Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0ZJK64)

• DOT Name: Semaphorin-7A (SEMA7A)
• Synonyms: CDw108; JMH blood group antigen; John-Milton-Hargen human blood group Ag; Semaphorin-K1; Sema K1; Semaphorin-L; Sema L; CD antigen CD108
• Gene Name: SEMA7A
• Related Disease:
  Hypogonadotropic hypogonadism 7 with or without anosmia
  Arteriosclerosis
  Atherosclerosis
  Autosomal dominant polycystic kidney disease
  Breast cancer
  Breast neoplasm
  Congenital myasthenic syndrome
  Epilepsy
  Glioma
  High blood pressure
  Inflammation
  Kallmann syndrome
  Lung adenocarcinoma
  Melanoma
  Multiple sclerosis
  Neoplasm
  Nervous system disease
  Nervous system inflammation
  Pneumonia
  Pneumonitis
  Pulmonary fibrosis
  Renal fibrosis
  Rheumatoid arthritis
  Sjogren syndrome
  Stroke
  Systemic lupus erythematosus
  Temporal lobe epilepsy
  Advanced cancer
  Ductal breast carcinoma in situ
  Metastatic malignant neoplasm
  Breast carcinoma
  Congenital hypogonadotropic hypogonadism
  Kaposi sarcoma
  Pancreatic cancer
• UniProt ID: SEM7A_HUMAN
• PDB ID: 3NVQ
• Pfam ID: PF13895 ; PF01437 ; PF01403
• Sequence:
  MTPPPPGRAAPSAPRARVPGPPARLGLPLRLRLLLLLWAAAASAQGHLRSGPRIFAVWKG
  HVGQDRVDFGQTEPHTVLFHEPGSSSVWVGGRGKVYLFDFPEGKNASVRTVNIGSTKGSC
  LDKRDCENYITLLERRSEGLLACGTNARHPSCWNLVNGTVVPLGEMRGYAPFSPDENSLV
  LFEGDEVYSTIRKQEYNGKIPRFRRIRGESELYTSDTVMQNPQFIKATIVHQDQAYDDKI
  YYFFREDNPDKNPEAPLNVSRVAQLCRGDQGGESSLSVSKWNTFLKAMLVCSDAATNKNF
  NRLQDVFLLPDPSGQWRDTRVYGVFSNPWNYSAVCVYSLGDIDKVFRTSSLKGYHSSLPN
  PRPGKCLPDQQPIPTETFQVADRHPEVAQRVEPMGPLKTPLFHSKYHYQKVAVHRMQASH
  GETFHVLYLTTDRGTIHKVVEPGEQEHSFAFNIMEIQPFRRAAAIQTMSLDAERRKLYVS
  SQWEVSQVPLDLCEVYGGGCHGCLMSRDPYCGWDQGRCISIYSSERSVLQSINPAEPHKE
  CPNPKPDKAPLQKVSLAPNSRYYLSCPMESRHATYSWRHKENVEQSCEPGHQSPNCILFI
  ENLTAQQYGHYFCEAQEGSYFREAQHWQLLPEDGIMAEHLLGHACALAASLWLGVLPTLT
  LGLLVH
• Function: Plays an important role in integrin-mediated signaling and functions both in regulating cell migration and immune responses. Promotes formation of focal adhesion complexes, activation of the protein kinase PTK2/FAK1 and subsequent phosphorylation of MAPK1 and MAPK3. Promotes production of pro-inflammatory cytokines by monocytes and macrophages. Plays an important role in modulating inflammation and T-cell-mediated immune responses. Promotes axon growth in the embryonic olfactory bulb. Promotes attachment, spreading and dendrite outgrowth in melanocytes.
