Vpliv retinojske kisline atra na izražanje gena HER3 pri celični liniji raka glave in vratu FaDu : magistrsko delo

Babič, Davor

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Title:	Vpliv retinojske kisline atra na izražanje gena HER3 pri celični liniji raka glave in vratu FaDu : magistrsko delo
Authors:	ID Babič, Davor (Author) ID Potočnik, Uroš (Mentor) More about this mentor... ID Büdefeld, Tomaž (Comentor)
Files:	MAG_Babic_Davor_2022.pdf (2,63 MB) MD5: 07A152424852F358AA5492A36C6A6911
Language:	Slovenian
Work type:	Master's thesis/paper
Typology:	2.09 - Master's Thesis
Organization:	FKKT - Faculty of Chemistry and Chemical Engineering
Abstract:	Rak glave in vratu (angl. Head and Neck Cancer, HNC) predstavlja raznoliko skupino rakov, v katere sodijo raki iz različnih predelov glave in vratu. Več kot 90 % rakov glave in vratu se razvije iz enostavnega enoskladnega epitela (angl. squamous epithelium, SE), ki tvori sluznico ustne in nosne votline ter grla in žrela, zato takšne rake imenujemo ploščatocelični raki glave in vratu (angl. Head and Neck Squamos Cell Carcinoma, HNSCC). Število obolelih s HNSCC vsako leto narašča. V letu 2020 je bilo 931.000 ljudem diagnosticiran HNSCC, kar ga uvršča na sedmo mesto najpogostejših rakov na svetu. Molekularna patogeneza HNSCC je zapleten proces, ki obsega genetske, epigenetske in okoljske dejavnike ter številne signalne poti. Pomembno vlogo pri razvoju HNSCC imajo receptorji tirozinskih kinaz, med katere spada tudi receptor ERBB3/HER3. HER3 vpliva na celično proliferacijo, diferenciacijo in preživetje. HER3 je povišano izražen pri večini HNSCC bolnikov in pri bolnikih s ponovljenim rakom po zdravljenju. Povišano izražanje HER3 pa zmanjšuje tudi učinkovitost zdravljenja s kemoterapijo. Aktivni metabolit ATRA uravnava celično diferenciacijo in apoptozo ter zavira rast rakavih celic. ATRA se uporablja za zdravljenje akutne promielocitne levkemije (angl. Acute Promyelocytic Leukemia, APL) pri odraslih in nevroblastomov pri otrocih. Pri raku dojk ATRA zavira izražanje HER3, medtem ko njen vpliv na izražanje HER3 pri HNSCC ni poznan. V magistrski nalogi smo proučili vpliv matabolita ATRA na izražanje mRNA za receptor HER3 in alternativnega prepisa za topno beljakovino p22-sERBB3 ter na celično rast, metabolizem in smrt pri celični liniji HNSCC FaDu. Celice FaDu smo izpostavili 2,5 M raztopini ATRA in spremljali celično rast/proliferacijo in preživetje v obdobju od 24 ur do 96 ur po nasaditvi. Metabolno aktivnost smo izmerili z uporabo reagenta MTT 72 ur po tretiranju. Izražanje HER3 smo izmerili z RT-qPCR 72 ur po tretiranju. Tretiranje z metabolitom ATRA je statistično značilno zmanjšalo rast/proliferacijo (p< 0,001) celic FaDu in njihovo metabolno aktivnost (p< 0,01), ni pa imelo vpliva na viabilnost in preživetje celic. Celice, ki so bile izpostavljene metabolitu ATRA 72 ur so imeli statistično značilno (p<0,001) znižano izražanje receptorja HER3 in krajšega prepisa p22-sERBB3. Naši rezultati potrjujejo protitumorske učinke metabolita retinojske kisline ATRA na celično rast in metabolizem in kažejo, da znižuje izražanje receptorja HER3 pri HNSCC. Metabolit retinojske kisline ATRA bi v prihodnje lahko vključili v protokole zdravljenja rakov glave in vratu, vendar je njegove učinke potrebno preveriti še in vivo v kliničnih študijah.
Keywords:	rak glave in vratu, FaDu, HER3, ATRA, RT-qPCR
Place of publishing:	Maribor
Place of performance:	Maribor
Publisher:	[D. Babič]
Year of publishing:	2022
Number of pages:	1 spletni vir (1 datoteka PDF (VIII, 31 f.))
PID:	20.500.12556/DKUM-82830
UDC:	616.91/.93-006.6(043.2)
COBISS.SI-ID:	121268995
Publication date in DKUM:	09.09.2022
Views:	833
Downloads:	69
Metadata:
Categories:	KTFMB - FKKT
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Licences

License:	CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International

Link:	http://creativecommons.org/licenses/by-nc-nd/4.0/
Description:	The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.
Licensing start date:	05.09.2022

Secondary language

Language:	English
Title:	Effect of the retinoic acid atra on HER3 gene expression in the head and neck cancer cell line FaDu
Abstract:	Head and Neck Cancer (HNC) is a diverse group of cancers that include cancers from different parts of the head and neck. More than 90% of head and neck cancers develop from the simple squamous epithelium that forms the lining of the oral and nasal cavities and the larynx and pharynx, and are therefore called Head and Neck Squamous Cell Carcinoma (HNSCC). HNC is the seventh most common cancer worldwide with 931,000 new cases in 2020. The molecular pathogenesis of HNSCC is a complex process involving genetic, epigenetic and environmental factors, as well as multiple signaling pathways. Tyrosine kinase receptors, including ERBB3/HER3, play an important role in the development of HNSCC. HER3 receptor influences cell proliferation, differentiation and survival. HER3 receptor overexpression is characeteristic for most of HNSCC patients as well as in relapse HNSCC patients and is associated with poor response to anticancer therapy. All-trans retinoic acid (ATRA) is an active metabolite of vitamin A. ATRA regulates cell differentiation and apoptosis and inhibits tumour growth. Currently, ATRA is used for treating Acute Promyelocytic Leukemia (APL) in adults and neuroblastoma in children. In breast cancer, ATRA inhibits HER3 receptor expression, while its effect on HER3 expression in HNSCC is unknown. In this Master's thesis, we investigated the effect of ATRA on the mRNA expression of HER3 receptor and alternative transcript for the soluble protein p22-sERBB3, as well as on cell growth, metabolism and death in the HNSCC cell line FaDu. FaDu cells were exposed to 2.5 M ATRA, and cell growth/proliferation and survival were monitored from 24 h to 96 h after plating. Metabolic activity was measured 72 hours after treatment using MTT assay. HER3 receptor and p22-sERBB3 mRNA expression was measured by RT-qPCR 72 hours after treatment. ATRA statistically significantly reduced cell growth/proliferation (p<0.001) and metabolic activity (p<0.01) of FaDu cells, but had no effect on cell viability and survival. Cells exposed to ATRA for 72 h exhibited significant (p<0.001) reduction of both HER3 receptor and p22-sERBB3 mRNA expression. Our results confirmed previous observations showing that ATRA supresses cell growth/proliferation and metabolism and further demostrated its antitumour activity in terms of HER3 receptor downregulation. Therefore, ATRA is a viable drug canditate that could potentially serve as an adjuvant in HNSCC therapies. However, its use in treatmant protocols for HNSCC requires additional non-clinical and clinical assessments.
Keywords:	head and neck cancer, FaDu, HER3, ATRA, RT-qPCR

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