Chromosomal breaks mediated by bile acid-induced apoptosis in nasopharyngeal epithelial cells : in relation to matrix association region/scaffold attachment region.

Tan, Sang Nee and Sim, Sai Peng (2016) Chromosomal breaks mediated by bile acid-induced apoptosis in nasopharyngeal epithelial cells : in relation to matrix association region/scaffold attachment region. In: 7th Biannual International Symposium on Nasopharyngeal Carcinoma 2015, 3-6 June 2015, Yogyakarta, Indonesia.

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Abstract

Introduction: Chronic rhinosinusitis (CRS) has been recognised as a risk factor for nasopharyngeal carcinoma (NPC). CRS can be triggered by gastroesophageal reflux (GER) that may reach the nasopharynx. Bile acid (BA), the main component of refluxate, is a potential carcinogen. BA-induced apoptosis has been implicated in various malignancies. Chromosomal breakage is an early event in both apoptosis and chromosomal rearrangement. Matrix Attachment Region/Scaffold Attachment Region (MAR/SAR) appears to be a preferential site of chromosomal breakage. We hypothesised that BA-induced apoptosis may cause chromosomal breaks at MAR/SAR leading to NPC chromosomal rearrangements. Aims: To identify BA-induced chromosomal breaks within AF9 (9p22) SAR and non-SAR regions. Methods: MAR/SAR sites in the AF9 gene were predicted by MARSCAN. NP69 cells were treated with BA at neutral and acidic pH. Flow cytometric analyses of phosphatidylserine (PS) externalization and mitochondrial membrane potential (MMP) disruption were performed. Inverse-PCR (IPCR) was employed to detect cleavages in SAR and non-SAR regions. IPCR bands were sequenced. Result and discussion: Treatment of NP69 cells with BA at neutral and acidic pH resulted in increased apoptosis and increased cleavage frequencies of the SAR region. No significant difference was detected in non-SAR cleavage frequency between untreated cells and cells treated with BA at neutral or acidic pH. A few breakpoints detected in the SAR region were mapped within the AF9 region that was previously reported to be involved in the formation of MLL (Mixed Lineage Leukaemia)-AF9 fusion gene in acute lymphoblastic leukaemia (ALL) patient. Our findings suggested that BA-induced apoptosis could be one of the mechanisms underlying NPC chromosomal rearrangements. MAR/SAR may play an important role in chromosomal breaks mediated by BA-induced apoptosis.

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