Vloga molekularnih in imunohistokemičnih označevalcev v epitelijsko-mezenhimskem prehodu svetloceličnega karcinoma ledvičnih celic

Čugura, Tanja (author), Jeruc, Jera (mentor), Boštjančič, Emanuela (comentor)

Epitelijsko-mezenhimski prehod (EMP) je večstopenjski biološki proces, vključen v številne fiziološke procese, pomembno vlogo pa ima tudi pri napredovanju in zasevanju različnih tumorjev. EMP se sproži prek signalov iz tumorskega mikrookolja, kar prek sprememb v izražanju ključnih genov in posttranslacijskih mehanizmov privede do zaviranja epitelijskih značilnosti in izražanja mezenhimskih značilnosti celic. Karcinom ledvičnih celic (KLC) je uvrščen med pogostejše maligne tumorje sečil, njegova incidenca pa tako v Sloveniji kot v svetu narašča. V primerjavi z nekaterimi pogostejšimi tumorji je pomen EMP pri napredovanju KLC slabše raziskan in še nepojasnjen. V naši raziskavi smo celovito analizirali vlogo EMP in njegovo regulacijo v KLC pri treh medsebojno povezanih procesih: v sarkomatoidni transformaciji KLC, v venski tumorski invaziji ter v možnih interakcijah med mikro RNA (miRNA) in dolgimi nekodirajočimi RNA (angl. long non coding RNA, lncRNA) v KLC. V prvem delu raziskave smo analizirali izražanje označevalcev, povezanih z EMP, ter jih primerjali med sarkomatoidnim KLC (sKLC) in svetloceličnim KLC nizkega gradusa brez sarkomatoidne diferenciacije. Rezultati so pokazali, da med sarkomatoidno komponento sKLC (sKLC-Sa), karcinomsko komponento sKLC (sKLC-Ka) in KLC obstajajo določene razlike v molekularnih označevalcih, ki nakazujejo možnost obstoja delnega EMP v razvoju sKLC, torej obstoja celic v različnih hibridnih celičnih stanjih. Vsako od teh stanj odraža različno močno aktivacijo EMP. V drugem delu naloge smo se osredotočili na KLC z žilno vensko invazijo. Izražanje označevalcev EMP smo analizirali v treh tumorskih predelih — v središču tumorja, na obrobju tumorja in v venskem tumorskem trombu — ter jih primerjali med seboj in z netumorskim ledvičnim tkivom. Rezultati primerjave venskega tumorskega tromba s središčem tumorja je nakazala na možnost obstoja delnega mezenhimsko-epitelijskega prehoda (MEP) med procesom žilne invazije. V tretjem delu naloge smo analizirali lncRNA, ki bi lahko vplivale na izražanje miRNA iz družine miR-200. Kot potencialno regulatorne za celotno družino miR-200 v KLC so se izkazale tri RNA. Rezultati so bili delno potrjeni tudi z analizo podatkov RNA sekvenciranja iz baze podatkov The Cancer Genome Atlas (TCGA), kar podpira njihovo potencialno vlogo v regulaciji miRNA.

• Language: Slovenian
• Keywords: Epitelijsko-mezenhimski prehod, ledvični karcinom, svetlocelični karcinom ledvičnih celic, sarkomatoidni karcinom ledvic, mikroRNA, mRNA, dolge nekodirajoče RNA, transkripcijski faktorji, venska invazija
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2026
• PID: 20.500.12556/RUL-183329
• Publication date in RUL: 11.06.2026

Secondary language

• Language: English
• Title: The role of molecular and immunohistochemical markers in epithelial-mesenchymal transition of clear cell renal cell carcinoma

Abstract

Epithelial-mesenchymal transition (EMT) is a multistep biological process involved in various physiological processes and plays a significant role in the progression and metastasis of different tumors. EMT is triggered by signals from the tumor microenvironment, which, through changes in the expression of key genes and post-translational mechanisms, lead to the repression of epithelial characteristics and the acquisition of mesenchymal traits by cells. Renal cell carcinoma (RCC) is among the more common malignant tumors of the urinary tract, and its incidence is increasing both in Slovenia and worldwide. Unlike some more prevalent tumors, the role of EMT in the progression of RCC is not extensively studied and remains underinvestigated. In our study, we comprehensively analyzed the role of EMT and its regulation in RCC through three interconnected processes: sarcomatoid transformation of RCC, venous tumor invasion, and potential interactions between microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in RCC. In the first part of the study, we analyzed the expression of EMT-related markers and compared them among components of sarcomatoid RCC (sRCC) — the sarcomatoid component, the carcinomatous component, and non-tumorous kidney tissue — and clear cell RCC (ccRCC) of low grade without sarcomatoid differentiation. The results indicated that there are certain differences in molecular markers between both components of sRCC and ccRCC, suggesting the possibility of a partial EMT in sRCC, i.e. the presence of cells in various hybrid states. Each of these states reflects a different degree of EMT activation. In the second part of the study, we focused on RCC with vascular venous invasion. We analyzed the expression of EMT markers in three tumor regions — the tumor center, tumor periphery and venous tumor thrombus — and compared them with each other and with non-tumorous kidney tissue. When comparing the venous tumor thrombus with the tumor center, the results suggested the possibility of a partial MET during the process of vascular invasion. In the third part of the study, we analyzed lncRNAs that could influence the expression of microRNAs from the miR-200 family. Three lncRNAs emerged as potential regulators of the entire miR-200 family in RCC. These results were partially confirmed by analysis of RNA-seq data from The Cancer Genome Atlas (TCGA) database, supporting their potential role in miRNA regulation.

• Keywords: Epithelial-mesenchymal transition, renal carcinoma, clear cell renal cell carcinoma, sarcomatoid renal carcinoma, microRNA, mRNA, long non-coding RNA, transcription factor, venous invasion