Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO4UIDB)

• DOT Name: Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1)
• Synonyms: Full of fluid protein homolog
• Gene Name: CCBE1
• Related Disease:
  Hennekam lymphangiectasia-lymphedema syndrome 1
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Hydrops fetalis
  Intellectual disability
  Lymphoid system disorder
  Non-immune hydrops fetalis
  Gastrointestinal stromal tumour
  Hennekam syndrome
  Primary sclerosing cholangitis
  Sclerosing cholangitis
• UniProt ID: CCBE1_HUMAN
• Pfam ID: PF01391 ; PF07645
• Sequence:
  MVPPPPSRGGAARGQLGRSLGPLLLLLALGHTWTYREEPEDGDREICSESKIATTKYPCL
  KSSGELTTCYRKKCCKGYKFVLGQCIPEDYDVCAEAPCEQQCTDNFGRVLCTCYPGYRYD
  RERHRKREKPYCLDIDECASSNGTLCAHICINTLGSYRCECREGYIREDDGKTCTRGDKY
  PNDTGHEKSENMVKAGTCCATCKEFYQMKQTVLQLKQKIALLPNNAADLGKYITGDKVLA
  SNTYLPGPPGLPGGQGPPGSPGPKGSPGFPGMPGPPGQPGPRGSMGPMGPSPDLSHIKQG
  RRGPVGPPGAPGRDGSKGERGAPGPRGSPGPPGSFDFLLLMLADIRNDITELQEKVFGHR
  THSSAEEFPLPQEFPSYPEAMDLGSGDDHPRRTETRDLRAPRDFYP
• Function: Required for lymphangioblast budding and angiogenic sprouting from venous endothelium during embryogenesis.
• Tissue Specificity: Detected in fibroblasts and urine (at protein level) . Not expressed in blood or lymphatic endothelial cells.

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hennekam lymphangiectasia-lymphedema syndrome 1	DISB203L	Definitive	Autosomal recessive	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[2]
Lung cancer	DISCM4YA	Definitive	Biomarker	[3]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[3]
Lung neoplasm	DISVARNB	Definitive	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Hydrops fetalis	DISD9BBF	Strong	Biomarker	[6]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[7]
Lymphoid system disorder	DIS20IIA	Strong	Genetic Variation	[8]
Non-immune hydrops fetalis	DISPUY8C	Strong	Biomarker	[6]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[9]
Hennekam syndrome	DISIQGJQ	Supportive	Autosomal recessive	[1]
Primary sclerosing cholangitis	DISTH5WJ	Limited	Genetic Variation	[10]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1).	[19]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1).	[20]
Maleic Acid	DM4L0R7	Investigative	Maleic Acid increases the expression of Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1).	[17]

References

• [1] Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet. 2009 Dec;41(12):1272-4. doi: 10.1038/ng.484.
• [2] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [3] Clinical significance of CCBE1 expression in lung cancer.Mol Med Rep. 2018 Feb;17(2):2107-2112. doi: 10.3892/mmr.2017.8187. Epub 2017 Nov 29.
• [4] Scanning copy number and gene expression on the 18q21-qter chromosomal region by the systematic multiplex PCR and reverse transcription-PCR methods.Electrophoresis. 2007 Jun;28(12):1882-95. doi: 10.1002/elps.200700093.
• [5] The clinical significance of CCBE1 expression in human colorectal cancer.Cancer Manag Res. 2018 Nov 30;10:6581-6590. doi: 10.2147/CMAR.S181770. eCollection 2018.
• [6] Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia.Hum Genet. 2010 Feb;127(2):231-41. doi: 10.1007/s00439-009-0766-y. Epub 2009 Nov 13.
• [7] A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature.BMC Med Genet. 2015 Apr 30;16:28. doi: 10.1186/s12881-015-0175-0.
• [8] Expanding the genotypic spectrum of CCBE1 mutations in Hennekam syndrome.Am J Med Genet A. 2016 Oct;170(10):2694-7. doi: 10.1002/ajmg.a.37803. Epub 2016 Jun 27.
• [9] CCBE1 promotes GIST development through enhancing angiogenesis and mediating resistance to imatinib.Sci Rep. 2016 Aug 10;6:31071. doi: 10.1038/srep31071.
• [10] CCBE1 mutation causing sclerosing cholangitis: Expanding the spectrum of lymphedema-cholestasis syndrome.Hepatology. 2017 Jul;66(1):286-288. doi: 10.1002/hep.29037. Epub 2017 May 9.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [16] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [17] 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.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.
• [21] Profiling transcriptomes of human SH-SY5Y neuroblastoma cells exposed to maleic acid. PeerJ. 2017 Apr 5;5:e3175.