Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

Semaphorin 5A drives melanoma progression: role of Bcl-2, miR-204 and c-Myb

Authors: Simona D’Aguanno, Elisabetta Valentini, Maria Grazia Tupone, Marianna Desideri, Marta Di Martile, Manuela Spagnuolo, Simonetta Buglioni, Cristiana Ercolani, Italia Falcone, Marco De Dominici, Michele Milella, Maria Giulia Rizzo, Bruno Calabretta, Carlo Cota, Andrea Anichini, Daniela Trisciuoglio, Donatella Del Bufalo

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Login to get access

Abstract

Background

Melanoma, the most aggressive form of skin cancer, is characterized by high rates of metastasis, drug resistance and mortality. Here we investigated the role of Semaphorin 5A (Sema5A) on the properties associated with melanoma progression and the factors involved in Sema5A regulation.

Methods

Western blotting, qRT-PCR, Chromatin immunoprecipitation (ChIP) assay, immunohistochemistry of melanoma patient specimens and xenograft tissues, in vitro Transwell assay for cell migration and invasion evaluation, in vitro capillary-like structure formation analysis.

Results

A significant correlation of Sema5A mRNA expression and melanoma progression was observed by analyzing GEO profile dataset. Endogenous Sema5A protein was detected in 95% of human melanoma cell lines tested, in 70% of metastatic specimens from patients affected by melanoma, and 16% of in situ melanoma specimens showed a focal positivity. We demonstrated that Sema5A regulates in vitro cell migration and invasion and the formation of vasculogenic structures. We also found an increase of Sema5A at both mRNA and protein level after forced expression of Bcl-2. By use of transcriptional and proteasome inhibitors, we showed that Bcl-2 increases the stability of Sema5A mRNA and protein. Moreover, by ChIP we demonstrated that Sema5A expression is under the control of the transcription factor c-Myb and that c-Myb recruitment on Sema5A promoter is increased after Bcl-2 overexpression. Finally, a concomitant decrease in the expression of Sema5A, Bcl-2 and c-Myb proteins was observed in melanoma cells after miR-204 overexpression.

