Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8QETQU)

• DOT Name: C-C motif chemokine 14 (CCL14)
• Synonyms: Chemokine CC-1/CC-3; HCC-1/HCC-3; HCC-1(1-74); NCC-2; Small-inducible cytokine A14
• Gene Name: CCL14
• Related Disease:
  Lupus
  Systemic lupus erythematosus
  Astrocytoma
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Chronic kidney disease
  Chronic renal failure
  End-stage renal disease
  Endometriosis
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Inflammatory bowel disease
  Liver cirrhosis
  Neoplasm
  Pancreatic adenocarcinoma
  Rheumatoid arthritis
  rubella
  Obesity
  Hepatitis C virus infection
  Melanoma
  Pancreatic cancer
• UniProt ID: CCL14_HUMAN
• PDB ID: 2Q8R; 2Q8T
• Pfam ID: PF00048
• Sequence:
  MKISVAAIPFFLLITIALGTKTESSSRGPYHPSECCFTYTTYKIPRQRIMDYYETNSQCS
  KPGIVFITKRGHSVCTNPSDKWVQDYIKDMKEN
• Function: Has weak activities on human monocytes and acts via receptors that also recognize MIP-1 alpha. It induces intracellular Ca(2+) changes and enzyme release, but no chemotaxis, at concentrations of 100-1,000 nM, and is inactive on T-lymphocytes, neutrophils, and eosinophil leukocytes. Enhances the proliferation of CD34 myeloid progenitor cells. The processed form HCC-1(9-74) is a chemotactic factor that attracts monocytes, eosinophils, and T-cells and is a ligand for CCR1, CCR3 and CCR5.
• Tissue Specificity: Expressed constitutively in several normal tissues: spleen, liver, skeletal and heart muscle, gut, and bone marrow, present at high concentrations (1-80 nM) in plasma.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lupus	DISOKJWA	Definitive	Genetic Variation	[1]
Systemic lupus erythematosus	DISI1SZ7	Definitive	Genetic Variation	[1]
Astrocytoma	DISL3V18	Strong	Biomarker	[2]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[4]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[4]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[4]
Endometriosis	DISX1AG8	Strong	Biomarker	[5]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[8]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[10]
rubella	DISXUI9P	Strong	Altered Expression	[11]
Obesity	DIS47Y1K	moderate	Biomarker	[12]
Hepatitis C virus infection	DISQ0M8R	Limited	Genetic Variation	[13]
Melanoma	DIS1RRCY	Limited	Biomarker	[14]
Pancreatic cancer	DISJC981	Limited	Biomarker	[14]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of C-C motif chemokine 14 (CCL14).	[15]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of C-C motif chemokine 14 (CCL14).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of C-C motif chemokine 14 (CCL14).	[18]

2 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of C-C motif chemokine 14 (CCL14).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of C-C motif chemokine 14 (CCL14).	[19]

References

• [1] CCL genes in multiple sclerosis and systemic lupus erythematosus.J Neuroimmunol. 2008 Aug 30;200(1-2):145-52. doi: 10.1016/j.jneuroim.2008.05.016. Epub 2008 Jul 3.
• [2] Characterization of a novel anti-cancer compound for astrocytomas.PLoS One. 2014 Sep 25;9(9):e108166. doi: 10.1371/journal.pone.0108166. eCollection 2014.
• [3] Binding of the JmjC demethylase JARID1B to LSD1/NuRD suppresses angiogenesis and metastasis in breast cancer cells by repressing chemokine CCL14.Cancer Res. 2011 Nov 1;71(21):6899-908. doi: 10.1158/0008-5472.CAN-11-1523. Epub 2011 Sep 21.
• [4] HCC-1, a novel chemokine from human plasma.J Exp Med. 1996 Jan 1;183(1):295-9. doi: 10.1084/jem.183.1.295.
• [5] The molecular signature of endometriosis-associated endometrioid ovarian cancer differs significantly from endometriosis-independent endometrioid ovarian cancer.Fertil Steril. 2010 Sep;94(4):1212-1217. doi: 10.1016/j.fertnstert.2009.06.039. Epub 2009 Jul 30.
• [6] Hepatitis C virus core protein fused to hepatitis B virus core antigen for serological diagnosis of both hepatitis C and hepatitis B infections by ELISA.J Med Virol. 1999 Feb;57(2):104-10.
• [7] CCL14 serves as a novel prognostic factor and tumor suppressor of HCC by modulating cell cycle and promoting apoptosis.Cell Death Dis. 2019 Oct 22;10(11):796. doi: 10.1038/s41419-019-1966-6.
• [8] A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa.Mucosal Immunol. 2010 Jan;3(1):40-8. doi: 10.1038/mi.2009.115. Epub 2009 Oct 7.
• [9] An integrated approach in the discovery and characterization of a novel nuclear protein over-expressed in liver and pancreatic tumors.FEBS Lett. 2001 May 11;496(2-3):109-16. doi: 10.1016/s0014-5793(01)02409-7.
• [10] An initial investigation into endothelial CC chemokine expression in the human rheumatoid synovium.Cytokine. 2017 Sep;97:133-140. doi: 10.1016/j.cyto.2017.05.023.
• [11] Gene expression profiling of rubella virus infected primary endothelial cells of fetal and adult origin.Virol J. 2016 Feb 2;13:21. doi: 10.1186/s12985-016-0475-9.
• [12] Cytokine, Chemokine, and Cytokine Receptor Changes Are Associated With Metabolic Improvements After Bariatric Surgery.J Clin Endocrinol Metab. 2019 Mar 1;104(3):947-956. doi: 10.1210/jc.2018-02245.
• [13] Genetic variants in chemokine CC subfamily genes influence hepatitis C virus viral clearance.J Hum Genet. 2018 Jul;63(7):831-839. doi: 10.1038/s10038-018-0452-9. Epub 2018 Apr 27.
• [14] Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model.Front Pharmacol. 2017 Jul 7;8:319. doi: 10.3389/fphar.2017.00319. eCollection 2017.
• [15] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [16] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [17] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.