종양 세포 대사에서의 MicroRNA: 역할 및 치료 기회

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917641/

MicroRNAs in Tumor Cell Metabolism: Roles and Therapeutic Opportunities

 

 

Drugs with clinical potential in cancer that modulate miRNAs implicated in cell metabolism

상자에는 종양 세포의 대사 재프로그래밍과 관련된 주요 miRNA를 잠재적으로 조절하는 약물이 표시됩니다. 

증가된 해당 과정, 

PI3K/AKT/mTOR 경로의 변경, 

상피-중간엽 전이(EMT)는 종양 세포가 생존, 

증식, 이동 및 새로운 틈새를 피하기 위해 대사를 재프로그래밍할 수 있도록 하는 핵심 과정입니다. 

다양한 miRNA가 효소(예: HK2, PKM2, IRS1, PI3K, AKT, mTOR), 

전사 인자(예: SP1, SIX1, ZEB1, ZEB2, GABPA) 및 

세포 수용체(e.g., GLUT3, ESRRG).의 발현을 억제하는 이러한 과정에 참여합니다.

 

Table 2

miRNAs target by metabolic-drugs or miRNAs related to therapy resistance.

DrugDruggable miRNA/Therapy-resistance miRNA*CancerReferences

Targeting glucose metabolism
Metformin	↑let-7a, let-7b, miR-26a, 101, 192, 200b and 200c. Over-expression of miR-26a decrease cancer stem-cells markers, an enhanced apoptosis rate. Let-7b re-expression blocks stem cells features	PC BRCA Oral Renal	(170–174)
	↑miR-34a in obese mice reducing its putative targets (Notch, Slug, Snail) ↑miR-34a which in turn restrict Sirt1/Pgc1α/Nrf2 signaling pathway and decrease proliferation rates	PC	(175) (176, 177)
	↓miR-27a which AMPKα and ↑miR-193 family that increased AMPKα and decrease FASN levels, resulting in limiting mammospheres phenotype	BRCA	(178, 179)
	Combined treatment of metformin + FuOx ↓miR-21 and ↑miR-145, that suppress β-catenin and c-Myc signaling expression colon cancer cells	CRC	(180)
	↑miR-141, 200a, 205 and 429 inhibiting EMT, thus, modulating metastatic traits	GC	(181)
	↑mir-124, 182, 27b, let7b and ↓miR-221 and 181a; inhibiting cell proliferation	CLC	(182)
	↑miR-192-5p, 584-3p, and 1246; suppressing cell motility and cell cycle	M	(183)
	↑DROSHA, modulate the miRNA biogenesis, to affect these miRNAs expression	CLC	(182)
	↓miR-222 resulting in enhance abundance of p27, p57, and PTEN ↓miR-222 resulting in enhance abundance of p27, p57, and PTEN	Lung	(184)
	↑DICER expression and miR-33a that targets c-MYC	BRCA	(185)
	↓miR-146a, 100, 425, 193a-3p and 106b involved in cell migration, invasion and proliferation	PCA	(186)
	↑miR-192-5p, miR-584-3p, and miR-1246 enhance EFEMP1 and SCAMP3 downmodulation favoring the suppression of cancer cell motility and growth through G2/M cell cycle arrest and cell apoptosis	M	(183)
	RS:↑miR-21 ↓miR-21 and ↑miR-145 over combined treatment with 5-fluorouracil and oxaliplatin, that suppress β-catenin and c-Myc expression, and consequently reduce cell growth and sphere formation ↓miR-21-5p in cell lines model, xenograft murine model and in tissue from human patients. Since also the pre-miRNA sequence is down-modulated the modulation seems to be at the transcriptional level. Functional reduction of miR-21-5p allow the expression of upstream activators of the AMPK, CAB39L and SESN1	CRCBRCA	(187) (180)(188)
Dichloroacetate (DCA)	Promising therapeutic agents to ↓miR-210	Cancer	(189)
	↑miR-375 resulting in anti-proliferating effects	PCA	(190)
CPI-613	May improve miR-497-5p,−449a,−25-3p,−6838-5p,−520d-3p that down-modulates the expression of Cyclin D3, E1, E2, F, A2, B1 and CDK2 genes of BxPC-3	Cancer	(189)
Targeting FA metabolism
Statins	Lovastatin upregulated miR-33b expression, reduced cell proliferation and impaired c-Myc expression	MB	(191)
	Simvastatin: inhibits the growth of human CRPC cells by suppressing NF-κB and LIN28B and ↑let-7 miRNA family	PCA	(192)
	Simvastatin: ↓miR-34a, which regulates the NAD+-dependent histone deacetylas e SIRT1. ↑miR-612, which is known to reduce stemness	BRCA, PCA, OsC	(193)
	Simvastatin is an activator of miR-192 which subsequently led to suppressed proliferation, migration and invasion	CRC	(194)
	Atorvastatin: ↑miR-182 that targets the anti-apoptotic Bcl-2 and p21	PCA	(195)
	↑miR-140-5p activating the transcription factor NRF1 that reduced cell proliferation and induced apoptosis	BRCA	(196)
	Fluvastatin: ↓miR-140-3p-1 and its downstream pathway such as cell growth	BRCA	(197)
	Statin: ↑miR-33a promoting a proliferation inhibitory effect	PCA	(198)
	lovastatin: ↓miR-133a promoting GCH1 important for endothelial nitric oxide synthase	Cancer	(199)
Rapamycin	Rapamycin-dependent miRNA: ↑miR-29b, 21, 24, 221, 106a, and 199a	Renal	(200)
	↑let-7, miR-125a,−125b,−21, and−26a. Rapamycin is mediated by let-7 family with anti-proliferative effects	Renal	(201)
	*RS: miR-21 supports mitochondrial function and adaptation to rapamycin	Renal	(200)
	Long-term rapamycin treatment RS: ↑MYC that results in ↑miR-17–92	Brain	(201)
Aspirin and non-steroidal anti-inflammatory agents	↑miR-98 that targets WNT1, suppressing cell proliferation	Lung	(202)
	Sulindac drug: ↓miR-9,−10b,−17, and−21 by suppressing NF-κB-mediated transcription of miRNAs	BRCA CRC	(203)
	↓miR-21 decreasing cell proliferation and invasion upon inactivation of β-catenin/TCF4 signaling	CRC	(204)
	↑let-7 by decreasing the miRNA-sponge H19, resulting in the down-modulation Hypoxia-inducible factor 1α reducing l PDK1, attenuating glycolysis	BRCA	(195)
	Celecoxib: ↑miR-29c supress the oncogen MCL-1 reducing apoptosis	GC	(205)
TVB-2640	miR-15 and miR-16-6: Inhibition of FASN: Agonist effect	BRCA	(206)
Targeting lactate metabolism: LDHA inhibitors
AZD3965	miR-342-3p: Inhibition of the monocarboxylate transporter MCT1: Agonist effect	BRCA	(103)
Antimetabolite chemotherapeutic agents
Methotrexate (MTX)	*RS: ↑miR-24 SNPresults		(207)
	*RS: ↑miR-140	OsC, CRC	(208)
	*RS: ↑miR-215 modulated DTL, a cell cycle-regulated gene	OsC, CRC	(209)
Capecitabine	↑miR-125b-5p ↑miR-137	Cancer	(189)
5-Fluorouracil	↓Relevant oncogenes such as miR-210	HCC CRCOsC	(208, 210, 211)
	↑Relevant tumor suppressor miRs: let-7 family, miR-15b,−16,−23a,−23b, and−200c	BRCA	(189)
	*ES: ↑miR122 through the inhibition of M2 splice isoform of pyruvate kinase (PKM2) in vitro and in vivo	CRC	(212)
	*RS: ↑miR-21 and−221	BRCA	(213)
	*RS: ↑miR-21,−34,−140	HCC CRCOsC	(212)
Gemcitabine	May impact the expression of 56 relevant miRNAs such as miR-200,−205,−27a,−27b, and let 7 family	Cancer	(214, 215)
	*ES: ↑microRNA-218 by inhibiting the secretion of HMGB1 by PANC-1 cells and the PI3K/Akt pathway	PC	(212)
	*RS: ↑miR-21,−34,−140	PC	(214, 215)
Targeting glutamine metabolism
Pegylated arginine deiminase (ADI-PEG)	Bioengineered pre-miR-1291 processed to high levels of mature miR-1291. *ER: ↑miR-1291 increases sensitivity to ADI-PEG (trough modulation of ASS1 and GLUT1)

*Therapy-resistance miRNA. ↑, over-expression; ↓, down-regulation. Therapy-resistance miRNA: RS, reduce sensitivity; ES, enhanced sensitivity. Cancer: BRCA, breast cancer; CRC, colorectal cancer; PCA, prostate cancer; PC, pancreatic cancer; HCC hepatacarcinoma; CLC, cholangiocarcinoma; MB, medulloblastoma; OsC, osteosarcoma; GC, Gastric; M,Melanoma.