Conclusion

Overall our data provide evidences supporting the role of Sema5A in melanoma progression and the involvement of Bcl-2, miR-204 and c-Myb in regulating its expression.
Appendix
Available only for authorised users
Literature
1.
Worzfeld T, Offermanns S. Semaphorins and plexins as therapeutic targets. Nat Rev Drug Discov. 2014;13(8):603–21.CrossRef
2.
Neufeld G, Mumblat Y, Smolkin T, Toledano S, Nir-Zvi I, Ziv K, Kessler O. The role of the semaphorins in cancer. Cell Adhes Migr. 2016;10(6):652–74.CrossRef
3.
Chakraborty G, Kumar S, Mishra R, Patil TV, Kundu GC. Semaphorin 3A suppresses tumor growth and metastasis in mice melanoma model. PLoS One. 2012;7(3):e33633.CrossRef
4.
Roodink I, Kats G, van Kempen L, Grunberg M, Maass C, Verrijp K, Raats J, Leenders W. Semaphorin 3E expression correlates inversely with Plexin D1 during tumor progression. Am J Pathol. 2008;173(6):1873–81.CrossRef
5.
Bielenberg DR, Hida Y, Shimizu A, Kaipainen A, Kreuter M, Kim CC, Klagsbrun M. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest. 2004;114(9):1260–71.CrossRef
6.
Casazza A, Finisguerra V, Capparuccia L, Camperi A, Swiercz JM, Rizzolio S, Rolny C, Christensen C, Bertotti A, Sarotto I, Risio M, Trusolino L, Weitz J, Schneider M, Mazzone M, Comoglio PM, Tamagnone L. Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J Clin Invest. 2010;120(8):2684–98.CrossRef
7.
Loria R, Bon G, Perotti V, Gallo E, Bersani I, Baldassari P, Porru M, Leonetti C, Di Carlo S, Visca P, Brizzi MF, Anichini A, Mortarini R, Falcioni R. Sema6A and Mical1 control cell growth and survival of BRAFV600E human melanoma cells. Oncotarget. 2015;6(5):2779–93.CrossRef
8.
Ma B, Herzog EL, Lee CG, Peng X, Lee CM, Chen X, Rockwell S, Koo JS, Kluger H, Herbst RS, Sznol M, Elias JA. Role of chitinase 3-like-1 and semaphorin 7a in pulmonary melanoma metastasis. Cancer Res. 2015;75(3):487–96.CrossRef
9.
Purohit A, Sadanandam A, Myneni P, Singh RK. Semaphorin 5A mediated cellular navigation: connecting nervous system and cancer. Biochim Biophys Acta. 2014;1846(2):485–93.PubMedPubMedCentral
10.
Li X, Law JW, Lee AY. Semaphorin 5A and plexin-B3 regulate human glioma cell motility and morphology through Rac1 and the actin cytoskeleton. Oncogene. 2012;31(5):595–610.CrossRef
11.
Lu TP, Tsai MH, Lee JM, Hsu CP, Chen PC, Lin CW, Shih JY, Yang PC, Hsiao CK, Lai LC, Chuang EY. Identification of a novel biomarker, SEMA5A, for non-small cell lung carcinoma in nonsmoking women. Cancer Epidemiol Biomark Prev. 2010;19(10):2590–7.CrossRef
12.
Pan G, Lv H, Ren H, Wang Y, Liu Y, Jiang H, Wen J. Elevated expression of semaphorin 5A in human gastric cancer and its implication in carcinogenesis. Life Sci. 2010;86(3–4):139–44.CrossRef
13.
Sadanandam A, Rosenbaugh EG, Singh S, Varney M, Singh RK. Semaphorin 5A promotes angiogenesis by increasing endothelial cell proliferation, migration, and decreasing apoptosis. Microvasc Res. 2010;79(1):1–9.CrossRef
14.
Sadanandam A, Varney ML, Singh S, Ashour AE, Moniaux N, Deb S, Lele SM, Batra SK, Singh RK. High gene expression of semaphorin 5A in pancreatic cancer is associated with tumor growth, invasion and metastasis. Int J Cancer. 2010;127(6):1373–83.CrossRef
15.
Sadanandam A, Sidhu SS, Wullschleger S, Singh S, Varney ML, Yang CS, Ashour AE, Batra SK, Singh RK. Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation. Br J Cancer. 2012;107(3):501–7.CrossRef
16.
Quast SA, Berger A, Plotz M, Eberle J. Sensitization of melanoma cells for TRAIL-induced apoptosis by activation of mitochondrial pathways via Bax. Eur J Cell Biol. 2014;93(1–2):42–8.CrossRef
17.
