doctoral thesis
IDENTIFICATION OF PROTEIN MARKERS IN METASTATIC LARYNGEAL SQUAMOUS CELL CARCINOMA AND CONTRIBUTION OF NCAM MOLECULE POLYSIALYLATION TO PROGRESSION OF SQUAMOUS CELL CARCINOMA OF THE LARYNX

Marko Klobučar (2017)
Sveučilište u Rijeci
Odjel za biotehnologiju
Metadata
TitleIDENTIFIKACIJA PROTEINSKIH BILJEGA KOD METASTATSKOGA PLANOCELULARNOG KARCINOMA GRKLJANA I DOPRINOS POLISIJALIZACIJE NCAM-MOLEKULE PROGRESIJI PLANOCELULARNOG KARCINOMA GRKLJANA
AuthorMarko Klobučar
Mentor(s)Sandra Kraljević Pavelić
Abstract
Planocelularni karcinom grkljana naj.e..i je oblik malignog oboljenja glave i vrata kojeg tijekom progresije karakterizira u.estala pojava metastaza u limfnim .vorovima vrata u ranim fazama razvoja bolesti. Ovaj tip karcinoma obilje.avaju mnogobrojne genetske abnormalnosti i promjene razine ekspresije niza proteinskih i glikoproteinskih molekula koje su neposredno povezane s procesom kancerogeneze. Unato. brojnim otkri.ima molekularni mehanizmi u pozadini patogeneze ovog oboljenja jo. uvijek nisu u potpunosti razja.njeni. Osim toga, sve je vi.e dokaza koji upu.uju na to da je abnormalna ekspresija i glikozilacija proteina posljedica inicijalne maligne transformacije stanica, a aberantna glikozilacija predstavlja jedan od klju.nih doga.aja u invaziji i metastaziranju mnogih malignih oboljenja. U svrhu identifikacije novih proteinskih biljega, koji bi dodatno razjasnili patogenezu metastatskog oblika bolesti i koji bi se mogli koristiti kao potencijalni dijagnosti.ki i prognosti.ki biljezi, u ovomu doktorskom radu je provedeno globalno diferencijalno proteomsko profiliranje uzoraka tkiva primarnih metastatskih tumora i pripadaju.eg tumorom nezahva.enog tkiva. Primijenjena je metoda masene spektrometrije spregnute s teku.inskom kromatografijom i naknadnom bioinfomati.kom analizom. Identificirano je ukupno 289 statisti.ki zna.ajno diferencijalno eksprimiranih proteina u metastatskim tumorima, a validacija odabranih potencijalnih markera je provedena uz pomo. metoda Western blot i 2D imunoblot. U primarnom metastatskom planocelularnom karcinomu grkljana su po prvi puta specifi.no potvr.eni potencijalni proteinski biljezi ladinin-1, antigen diferencijacije monocita- CD 14, lumikan, alfa 4A lanac tubulina- TUBA4A, afamin, ali i s njima povezani stani.ni signalni putevi poput CD44-Ŕ1 integrinskoga signalnog puta induciranog faktorom inhibicije migracije makrofaga-MIF i signalnog puta nuklearnog faktora kapa B. Nadalje, uz pomo. imunohistokemijske analize je u svim uzorcima tkiva primarnih tumora utvr.ena i ekspresija polisijalizirane forme adhezijske molekule neuralnih stanica (engl. PSA-NCAM -Polysialylated neural cell adhesion molecule), onkofetalnoga glikoproteinskog antigena, koji se povezuje s patogenezom i metastatskom diseminacijom nekih izrazito malignih oboljenja. Utjecaj PSA-NCAM na promjenu statusa stani.nih signalnih kaskada, koje su uklju.ene u odr.anje normalne homeostaze tkiva sluznice, bio je negativan .to upu.uje na .injenicu da ekspresija PSA-NCAM doprinosi ranim fazama maligne transformacije planocelularnog karcinoma grkljana.