• Tissue Specificity: Detected in skin keratinocytes and on endothelial cells from skin blood vessels (at protein level). Expressed in fibroblasts, keratinocytes, melanocytes, placenta, testis, ovary, spleen, brain, spinal chord, lung, heart, adrenal gland, lymph nodes, thymus, intestine and kidney.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway: Other semaphorin interactions (R-HSA-416700)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypogonadotropic hypogonadism 7 with or without anosmia	DISPBWEU	Definitive	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Congenital myasthenic syndrome	DISJLG2T	Strong	Biomarker	[6]
Epilepsy	DISBB28L	Strong	Altered Expression	[7]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
High blood pressure	DISY2OHH	Strong	Biomarker	[2]
Inflammation	DISJUQ5T	Strong	Biomarker	[9]
Kallmann syndrome	DISO3HDG	Strong	Genetic Variation	[10]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[11]
Melanoma	DIS1RRCY	Strong	Biomarker	[12]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[7]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[13]
Pneumonia	DIS8EF3M	Strong	Biomarker	[14]
Pneumonitis	DIS88E0K	Strong	Biomarker	[14]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[15]
Renal fibrosis	DISMHI3I	Strong	Altered Expression	[3]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[16]
Sjogren syndrome	DISUBX7H	Strong	Altered Expression	[16]
Stroke	DISX6UHX	Strong	Biomarker	[2]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[16]
Temporal lobe epilepsy	DISNOPXX	Strong	Altered Expression	[7]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[17]
Ductal breast carcinoma in situ	DISLCJY7	moderate	Biomarker	[18]
Metastatic malignant neoplasm	DIS86UK6	moderate	Genetic Variation	[18]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[4]
Congenital hypogonadotropic hypogonadism	DISEV092	Limited	Genetic Variation	[19]
Kaposi sarcoma	DISC1H1Z	Limited	Genetic Variation	[19]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Semaphorin-7A (SEMA7A).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Semaphorin-7A (SEMA7A).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Semaphorin-7A (SEMA7A).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Semaphorin-7A (SEMA7A).	[23]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Semaphorin-7A (SEMA7A).	[24]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Semaphorin-7A (SEMA7A).	[25]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Semaphorin-7A (SEMA7A).	[26]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Semaphorin-7A (SEMA7A).	[27]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Semaphorin-7A (SEMA7A).	[28]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Semaphorin-7A (SEMA7A).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Semaphorin-7A (SEMA7A).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Semaphorin-7A (SEMA7A).	[32]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Semaphorin-7A (SEMA7A).	[33]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Semaphorin-7A (SEMA7A).	[34]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Semaphorin-7A (SEMA7A).	[35]

References

• [1] Mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism.Fertil Steril. 2018 Aug;110(3):486-495.e5. doi: 10.1016/j.fertnstert.2018.04.010.
• [2] Serum semaphorin 7A is associated with the risk of acute atherothrombotic stroke.J Cell Mol Med. 2019 Apr;23(4):2901-2906. doi: 10.1111/jcmm.14186. Epub 2019 Feb 7.
• [3] Semaphorin 7A in circulating regulatory T cells is increased in autosomal-dominant polycystic kidney disease and decreases with tolvaptan treatment.Clin Exp Nephrol. 2018 Aug;22(4):906-916. doi: 10.1007/s10157-018-1542-x. Epub 2018 Feb 16.
• [4] Semaphorin 7A Promotes Macrophage-Mediated Lymphatic Remodeling during Postpartum Mammary Gland Involution and in Breast Cancer.Cancer Res. 2018 Nov 15;78(22):6473-6485. doi: 10.1158/0008-5472.CAN-18-1642. Epub 2018 Sep 25.
• [5] Suppression of tumor-derived Semaphorin7A and genetic ablation of host-derived Semaphorin7A impairs tumor progression in a murine model of advanced breast carcinoma.Int J Oncol. 2017 Nov;51(5):1395-1404. doi: 10.3892/ijo.2017.4144. Epub 2017 Oct 3.
