Systems-level biomarkers identification and drug repositioning in colorectal cancer

Table 1 Diagnostic biomarkers found in colorectal cancer

Diagnostic biomarker	Molecular level	Sample	Expression	Ref.
Actin Beta-Like 2	Protein	Fresh frozen tissue	↑	Ghazanfar et al[30], 2017
Dipeptidase 1	Protein	Fresh frozen tissue	↑	Hao et al[31], 2017
Olfamectomedin-4	Protein	FFPE tissue	↑	Quesada-Calvo et al[32], 2017
Kininogen-1
Transport Protein Sec-24
Cyclophilin A	Protein	FFPE tissue	↑	Yamamoto et al[33], 2016
Annexin A2
Aldolase A
Leucine-Rich Alpha-2 Glycoprotein 1	Protein	Serum	↑	Ivancic et al[36], 2020
Epidermal Growth Factor Receptor
Hemopexin
Superoxide Dismutase 3
Inter-Alpha-Trypsin Inhibitor Heavy-Chain Family Member 4
Mannan Binding Lectin Serine Protease 1	Protein	Plasma	-	Bhardwaj et al[37], 2019
Osteopontin
Serum Paraoxonase Lactonase 3
Transferrin Receptor Protein 1
Amphiregulin
Adipophilin	Protein	Plasma	-	Matsubara et al[41], 2011
Caldesmon 1	Protein	Fresh Frozen Tissue	-	Ilyas et al[34], 2020
Catenin Beta 1
C-X-C Motif Chemokine Ligand 14
Protein patched homolog 1
Interleukin-8, Tumor necrosis factor-alpha induced protein 3, Nicotinamide N-methyltransferase
Mitogen-activated protein kinase
Adenomatous polyposis coli
Zinc finger protein
Serine/Threonine Kinase 4	Protein	Serum	↓	Yu et al[38], 2017
Macrophage mannose receptor 1	Protein		↑	Fan et al[39], 2016
S100 calcium binding protein
Alpha-1-antitrypsin	Protein	Serum	↑	Peltier et al[40], 2016
Alpha-1-antichymotrypsin
Anti- Thombin 3	Protein	Serum	↓	Peltier et al[40], 2016
3- Hydroxybutyric Acid		Serum	↑	Ma et al[43], 2012
Microtubule Actin Crosslinking Factor 1	Protein	Serum	↑	Ma et al[43], 2012
L-Valine	Amino acid	Serum	↓	Ma et al[43], 2012
L-Threonine
1-Deoxyglucose
Glycine
Apolipoprotein H	Protein	Serum	↓	Ma et al[43], 2012
Alpha-2-Macroglobulin
Immunoglobulin Lambda Locus
Vitamin-D-binding protein
Acetoacetate, Guanidinoacetate	Amino acid	Urine	↑/High	Wang et al[48], 2017
Cis-aconitate, Trans-aconitate, Glutamine
Homocysteine
Creatinine, Phosphorylcholine	Amino acid	Urine	↓/Low	Wang et al[48], 2017
Dimethyl sulfone, Asparagine, Alanine
Isocitrate, Hippurate, Methylamine
Cysteine, Phenylalanine
Isoleucine, β-Hydroxybutyrate, lactate, acetate, glutamate, choline, glycine, serine, glucose	Amino acid	Biopsy	High	Nishiumi et al[46], 2012
Taurine, alanine, β –Aminoisobutyrate, valine	Amino acid	Urine	High	Kim et al[47], 2019
Threonine, glycerol, hippurate, ascorbate, creatinine and citrate	Amino acid	Urine	Less	Kim et al[47], 2019
Proline, succinate, isoleucine, leucine valine, alanine, glutamate, dimethylglycine and lactate	Amino acid	Fecal	High	Lin et al[44], 2019
Short Chain Fatty Acids, (acetate, propionate and butyrate), glucose, glutamine	Amino acid	Fecal	Less	Lin et al[44], 2019
Sphinganine, endocannabinoids		Serum	High	Martín-Blázquez et al[51], 2019
CRCAL-4, CRCAL-3, CRCAL-2 (Long Intergenic Non-Protein Coding RNA 858), and CRCAL-1	lncRNA	CRC cell line	↑	Yamada et al[27], 2018
NONHSAT074176.2	lncRNA	Fresh frozen tissue	↓	Zhang et al[28], 2018
CircDDX17	lncRNA	Fresh frozen tissue	Dysregylated	Li et al[29], 2018
Syndecan 2	Gene	Fresh frozen tissue	↑	Oh et al[20], 2013
PHOX1B, Glutamic acid de-carboxylase 2, and Fibroblast Growth Factor 12	Gene	Fresh frozen tissue	↑	Li et al[21], 2012
Visual System Homeobox 2	Gene	Neoplastic colonic tissue	↑	Mori et al[22], 2011