KeywordsLadinin-1 monocyte differentiation antigen CD-14 lumican alpha-tubulin chain 4A afamin CD44-1 integrin- MIF nuclear factor kappa B metastases proteomics laryngeal squamous cell carcinoma polysialylation NCAM primary laryngeal squamous cell carcinoma progression
Parallel title (English)IDENTIFICATION OF PROTEIN MARKERS IN METASTATIC LARYNGEAL SQUAMOUS CELL CARCINOMA AND CONTRIBUTION OF NCAM MOLECULE POLYSIALYLATION TO PROGRESSION OF SQUAMOUS CELL CARCINOMA OF THE LARYNX
Committee MembersKrešimir Pavelić (committee chairperson)
Anđelka Radoičić Badovinac (committee member)
Roberto Antolović (committee member)
GranterSveučilište u Rijeci
Lower level organizational unitsOdjel za biotehnologiju
PlaceRijeka
StateCroatia
Scientific field, discipline, subdisciplineBIOTECHNICAL SCIENCES
Biotechnology
UDK612
APPLIED SCIENCES. MEDICINE. TECHNOLOGY
Physiology
Study programme typeuniversity
Study levelpostgraduate
Study programmeMedicinal chemistry
Academic title abbreviationdr. sc.
Genredoctoral thesis
Language Croatian
Defense date2017-02-10
Promoted date2017-02-10
Parallel abstract (English)
Laryngeal squamous cell carcinoma (LSCC) is the most common form of malignant disease in the head and neck region characterized by the frequent occurrence of metastases in the neck lymph nodes early in the disease progression. This form of cancer is characterised with numerous genetic abnormalities and changes in expression levels of proteins and glycoproteins associated with the process of carcinogenesis. Despite numerous findings molecular mechanism of metastatic disease has not yet been fully elucidated. In addition, there is increasing evidence that abnormal expression and glycosylation of proteins result of initial malignant transformation of cells, and aberrant glycosylation is one of the key events in the invasion and metastasis of many malignant diseases. In addition, there is increasing evidence indicating that abnormal expression and glycosylation of proteins is a result of cellular initial malignant transformation, and aberrant glycosylation is one of the key events in the invasion and metastasis of many malignant diseases. To identify novel protein markers which would further elucidate the pathogenesis of the metastatic disease and that could be also used as potential diagnostic and prognostic biomarkers, the global differential proteomic profiling of primary metastatic tumour and matched tumour non-affected tissues was performed. For proteomic profiling the method of mass spectrometry coupled with liquid chromatography and subsequent bioinformatic analysis was applied. A total number of 289 differentially expressed proteins were identified in metastatic tumors and selected protein markers were further validated by Western blot and 2D-imunoblot method. Potential protein biomarkers Ladinin-1, monocyte differentiation antigen CD-14, lumican, alpha-tubulin 4A chain TUBA4A, afamin and their associated cellular signaling pathways such as CD44-1 integrin induced macrophage migration inhibitory factor MIF and nuclear factor kappa B signaling pathway, were for the first time to our knowledge specifically determined in metastatic LSCC. Furthermore, in all analysed primary tumor tissue samples the expression of polysialylated neural cell molecule (PSANCAM), an oncofetal glycoprotein antigen previously associated with pathogenesis and metastatic dissemination of highly malignant diseases, was determined by immunohistochemical analysis. The impact of PSA-NCAM expression on the cellular signaling cascades involved in maintainance of normal mucosa tissue homeostasis was negative, which indicates that the expression of PSA-NCAM contribute to the initial stages of malignant transformation in laryngeal squamous cell carcinoma.
Parallel keywords (Croatian)Ladinin-1 antigen diferencijacije monocita- CD 14 lumikan alfa 4A lanac tubulina afamin CD44-â1integrin -MIF nuklearni faktora kapa B metastaziranje proteomika planocelularni karcinom grkljana polisijalizacija primarni planocelularni karcinom grkljana progresija
Versionaccepted version
Resource typetext
Access conditionOpen access
Terms of usehttp://creativecommons.org/licenses/by-nc-nd/4.0/
Noteaccepted version
URN:NBNhttps://urn.nsk.hr/urn:nbn:hr:193:859507
CommitterLea Lazzarich