Search

PDF file - 145K

PDF file - 75K, IHC scores of ADAR1 in 136 matched pairs of primary ESCCs and (NT) tissues (S1); The positive correlation between the tumoral overexpression of ADAR1 and tumoral genomic amplification of ADAR1 (S2).

Esophageal squamous cell carcinoma (ESCC), the major histologic form of esophageal cancer, is a heterogeneous tumor displaying a complex variety of genetic and epigenetic changes. Aberrant RNA editing of adenosine-to-inosine (A-to-I), as it is catalyzed by adenosine deaminases acting on RNA (ADAR), represents a common posttranscriptional modification in certain human diseases. In this study, we investigated the status and role of ADARs and altered A-to-I RNA editing in ESCC tumorigenesis. Among the three ADAR enzymes expressed in human cells, only ADAR1 was overexpressed in primary ESCC tumors. ADAR1 overexpression was due to gene amplification. Patients with ESCC with tumoral overexpression of ADAR1 displayed a poor prognosis. In vitro and in vivo functional assays established that ADAR1 functions as an oncogene during ESCC progression. Differential expression of ADAR1 resulted in altered gene-specific editing activities, as reflected by hyperediting of FLNB and AZIN1 messages in primary ESCC. Notably, the edited form of AZIN1 conferred a gain-of-function phenotype associated with aggressive tumor behavior. Our findings reveal that altered gene-specific A-to-I editing events mediated by ADAR1 drive the development of ESCC, with potential implications in diagnosis, prognosis, and treatment of this disease. Cancer Res; 74(3); 840–51. ©2013 AACR.

Correlation between the expression level of ADAR1 and the editing level of AZIN1 (left panel) or FLNB (right panel) among nine ESCC cell lines.

PDF file - 375K, The relative ADAR1 expression level in nine ESCC cell lines, as detected by QPCR.

PDF file - 39K, Correlation between the expression level of ADAR1 and the editing level of AZIN1 (left panel) or FLNB (right panel) among nine ESCC cell lines.

PDF file - 759K, The total mRNA levels of AZIN1 (left panel) and FLNB (right panel) in 69 matched pairs of ESCC and NT specimens in Cohort 1 (Paired Student's t test).

PDF file - 93K

PDF file - 2499K, A, Western blot analyses showing expression of AZIN1 protein in the indicated cell lines. β-actin was the loading control. B, Quantification of cells from the indicated cells that migrated through the PET-membrane or invaded through the Matrigel-coated membrane.

IHC scores of ADAR1 in 136 matched pairs of primary ESCCs and (NT) tissues (S1); The positive correlation between the tumoral overexpression of ADAR1 and tumoral genomic amplification of ADAR1 (S2).

Description of additional methods and procedures used in the study. Also includes supplemental reference.

Esophageal Squamous Cell Carcinoma (ESCC) is a heterogeneous tumor with enormous genetic and epigenetic changes. RNA editing is an epigenetic mechanism that serves as an additional layer of 'RNA mutations' in parallel to DNA mutations. The most frequent type of RNA editing, A-to-I (adenosine-to-inosine) editing catalyzed by Adenosine DeAminase that act on RNA (ADARs), modulates RNA transcripts with profound impact on cellular functions. RNA editing dysregulation has been found to be associated with cancers. Our recent study demonstrated that among all the three RNA editing enzymes, only ADAR1 was overexpressed in primary ESCCs compared with matched non-tumor specimens. In this review, we will discuss current views on the involvement of abnormal A-to-I editing in cancer development, more specifically on the ADAR1-mediated editing in ESCC. Although much is not yet learned about the role of ADAR1 in ESCC, ADAR1 may present an attractive option as a new biomarker for ESCC and as a new molecular therapeutic target.

Esophageal squamous cell carcinoma (ESCC), the major histologic form of esophageal cancer, is a heterogeneous tumor displaying a complex variety of genetic and epigenetic changes. Aberrant RNA editing of adenosine-to-inosine (A-to-I), as it is catalyzed by adenosine deaminases acting on RNA (ADAR), represents a common posttranscriptional modification in certain human diseases. In this study, we investigated the status and role of ADARs and altered A-to-I RNA editing in ESCC tumorigenesis. Among the three ADAR enzymes expressed in human cells, only ADAR1 was overexpressed in primary ESCC tumors. ADAR1 overexpression was due to gene amplification. Patients with ESCC with tumoral overexpression of ADAR1 displayed a poor prognosis. In vitro and in vivo functional assays established that ADAR1 functions as an oncogene during ESCC progression. Differential expression of ADAR1 resulted in altered gene-specific editing activities, as reflected by hyperediting of FLNB and AZIN1 messages in primary ESCC. Notably, the edited form of AZIN1 conferred a gain-of-function phenotype associated with aggressive tumor behavior. Our findings reveal that altered gene-specific A-to-I editing events mediated by ADAR1 drive the development of ESCC, with potential implications in diagnosis, prognosis, and treatment of this disease. Cancer Res; 74(3); 840–51. ©2013 AACR.

To investigate the role of fascin, an actin bundling protein, in the development and progression of human esophageal squamous cell carcinoma (ESCC), and explore its association with the clinicopathologic characteristics and 5-year survival of the patients.Using tissue array and immunohistochemistry, the expression of fascin was determined in 241 ESCC tissues and the corresponding normal esophageal mucosal tissues.ESCC tissues showed a significantly higher overexpression rate of fascin than the corresponding normal esophageal mucosal tissues (68.9% vs 15.5%, P0.05). The overexpression of fascin was correlated to lymph node metastasis and TMN stage, but not to the patients' age, gender, tumor differentiation and general classification. Survival analysis showed that abnormal expression of fascin was associated with the 5-year survival rate of patients with ESCC.The abnormal expression of fascin may play an important role in the progression of ESCC, and detection of fascin expression may have important prognostic values.

Aim Esophageal squamous cell carcinoma (ESCC) is one of the most common fatal malignances of the digestive tract. Its prognosis is poor mainly due to the lack of reliable markers for early detection and prognostic prediction. Here we aim to identify the molecules involved in ESCC carcinogenesis and those as potential markers for prognosis and as new molecular therapeutic targets. Methods We performed genome-wide gene expression profile analyses of 10 primary ESCCs and their adjacent normal tissues by cDNA microarrays representing 47,000 transcripts and variants. Candidate genes were then validated by semi quantitative reverse transcription-PCR (RT-PCR), tissue microarrays (TMAs) and immunohistochemistry (IHC) staining. Results Using an arbitrary cutoff line of signal log ratio of ≥1.5 or ≤−1.5, we observed 549 up-regulated genes and 766 down-regulated genes in ESCCs compared with normal esophageal tissues. The functions of 302 differentially expressed genes were associated with cell metabolism, cell adhesion and immune response. Several candidate deregulated genes including four overexpressed (CTTN, DMRT2, MCM10 and SCYA26) and two underexpressed (HMGCS2 and SORBS2) were subsequently verified, which can be served as biomarkers for ESCC. Moreover, overexpression of cortactin (CTTN) was observed in 126/198 (63.6%) of ESCC cases and was significantly associated with lymph node metastasis (P = 0.000), pathologic stage (P = 0.000) and poor survival (P