CRC: Colorectal cancer.

Table 2 Prognostic markers found in colorectal cancer

Prognostic biomarker	Molecular level	Sample	Expression	Ref.
Carcinoembryonic antigen	Protein	Plasma	↑	Li et al[79], 2018
Major histocompatibility complex, class I, B (HLAB)	Protein	Fresh Frozen Tissue	↑	Kirana et al[80], 2019
14-3-3b protein (YWHAB)
A disintegrin and metalloproteinase with thrombospondin motifs 2
Leukotriene B3
Nucleoside Diphosphate Kinase 2
Jagged Canonical Notch Ligand 2
Collagen type XII (FACIT)	Protein	Colorectal liver metastasis tissue	↑	van Huizen et al[81], 2019
Heat shock protein 47	Protein	Fresh Frozen Tissue	↑	Mori et al[82], 2017
Ezrin protein	Protein	Cells and tissue	↑	Patara et al[85], 2011
Collagen VI (COL6)	Protein	Fresh Frozen Tissue	↑	Clarke et al[86], 2017
Forkhead box O3
RAD51 (DNA repair protein RAD51 homolog 1)
Lymphocyte-specific protein tyrosine kinase
Inositol polyphosphate-4-phosphatase
Phospho-PEA15 (Ser116)
Phosho-S6 (Ser240-244)
Phospho-PRAS40 (Thr-246)
Mammary serine protease inhibitor	Protein	Fresh Frozen Tissue	↑	Snoeren et al[87], 2013
Alpha-fetoprotein	Protein	Serum	-	Zhu et al[88], 2013
Complement C4-A (C4A)
Fibrinogen alpha
Eukaryotic peptide chain release factor GTP-binding subunit ERF3B (GSPT2)
Angiotensinogen
Hippurate, Butyrate	Amino acid	Urine	↑	Liesenfeld et al[89], 2015
Glycerol, Galactarate
Urea, Carnitine	Amino acid	Urine	↓	Liesenfeld et al[89], 2015
AFAP1 Antisense RNA 1	lncRNA	Datasets	↑	Li et al[72], 2016
Breast Cancer Anti-Estrogen Resistance 4
H19
HOXA Cluster Antisense RNA 2
Metastasis Associated
Lung Adenocarcinoma Transcript 1 (MALAT1)
Plasmacytoma Variant Translocation 1
ADAMTS9 Antisense RNA 2	lncRNA	Datasets	↓	Li et al[72], 2016
miR-429	microRNA	Fresh Frozen Tissue	↓	Li et al[73], 2013
hsa-mir-191, hsa-mir-200b	microRNA	Datasets	-	Kandimalla et al[75], 2018
hsa-mir-30b, hsa-mir-30c2
hsa-mir-33a, hsamir-362
hsa-mir 429, and hsa-mir-744
VNN1-AB	Transcript	Datasets	-	Løvf et al[76], 2014
Kirsten rat sarcoma oncogene 2 (KRAS)	Gene	Datasets	-	Kadowaki et al[67], 2015
Murine sarcoma viral oncogene homolog B1 (BRAF)
Tumor protein 53	Gene	Datasets	-	Ting et al[59], 2013
SMAD Family Member 4	Gene	Datasets	-	Mei et al[65], 2018
Neurofibromatosis type 1

Table 3 Drug repurposing candidates for the prevention and/or treatment of colorectal cancer

