A Systems Biology Approach to Identify Novel Biomarkers in Progression from Crohn's Disease to Colorectal Cancer.

OBJECTIVE This study aimed to find the key genes and miRNAs as potential biomarkers related to the progression of colorectal cancer (CRC) from Crohn's disease (CD). BACKGROUND CD is widely accepted as one of the main risk factors leading to CRC. So, Identifying the novel molecular pathways involved in the development of CRC from CD can provide potential solutions for therapeutic interventions. METHODS By implementing a systematic approach, we have analyzed mRNA and miRNA datasets containing CRC and CD samples to determine differentially expressed genes (DEGs) and miRNAs (DEmiRNA). Then by selecting common genes involved in the progression from CD to CRC, different downstream analyses including mRNA-miRNA network, functional enrichment analysis, gene set enrichment analysis, and survival analysis were performed. Finally, quantitative real-time PCR (RT-PCR) analysis of tissue samples obtained from Normal/CRC samples was used to confirm the differential expression of selected genes and miRNA. RESULTS There were 10 DE miRNA and 181 genes DEGs common between progression from CD to CRC. The genes obtained for each of the 10 miRNAs were considered as the final target for downstream analyzes. In addition, analysis of RT-PCR indicated that miR-195-5p, PHLPP2, and LITAF   were downregulated in the cancer group compared to the control group. CONCLUSION This study showed that PHLPP2, LITAF, and miR-195-5p may have key roles in the tumorigenesis of CRC and they can be used as therapeutic targets and diagnostic biomarkers after further in-vitro and in-vivo evaluation.

[1]  F. Rahbarizadeh,et al.  An integrative transcriptome analysis reveals potential predictive, prognostic biomarkers and therapeutic targets in colorectal cancer , 2022, BMC Cancer.

[2]  G. Giannelli,et al.  miR-195-5p Regulates Tight Junctions Expression via Claudin-2 Downregulation in Ulcerative Colitis , 2022, Biomedicines.

[3]  F. Gao,et al.  Integrated Analysis of Ulcerative Colitis Revealed an Association between PHLPP2 and Immune Infiltration , 2022, Disease markers.

[4]  Zhixiong Lei,et al.  PLHPP2 inhibits the stemness of colorectal cancer by inactivating the Nrf2 signaling pathway , 2022, Journal of Cancer.

[5]  M. Alvandi,et al.  Human exposure to low dose ionizing radiation affects miR-21 and miR-625 expression levels , 2021, Molecular Biology Reports.

[6]  G. Decorti,et al.  Inflammatory Bowel Disease and Risk of Colorectal Cancer: An Overview From Pathophysiology to Pharmacological Prevention , 2021, Frontiers in Pharmacology.

[7]  L. D. Di Stasi,et al.  MicroRNA expression in inflammatory bowel disease-associated colorectal cancer , 2021, World journal of gastrointestinal oncology.

[8]  Xin Chang,et al.  Colonic Epithelial PHLPP2 Deficiency Promotes Colonic Epithelial Pyroptosis by Activating the NF-κB Signaling Pathway , 2021, Oxidative medicine and cellular longevity.

[9]  D. Jiao,et al.  Clinical Significance and Inflammatory Landscape of aNovel Recurrence-Associated Immune Signature in Stage II/III Colorectal Cancer , 2021, Frontiers in Immunology.

[10]  Robin T. Varghese,et al.  An integrated approach to biomarker discovery reveals gene signatures highly predictive of cancer progression , 2020, Scientific Reports.

[11]  Qingqiang Yang,et al.  Identification of novel survival-related lncRNA-miRNA-mRNA competing endogenous RNA network associated with immune infiltration in colorectal cancer. , 2020, American journal of translational research.

[12]  Zhanju Liu,et al.  LncRNA CDKN2B-AS1 relieved inflammation of ulcerative colitis via sponging miR-16 and miR-195. , 2020, International immunopharmacology.

[13]  G. Dalmasso,et al.  Differential miRNA-Gene Expression in M Cells in Response to Crohn’s Disease-Associated AIEC , 2020, Microorganisms.

[14]  R. Amini,et al.  Cross-Resistance of Acquired Radioresistant Colorectal Cancer Cell Line to gefitinib and regorafenib , 2020, Iranian journal of medical sciences.

[15]  R. Scott,et al.  Colorectal carcinoma in the course of inflammatory bowel diseases , 2019, Hereditary Cancer in Clinical Practice.

[16]  Guiyu Wang,et al.  Overcoming stemness and chemoresistance in colorectal cancer through miR-195-5p-modulated inhibition of notch signaling. , 2018, International journal of biological macromolecules.

[17]  Lei Liu,et al.  GDPD5, a target of miR-195-5p, is associated with metastasis and chemoresistance in colorectal cancer. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[18]  G. Ren,et al.  LITAF is a potential tumor suppressor in pancreatic cancer , 2017, Oncotarget.

[19]  Hidetoshi Eguchi,et al.  MicroRNAs as Biomarkers in Colorectal Cancer , 2017, Cancers.

[20]  Zhongyong Zhou,et al.  miR-195 enhances the radiosensitivity of colorectal cancer cells by suppressing CARM1 , 2017, OncoTargets and therapy.

[21]  Yun Lu,et al.  MicroRNA-195 suppresses colorectal cancer cells proliferation via targeting FGF2 and regulating Wnt/β-catenin pathway. , 2016, American journal of cancer research.

[22]  Junrong Zou,et al.  Lipopolysaccharide-induced tumor necrosis factor-α factor enhances inflammation and is associated with cancer (Review). , 2015, Molecular medicine reports.

[23]  F. Liu,et al.  miR-195 plays a role in steroid resistance of ulcerative colitis by targeting Smad7. , 2015, The Biochemical journal.

[24]  Guoxin Li,et al.  Novel Epigenetic CREB-miR-630 Signaling Axis Regulates Radiosensitivity in Colorectal Cancer , 2015, PloS one.

[25]  Judy H. Cho,et al.  Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations , 2015, Nature Genetics.

[26]  H. Einarsdóttir,et al.  [Colorectal cancer - review]. , 2014, Laeknabladid.

[27]  Constance M. Johnson,et al.  Meta-analyses of colorectal cancer risk factors , 2013, Cancer Causes & Control.

[28]  S. Dalal,et al.  The Role of MicroRNA in Inflammatory Bowel Disease. , 2010, Gastroenterology & hepatology.

[29]  Lin Chen,et al.  microRNA-195 promotes apoptosis and suppresses tumorigenicity of human colorectal cancer cells. , 2010, Biochemical and biophysical research communications.

[30]  William Ritchie,et al.  Conserved Expression Patterns Predict microRNA Targets , 2009, PLoS Comput. Biol..

[31]  J. Satsangi,et al.  The genetics of Crohn's disease. , 2009, Annual review of genomics and human genetics.

[32]  S. Cerda,et al.  A new transcription factor that regulates TNF‐&agr; gene expression, LITAF, is increased in intestinal tissues from patients with CD and UC , 2006, Inflammatory bowel diseases.

[33]  C. Ko,et al.  Colorectal cancer: epidemiology, risk factors, and health services. , 2005, Clinics in colon and rectal surgery.

[34]  Olaf Wolkenhauer,et al.  MicroRNA-regulated networks: the perfect storm for classical molecular biology, the ideal scenario for systems biology. , 2013, Advances in experimental medicine and biology.

[35]  S. Parlee,et al.  This Work Is Licensed under a Creative Commons Attribution-noncommercial 4.0 International License , 2022 .