in alcohol dependence).
FOXP3 importance for carcinogenesis The tumor suppressor gene p53 increases Foxp3 expression by binding directly to the its promoter region of the conserved non-coding DNA sequence CNS-2. (Kawashima et al., 2013) P53 may not only play its immunosuppressive but also its anticarcinogenic role through FOXP3 activation. As already mentioned, protooncogene p53 plays an important role in aging and aging relevant diseases.(Reinhardt And Schumacher, 2012; Carrasco‐Garcia et al., 2017; Nicolai et al., 2015) p53 controls ROS in connection with expression of GLS2 via Tap63. p53 plays a role in apoptosis (Li et al., 2014) especially with the help of mitochondrial pathway of PUMA (Westphal et al., 2014; Yu et al., 2003) and with the help of pro-apoptotic proteins.(Zahran et al., 2014) e.g., via NOXA (Cuadrado Cuadrado et al.,2007) p53 also activates tumor metastasis via SNAI2 (Wu et al., 2005). Further ATP-dependent chromatin remodeler p53 interacts with CSB, which is important for DNA repair.(Lake et al., 2011) It would be interesting to investigate whether and to what extent FOXP3 is involved in a variety of carcinogenic diseases with T inflammatory response.
According to the 28th annual meeting of the „German Association for the Study of the Liver“ (GASL) almost every 5th cancer is caused by chronic inflammation. For example, H. pylori produces the toxic ammonia and vacuolating cytotoxin A, they are demaging gastric tissue. This activates cytokines, which in turn activate neutrophilic granulocytes, T cells and macrophages. H. Pylori attempts to induce apoptosis of macrophages and T cells. This dysregulation of tumor-protective immune processes leads to the development of gastric carcinoma. (Liliane Sygulla, 1998) Human herpesvirus-8 (HHV-8) also involves vascular endothelial growth factor interleukin-6 and VEGF-like genes, which promotes tumorigenesis. (Masood et al., 2002) Human T-lymphotropic virus 1 (HTLV-1) can induce tropical spastic paraparesis or adult T-cell leukaemia (ATL) in which T cells respond independently of the external growth signals. (Liesz et al., 2012)
Gerontologic medicine also tries to prevent the inflammations on a cellular level. For example: many natural anti-aging agents protect against inflammatory process (e.g. curcumin and cayenne pepper) (Aggarwal, 2010) or to influence growth processes (polyphenols, e.g. epigallocatechin EGCG from green tea or procyanidin from apples). (Lombardo et al, 2015)
Posselt's et al. working group investigated 2016 in their work „Spatial distribution of FoxP3 + and CD8 + tumor infiltrating T cells reflects their functional activity“ FoxP + and CD8 + distribution in regulatory and cytotoxic T cells. According to their results the cytotoxic T cells play the key role in the immunological cancer response and offer promising new ways in the fight against cancer. Further results were reported by Schmidt et al. (2011), Lin et al. (2015), Gerber et al. (2014), Li et al. (2016) and Balbaco et al. (2014). These studies showed that T-cell activity were decreased by the PD-L1 and increased by the CTLA-4 antibodies. Both molecules are influenced by the FOXP3 gene. Jim Allison took advantage of this feature in the development of the cancer immunotherapeutic Ipilipumab 2008. FOXP3 interaction with other chemotherapeutic agents has been reported by Takada et al. (2018), Tang et al. (2008) and Landoire et al. (2016). Interestingly, Programmed Cell Death Ligand 1 correlated with FOXP3 expression. (Enkhbat et al., 2018)
The role of l n RNA in aging
Long noncoding RNAs are also aging relevant (Kim et al., 2016) e.g. via phosphatase and tensin homolog PTEN. ln RNA represses expression of the age related tumor-suppressor gene via its interaction with DNMT3a. lncRNA TARID induces promoter demethylation of TCF21. lncRNAs 7SL and MEG3, which is of importance in carcinogen processes (Li et al., 2018), decreased cell proliferation via MDM2 and the tumor suppressor p53 inhibition (Zhou et al, 2007) is decreased in liver, bladder cancer and in pituitary cancer (Braconi et al. 2011; Zhang et al. 2003; Ying et al., 2013) It influences autophagy inversely in age related gastric cancer. LncRNA HULC triggers autophagy direct via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells (Xiong et al., 2017) As others lncRNAs (Reviewed Yanget al., 2014) HULC influences tumorigenesis in liver and colorectal cancer. (Panzitet al., 2007; Wang et al., 2010)
ncRNAs also modulate protein transcription indirectly via microRNAs. E.g., lncRNAs such as linc-MD1 and lincRNA-RoR change the level of another mRNAs. Grammatikakis
et al., 2014; Cesanaet al., 2011; Wanget al., 2013) In the same time Uchl1 lncRNA may influence senescence directly via p14ARF and p53 and its repressor MDM2 (via proteasome). NF90, required for hypoxia-induced cancer cell invasion (Petrovics et al, 2004; Yang et al., 2013) also effects lnc RNA decrease and is also cancer and apoptosis relevant , because it reduces p21, P53, caspase 7, PARP and PCGEM1 level. (Fu et al., 2006) Cancer relevant lncRNA PVT1 is downregulated via MYC, which is also associated with proliferation and apoptosis of breast and ovarian cancer (Carramusaet al., 2007).
