Impaired Metabolic Pathways Related to Colorectal Cancer Progression and Therapeutic Implications
Background: Risk of colorectal cancer (CRC) is defined by genetic predisposition and environmental factors that often co-occur and interact, resulting in diversiform biological reactions. The present study attempted to investigate transcriptome alteration and adaptation associated with CRC progression.
Methods: The study consisted of patients who presented at Memorial Sloan-Kettering Cancer Center, Guangzhou, China with a colonic neoplasm in 1992-2004. Microarray GSE41258 of the study was acquired from Gene Expression Omnibus and 253 included microarrays were categorized by groups of normal colon, early primary tumor, lymph node metastases primary tumor, advanced primary tumor and distant metastases. Short Time-series Expression Miner (STEM) was applied to discover tumor grade-dependent gene expression patterns. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out to explore functional enrichment of differential expression genes (DEGs).
Results: Overall, 2870 significant DEGs were screened out on all groups. Six significant grade-dependent gene expression patterns were statistically significant. DEGs in all significant patterns were mainly assembled in GO terms of metastases and deterioration of tumor, epithelial proteins and cytokines, and protein binding and bridging. DEGs in profile 0 down-regulated with higher tumor grade, prominently enriched in KEGG pathways of metabolism.
Conclusion: Besides many well-known colorectal cancer-related pathways, DEGs of profiles especially those down-regulated with CRC progression, clustered in various metabolic pathways including starch and sucrose metabolism, fatty acid metabolism, nitrogen metabolism, as well as xenobiotics biotransformation that link to tumorigenesis, demonstrating the impairment of physiological metabolic pathways in the context of tumor progression. These results gave a high potential for therapeutic strategies.
2. Lucas C, Barnich N, Nguyen HTT (2017). Microbiota, Inflammation and Colorectal Cancer. Int J Mol Sci,18(6): E1310.
3. Brenner H, Kloor M, Pox CP (2014). Colo-rectal cancer. Lancet, 383(9927): 1490-1502.
4. Bert V, Eric RF, Stanley R H (1988). Genetic alterations during colorectal-tumor devel-opment. N Engl J Med, 319(9): 525-32.
5. Colin CP, William MG (2011). Colorectal cancer molecular biology moves into clin-ical practice. Gut, 60(1): 116-29.
6. Janneke FL, Xin W, Jan Paul M (2015). Col-orectal cancer heterogeneity and targeted therapy: a case for molecular disease sub-types. Cancer Res, 75(2): 245-9.
7. Sheffer M1, Bacolod MD, Zuk O et al (2009). Association of survival and dis-ease progression with chromosomal in-stability: a genomic exploration of colo-rectal cancer. Proc Natl Acad Sci U S A, 106(17): 7131-6.
8. Ernst J, Bar-Joseph Z (2006). STEM: a tool for the analysis of short time series gene expression data. BMC Bioinformatics, 7: 191.
9. Ashburner M, Ball CA, Blake JA (2000). Gene ontology: tool for the unification of biology. The Gene Ontology Consorti-um. Nat Genet, 25(1): 25-29.
10. Kanehisa M, Goto S (2000). KEGG: kyoto encyclopedia of genes and genomes. Nu-cleic Acids Res, 28(1): 27-30.
11. Blake JA, Chan J, Kishore R (2015). Gene Ontology Consortium: going forward. Nucleic Acids Research, 43(D1):D1049–D1056.
12. Kanehisa M, Furumichi M, Tanabe M et al (2017). KEGG: new perspectives on ge-nomes, pathways, diseases and drugs. Nucleic Acids Res, 45(D1): D353-D361.
13. Li Y, Sun Z, Liu B et al (2017). Tumor-suppressive miR-26a and miR-26b inhibit cell aggressiveness by regulating FUT4 in colorectal cancer. Cell Death Dis, 8(6): e2892.
14. Tan X, Chen S, Wu J et al (2017). PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer me-tastasis by directly targeting ZNF407. Cell Death Dis, 8(3): e2686.
15. Takemasa I, Kittaka N, Hitora T et al (2012). Potential biological insights revealed by an integrated assessment of proteomic and transcriptomic data in human colo-rectal cancer. Int J Oncol, 40(2): 551-9.
16. Zhou J, Chen M, Ma L et al (2016). Role of CD44(high)/CD133(high) HCT-116 cells in the tumorigenesis of colon cancer. On-cotarget, 7(7): 7657-66.
17. Park M, Sundaramoorthy P, Sim JJ et al (2017). Synergistically Anti-metastatic Ef-fect of 5-Flourouracil on Colorectal Can-cer Cells via Calcium-mediated Focal Ad-hesion Kinase Proteolysis. Anticancer Res, 37(1): 103-114.
18. Li H, Rokavec M, Jiang L et al (2017). An-tagonistic Effects of p53 and HIF1A on microRNA-34a Regulation of PPP1R11 and STAT3 and Hypoxia-induced Epi-thelial to Mesenchymal Transition in Colorectal Cancer Cells. Gastroenterology, 153(2):505-520.
19. Sui H, Zhao J, Zhou L et al (2017). Tanshinone IIA inhibits β-catenin/VEGF-mediated angiogenesis by targeting TGF-β1 in normoxic and HIF-1α in hypoxic microenvironments in hu-man colorectal cancer. Cancer Lett, 403:86-97.
20. Shapiro M, Nandi B, Gonzalez G et al (2017). Deficiency of the immunostimula-tory cytokine IL-21 promotes intestinal neoplasia via dysregulation of the Th1/Th17 axis. Oncoimmunology, 6(1): e1261776.
21. Braga EA, Fridman MV, Kushlinskii NE (2017). Molecular Mechanisms of Ovari-an Carcinoma Metastasis: Key Genes and Regulatory MicroRNAs. Biochemistry (Mosc), 82(5): 529-541.