Gabellini C, Trisciuoglio D, Del Bufalo D. Non-canonical roles of Bcl-2 and Bcl-xL proteins: relevance of BH4 domain. Carcinogenesis. 2017;38(6):579–87.CrossRef
18.
Trisciuoglio D, Desideri M, Ciuffreda L, Mottolese M, Ribatti D, Vacca A, Del Rosso M, Marcocci L, Zupi G, Del Bufalo D. Bcl-2 overexpression in melanoma cells increases tumor progression-associated properties and in vivo tumor growth. J Cell Physiol. 2005;205(3):414–21.CrossRef
19.
Trisciuoglio D, Iervolino A, Zupi G, Del Bufalo D. Involvement of PI3K and MAPK signaling in bcl-2-induced vascular endothelial growth factor expression in melanoma cells. Mol Biol Cell. 2005;16(9):4153–62.CrossRef
20.
Trisciuoglio D, Gabellini C, Desideri M, Ziparo E, Zupi G, Del Bufalo D. Bcl-2 regulates HIF-1alpha protein stabilization in hypoxic melanoma cells via the molecular chaperone HSP90. PLoS One. 2010;5(7):e11772.CrossRef
21.
Gabellini C, De Luca T, Trisciuoglio D, Desideri M, Di Martile M, Passeri D, Candiloro A, Biffoni M, Rizzo MG, Orlandi A, Del Bufalo D. BH4 domain of bcl-2 protein is required for its proangiogenic function under hypoxic condition. Carcinogenesis. 2013;34(11):2558–67.CrossRef
22.
Trisciuoglio D, Tupone MG, Desideri M, Di Martile M, Gabellini C, Buglioni S, Pallocca M, Alessandrini G, D'Aguanno S, Del Bufalo D. BCL-XL overexpression promotes tumor progression-associated properties. Cell Death Dis. 2017;8(12):3216–017.CrossRef
23.
Del Bufalo D, Trisciuoglio D, Scarsella M, Zangemeister-Wittke U, Zupi G. Treatment of melanoma cells with a bcl-2/bcl-xL antisense oligonucleotide induces antiangiogenic activity. Oncogene. 2003;22(52):8441–7.CrossRef
24.
De Cesare M, Perego P, Righetti SC, Pratesi G, Carenini N, Rivoltini L, Zupi G, Del Bufalo D, Balsari A, Zunino F. Enhanced antitumour efficacy of gimatecan in combination with Bcl-2 antisense oligonucleotide in human melanoma xenografts. Eur J Cancer. 2005;41(8):1213–22.CrossRef
25.
De Luca T, Pelosi A, Trisciuoglio D, D'Aguanno S, Desideri M, Farini V, Di Martile M, Bellei B, Tupone MG, Candiloro A, Regazzo G, Rizzo MG, Del Bufalo D. miR-211 and MITF modulation by Bcl-2 protein in melanoma cells. Mol Carcinog. 2016;55(12):2304–12.CrossRef
26.
Ciuffreda L, Del Bufalo D, Desideri M, Di Sanza C, Stoppacciaro A, Ricciardi MR, Chiaretti S, Tavolaro S, Benassi B, Bellacosa A, Foa R, Tafuri A, Cognetti F, Anichini A, Zupi G, Milella M. Growth-inhibitory and antiangiogenic activity of the MEK inhibitor PD0325901 in malignant melanoma with or without BRAF mutations. Neoplasia. 2009;11(8):720–31.CrossRef
27.
Milella M, Falcone I, Conciatori F, Matteoni S, Sacconi A, De Luca T, Bazzichetto C, Corbo V, Simbolo M, Sperduti I, Benfante A, Del Curatolo A, Cesta Incani U, Malusa F, Eramo A, Sette G, Scarpa A, Konopleva M, Andreeff M, McCubrey JA, Blandino G, Todaro M, Stassi G, De Maria R, Cognetti F, Del Bufalo D, Ciuffreda L. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer. Sci Rep. 2017;7:43013.CrossRef
28.
Visser JJ, Cheng Y, Perry SC, Chastain AB, Parsa B, Masri SS, Ray TA, Kay JN, Wojtowicz WM. An extracellular biochemical screen reveals that FLRTs and Unc5s mediate neuronal subtype recognition in the retina. Elife. 2015;4:e08149.CrossRef
29.
De Dominici M, Porazzi P, Soliera AR, Mariani SA, Addya S, Fortina P, Peterson LF, Spinelli O, Rambaldi A, Martinelli G, Ferrari A, Iacobucci I, Calabretta B. Targeting CDK6 and BCL2 exploits the “MYB addiction” of Ph+ acute lymphoblastic leukemia. Cancer Res. 2018;78(4):1097–109.CrossRef
30.
Careccia S, Mainardi S, Pelosi A, Gurtner A, Diverio D, Riccioni R, Testa U, Pelosi E, Piaggio G, Sacchi A, Lavorgna S, Lo-Coco F, Blandino G, Levrero M, Rizzo MG. A restricted signature of miRNAs distinguishes APL blasts from normal promyelocytes. Oncogene. 2009;28(45):4034–40.CrossRef
