Influence of FOX genes on aging and aging-associated diseases. Elena Tschumak

Map2k1 Wnt4. MiR-34-5p influences GABAergic neurons, vascular aging response and cancer relevant Notch1, Notch4, Ccne2, E2f3, Gabra3 and Cylcin E2 through a Notch-dependent mechanism and Sirt1 (Li et al. 2011) Prop1 leads to decreased level of GH, Igf-1 and TSH. (Bartkeet al. 2001; Victoria et al., 2015) Lysine-, Valine-, Arginine-, Cysteine-, Glycine tRNA were decreased and Histidine- and Aspartic- acid derived 5′ tRNA increased in age. These changes were also CR sensitive (Dhahbi et al. 2013)

      Aging is also associated with increased mRNAs level of CSF2, which is necessary for monocytes activation (Croxfordet al. 2015), granulocyte and macrophage maturation (Hamilton, 2002), energy homeostasis and metabolism. mRNA of subunit of pyruvate dehydrogenase enzyme DLD, which is necessary for exocytosis is also increased. RAB3 GTPase activating Protein Subunit 2 (Bem et al., 2011), an alternative splicing nuclear protein, which is involved in metastasis suppression with the help of splicing factor SRSF1 RRP1B (Lee et al. 2014), CSF2RA, SLC35B4, LAMB2 (Schaeffer, 2012), LAMB2 and LC35B4 showed increased mRNA level. Some lncRNAs were also hyperexpessed in ageing. At the same time 12 snoRNAs and 20 piRNAs were decreased. Decreased rRNA, which interacts with TTF1, may play a role in age related Alzheimer disease. (Freedman et al.,2016) miR-31 decrease is associated with aging relevant chronic myeloid leukaemia and ovarian carcinoma (Mitamura et al., 2013; Rokah et al.,2012; Korner et al., 2013; Zhong et al., 2013) miR-485-5p expression also alternates in aging. (Faghihi et al.,2008; 2010;Lee et al. 2014)

      

       FOXP2 and mi RNA in oncological processes

       Like the other genes in the FOXP family, the Fox P2 gene can be inactivated in cancer cells through miRNAs and alter its action this way. The recent study by Herrero and Gitton (2018) showed that FOXP2 can be blocked by TWIST activated miRs 199a-214, miR-762, miR-1915, let-7b and miR-34a and miR-3666. let-7a-d, miRs, miR-26a, miR-10,1miR-200b (which leads to increased MT1-MMPu und decreased PTEN- expression) (Soubani et al., 2012) and decreases prostaglandin, NF-kappaB,PEG2, VEGF activity ( Ali et al., 2010; Bao et al., 2011), EpCAM and EZH2 level and inhibits NOTCH-1 in pancreatic cancer (Bao et al., 2012). Wen-Zhuo et al. (2016) investigated the regulation of the FOXP2 gene by the microRNA-190 in gastric cancer. Valencia-Sanchez et al. (2006) showed that miRNAs destroy FOXP2-mRNA through its interaction with 3 'UTR, prevent its translation and this way negatively regulate the FOXP2 target genes. Many other studies also indicated that miRNA dysregulation may play an important role in the initiation and progression of oncological processes. (Barbrotto et al., 2008; Kasinski and Slack, 2011) Two years earlier the group of Wen-Zhuo et al. used the dual luciferase enzyme assays and confirmed that the miR-190 interacts with the FOXP2. RT-PCR and Western blot verified that miR-190 overexpression suppresses expression of FOXP2. Decrease of miRNA-190 expression leads in turn to FOXP2-mRNA and -protein increase. Because FoxP2 plays an important role in many oncological processes, the miR-190 could serve as a potential gastric cancer marker. Zhang et al. (2009) investigated various miRNAs and identified eight of them, which levels were increased in pancreatic cancer, e.g. the miR-190. This miRNA correlated with the progression of gliomas (Almog et al., 2012; Cuiffo et al.,2014) demonstrated suppression of FOXP2 expression by miR-199a in breast cancer mesenchymal cells. In lung, breast, bladder, colerectal and liver cancers MiRNA expression was also increased. (Ichimi et al., 2009; Lowery et al., 2009; Navon et al., 2009; Ura et al., 2009; Ng et al., 2009)

       The results indicate that miRNAs play a different role in different tumor types at different stages. The influence of various miRNAs on pancreatic cancer (Zhang et al., 2009), lymphoma (Musilova and Mraz, 2014; Jones et al., 2014) and breast cancer (Wu et al., 2009) was also shown. It would be useful to study whether this miRNAs dysregulation also influences these and other cancers in connection with FOXP2?

