Mougeot Jean-Luc C, Bahrani-Mougeot Farah K, Lockhart Peter B, Brennan Michael T
Cannon Research Center, Carolinas Medical Center, Charlotte, NC, USA.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011 Oct;112(4):446-52. doi: 10.1016/j.tripleo.2011.05.009. Epub 2011 Sep 8.
Understanding the pathogenesis of chemotherapy-induced oral mucositis (CIOM) is vital to develop therapies for this common, dose-limiting side effect of cancer treatment. We investigated molecular events in CIOM from buccal mucosa tissue collected before and 2 days after chemotherapy from patients with acute myeloid leukemia (AML) and healthy controls by microarray analysis.
Microarray analysis was performed using Human Genome U133 Plus 2.0 Array on buccal mucosa punch biopsies from patients with AML before (n = 4) or after chemotherapy (n = 4), and from healthy controls (n = 3). Following Robust Multichip Average (RMA) normalization, we applied Linear Models for Microarray data (LIMMA) and Significance Analysis of Microarrays (SAM) for data analysis using the TM4/TMeV v4.5.1 program.
LIMMA and SAM identified genes potentially affected by the presence of AML, including homeodomain-interacting protein kinase 1 (HIPK1), mex-3 homolog D (MEX3D), and genes potentially affected by chemotherapy, including argininosuccinate synthase 1 (ASS1), notch homolog 1 (NOTCH1), zinc transporter ZIP6 (SLC39A6), and TP53-regulated inhibitor of apoptosis 1 (TRIAP1). The expression of 2 genes with potential biological significance in oral mucositis, ASS1 and SLC39A6 (alias LIV-1), was confirmed by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR).
Our results suggest that AML-specific deregulated immune responses and inflammatory tissue damage to the oral mucosa caused by chemotherapy may not be overcome by the natural cellular repair processes and therefore contribute to CIOM.
了解化疗引起的口腔黏膜炎（CIOM）的发病机制对于开发针对这种癌症治疗中常见的剂量限制性副作用的疗法至关重要。我们通过微阵列分析，研究了急性髓系白血病（AML）患者和健康对照者在化疗前和化疗后2天采集的颊黏膜组织中CIOM的分子事件。
使用人类基因组U133 Plus 2.0阵列对AML患者化疗前（n = 4）或化疗后（n = 4）以及健康对照者（n = 3）的颊黏膜穿刺活检组织进行微阵列分析。经过稳健多芯片平均（RMA）标准化后，我们使用TM4/TMeV v4.5.1程序应用微阵列数据线性模型（LIMMA）和微阵列显著性分析（SAM）进行数据分析。
LIMMA和SAM鉴定出可能受AML存在影响的基因，包括同源结构域相互作用蛋白激酶1（HIPK1）、mex-3同源物D（MEX3D），以及可能受化疗影响的基因，包括精氨琥珀酸合酶1（ASS1）、Notch同源物1（NOTCH1）、锌转运蛋白ZIP6（SLC39A6）和TP53调节的凋亡抑制因子1（TRIAP1）。通过定量实时逆转录聚合酶链反应（qRT-PCR）证实了在口腔黏膜炎中具有潜在生物学意义的2个基因ASS1和SLC39A6（别名LIV-1）的表达。
我们的结果表明，AML特异性的免疫反应失调以及化疗对口腔黏膜造成的炎症性组织损伤可能无法被自然细胞修复过程克服，因此会导致CIOM。