31.
Trisciuoglio D, De Luca T, Desideri M, Passeri D, Gabellini C, Scarpino S, Liang C, Orlandi A, Del Bufalo D. Removal of the BH4 domain from Bcl-2 protein triggers an autophagic process that impairs tumor growth. Neoplasia. 2013;15(3):315–27.CrossRef
32.
Zeng L, Chen Y, Wang Y, Yu LR, Knox B, Chen J, Shi T, Chen S, Ren Z, Guo L, Wu Y, Liu D, Huang K, Tong W, Yu D, Ning B. MicroRNA hsa-miR-370-3p suppresses the expression and induction of CYP2D6 by facilitating mRNA degradation. Biochem Pharmacol. 2017;140:139–49.CrossRef
33.
Verdone L, La Fortezza M, Ciccarone F, Caiafa P, Zampieri M, Caserta M. Poly(ADP-Ribosyl)ation affects histone acetylation and transcription. PLoS One. 2015;10(12):e0144287.CrossRef
34.
Cheng HW, Chen YF, Wong JM, Weng CW, Chen HY, Yu SL, Chen HW, Yuan A, Chen JJ. Cancer cells increase endothelial cell tube formation and survival by activating the PI3K/Akt signalling pathway. J Exp Clin Cancer Res. 2017;36(1):27.CrossRef
35.
Menzies AM, Long GV. Systemic treatment for BRAF-mutant melanoma: where do we go next? Lancet Oncol. 2014;15(9):e371–81.CrossRef
36.
Del Curatolo A, Conciatori F, Cesta Incani U, Bazzichetto C, Falcone I, Corbo V, D'Agosto S, Eramo A, Sette G, Sperduti I, De Luca T, Marabese M, Shirasawa S, De Maria R, Scarpa A, Broggini M, Del Bufalo D, Cognetti F, Milella M, Ciuffreda L. Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models. J Exp Clin Cancer Res. 2018;37(1):140.CrossRef
37.
Hendrix MJ, Seftor EA, Seftor RE, Chao JT, Chien DS, Chu YW. Tumor cell vascular mimicry: novel targeting opportunity in melanoma. Pharmacol Ther. 2016;159:83–92.CrossRef
38.
Cong R, Sun Q, Yang L, Gu H, Zeng Y, Wang B. Effect of Genistein on vasculogenic mimicry formation by human uveal melanoma cells. J Exp Clin Cancer Res. 2009;28:124.CrossRef
39.
Quintana AM, Liu F, O'Rourke JP, Ness SA. Identification and regulation of c-Myb target genes in MCF-7 cells. BMC Cancer. 2011;11:30.CrossRef
40.
Luan W, Qian Y, Ni X, Bu X, Xia Y, Wang J, Ruan H, Ma S, Xu B. miR-204-5p acts as a tumor suppressor by targeting matrix metalloproteinases-9 and B-cell lymphoma-2 in malignant melanoma. Onco Targets Ther. 2017;10:1237–46.CrossRef
41.
Vitiello M, Tuccoli A, D'Aurizio R, Sarti S, Giannecchini L, Lubrano S, Marranci A, Evangelista M, Peppicelli S, Ippolito C, Barravecchia I, Guzzolino E, Montagnani V, Gowen M, Mercoledi E, Mercatanti A, Comelli L, Gurrieri S, Wu LW, Ope O, Flaherty K, Boland GM, Hammond MR, Kwong L, Chiariello M, Stecca B, Zhang G, Salvetti A, Angeloni D, Pitto L, Calorini L, Chiorino G, Pellegrini M, Herlyn M, Osman I, Poliseno L. Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells. Oncotarget. 2017;8(15):25395–417.CrossRef
42.
Todorova K, Metodiev MV, Metodieva G, Zasheva D, Mincheff M, Hayrabedyan S. miR-204 is dysregulated in metastatic prostate cancer in vitro. Mol Carcinog. 2016;55(2):131–47.CrossRef
43.
Sacconi A, Biagioni F, Canu V, Mori F, Di Benedetto A, Lorenzon L, Ercolani C, Di Agostino S, Cambria AM, Germoni S, Grasso G, Blandino R, Panebianco V, Ziparo V, Federici O, Muti P, Strano S, Carboni F, Mottolese M, Diodoro M, Pescarmona E, Garofalo A, Blandino G. miR-204 targets Bcl-2 expression and enhances responsiveness of gastric cancer. Cell Death Dis. 2012;3:e423.CrossRef
44.
Meyer LA, Fritz J, Pierdant-Mancera M, Bagnard D. Current drug design to target the Semaphorin/Neuropilin/Plexin complexes. Cell Adhes Migr. 2016;10(6):700–8.CrossRef
45.