       Regulation of other FOXP genes by various factors on the example of carcinogenic processes In oncological tissue FoxP genes as well as other FOX genes can be modulated by microRNA . (Zheng et al., 2015), (Shao et al., 2013), (Kong et al., 2013), (Zhang et al., 2015), (Kundu et al., 2016), (Mei et al., 2015), (Yu et al., 2017). This modulation determines whether FOXP2 acts as an oncogene or as a tumor suppressor gene. In these processes the FoxP genes can also be deactivated by micro RNAs. (Choi et, 2016) According to Chang et al. (2007), He et al. (2010) and Raver-Shapira et al. (2007) the transcription factor p53 induces the transcription of the microRNA miR-34s, which in turn suppresses anti-apoptotic genes, which are required for cell development and growth. According to Choi et al. (2016), Isken et al. (2008), Mraz et al. (2009), Zenz et al. (2009), miR-34a plays an important role in both chronic lymphatic and acute myeloid leukaemia and the Foxp1 is regulated by miR-34a. The miR-34a also builds a direct link between the tumor suppressor p53 and the oncoprotein Bcl-2. Rao et al. (2010) pointed out that in B lymphocytes too miR-34 modulates Foxp1 via the tumor suppressor gene p53. The tumor suppressor p53 could also be a direct FOXP2 target gene. (Herrero and Gitton, 2018)There are also further indications of androgen influences on the FoxP1 expression and associated carcinogenic processes. (Banham et al, 2007; Bates et al., 2008; Fox et al., 2004; Giatromanolaki et al., 2006; Takayama et al., 2008) Further FOXP1 appears to affect follicular lymphoma as well as in aging dependent ovarian and colorectal carcinoma. (Brown et al., 2004; Choi et al., 2016; De Smedt et al., 2015) In B cell lymphomas or hepatocellular carcinomas FOXP-1 serves as an oncogene. (Zhang et al., 2012; Jiang et al., 2012; Xia et al., 2014) In lungs, prostate and endometrial tumors FOXP1 is a potential predictor of disease progression. (Feng et al., 2012; Toma et al., 2011; Giatromanolaki et al., 2006; Takayama et al., 2008; Takayama et al., 2014)

       FOXP2 and neuroplasticity

      FOXP2 plays an extremely important role in neuroplasticity (Haesler et al., 2006; Ebisu et al., 2017; Konopka et al., 2009; Boeckx et al., 2014; Dodson et al., 2015; Garcia-Calero et al., 2016) and review of Wohlgemuth et al. (2014) showed that FOXP2 also provided the NMDAR-mediated neuronal plasticity affecting MAPKK and tyrosine phosphatase. The MARK is a RAS downstream effector. RAS is a a GTPase that indirectly interacts with oncological relevant ant p21 and p53 indirectly. RAS, in turn, is activated by growth factor signalling and interacts with FOXO-inhibiting PIK3. Further interaction with neuro and oncoactive Trk is also discussed. (Santos, 2011), (Mengeselt et al., 2008) It influences cell proliferation and this plays a role in the development of cancer. A direct FOXO4-p53 interaction and its importance in cell aging has been demonstrated too. (Baar et al., 2017) It would be interesting to look more closely at the role of FOXP in these processes. Possibly Fisetin, related to Qis (Zhu et al., 2017), but also FOXO4-related peptide that inhibits the PI3K/AKT/p53/p21/Serpine SCAP (Zhu et al., 2015b), recently noted to be senolytic (Baar et al., 2017) could have positive effect on cancer and aging.

      Guibinga et al. showed in "Neuropathogenesis of LNS. Striatal Neurodevelopment is Dysregulated in Purine Metabolism Deficiency and Impacts DARPP-32, BDNF / TrkB Expression and Signaling: New Insights on the Molecular and Cellular Basis of Lesch-Nyhan Syndrome" (2014) that downregulating Bcl11b in HPRT-deficient cells elicited a change in DARPP-32 level in the neural stem cells. This phosphoprotein is regulated by dopamine and cAMP. Its altered level in turn led to striatal B-cell leukaemia 11b (Bcl11b). The activator of the DARPP-32 striatal BDNF / TrkB signalling pathway was highly increased in HPRT-deficient cells as well as in the striatum of the HPRT knockout mice. This protected the cells from reactive oxygen species (ROS)-mediated cell death.

       There are also FOXP2 interactions with members of the histone family (H2AFX; H3f3B), two heat shock proteins (Hsp25; Hsp90a) and Calcycline-binding proteins ARHGEF9, CtBP1 and effectors Gli1, Gli2 and Gli3, EGR1, IEGs, D1R and DARPP32. In addition, FOXP2 affects NMDAR-mediated neuronal plasticity, MAPKK and tyrosine phosphatase. (Mc Auley et al., 2017)

      γH2AX foci in aged HSCs is increased (Rossi et al., 2007; Beerman et al., 2014; Moehrle et al., 2015; Flach et al., 2014)

       FOXP2 and neurodegeneration

       Several studies showed the significance of FoxP2 for the brain and skull development (Benítez-Burraco et al., 2015) but above all for the language. (Watkins et al., 2002; Vargha-Khadem et al., 1998; Middleton ad Strick, 2000; Watkins et al., 2002; Liegeois et al., 2003; Lai