Yeungnam Univ J Med.  2021 Apr;38(2):107-117. 10.12701/yujm.2020.00836.

The role of microRNAs in cell death pathways

• Jang JH
• Lee TJ

• KMID: 2515184
• DOI: http://doi.org/10.12701/yujm.2020.00836

Abstract

MicroRNAs (miRNAs) are a class of noncoding RNAs that negatively regulate target messenger RNAs. In multicellular eukaryotes, numerous miRNAs perform basic cellular functions, including cell proliferation, differentiation, and death. Abnormal expression of miRNAs weakens or modifies various apoptosis pathways, leading to the development of human cancer. Cell death occurs in an active manner that maintains tissue homeostasis and eliminates potentially harmful cells through regulated cell death processes, including apoptosis, autophagic cell death, and necroptosis. In this review, we discuss the involvement of miRNAs in regulating cell death pathways in cancers and the potential therapeutic functions of miRNAs in cancer treatment.

Keyword

Apoptosis; Autophagy; Endoplasmic reticulum stress; MicroRNAs; Necroptosis

Figure

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  Fig. 1. MicroRNAs (miRs) that regulate the apoptotic signaling pathways. The yellow box indicates the components of the extrinsic apoptotic signaling pathway. When a death ligand binds to a death receptor (DR), an exogenous pathway is initiated. The light green box indicates the components of the intrinsic pathway. Activation of the intrinsic pathway or mitochondrial pathway releases cytochrome c into the cytoplasm. TRAIL, tumor necrosis factor (TNF)-related apoptosis-inducing ligand; FasL, Fas ligand; TNFR, TNF receptor 1; FADD, Fas-associated death domain protein; c-FLIP, cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein; Bid, BH3 interacting-domain death agonist; tBid, truncated Bid; Smac, second mitochondria-derived activator of caspases, also referred to as DIABLO; Bak, Bcl-2 homologous antagonist killer; Bax, Bcl-2-like protein 4; Bcl-2, B-cell lymphoma 2; Bcl-xL, B-cell lymphoma-extra large; XIAP, X-linked inhibitor of apoptosis; Apaf1, apoptotic protease activating factor 1.

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  Fig. 2. MicroRNAs (miRNAs or miRs) that regulate the endoplasmic reticulum (ER) stress pathways. Various miRNAs play a role in survival or apoptosis under ER stress conditions. A critical step in unfolded protein response (UPR) signaling is the initial detection of ER stress. PERK, ATF6, and IRE1α possess UPR sensors that are activated by ER stress. BIP, binding immunoglobulin protein, also known as GRP78; PERK, protein kinase RNA-like ER kinase; ATF, activating transcription factor; IRE1α, inositol-requiring enzyme 1 alpha; EIF2α, eukaryotic initiation factor 2 alpha; CHOP, CCAAT-enhancer-binding protein homologous protein; XBP1, X box-binding protein 1.

• 

  Fig. 3. MicroRNAs (miRs) that regulate necroptotic signaling pathways. Necroptosis is stimulated by TLR, IFNR, and TCR, which are members of the tumor necrosis factor (TNF) receptor superfamily. Extrisic stimili such as cellular stress, damage, and infection activated TNFR1, which can lead to cell survival, apoptosis, or necroptosis. cIAP1 and cIAP2 ubiquitinate RIP1, whereas CYLD deubiquitinates RIP1. MLKL is a critical substrate of RIP3 during the induction of necroptosis. TNFR1, TNF-α receptor 1; CYLD, cylindromatosis; TRAF2, TNF receptor-associated factor 2; RIP1, receptor-interacting protein kinase 1; TRADD, TNFR1-associated death domain protein; c-IAP1/2, cellular inhibitor of apoptosis protein 1/2; IKK, IκB kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; FADD, Fas-associated protein with death domain; TLRs, toll-like receptors; TCR, T-cell receptor; IFNRs, interferon receptors; c-FLIP, cellular FLICE (FADD-like interleukin-1β-converting enzyme) inhibitory protein; MLKL, mixed lineage kinase domain-like; PGAM5, phosphoglycerate mutase 5; Drp1, dynamin-related protein 1.

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  Fig. 4. miRNAs involved in the autophagy pathways. Autophagy occurs under a variety of conditions, such as cell growth signaling, glucose deficiency, hypoxia, genotoxicity, and endoplasmic reticulum (ER) stress, and activates signaling pathways that initiate or inhibit the autophagy cascade. The mTOR and AMPK proteins are important regulators of the autophagy pathway. mLST8, mammalian lethal with Sec13 protein 8, also referred to as GβL; mTOR, mammalian target of rapamycin; Raptor, regulatory-associated protein of mTOR; mTORC1, mTOR complex 1; ULK, Unc-51-like kinase; AMPK, AMP-activated protein kinase; TAK1, transforming growth factor β-activated kinase 1; ATG4, autophagy-related 4 cysteine peptidase; LC3, microtubule-associated proteins 1A/1B light chain 3B; AMP, adenosine monophosphate; ATP, adenosine triphosphate; LKB1, liver kinase B1; CAMKKβ, calcium/calmodulin kinase kinase beta; eIF2α, eukaryotic initiation factor 2 alpha; DAPK, death-associated protein kinase.

Reference

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