Oxidative Medicine and Cellular Longevity

Review Article

Advances in Understanding Mitochondrial MicroRNAs (mitomiRs) on the Pathogenesis of Triple-Negative Breast Cancer (TNBC)

Table 1

Roles and mechanisms of mitomiRs in metabolic reprogramming.


mitomiR	Function	Target gene	Mechanism of action	Outcome	PMID	Reference

Glucose metabolism
miR-29a	(-)TNBC	ARG2	↓AGR2→↓HIF-1α	↑Apoptosis ↓Proliferation ↓Migration ↓Invasion ↓Tumor growth	33223849	Wang et al., 2020 [28]
miR-210	(+)TNBC	GPD1L, CYGB	↓GPD1L→↑HIF-1α→↑glycolysis ↓CYGB→↓p53→↑glycolysis	↓Apoptosis ↑Tumor growth	32908121	Du et al., 2020 [29]
miR-140	(-)TNBC	GLUT1	↓GLUT1→↓glycolysis	↑OCR/↓ECAR ↓Proliferation ↓Tumor growth	31184216	He et al., 2019 [30]
let-7a	(-)TNBC	STAT3	↓STAT3→↓hnRNPA1→↓PKM2 →↓Glycolysis	↓Proliferation	30368881	Yao et al., 2019 [31]
miR-155	(+)TNBC	PIK3R1, FOXO3a	↓PI3K/↓FOXO3a→↑cMYC →↑HK2/↑PKM2/↑LDHA →↑Glycolysis	↑Tumor growth	29527004	Kim et al., 2018 [32]
miR-128	(-)TNBC	INSR, IRS1	↓INSR/↓INS1→↓p-AKT/↓HK2/↓PFK →↓Glycolysis	↓Mitochondrial bioenergetics ↓Proliferation ↓Tumor growth	29116653	Xiao et al., 2018 [33]
miR-342	(-)TNBC	MCT1	↓MCT1→↓lactate uptake	↓Proliferation ↓Migration	30115973	Romero-Cordoba et al., 2018 [34]
miR-30a	(-)TNBC	LDHA	↓LDHA→↓glycolysis	↑OCR/↓ECAR ↓Proliferation ↓Migration ↓Invasion ↓Tumor growth ↓Tumor metastasis	28461244	Li et al., 2017 [35]
miR-21	(+)TNBC	CAB39L, SESN1	↓CAB39L, ↓SESN1→↓p-AMPK→↑mTOR	↑Proliferation ↑Migration ↑Invasion ↑Tumor growth	28698800	Pulito et al., 2017 [36]
miR-340	(-)TNBC	MCU	↓MCU→↓[Ca²⁺]_m→↓LDH →↓Glycolysis	↓ATP production ↓Lactate production ↓Migration ↓Tumor metastasis	29137386	Yu et al., 2017 [37]
miR-101	(-)TNBC	AMPK	↓AMPK→↓glycolysis	↓Proliferation	27145268	Liu et al., 2016 [38]
miR-18a	(-)TNBC	HIF1A	↓HIF-1α→↓hypoxic gene expression	↓Tumor growth ↓Tumor metastasis	25069832	Krutilina et al., 2014 [39]
miR-143	(-)TNBC	HK2	↓HK2→↓glycolysis	↑Apoptosis ↓Proliferation ↓Tumor growth	22354042	Jiang et al., 2012 [40]
miR-155	(+)TNBC	mir-143	↑miR-155→↓C/EBPβ→ ↓miR-143→↑HK2→↑glycolysis	↑Tumor growth	22354042	Jiang et al., 2012 [40]
Fatty acid metabolism
miR-1291	(-)TNBC	ESRRA	↓ERRα→↓CPT1C	↓Proliferation ↓Tumor growth ↑TNBC sensitivity to 2-DG	32641987	Chen et al., 2020 [41]
let-7a	(-)TNBC	SCD	↓SCD, ↓G6PD, ↓FASN, ↓ASSDHPPT →↑OCR/↑ECR/↑ΔΨm	↓Proliferation ↑TNBC sensitivity to doxorubicin	25669981	Serguienko et al., 2015 [42]
miR-195	(-)TNBC	ACACA, FASN, HMGCR	↓Cellular triglyceride ↓Cellular cholesterol ↓ΔΨm	↓EMT ↓Proliferation ↓Migration ↓Invasion	26632252	Singh et al., 2015 [43]
Glutamine/cystine metabolism
miR-27a	(-)TNBC	SLC7A11, CTH	↓xCT→↓cystine uptake ↓CTH→↓cystine production	↓Mammosphere formation ↓CSC markers ↑TNBC sensitivity to doxorubicin and paclitaxel	32066826	Ueda et al., 2020 [36]
OXPHOS
miR-4485	(-)TNBC	16S rRNA	↓16S rRNA→↓ETC enzymes	↑Cell death ↓Proliferation ↓Tumor growth	28220193	Sripada et al., 2017 [44]
miR-663	(-)TNBC	UQCC2	↓UQCC2→↓complex III activity	↑OXPHOS subunits ↓Invasion ↓Tumor growth	29066618	Carden et al., 2017 [45]

(+): oncogenic; (-): tumor suppressor; “↑”: enhanced; “↓”: reduced; ΔΨm: mitochondrial membrane potential; AASDHPPT: 4-phosphopantetheinyl transferase; ACACA: acetyl-CoA carboxylase; AGR2: anterior gradient 2; [Ca²⁺]_m: mitochondrial calcium; AMPK: AMP-activated protein kinase; CAB39L: calcium-binding protein 39-like; C/EBPβ: CCAAT-enhancer-binding protein β; CPT1C: carnitine palmitoyltransferase 1C; CTH: cystathionine gamma-lyase; CYGB: cytoglobin; ECAR: extracellular acidification rate; EMT: epithelial-mesenchymal transition; ERRα (encoded by ESRRA): estrogen-related receptor alpha; FASN: fatty acid synthase; FOXO3a: forkhead box O3; G6PD: glucose-6-phosphate dehydrogenase; GLUT1: glucose transporter 1; GPD1L: glycerol-3-phosphate dehydrogenase 1; HIF1A/HIF-1α: hypoxia-inducible factor 1-alpha; HK2: hexokinase 2; HMGCR: 3-hydroxy-3-methylglutaryl CoA reductase; INSR: insulin receptor; IRS1: insulin receptor substrate 1; LDHA: lactate dehydrogenase A; MCT1: monocarboxylate transporter 1; MCU: mitochondrial calcium uniporter; mtDNA: mitochondrial DNA; mt-ROS: mitochondrial reactive oxygen species; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; PFK: phosphofructokinase; PI3K: phosphoinositide 3-kinases; PKM2: pyruvate kinase M1/2; SCD: stearoyl-CoA desaturase; SESN1: sestrin-1; STAT3: signal transducers and activators of transcription 3; UQCC2: ubiquinol-cytochrome c reductase complex assembly factor 2; xCT (encoded by SLC7A11): cystine/glutamate transporter.