Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQFD2J5)

• DOT Name: BPI fold-containing family A member 1 (BPIFA1)
• Synonyms: Lung-specific protein X; Nasopharyngeal carcinoma-related protein; Palate lung and nasal epithelium clone protein; Secretory protein in upper respiratory tracts; Short PLUNC1; SPLUNC1; Tracheal epithelium-enriched protein; Von Ebner protein Hl
• Gene Name: BPIFA1
• Related Disease:
  Acute otitis media
  Adenocarcinoma
  Allergic rhinitis
  Colorectal carcinoma
  Craniosynostosis
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Malignant tumor of nasopharynx
  Nasal polyp
  Nasopharyngeal carcinoma
  Otitis media
  Polyp
  Pulmonary disease
  Advanced cancer
  Chronic obstructive pulmonary disease
  Influenza
  Pneumonia
  Pneumonitis
  Lung neoplasm
  Non-insulin dependent diabetes
  Asthma
  Dental caries
  Epstein barr virus infection
  Meningococcal disease
  Non-small-cell lung cancer
• UniProt ID: BPIA1_HUMAN
• PDB ID: 4KEG; 4KGH; 4KGO; 4N4X; 5I7J; 5I7K; 5I7L
• Pfam ID: PF01273
• Sequence:
  MFQTGGLIVFYGLLAQTMAQFGGLPVPLDQTLPLNVNPALPLSPTGLAGSLTNALSNGLL
  SGGLLGILENLPLLDILKPGGGTSGGLLGGLLGKVTSVIPGLNNIIDIKVTDPQLLELGL
  VQSPDGHRLYVTIPLGIKLQVNTPLVGASLLRLAVKLDITAEILAVRDKQERIHLVLGDC
  THSPGSLQISLLDGLGPLPIQGLLDSLTGILNKVLPELVQGNVCPLVNEVLRGLDITLVH
  DIVNMLIHGLQFVIKV
• Function: Lipid-binding protein which shows high specificity for the surfactant phospholipid dipalmitoylphosphatidylcholine (DPPC). Plays a role in the innate immune responses of the upper airways. Reduces the surface tension in secretions from airway epithelia and inhibits the formation of biofilm by pathogenic Gram-negative bacteria, such as P.aeruginosa and K.pneumoniae. Negatively regulates proteolytic cleavage of SCNN1G, an event that is required for activation of the epithelial sodium channel (ENaC), and thereby contributes to airway surface liquid homeostasis and proper clearance of mucus. Plays a role in the airway inflammatory response after exposure to irritants. May attract macrophages and neutrophils.
• Tissue Specificity: Highly expressed in lung, upper airways and nasopharyngeal regions, including trachea and nasal epithelium (at protein level) . Specifically expressed in the secretory ducts and submucosal glands of tracheobronchial tissues (at protein level) . Also expressed in the eye where it is detected in lacrimal gland, eyelid, conjunctiva and cornea (at protein level) . Specifically localizes to epithelial cell layers in cornea, eyelid (basal epithelium) and conjunctiva (at protein level) . Detected within acinar cells and ducts in the lacrimal and Meibomian glands (at protein level) . In lung, shows highest expression in the trachea and progressive decrease from proximal (bronchial) to distal (bronchiolar) airways . Also expressed in lung cancers and some other types of cancer .
• Reactome Pathway: Antimicrobial peptides (R-HSA-6803157)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute otitis media	DISL8D8G	Strong	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Allergic rhinitis	DIS3U9HN	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Craniosynostosis	DIS6J405	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[6]
Malignant tumor of nasopharynx	DISTGIGF	Strong	Biomarker	[7]
Nasal polyp	DISLP3XE	Strong	Altered Expression	[8]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[9]
Otitis media	DISGZDUO	Strong	Biomarker	[1]
Polyp	DISRSLYF	Strong	Altered Expression	[10]
Pulmonary disease	DIS6060I	Strong	Altered Expression	[11]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[9]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[12]
Influenza	DIS3PNU3	moderate	Altered Expression	[13]
Pneumonia	DIS8EF3M	moderate	Biomarker	[11]
Pneumonitis	DIS88E0K	moderate	Biomarker	[11]
Lung neoplasm	DISVARNB	Disputed	Altered Expression	[14]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Biomarker	[15]
Asthma	DISW9QNS	Limited	Biomarker	[16]
Dental caries	DISRBCMD	Limited	Genetic Variation	[17]
Epstein barr virus infection	DISOO0WT	Limited	Biomarker	[18]
Meningococcal disease	DISGDM2Z	Limited	Genetic Variation	[19]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[20]

3 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 BPI fold-containing family A member 1 (BPIFA1).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of BPI fold-containing family A member 1 (BPIFA1).	[22]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of BPI fold-containing family A member 1 (BPIFA1).	[23]

