ROLE OF miR-23b AND miR-133a IN REGULATION OF TRAIL-INDUCED APOPTOSIS PATHWAY IN RENAL CARCINOMA CELLS

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https://storage.unitedwebnetwork.com/files/1099/4491d78041d9e9d53e39b1cdbc1e2d42.pdf

Abstract Title

First Name *

Bianca

Last Name *

Silva

Co-author 1

Bianca Silva bianca.alcantara2@live.com Federal University of São Paulo Medicine Department Renal Division São Paulo

Co-author 2

Denise Leite leitedenise@hotmail.com Federal University of São Paulo Medicine Department Renal Division São Paulo

Co-author 3

Tiffany Menezes tm.menezes@uni9.edu.br Federal University of São Paulo Medicine Department Renal Division São Paulo

Co-author 4

Mirian Boim maboim@unifesp.br Federal University of São Paulo Medicine Department Renal Division São Paulo

Co-author 5

Edgar Maquigussa edgarmaquigussa@gmail.com Federal University of São Paulo Medicine Department Renal Division São Paulo

Co-author 6

Co-author 7

Co-author 8

Co-author 9

Co-author 10

Co-author 11

Co-author 12

Co-author 13

Co-author 14

Co-author 15

Introduction

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Despite recent therapeutic advances, renal carcinoma invariably becomes resistant to systemic treatment. Tumor Necrosis Factor-Related Ligand (TRAIL)-induced apoptosis is a potential target of drugs; however, the majority of malign tumors are TRAIL-resistant. Moreover, TRAIL receptors, DR4 and DR5, may be associated with TRAIL-resistance since they can lose the function when internalized

through clathrin (CLTA). Apoptosis pathway induced by TRAIL involves specific molecules including APAF-1 and culin-3. Recent studies indicated that microRNAs play

an important role in regulating TRAIL-induced apoptosis in many types of cancer. The aim of this study was to investigate the role of miR-23b and miR-133a in the

expression of the CLTA, APAF-1 and culin-3.and if they have a role in the resistance of TRAIL-induced apoptosis in ccRCC in vitro.

Methods

The renal cell carcinoma line (Caki-2) and proximal tubular cell line (HK2) were used. To test the sensitivity of cells to TRAIL, the cells were treated with TRAIL at

different doses for 24 hours. Cell viability was assessed by MTT assay. The expression of miRNAs (miR-23b and miR-133a) was evaluated by RT-PCR. The transfection of miR-133a mimic or miR-23b inhibitor was used to identify the targets of these miRNAs. The expression of DR4, DR5, clathrin (CLTA), APAF-1, and culin-3 was assessed by RT-PCR.

Results

Caki-2 treated with TRAIL presented reduced cell viability in a dose-dependent manner, indicating that this lineage is sensitive to TRAIL. The miR-23b was upregulated and miR-133a was downregulated in Caki-2 cells. Both receptors, DR4 and DR5, are overexpressed in Caki-2 compared to HK-2. miR-23 inhibition did not change the expression of the components of TRAIL pathway. However, mimic-133a transfection resulted in downregulation of CLTA expression.

Conclusions

The mir-23b did not regulate the TRAIL-induced apoptosis pathway in Caki-2 cells, while mir-133a can regulate the trail receptors translocation through clathrin expression.

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