• [6] Premyogenic progenitors derived from human pluripotent stem cells expand in floating culture and differentiate into transplantable myogenic progenitors.Sci Rep. 2018 Apr 26;8(1):6555. doi: 10.1038/s41598-018-24959-y.
• [7] Sema7A, a brain immune regulator, regulates seizure activity in PTZ-kindled epileptic rats.CNS Neurosci Ther. 2020 Jan;26(1):101-116. doi: 10.1111/cns.13181. Epub 2019 Jun 9.
• [8] Semaphorin-7A on Exosomes: A Promigratory Signal in the Glioma Microenvironment.Cancers (Basel). 2019 May 30;11(6):758. doi: 10.3390/cancers11060758.
• [9] Expression of hypoxia-induced semaphorin 7A correlates with the severity of inflammation and osteoclastogenesis in experimentally induced periapical lesions.Arch Oral Biol. 2017 Mar;75:114-119. doi: 10.1016/j.archoralbio.2016.10.032. Epub 2016 Oct 29.
• [10] A novel heterozygous intron mutation in SEMA7A causing kallmann syndrome in a female.Gynecol Endocrinol. 2020 Mar;36(3):218-221. doi: 10.1080/09513590.2019.1680624. Epub 2019 Oct 25.
• [11] Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells.JCI Insight. 2018 Dec 20;3(24):e123093. doi: 10.1172/jci.insight.123093.
• [12] Plexin C1, a receptor for semaphorin 7a, inactivates cofilin and is a potential tumor suppressor for melanoma progression.J Invest Dermatol. 2009 Apr;129(4):954-63. doi: 10.1038/jid.2008.329. Epub 2008 Nov 6.
• [13] Semaphorin 7A as a Potential Therapeutic Target for Multiple Sclerosis.Mol Neurobiol. 2017 Aug;54(6):4820-4831. doi: 10.1007/s12035-016-0154-2. Epub 2016 Oct 6.
• [14] Anti-Semaphorin-7A single chain antibody demonstrates beneficial effects on pulmonary inflammation during acute lung injury.Exp Ther Med. 2018 Mar;15(3):2356-2364. doi: 10.3892/etm.2018.5724. Epub 2018 Jan 8.
• [15] Endogenous Semaphorin-7A Impedes Human Lung Fibroblast Differentiation.PLoS One. 2017 Jan 17;12(1):e0170207. doi: 10.1371/journal.pone.0170207. eCollection 2017.
• [16] Decreased Expression of Semaphorin 3A and Semaphorin 7A Levels and Its Association with Systemic Lupus Erythematosus.Immunol Invest. 2020 Feb;49(1-2):69-80. doi: 10.1080/08820139.2019.1649280. Epub 2019 Aug 15.
• [17] Semaphorin-7A contributes to growth, migration and invasion of oral tongue squamous cell carcinoma through TGF--mediated EMT signaling pathway.Eur Rev Med Pharmacol Sci. 2018 Feb;22(4):1035-1043. doi: 10.26355/eurrev_201802_14386.
• [18] Semaphorin 7a exerts pleiotropic effects to promote breast tumor progression.Oncogene. 2016 Sep 29;35(39):5170-8. doi: 10.1038/onc.2016.49. Epub 2016 Apr 11.
• [19] Mutation screening of SEMA3A and SEMA7A in patients with congenital hypogonadotropic hypogonadism.Pediatr Res. 2014 May;75(5):641-4. doi: 10.1038/pr.2014.23. Epub 2014 Feb 12.
• [20] LncRNA LOXL1-AS1/miR-28-5p/SEMA7A axis facilitates pancreatic cancer progression.Cell Biochem Funct. 2020 Jan;38(1):58-65. doi: 10.1002/cbf.3449. Epub 2019 Nov 15.
• [21] 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.
• [22] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [23] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [24] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [25] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [26] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [27] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] 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.
• [30] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [31] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [32] 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.
• [33] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [34] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [35] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.