References

• [1] Loss of the homeostatic protein BPIFA1, leads to exacerbation of otitis media severity in the Junbo mouse model.Sci Rep. 2018 Feb 15;8(1):3128. doi: 10.1038/s41598-018-21166-7.
• [2] Gene expression profiling with microarray and SAGE identifies PLUNC as a marker for hepatoid adenocarcinoma of the stomach.Mod Pathol. 2008 Apr;21(4):464-75. doi: 10.1038/modpathol.3801050. Epub 2008 Jan 18.
• [3] The effects of physical exercise and smoking habits on the expression of SPLUNC1 in nasal lavage fluids from allergic rhinitis subjects.Int J Pediatr Otorhinolaryngol. 2014 Apr;78(4):618-22. doi: 10.1016/j.ijporl.2014.01.014. Epub 2014 Jan 23.
• [4] Increased expression of BPI fold-containing family A member 1 is associated with metastasis and poor prognosis in human colorectal carcinoma.Oncol Lett. 2017 Oct;14(4):4231-4236. doi: 10.3892/ol.2017.6662. Epub 2017 Jul 25.
• [5] Reduced expression of antimicrobial PLUNC proteins in nasal polyp tissues of patients with chronic rhinosinusitis.Allergy. 2012 Jul;67(7):920-8. doi: 10.1111/j.1398-9995.2012.02848.x.
• [6] Multiplex PCR-based detection of circulating tumor cells in lung cancer patients using CK19, PTHrP, and LUNX specific primers.Clin Lung Cancer. 2013 Sep;14(5):513-20. doi: 10.1016/j.cllc.2013.04.007. Epub 2013 Jun 27.
• [7] SPLUNC1 is associated with nasopharyngeal carcinoma prognosis and plays an important role in all-trans-retinoic acid-induced growth inhibition and differentiation in nasopharyngeal cancer cells.FEBS J. 2014 Nov;281(21):4815-29. doi: 10.1111/febs.13020. Epub 2014 Sep 24.
• [8] Decreased PLUNC expression in nasal polyps is associated with multibacterial colonization in chronic rhinosinusitis patients.Eur Arch Otorhinolaryngol. 2014 Feb;271(2):299-304. doi: 10.1007/s00405-013-2535-8. Epub 2013 May 5.
• [9] SPLUNC1 and MLL3 regulate cancer stem cells in nasopharyngeal carcinoma.J BUON. 2019 Jul-Aug;24(4):1700-1705.
• [10] The antimicrobial protein short palate, lung, and nasal epithelium clone 1 (SPLUNC1) is differentially modulated in eosinophilic and noneosinophilic chronic rhinosinusitis with nasal polyps.J Allergy Clin Immunol. 2014 Feb;133(2):420-8. doi: 10.1016/j.jaci.2013.09.052. Epub 2013 Dec 15.
• [11] BPIFA1 regulates lung neutrophil recruitment and interferon signaling during acute inflammation.Am J Physiol Lung Cell Mol Physiol. 2019 Feb 1;316(2):L321-L333. doi: 10.1152/ajplung.00056.2018. Epub 2018 Nov 21.
• [12] Association of innate defense proteins BPIFA1 and BPIFB1 with disease severity in COPD.Int J Chron Obstruct Pulmon Dis. 2017 Dec 19;13:11-27. doi: 10.2147/COPD.S144136. eCollection 2018.
• [13] Tobacco exposure inhibits SPLUNC1-dependent antimicrobial activity.Respir Res. 2019 May 21;20(1):94. doi: 10.1186/s12931-019-1066-2.
• [14] Expression of molecular markers in mediastinal nodes from resected stage I non-small-cell lung cancer (NSCLC): prognostic impact and potential role as markers of occult micrometastases.Ann Oncol. 2009 Jan;20(1):91-7. doi: 10.1093/annonc/mdn538. Epub 2008 Jul 29.
• [15] Associations of Salivary BPIFA1 Protein in Chronic Periodontitis Patients with Type 2 Diabetes Mellitus.Int J Endocrinol. 2017;2017:1087017. doi: 10.1155/2017/1087017. Epub 2017 Oct 4.
• [16] The effect of BPIFA1/SPLUNC1 genetic variation on its expression and function in asthmatic airway epithelium.JCI Insight. 2019 Apr 18;4(8):e127237. doi: 10.1172/jci.insight.127237. eCollection 2019 Apr 18.
• [17] Genome-wide association study of primary dentition pit-and-fissure and smooth surface caries.Caries Res. 2014;48(4):330-8. doi: 10.1159/000356299.
• [18] SPLUNC1 reduces the inflammatory response of nasopharyngeal carcinoma cells infected with the EB virus by inhibiting the TLR9/NF-B pathway.Oncol Rep. 2015 Jun;33(6):2779-88. doi: 10.3892/or.2015.3913. Epub 2015 Apr 17.
• [19] A Rare Mutation in SPLUNC1 Affects Bacterial Adherence and Invasion in Meningococcal Disease.Clin Infect Dis. 2020 May 6;70(10):2045-2053. doi: 10.1093/cid/ciz600.
• [20] Multi-Gene Expression in Anthracosis of the Lungs as One of the Risk Factors for Non-Small Cell Lung Cancer.Asian Pac J Cancer Prev. 2017 Nov 26;18(11):3129-3133. doi: 10.22034/APJCP.2017.18.11.3129.
• [21] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [22] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [23] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.