Yan Wusheng, Shih Joanna H, Rodriguez-Canales Jaime, Tangrea Michael A, Ylaya Kris, Hipp Jason, Player Audrey, Hu Nan, Goldstein Alisa M, Taylor Philip R, Emmert-Buck Michael R, Erickson Heidi S
Pathogenetics Unit, Laboratory of Pathology, National Cancer Institute, Bethesda, USA.
BMC Res Notes. 2012 Jan 26;5:73. doi: 10.1186/1756-0500-5-73.
Esophageal squamous cell carcinoma (ESCC), the predominant histological subtype of esophageal cancer, is characterized by high mortality. Previous work identified important mRNA expression differences between normal and tumor cells; however, to date there are limited ex vivo studies examining expression changes occurring during normal esophageal squamous cell differentiation versus those associated with tumorigenesis. In this study, we used a unique tissue microdissection strategy and microarrays to measure gene expression profiles associated with cell differentiation versus tumorigenesis in twelve cases of patient-matched normal basal squamous epithelial cells (NB), normal differentiated squamous epithelium (ND), and squamous cell cancer. Class comparison and pathway analysis were used to compare NB versus tumor in a search for unique therapeutic targets.
As a first step towards this goal, gene expression profiles and pathways were evaluated. Overall, ND expression patterns were markedly different from NB and tumor; whereas, tumor and NB were more closely related. Tumor showed a general decrease in differentially expressed genes relative to NB as opposed to ND that exhibited the opposite trend. FSH and IgG networks were most highly dysregulated in normal differentiation and tumorigenesis, respectively. DNA repair pathways were generally elevated in NB and tumor relative to ND indicating involvement in both normal and pathological growth. PDGF signaling pathway and 12 individual genes unique to the tumor/NB comparison were identified as therapeutic targets, and 10 associated ESCC gene-drug pairs were identified. We further examined the protein expression level and the distribution patterns of four genes: ODC1, POSTN, ASPA and IGF2BP3. Ultimately, three genes (ODC1, POSTN, ASPA) were verified to be dysregulated in the same pattern at both the mRNA and protein levels.
These data reveal insight into genes and molecular pathways mediating ESCC development and provide information potentially useful in designing novel therapeutic interventions for this tumor type.
食管鳞状细胞癌（ESCC）是食管癌的主要组织学亚型，其特点是死亡率高。以往的研究确定了正常细胞与肿瘤细胞之间重要的mRNA表达差异；然而，迄今为止，体外研究有限，未能考察正常食管鳞状细胞分化过程中发生的表达变化与肿瘤发生相关的表达变化。在本研究中，我们采用独特的组织显微切割策略和微阵列技术，测量了12例患者匹配的正常基底鳞状上皮细胞（NB）、正常分化鳞状上皮（ND）和鳞状细胞癌中与细胞分化和肿瘤发生相关的基因表达谱。采用类比较和通路分析比较NB与肿瘤，以寻找独特的治疗靶点。
作为实现这一目标的第一步，对基因表达谱和通路进行了评估。总体而言，ND的表达模式与NB和肿瘤明显不同；而肿瘤和NB的关系更为密切。与NB相比，肿瘤中差异表达基因总体上减少，而ND则呈现相反趋势。FSH和IgG网络在正常分化和肿瘤发生中分别表现出最高程度的失调。与ND相比，DNA修复通路在NB和肿瘤中普遍升高，表明其参与正常和病理生长。PDGF信号通路以及肿瘤/NB比较中特有的12个个体基因被确定为治疗靶点，并鉴定出10对相关的ESCC基因-药物对。我们进一步检测了4个基因（ODC1、POSTN、ASPA和IGF2BP3）的蛋白表达水平和分布模式。最终，验证了3个基因（ODC1、POSTN、ASPA）在mRNA和蛋白水平上以相同模式失调。
这些数据揭示了介导ESCC发生发展的基因和分子通路，为设计针对这种肿瘤类型的新型治疗干预措施提供了潜在有用的信息。