According to Kim et al. „Long noncoding RNAs in Diseases of Aging“, 2016 MALAT1 interact with TP53 and decreases with aging, based on changing serine/arginine (SR) splicing factors level. (Abdelmohsen al. 2013 Tripathi et al.; Tripathi et al., 2010; Melzeret al., 2013) Its level is increased lung and liver carcinoma (Qi et al., 2013; Luo et al., 2006) and influences muscle aging.
ANRIL influences cell cycle as well senescence via upregulation of the tumor suppressor gene p15 (INK4B) (Latrese et al, 2000; Kotake et al., 2011; Peters 2008) and plays a role in breast and another carcinoma, e.g. in gastric, prostate cancer cells and non-small cell lung cancer cell via KLF2 and p21 downregulation (Yap et al., 2010; Nie et al., 2014;1:268–277; Zhang et al., 2014; Hannou et al., 2015; Pasmant et al., 2011) and disturbs miR-99 and miR-449a. LncRNA PINT interacts with PRC2 complex via SUZ12, with plays a role in histone modification and cancer. (Marin-Bejar et al., 2013)
HOTAIR also influences senescence and cancer, e.g., breast tumors as well as endometrial, colorectal, cervical carcinomas and metastasis via H3K27me3 changes and chromatin modifiers, e.g. PRC2. (Kogo et al., 2011; Zhang et al., 2013; Heet al, 2014; Huanget al., 2014; Gupta et al., 2010)
The lncRNA XIST is decreased in breast cancer (Vincent-Salomon et al., 2007) and correlates with Taxol sensitivity. (Huang et al., 2002)
a 200-nt-long ncRNA BCYRN1 is associated with AD b and aging (Mus et al., 2007) but also with breast (Iacoangeli et al. 2004), parotid, tongue, oesophagus, lung, cervix and ovary cancer (Chen et al, 1997).
GAS5 lncRNA suppressed GR and induced apoptosis (Mourtada-Maarabouni et al., 2009) and is downregulated in human HCC and breast cancer (Tu and al., 2014).
lncRNA-17A BACE1, repressed GABABR2 variant A, promoted variant B, and enhanced accumulation of peptides Aβ42 and Aβ40 (Massone et al., 2011), BCYRN1 (Mus et al.,2007) and GOMAFU (MIAT)BC089918 GAS5 RMSTAS are associated with neurodegeneration. (Wapinski et al.; 2011Yu et al., 2013; Ng et al., 2013; Kim et al., 2013; Meier et al., 2010) and cancer (Mourtada-Maarabouni et al., 2009)
BACE1 protein levels and activity increase with brain aging and AD (Modarresi et al., 2011; Fukumoto et al., 2002)
7 SL interacts with the TP53 mRNA and suppresses p53 translation, during HuR can displace 7SL and increase p53 translation. lncRNA 7SLsuppresses TP53 (Abdelmohsen et al., 2014) and influences autophagy, senescence and cancer (Grammatikakis et al., 2014; Chen et al., 1997).
FOXP2 and mRNA in aging
But other RNAs are also an important component of aging, e.g., extracellular RNA play an important role in this process.(Douglas et al. 2016) 24–31nts piRNAs are responsible for proper genome in germ-line cells. 142.22 nts microRNAs cooperate with the 3′ UTR of target mRNAs binding RISC. This complex leads to mRNA degradation and disturbs protein translation. This affects components of the RNA spliceosome, 100–300 nucleotides Small nuclear RNAs (snRNAs), which process