Saxena S, Hayashi Y, Wu L, Awaji M, Atri P, Varney ML, Purohit A, Rachagani S, Batra SK, Singh RK. Pathological and functional significance of Semaphorin-5A in pancreatic cancer progression and metastasis. Oncotarget. 2017;9(5):5931–43.PubMedPubMedCentral
46.
Pan GQ, Ren HZ, Zhang SF, Wang XM, Wen JF. Expression of semaphorin 5A and its receptor plexin B3 contributes to invasion and metastasis of gastric carcinoma. World J Gastroenterol. 2009;15(22):2800–4.CrossRef
47.
Du Y, Wu X, Chen M, Wang W, Xv W, Ye L, Wu D, Xue J, Sun W, Luo J, Wu H. Elevated semaphorin5A in systemic lupus erythematosus is in association with disease activity and lupus nephritis. Clin Exp Immunol. 2017;188(2):234–42.CrossRef
48.
Gras C, Eiz-Vesper B, Jaimes Y, Immenschuh S, Jacobs R, Witte T, Blasczyk R, Figueiredo C. Secreted semaphorin 5A activates immune effector cells and is a biomarker for rheumatoid arthritis. Arthritis Rheumatol. 2014;66(6):1461–71.CrossRef
49.
Oh IH, Reddy EP. The myb gene family in cell growth, differentiation and apoptosis. Oncogene. 1999;18(19):3017–33.CrossRef
50.
Introna M, Golay J. How can oncogenic transcription factors cause cancer: a critical review of the myb story. Leukemia. 1999;13(9):1301–6.CrossRef
51.
Ramsay RG, Gonda TJ. MYB function in normal and cancer cells. Nat Rev Cancer. 2008;8(7):523–34.CrossRef
52.
Schultz J, Lorenz P, Ibrahim SM, Kundt G, Gross G, Kunz M. The functional -443T/C osteopontin promoter polymorphism influences osteopontin gene expression in melanoma cells via binding of c-Myb transcription factor. Mol Carcinog. 2009;48(1):14–23.CrossRef
53.
Kozubek J, Ma Z, Fleming E, Duggan T, Wu R, Shin DG, Dadras SS. In-depth characterization of microRNA transcriptome in melanoma. PLoS One. 2013;8(9):e72699.CrossRef
54.
Liu X, Chen X, Yu X, Tao Y, Bode AM, Dong Z, Cao Y. Regulation of microRNAs by epigenetics and their interplay involved in cancer. J Exp Clin Cancer Res. 2013;32:96.CrossRef
55.
Butrym A, Rybka J, Baczynska D, Tukiendorf A, Kuliczkowski K, Mazur G. Low expression of microRNA-204 (miR-204) is associated with poor clinical outcome of acute myeloid leukemia (AML) patients. J Exp Clin Cancer Res. 2015;34:68.CrossRef
56.
Diaz-Martinez M, Benito-Jardon L, Alonso L, Koetz-Ploch L, Hernando E, Teixido J. miR-204-5p and miR-211-5p contribute to BRAF inhibitor resistance in melanoma. Cancer Res. 2018;78(4):1017–30.CrossRef
Metadata
Title
Semaphorin 5A drives melanoma progression: role of Bcl-2, miR-204 and c-Myb
Authors
Simona D’Aguanno
Elisabetta Valentini
Maria Grazia Tupone
Marianna Desideri
Marta Di Martile
Manuela Spagnuolo
Simonetta Buglioni
Cristiana Ercolani
Italia Falcone
Marco De Dominici
Michele Milella
Maria Giulia Rizzo
Bruno Calabretta
Carlo Cota
Andrea Anichini
Daniela Trisciuoglio
Donatella Del Bufalo
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0933-x

Other articles of this Issue 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Go to the issue

Research

FBP1 loss contributes to BET inhibitors resistance by undermining c-Myc expression in pancreatic ductal adenocarcinoma

Research

Attenuation of TGFBR2 expression and tumour progression in prostate cancer involve diverse hypoxia-regulated pathways

Research

MicroRNA-150 enhances radiosensitivity by inhibiting the AKT pathway in NK/T cell lymphoma

Research

RETRACTED ARTICLE: Long noncoding RNA MLK7-AS1 promotes ovarian cancer cells progression by modulating miR-375/YAP1 axis

Correction

Correction to: PHF8 upregulation contributes to autophagic degradation of E-cadherin, epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma

Research

GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits