Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQFMS8S)

• DOT Name: Semaphorin-3F (SEMA3F)
• Synonyms: Sema III/F; Semaphorin IV; Sema IV
• Gene Name: SEMA3F
• Related Disease:
  T-cell acute lymphoblastic leukaemia
  Advanced cancer
  Autism spectrum disorder
  Benign prostatic hyperplasia
  Breast cancer
  Breast carcinoma
  Cardiac arrest
  Colon cancer
  Colon carcinoma
  Colorectal adenoma
  Colorectal carcinoma
  Corneal neovascularization
  Coronary heart disease
  Endometrium neoplasm
  Inflammation
  Lung neoplasm
  Neuroma
  Polyp
  Prostate cancer
  Prostate carcinoma
  Small-cell lung cancer
  Squamous cell carcinoma
  Benign neoplasm
  Carcinoma
  Endometrial carcinoma
  High blood pressure
  Metastatic malignant neoplasm
  Neuroendocrine neoplasm
  Type-1/2 diabetes
  Endometrial cancer
  Brain neoplasm
  Lung cancer
  Lung carcinoma
  Myocardial infarction
  Neoplasm
  Neurofibromatosis type 2
  Schwannoma
• UniProt ID: SEM3F_HUMAN
• Pfam ID: PF01403
• Sequence:
  MLVAGLLLWASLLTGAWPSFPTQDHLPATPRVRLSFKELKATGTAHFFNFLLNTTDYRIL
  LKDEDHDRMYVGSKDYVLSLDLHDINREPLIIHWAASPQRIEECVLSGKDVNGECGNFVR
  LIQPWNRTHLYVCGTGAYNPMCTYVNRGRRAQATPWTQTQAVRGRGSRATDGALRPMPTA
  PRQDYIFYLEPERLESGKGKCPYDPKLDTASALINEELYAGVYIDFMGTDAAIFRTLGKQ
  TAMRTDQYNSRWLNDPSFIHAELIPDSAERNDDKLYFFFRERSAEAPQSPAVYARIGRIC
  LNDDGGHCCLVNKWSTFLKARLVCSVPGEDGIETHFDELQDVFVQQTQDVRNPVIYAVFT
  SSGSVFRGSAVCVYSMADIRMVFNGPFAHKEGPNYQWMPFSGKMPYPRPGTCPGGTFTPS
  MKSTKDYPDEVINFMRSHPLMYQAVYPLQRRPLVVRTGAPYRLTTIAVDQVDAADGRYEV
  LFLGTDRGTVQKVIVLPKDDQELEELMLEEVEVFKDPAPVKTMTISSKRQQLYVASAVGV
  THLSLHRCQAYGAACADCCLARDPYCAWDGQACSRYTASSKRRSRRQDVRHGNPIRQCRG
  FNSNANKNAVESVQYGVAGSAAFLECQPRSPQATVKWLFQRDPGDRRREIRAEDRFLRTE
  QGLLLRALQLSDRGLYSCTATENNFKHVVTRVQLHVLGRDAVHAALFPPLSMSAPPPPGA
  GPPTPPYQELAQLLAQPEVGLIHQYCQGYWRHVPPSPREAPGAPRSPEPQDQKKPRNRRH
  HPPDT
• Function: May play a role in cell motility and cell adhesion.
• Tissue Specificity: Expressed abundantly but differentially in a variety of neural and nonneural tissues. There is high expression in mammary gland, kidney, fetal brain, and lung and lower expression in heart and liver.
• KEGG Pathway: Axon guidance (hsa04360)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Cardiac arrest	DIS9DIA4	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Colorectal adenoma	DISTSVHM	Strong	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Corneal neovascularization	DISKOGZP	Strong	Biomarker	[10]
Coronary heart disease	DIS5OIP1	Strong	Altered Expression	[6]
Endometrium neoplasm	DIS6OS2L	Strong	Biomarker	[11]
Inflammation	DISJUQ5T	Strong	Altered Expression	[6]
Lung neoplasm	DISVARNB	Strong	Biomarker	[12]
Neuroma	DISIENZM	Strong	Biomarker	[13]
Polyp	DISRSLYF	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Altered Expression	[4]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[4]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[14]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[2]
Benign neoplasm	DISDUXAD	moderate	Biomarker	[15]
Carcinoma	DISH9F1N	moderate	Biomarker	[15]
Endometrial carcinoma	DISXR5CY	moderate	Altered Expression	[16]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[17]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[18]
Neuroendocrine neoplasm	DISNPLOO	moderate	Biomarker	[18]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[17]
Endometrial cancer	DISW0LMR	Disputed	Altered Expression	[16]
Brain neoplasm	DISY3EKS	Limited	Biomarker	[19]
Lung cancer	DISCM4YA	Limited	Altered Expression	[20]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[20]
Myocardial infarction	DIS655KI	Limited	Genetic Variation	[21]
Neoplasm	DISZKGEW	Limited	Altered Expression	[16]
Neurofibromatosis type 2	DISI8ECS	Limited	Biomarker	[19]
Schwannoma	DISTTVLA	Limited	Biomarker	[19]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mifepristone	DMGZQEF	Approved	Semaphorin-3F (SEMA3F) increases the response to substance of Mifepristone.	[11]

3 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-3F (SEMA3F).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Semaphorin-3F (SEMA3F).	[36]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Semaphorin-3F (SEMA3F).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Semaphorin-3F (SEMA3F).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Semaphorin-3F (SEMA3F).	[24]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Semaphorin-3F (SEMA3F).	[25]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Semaphorin-3F (SEMA3F).	[26]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Semaphorin-3F (SEMA3F).	[27]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Semaphorin-3F (SEMA3F).	[28]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Semaphorin-3F (SEMA3F).	[29]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Semaphorin-3F (SEMA3F).	[30]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Semaphorin-3F (SEMA3F).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Semaphorin-3F (SEMA3F).	[32]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Semaphorin-3F (SEMA3F).	[33]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Semaphorin-3F (SEMA3F).	[34]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Semaphorin-3F (SEMA3F).	[35]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Semaphorin-3F (SEMA3F).	[28]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Semaphorin-3F (SEMA3F).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Semaphorin-3F (SEMA3F).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Semaphorin-3F (SEMA3F).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Semaphorin-3F (SEMA3F).	[39]

References

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• [2] The crucial role of SEMA3F in suppressing the progression of oral squamous cell carcinoma.Cell Mol Biol Lett. 2017 Dec 28;22:32. doi: 10.1186/s11658-017-0064-y. eCollection 2017.
• [3] Temporal Regulation of Dendritic Spines Through NrCAM-Semaphorin3F Receptor Signaling in Developing Cortical Pyramidal Neurons.Cereb Cortex. 2019 Mar 1;29(3):963-977. doi: 10.1093/cercor/bhy004.
• [4] SSeCKS/AKAP12 induces repulsion between human prostate cancer and microvessel endothelial cells through the activation of Semaphorin 3F.Biochem Biophys Res Commun. 2017 Sep 2;490(4):1394-1398. doi: 10.1016/j.bbrc.2017.07.043. Epub 2017 Jul 8.
• [5] Alternative Splicing in Adhesion- and Motility-Related Genes in Breast Cancer.Int J Mol Sci. 2016 Jan 16;17(1):121. doi: 10.3390/ijms17010121.
• [6] Semaphorin 3F Promotes Transendothelial Migration of Leukocytes in the Inflammatory Response After Survived Cardiac Arrest.Inflammation. 2019 Aug;42(4):1252-1264. doi: 10.1007/s10753-019-00985-4.
• [7] Endogenous axon guiding chemorepulsant semaphorin-3F inhibits the growth and metastasis of colorectal carcinoma.Clin Cancer Res. 2011 May 1;17(9):2702-11. doi: 10.1158/1078-0432.CCR-10-0839. Epub 2011 Feb 24.
• [8] Loss of sensory and noradrenergic innervation in benign colorectal adenomatous polyps--a putative role of semaphorins 3F and 3A.Neurogastroenterol Motil. 2012 Feb;24(2):120-8, e83. doi: 10.1111/j.1365-2982.2011.01818.x. Epub 2011 Nov 16.
• [9] SEMA3F prevents metastasis of colorectal cancer by PI3K-AKT-dependent down-regulation of the ASCL2-CXCR4 axis.J Pathol. 2015 Aug;236(4):467-78. doi: 10.1002/path.4541. Epub 2015 May 22.
• [10] Semaphorin 3F Modulates Corneal Lymphangiogenesis and Promotes Corneal Graft Survival.Invest Ophthalmol Vis Sci. 2018 Oct 1;59(12):5277-5284. doi: 10.1167/iovs.18-24287.
• [11] Progesterone and 1,25-dihydroxyvitamin D? inhibit endometrial cancer cell growth by upregulating semaphorin 3B and semaphorin 3F. Mol Cancer Res. 2011 Nov;9(11):1479-92. doi: 10.1158/1541-7786.MCR-11-0213. Epub 2011 Sep 20.
• [12] Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells.Neoplasia. 2005 May;7(5):457-65. doi: 10.1593/neo.04721.
• [13] Human neuroma contains increased levels of semaphorin 3A, which surrounds nerve fibers and reduces neurite extension in vitro.J Neurosci. 2007 Dec 26;27(52):14260-4. doi: 10.1523/JNEUROSCI.4571-07.2007.
• [14] Semaphorin 3F gene from human 3p21.3 suppresses tumor formation in nude mice.Cancer Res. 2002 May 1;62(9):2637-43.
• [15] Expression of semaphorins, vascular endothelial growth factor, and their common receptor neuropilins and alleic loss of semaphorin locus in epithelial ovarian neoplasms: increased ratio of vascular endothelial growth factor to semaphorin is a poor prognostic factor in ovarian carcinomas.Hum Pathol. 2006 Nov;37(11):1414-25. doi: 10.1016/j.humpath.2006.04.031. Epub 2006 Sep 28.
• [16] Changes in Expression Pattern of SEMA3F Depending on Endometrial Cancer Grade - Pilot Study.Curr Pharm Biotechnol. 2019;20(9):727-732. doi: 10.2174/1389201020666190619145655.
• [17] Association of genetic variants with myocardial infarction in individuals with or without hypertension or diabetes mellitus.Int J Mol Med. 2009 Nov;24(5):701-9. doi: 10.3892/ijmm_00000282.
• [18] The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors.Oncotarget. 2015 Nov 3;6(34):36731-45. doi: 10.18632/oncotarget.5481.
• [19] Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F-dependent mechanism.Neoplasia. 2012 Feb;14(2):84-94. doi: 10.1593/neo.111600.
• [20] Neuropilin-2 Is upregulated in lung cancer cells during TGF-1-induced epithelial-mesenchymal transition.Cancer Res. 2013 Dec 1;73(23):7111-21. doi: 10.1158/0008-5472.CAN-13-1755. Epub 2013 Oct 11.
• [21] Association of genetic variants with myocardial infarction in Japanese individuals with different lipid profiles.Int J Mol Med. 2010 Apr;25(4):607-16. doi: 10.3892/ijmm_00000383.
• [22] 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.
• [23] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [24] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [25] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [26] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [27] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [28] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [29] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [30] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [31] Progesterone and 1,25-dihydroxyvitamin D? inhibit endometrial cancer cell growth by upregulating semaphorin 3B and semaphorin 3F. Mol Cancer Res. 2011 Nov;9(11):1479-92. doi: 10.1158/1541-7786.MCR-11-0213. Epub 2011 Sep 20.
• [32] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [33] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [34] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [35] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [36] 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.
• [37] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [38] 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.
• [39] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [40] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [41] Progesterone and 1,25-dihydroxyvitamin D? inhibit endometrial cancer cell growth by upregulating semaphorin 3B and semaphorin 3F. Mol Cancer Res. 2011 Nov;9(11):1479-92. doi: 10.1158/1541-7786.MCR-11-0213. Epub 2011 Sep 20.