RESUMO
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.
Assuntos
Adenosina Desaminase/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Proteínas de Ligação a RNA/genética , Epigênese Genética , Carcinoma de Células Escamosas do Esôfago , Humanos , Mutação , Edição de RNARESUMO
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.
Assuntos
Adenosina Desaminase/metabolismo , Adenosina , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Inosina , Edição de RNA , Adenosina Desaminase/genética , Carcinoma de Células Escamosas/mortalidade , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Progressão da Doença , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Proteínas de Ligação a RNARESUMO
OBJECTIVE: 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. METHODS: Using tissue array and immunohistochemistry, the expression of fascin was determined in 241 ESCC tissues and the corresponding normal esophageal mucosal tissues. RESULTS: ESCC tissues showed a significantly higher overexpression rate of fascin than the corresponding normal esophageal mucosal tissues (68.9% vs 15.5%, P<0.05). 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. CONCLUSIONS: 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.
