IndexOther metabolic genes overexpressed in lung cancerElevated ribosomal biogenesis in c-Myc-induced lung cancerRegulatory gene networksIn numerous studies, both at the transcriptional and protein levels, increased expression was observed of Rrm1, Rrm2 and Type I biomarkers have been observed in NSCLC patients and suggested for their implications in cancer therapy (Grossi F et al. 2015, PMID: 26663950, Maus MK et al. 2013, PMID: 23470290). Silencing of Rrm1 and Rrm2 markedly increased the tumor cytotoxicity of camptothecin (CPT), a topoisomerase I inhibitor, which could be exploited in chemotherapeutic strategies (Zhang YW et al. 2009, PMID: 19416980). Furthermore, in the cellular response to DNA damage, upregulation of RRM2 transcription in human cells involves an ATR/ATM-Chk1-E2F1 pathway for cell survival. Accordingly, in PLACs, the Rrm1 and Rrm2 genes were identified with TF binding sites for E2F1 in the promoter analysis (see the composite module supplementary table), and the expression of E2F1 transcript was slightly increased. This suggests that the transcription factor E2F1 is involved in the regulation of c-Myc-responsive Rrm1 and Rrm2 genes in PLACs. Furthermore, the expression of RRM1 and RRM2 has been reported as a novel prognostic marker in advanced NSCLC undergoing chemotherapy (Wang L. et al. 2014, PMID: 24155212). Say no to plagiarism. Get a tailor-made essay on "Why Violent Video Games Shouldn't Be Banned"? Get an original essay Other metabolic genes overexpressed in lung cancer An important finding of the present study was a nearly 15-fold overexpression of arginase-1 in the lung tumor of c-Myc transgenic mice, suggesting arginase-1-dependent tumor growth arginine. Arginase-1 is mainly expressed in liver cells and plays an important role in the urea cycle. In addition to microarray analysis, overexpression of Arg1 was observed in reverse transcription-polymerase chain reaction (RT-PCR) analysis and in the conformation of its protein expression in western blotting. Furthermore, induced expression of Arg1 is associated with poor survival in human lung cancer patients. It is the subject of intense research to target arginine-dependent tumors. In this regard, arginine deprivation through the induction of arginine-degrading/reducing enzymes such as arginine deiminase will regulate the arginine metabolome in cancer; thus, it shows a new anti-metabolite strategy for the treatment of arginine auxotrophy in lung tumors (Phillips MM et al. 2013, PMID: 24453997). Fatty acid synthase (FASN) is a key metabolic multienzyme (multifunctional protein) that catalyzes the synthesis of the 16-carbon saturated fatty acid palmitate from acetyl-CoA and malonyl-CoA in the presence of NADPH. Fatty acids are integral components of pulmonary surfactant, which is composed of phospholipids and proteins specific and essential for the normal functioning of the lungs. In PLACs, c-Myc-responsive Fasn expression was induced more than 3-fold. In previous research, overexpression of the FASN gene was observed in type II alveolar cells of lung adenomas for the production of pulmonary surfactants (Voelker DR et al. 1976, PMID: 10854) and was regulated by the hormone, one of the possible regulators , in type II alveolar cells. human fetal lung epithelial cells (Wagle S et al. 1999, PMID: 10444533). Furthermore, FASN is overexpressed in multiple tumors, including lung cancer, and is a promising target to selectively inhibit its activity for cancer treatment (Orita H. et al. 2007, PMID: 18056164).A recent study reported that FASNs promote the growth and chemoresistance of NSCLC by inducing PKM2 expression and enhancing aerobic glycolysis, i.e., the Warburg effect. Spermidine synthase is part of the polyamine biosynthetic pathway and using decarboxylated S-adenosylmethionine (dcSAM), catalyzes the conversion of putrescine to spermidine in the final step of spermidine biosynthesis. Genetic codes for spermidine synthase (Srm) were upregulated >5-fold in PLACs. This significant finding of Srm is growing evidence for c-Myc in regulating polyamine metabolism genes, as previously reported in our research article (Ciribilli Y et al. 2015, PMID: 26427040). The intracellular concentration of polyamines is tightly regulated, and polyamine metabolism is often dysregulated for tumor cell growth; Induced expression of enzymes involved in polyamine biosynthesis has been associated with many tumors, including lung cancer, and has implications for chemotherapy and chemoprevention (Luk GD et al. 1981, PMID: 6264474, Nowotarski SL et al. 2013, PMID: 23432971,). In addition to arginase 1 and spermidine synthase, other polyamine metabolic genes such as L-ornithine decarboxylase 1 and S-adenosylmethionine decarboxylase 1 and 2 were significantly (P < 0.001) upregulated by almost 2-fold, however did not qualify the threshold criteria (3 times) established for Table 1 of Publication III. Furthermore, the resurgence of polyamine metabolism inhibitors in cancer treatment was highlighted in a prospective article on lung cancer research (Gautschi O. 2010, PMID: 20199972). In addition to targeting ornithine decarboxylase, spermidine synthase, which is upregulated in Myc-induced cancer, is a promising target for the treatment of B-cell lymphomas (Forshell TP et al. 