Studies On UV Induced MicroRNAs And Their Regulation Of Cell Survival

Ultraviolet (UV) light is electromagnetic radiation with a wavelengthshorter than that of visible light, but longer than X-rays, in the range10nm to400nm. An overexposure to UV radiation can cause sunburn andsome forms of skin cancer, but the molecular mechanism remains unclear.After exposed to UV radiation, a large number of biochemicalreactions will happen in cells, and lots of specific genes will be inducedor reduced, which will play critical roles in modulating cell cycle arrest,DNA repair and cell survival. UV radiation is known to activate multiplesignaling cascades including NF-B pathway. NF-B (Nuclear FactorkappaB) is a family of pivotal transcription factors in orchestratingcellular response to environmental stresses via modulating responsivegene expression.Besides transcription factors, activated ataxia telangiectasia mutated(ATM), which is a nuclear protein kinase belongs to PI3K family, canalso be activated by UV induced DNA double-strand breaks, andregulates apoptosis and cell cycle checkpoint responses. Previous reportshowed that NF-B activation was ATM-dependent in response toreplication stress inducer.Recently, microRNAs have been found to be altered in cells exposedto UV, yet their function in UV stress response remains elusive.MicroRNAs are a group of small noncoding RNAs(≈22nt) involved innegatively regulating posttranscriptional gene expression by binding tothe3’-untranslated region (3’-UTR) of target mRNA. The microRNAprocess can be regulated by lots of posttranscriptional regulators, and as one of them, NF-B can regulate microRNA expression by direct bindingof NF-B subunits to the promoter elements. Also, it has been shown thatATM can regulate microRNA process by promoting its maturation.Here, we found several microRNAs were induced after UV radiation,and we are interested in two of them, which are miR-125b and miR-22. Inour research, miR-125b, which is a well studied microRNA, couldnegatively regulate p38α expression through targeting its3’-UTR.Increase of miR-125b depends on UV-induced NF-B activation, whichenhances miR-125b gene transcription upon UV radiation. The DNAdamage responsive kinase ATM is indispensible for UV-induced NF-Bactivation, which may regulate p38α activation and IKKβ-dependentI Bα degradation in response to UV. Repression of p38α by miR-125bprohibits prolonged hyperactivation of p38α by UV radiation, which isrequired for protecting cells from UV-induced apoptosis. Collectively, ourdata support a critical role of NF-B-dependent upregulation ofmiR-125b, which forms a negative-feedback loop to repress p38αactivation and promote cell survival upon UV radiation.And we also found that UV radiation could induce significant miR-22upregulation, which also appears to be dependent on the activation ofATM (ataxia telan-giectasia mutated). Increased miR-22expression mayresult from enhanced miR-22maturation in cells exposed to UV. Wefurther found that tumor suppressor gene phosphatase and tensin homolog(PTEN) expression was inversely correlated with miR-22induction andUV-induced PTEN repression was attenuated by overexpression of amiR-22inhibitor. Moreover, increased miR-22expression significantlyinhibited the activation of caspase signaling cascade, leading to enhancedcell survival upon UV radiation. Collectively, these results indicate thatmiR-22is an important player in the cellular stress response upon UV radiation, which may promote cell survival via the repression of PTENexpression.In summary, in order to survive, cells develop an anti-apoptosissystem after UV radiation through either induce or reduce some specificgenes expression, we found miR-22and miR-125b, which aresignificantly up-regulated after UV treatment, could separately inhibittwo tumor suppressor genes, PTEN and p38α, and promote cell survival.miR-22might be induced through enhancing its maturation in an ATMdependent manner, while the induction of miR-125b depends on ATMdependent NF-B activation. All these research data may give us a betterunderstand of the tumorigenesis mechanism of skin cancer.