circTMEM87A suppressed cell growth, migration, invasion and induced apoptosis in vitro, as well as inhibited GC tumorigenicity and lung metastasis potential in vivo. Meanwhile, circTMEM87A overexpression had the opposite effects. Furthermore, we demonstrated that circTMEM87A could act as a sponge of miR-142-5p to regulate ULK1 expression and GC progression. Conclusions:Our findings suggest that circTMEM87A functions as an oncogene through the miR-142-5p/ULK1 axis in GC. CircTMEM87A might be a prognostic biomarker as well as a promising therapeutic target for GC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157013 | GEO | 2023/08/19

REPOSITORIES: GEO

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Project description:MiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.

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Circular RNA TMEM87A promotes cell proliferation and metastasis of gastric cancer by elevating ULK1 via sponging miR-142-5p (circRNA)

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