2010, PMID: 20103729, Gerner EW. 2010, PMID: 20103728 Importantly, the induced expression of Arg1, Fasn, Hk2, and Shmt1 was also observed in reverse transcription-polymerase chain reaction (RT-PCR) analysis and the conformation of its protein expression in the western blotting. This confirms the significantly induced expression of these four genes in PLACs of c-Myc transgenic mice. Elevated ribosomal biogenesis in c-Mycc-induced lung cancer-MYC transcriptionally regulates RNAs and protein components of ribosomes for protein synthesis, essential gene products for ribosomal RNA processing and nuclear export of ribosomal subunits (van Riggelen J et al. 2010, PMID: 20332779); thus, c-MYC is a regulator of ribosome biogenesis and dysregulation of ribosome biogenesis may play an important role in tumorigenesis (van Riggelen J et al. 2010, PMID: 20332779). Accordingly, several genes encoding the ribosome and associated with ribosome biogenesis were significantly upregulated in lung tumors of c-Myc transgenic mice. Ribosome biogenesis is the target of interest for several chemotherapy-based anticancer treatments (Bruno PM et al. 2017, PMID: 28263311). Nucleophosmin/B23 (Npm1) encodes protein that participates in various cellular functions, including ribosome biogenesis and protein synthesis, DNA replication, centrosome duplication, and cell proliferation. In addition to this, NPM1 together with several ribosomal proteins are transcriptional targets of MYC (Zeller KI et al. 2001, PMID: 11604407, Grisendi S et al. 2006, PMID: 16794633). As another function, upregulation of nucleophosmin 1 has been observed to inhibit p53-mediated cellular senescence in colon cancer (Wong JC et al. 2013, PMID: 23536448). In PLACs, a significant 4-fold upregulation was identified and predictedof nucleophosmin 1 (Npm1) as one of seven potential master regulators. Regarding the processing and assembly function of ribosomes, this nucleolar phosphoprotein acts as a molecular chaperone and prevents protein aggregation within the nucleolus (Grisendi S et al. 2006, PMID: 16794633). However, the Npm1 protein is frequently overexpressed in various solid tumors, but translocations are observed specifically in leukemias (Grisendi S et al. 2006, PMID: 16794633, Jeong EG et al. 2007, PMID: 17504301). Notably, a recent report demonstrated that YTR107-mediated targeting of NPM1 reduces DNA double-strand break repair is a promising radiosensitization approach for NSCLC therapy (Sekhar KR et al. 2014, PMID: 25035215). The DNA binding activity of c-Myc at the gene-specific promoter of Npm1 and Npm3 was supported by various data from experimental techniques, which include the strong EMSA bands and independent ChIP-seq results (Supplementary Table S7 of Publication III) . Another gene encoding ribosome biogenesis is nucleolin/C23 (Ncl), a nucleolar phosphoprotein upregulated in PLACs and predicted to be a master regulator, has been reported as a transcriptional target of c-Myc ( Greasley PJ et al. 2000, PMID: 10606642 ). Overexpression of nucleolin has been observed in various tumors, and research has reported that the expression level of nucleolin is positively correlated with DNA damage repair (i.e., DNA-dependent protein kinases); therefore, nucleolin could serve as a promising therapeutic target as well as a prognostic factor for human NSCLC (Xu JY et al. 2016, PMID: 26846099). It suggests that c-Myc influences DNA base excision repair (BER) and non-homologous end joining (NHEJ) of DNA double-strand breaks. In this regard, genes encoding DNA-BER enzymes were upregulated, including apurinic/apyrimidinic endonuclease 1 (Apex1) and replication factor C subunit 4 (Rfc4). Furthermore, the genetic codes for base excision repair enzymes such as Rfc5, flap structure-specific endonuclease 1 (Fen1), and DNA polymerase delta-interacting protein 2 (Poldip2) were significantly (P < 0.001) upregulated by nearly 2-fold, yet did not exceed the threshold criteria (3-fold) established for Table 1 of Publication III. In addition to BER, supporting angiogenesis and tumor progression, Apex1 also increases the DNA binding activity of several transcription factors and could be a potential target for consolidation of cisplatin-based chemotherapy in NSCLC patients ( Wang D et al. 2009, PMID: 19324449). Importantly, the genetic code for DNA topoisomerase II alpha (Top2a) is strongly upregulated in PLACs by >10-fold and 7-fold in small and large tumors, respectively. It is a well-known nuclear enzyme that catalyzes the transient breaking and rejoining of DNA double strands and allows alteration of DNA topology. Importantly, high expression of Top2a is often detected in highly proliferative cells including NSCLC (Giaccone G et al. 1995, PMID: 8547322) and promising targets for anticancer agents (such as anthracyclines) that bind and block the activity of TopIIα. Furthermore, a positive correlation has been reported between the expression of cell proliferation markers TopIIα and Ki67 in NSCLC patients in which the expression of TopIIα can be used as a prognostic biomarker for chemotherapy (Yan S et al. 2010, PMID: 21067592). Accordingly, the genes encoding the Ki67 protein (Publication II) and the Ki67 interacting protein were strongly upregulated in PLACs (Table 1 of Publication III).