22. Deryugina EI, Kiosses WB (2017). Intra-tumoral Cancer Cell Intravasation Can Occur Independent of Invasion into the Adjacent Stroma. Cell Rep, 19(3): 601-616.
23. Goreczny GJ, Ouderkirkpecone JL, Olson EC et al (2017). Hic-5 remodeling of the stromal matrix promotes breast tumor progression. Oncogene, 36(19): 2693-2703.
24. Vecchi M, Confalonieri S, Nuciforo P et al (2008). Breast cancer metastases are mo-lecularly distinct from their primary tu-mors. Oncogene, 27(15): 2148-58.
25. Kouno J, Nagai H, Nagahata T et al (2004). Up-regulation of CC chemokine, CCL3L1, and receptors, CCR3, CCR5 in human glioblastoma that promotes cell growth. J Neurooncol, 70(3): 301-7.
26. Spaks A (2017). Role of CXC group chem-okines in lung cancer development and progression. J Thorac Dis, 9(Suppl 3): S164-S171.
27. Jian P, Yanfang T, Zhuan Z et al (2011). MMP28 (epilysin) as a novel promoter of invasion and metastasis in gastric cancer. BMC Cancer, 11: 200.
28. Deberardinis RJ (2008). Is cancer a disease of abnormal cellular metabolism? New angles on an old idea. Genet Med, 10(11): 767-77.
29. Mashima T, Seimiya H, Tsuruo T (2009). De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br J Cancer, 100(9): 1369-72.
30. Hu DG, Mackenzie PI, Mckinnon RA et al (2016). Genetic polymorphisms of hu-man UDP-glucuronosyltransferase (UGT) genes and cancer risk. Drug Metab Rev, 48(1): 47-69.
31. Yeh C, Wang J, Cheng T et al (2006). Fatty acid metabolism pathway play an im-portant role in carcinogenesis of human colorectal cancers by Microarray-Bioinformatics analysis. Cancer Lett, 233(2): 297-308.
32. Macfarlane AJ, Perry CA, Mcentee MF et al (2011). Shmt1 heterozygosity impairs fo-late-dependent thymidylate synthesis ca-pacity and modifies risk of Apc(min)-mediated intestinal cancer risk. Cancer Res, 71(6): 2098-107.
33. Ye K, Wu Y, Sun Y et al (2016). TLR4 siR-NA inhibits proliferation and invasion in colorectal cancer cells by downregulating ACAT1 expression. Life Sci, 155: 133-9.
34. Guo H, Zeng W, Feng L et al (2017). Inte-grated transcriptomic analysis of dis-tance-related field cancerization in rectal cancer patients. Oncotarget, 8(37):61107-61117.
35. Moon JW, Lee SK, Lee JO et al (2014). Identification of novel hypermethylated genes and demethylating effect of vincris-tine in colorectal cancer. J Exp Clin Cancer Res, 33: 4.
36. Beyerle J, Frei E, Stiborova M et al (2015). Biotransformation of xenobiotics in the human colon and rectum and its associa-tion with colorectal cancer. Drug Metab Rev, 47(2): 199-221.
37. Wohak LE, Krais AM, Kucab JE et al (2016). Carcinogenic polycyclic aromatic hydrocarbons induce CYP1A1 in human cells via a p53-dependent mechanism. Arch Toxicol, 90(2): 291-304.
38. Moonen HJ, Engels LG, Kleinjans JC et al (2005). The CYP1A2-164A-->C poly-morphism (CYP1A2*1F) is associated with the risk for colorectal adenomas in humans. Cancer Lett, 229(1): 25-31.
39. Fernandes GM, Russo A, Proenca MA et al (2016). CYP1A1, CYP2E1 and EPHX1 polymorphisms in sporadic colorectal neoplasms. World J Gastroenterol, 22(45): 9974-9983.
40. Economopoulos KP, Sergentanis TN (2010). GSTM1, GSTT1, GSTP1, GSTA1 and colorectal cancer risk: a comprehen-sive meta-analysis. Eur J Cancer, 46(9): 1617-31.
41. Bamber DE, Fryer AA, Strange RC et al (2001). Phenol sulphotransferase SULT1A1*1 genotype is associated with reduced risk of colorectal cancer. Phar-macogenetics, 11(8): 679-85.
42. Angstadt AY, Hartman TJ, Lesko SM et al (2014). The effect of UGT1A and UGT2B polymorphisms on colorectal cancer risk: haplotype associations and gene-environment interactions. Genes Chromosomes Cancer, 53(6): 454-66.
43. Xu W, Zhang Z, Zou K et al (2017). MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. Cell Death Dis, 8(5): e2761.
44. Zaytseva YY, Rychahou PG, Gulhati P et al (2012). Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res, 72(6): 1504-17.
45. Patel S, Bhambra U, Charalambous MP et al (2014). Interleukin-6 mediated upregula-tion of CYP1B1 and CYP2E1 in colorec-tal cancer involves DNA methylation, miR27b and STAT3. Br J Cancer, 111(12): 2287-96.
46. Kabatkova M, Zapletal O, Tylichova Z et al (2015). Inhibition of beta-catenin signal-ling promotes DNA damage elicited by benzo(a)pyrene in a model of human co-lon cancer cells via CYP1 deregulation. Mutagenesis, 30(4): 565-76.
47. Rattray NJ, Charkoftaki G, Rattray Z et al (2017). Environmental influences in the etiology of colorectal cancer: the premise of metabolomics. Curr Pharmacol Rep, 3(3): 114-125.
|Issue||Vol 49 No 1 (2020)|
|Colorectal cancer Metabolism Short time series expression miner Bioinformatics Therapeutics|
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