Drug (s)	Pharmacological class	Original indication	CRC effect	Ref.
Based on computational approaches
GW-8510, ethacrynic acid, ginkgolide A and 6-azathymine	GW-8510: Inhibitor of cyclin-dependent kinase-2; ethacrynic acid: Diuretic; ginkgolide A: Platelet-activating factor antagonist; 6-azathymine: D-3-aminoisobutyrate-pyruvate aminotransferase inhibitor	GW-8510: Prevention of chemotherapy-induced alopecia; ethacrynic acid: Treatment of high blood pressure and swelling; ginkgolide A: Treatment of a wide variety of cognitive and vascular disorders	Inhibit CRC cells	Chung et al[97], 2014
		6-azathymine: Has antibacterial and antiviral activities
GW-8510	Inhibitor of cyclin-dependent kinase-2	Prevention of chemotherapy-induced alopecia	CRC therapeutic agent which targets RRM2 inhibition	Hsieh et al[98], 2016
Abemaciclib	Anti-neoplastic	Treatment of advanced or metastatic breast cancers	CRC therapeutic agent which targets FABP6	Liñares-Blanco et al[99], 2020
AG 957, Ro-28-1675, Brazilin, Importazole, PD 407824	AG 957: Inhibitor; Ro-28-1675: Activator; Brazilin: Anti-inflammatory agent; Importazole: Inhibitor; PD 407824: Indoles and derivatives	AG 957: Protein tyrosine kinase; Ro-28-1675: Glucokinase activator; Brazilin: NF-kappaB inhibitor and a hepatoprotective agent; Importazole: Transport receptor importin-β; PD 407824: Wee1/Chk1 inhibitor	CRC drug candidates	Beklen et al[100], 2020
Based on clinically or experimentally validated approaches
Metformin	Antidiabetic agent	Treatment of type 2 diabetes mellitus	Reduces pre-cancerous lesions and cancerous cell proliferation	Jia et al[102], 2015
			Results in better overall survival	Bishnoi et al[104], 2018
			Causes both apoptosis and autophagy of cultured HT29 cells	Sena et al[103], 2018
Aspirin	Nonsteroidal anti-inflammatory	Relieves minor aches, pains, and fevers	Regular, long-term aspirin use reduces CRC risk	Chan et al[105], 2005
			Reduces CRC cell proliferation	Reddy et al[106], 2006
			Daily use for about 5 yr is efficient in prevention, with a latency time of about 10 yr	Flossmann et al[107], 2007
			Restrains CRC tumor metastasis	Jin et al[108], 2019
Cimetidine	Gastrointestinal agent	Treatment of ulcers and gastroesophageal reflux disease	Short course of cimetidine treatment has an impact on patient survival	Kelly et al[110], 1999
			Inhibits the adhesion of CRC cells and represses spread of cancer cells	Kobayashi et al[111], 2000
			Reduces frequency of metastasis and increases survival rate	Matsumoto et al[112], 2002
			Prolongs the probability of recurrence	Ali et al[113], 2018
Diclofenac	Nonsteroidal anti-inflammatory	Relieves pain and inflammation	Contributes to tumor growth inhibition in colon cancer	Falkowski et al[116], 2003
			Promotes cell death	Arisan et al[117], 2018
Chloroquine	Antimalarial	Treatment of malaria	Increases cell inhibition and decreases reproduction	Sasaki et al[119], 2010
			Use at high doses (40–160 μM) encourages lysosomal membrane permeabilization and cell death	Park et al[120], 2014
Sulindac	Nonsteroidal anti-inflammatory	Reduces pain, swelling, and joint stiffness due to arthritis	Decreases final tumor counts and prevents CRC especially when given in intermittent doses	Chandra et al[122], 2017
			Decreases polyp count	Davis et al[123], 2020
Mesalazine	Anti-inflammatory	Treatment of mild to moderate ulcerative colitis	Decreases CRC cell number and enhances apoptosis	Reinacher-Schick et al[125], 2003
			Causes CRC cell cycle arrest and cell death	Koelink et al[126], 2010
Disulfiram	Enzyme inhibitor	Alcohol addictive disorder	Promotes cell viability inhibition	Stenvang et al[128], 2018
Erlotinib	Anti-neoplastic	Treatment of non-small cell lung and pancreatic cancer	Contributes to enhanced progression-free survival and overall survival of metastatic CRC patients	Shi et al[130], 2017

CRC: Colorectal cancer.