ABSTRACT
EZH2, the catalytic subunit of polycomb repressor complex 2, has oncogenic properties, whereas RASSF2A, a Ras association domain family protein, has a tumor suppressor role in many types of human cancer. However, the interrelationship between these two genes remains unclear. Here, we showed that the downregulation of EZH2 reduces CpG island methylation of the RASSF2A promoter, thereby leading to increased RASSF2A expression. Our findings also showed that knockdown of EZH2 increased RASSF2A expression in the human breast cancer cell line MCF-7 in cooperation with DNMT1. This was similar to the effect of 5-Aza-CdR, a DNA methylation inhibitor that reactivates tumor suppressor genes and activated RASSF2A expression in our study. The EZH2 inhibitor DZNep markedly suppressed the proliferation, migration, and invasion of MCF-7 cells treated with ADR and TAM. EZH2 inhibits the expression of tumor suppressor gene RASSF2A via promoter hypermethylation. Thus, it plays an important role in tumorigenesis and is a potential therapeutic target for the treatment of breast cancer.
Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/metabolism , DNA Methylation , Enhancer of Zeste Homolog 2 Protein/biosynthesis , Tumor Suppressor Proteins/metabolism , Antimetabolites, Antineoplastic/pharmacology , Azacitidine/pharmacology , Base Sequence , Breast Neoplasms/drug therapy , Cell Line, Tumor , CpG Islands , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/biosynthesis , DNA (Cytosine-5-)-Methyltransferases/genetics , Down-Regulation , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Female , Gene Knockdown Techniques , Humans , MCF-7 Cells , Promoter Regions, Genetic , Up-RegulationABSTRACT
OBJECTIVES: The aim of our study is to analyze the clinicopathological characteristics and treatment options for papillary thyroid microcarcinomas with multifocality and investigated whether the number of foci in papillary thyroid microcarcinomas with multifocality can predict central lymph node metastases. Methods Records of 329 consecutive PTMC patients with multifocality, and who were treated surgically between 2003 and 2014 were reviewed. Patients with multifocality were identified by histopathology. The number of foci, size of the largest tumour, presence of extrathyroidal invasion, infiltration, and other clinicopathological parameters were collected and analyzed for all the cases. RESULTS: Univariate analysis, age, sex, maximum tumour size, and extrathyroidal invasion were found to be significant prognostic factors (P = 0.001, 0.020, < 0.001, 0.043; respectively). Multivariate analysis found that age, sex, and maximum tumour size were independent prognostic factors for CLNM in PTMCs. Among them, Male patients (odds ratio 1.887; 95% confidence interval [CI] 1.053-3.380) and with maximum tumour size > 0.5 cm (odds ratio 2.819; 95% CI 1.721-4.616) were risk factors for increased incidence of CLNM. Patients ≥ 45 years (odds ratio 0. 497; 95% CI 0.309-0.800) were less likely to present with CLNM. However, extrathyroid invasion was not an independent predictor of CLNM according to our results. PTMCs with 2, 3, ≥ 4 foci had a significantly greater risk of CLNM (odds ratio 1.675, 2.360, 2.703; 95% CI 1.195-2.347, 1.425-3.906, 1.411-5.178; respectively) compared to PTMCs with unifocality. CONCLUSIONS: Foci numbers were linked to an increased incidence of central lymph node metastases in papillary thyroid microcarcinomas with multifocality, and we could choose to perform more radical treatment in patients with multifocality.
