ABSTRACT
Seven in absentia homolog1 (SIAH1) was reported as a tumor suppressor and played an important role in regulating cell apoptosis. However, its effects on the breast carcinogenesis remain unclear. In this study, our aims were to examine the relationship between SIAH1 and Bcl-2-interacting mediator of cell death (Bim) and to explore the effects of SIAH1 on the breast carcinogenesis. Immunohistochemical analysis in 231 cases of breast tissues showed that the expression of SIAH1 and Bim were significantly decreased in the breast carcinogenesis. Moreover, SIAH1 expression was significantly correlated with Bim. Both SIAH1 and Bim expression were significantly higher in well to moderately differentiated and in early-stage breast cancer. Reverse transcription (RT)-polymerase chain reaction (PCR) and Western blot analysis in paired breast cancer tissues and breast cell lines found that the expression of SIAH1 was lower in the breast cancer tissues and cell lines. SIAH1 inducing apoptosis of the breast cancer cells was dependent on Bim. However, SIAH1 inhibiting invasion of the breast cancer cells was independent of Bim. The increase of the function of SIAH1 to upregulate the expression of Bim may play an important role in the progression of breast cancer. Restoration of the function of SIAH1 may be a new therapeutic target of human breast cancer.
Subject(s)
Apoptosis Regulatory Proteins/metabolism , Apoptosis/physiology , Breast Neoplasms/metabolism , Down-Regulation , Membrane Proteins/metabolism , Nuclear Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Base Sequence , Bcl-2-Like Protein 11 , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Transformation, Neoplastic , DNA Primers , Female , Flow Cytometry , Humans , Immunohistochemistry , Middle Aged , Nuclear Proteins/physiology , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Ubiquitin-Protein Ligases/physiologyABSTRACT
Seven in absentia homolog 1 (SIAH1), a homologue of Drosophila seven in absentia (Sina), has emerged as a tumor suppressor and plays an important role in regulating cell apoptosis. To investigate the role and possible mechanism of SIAH1 in breast cancer cells, we up-regulated the expression of SIAH1 using pcDNA3-myc-SIAH1 and knocked down SIAH1 using SIAH1 siRNA. We found that the overexpression of SIAH1 induced cell apoptosis by up-regulating the level of Bim through the activation of the JNK signaling pathway, and the suppression of SIAH1 expression increased cell invasion via the activation of the ERK signaling pathway in breast cancer cells. All these results indicate that the JNK and ERK signaling pathways may play an important role in the SIAH1-dependent biological behavior of breast cancer, and it may be a good molecular therapeutic target to increase the expression level of SIAH1 through promoting cell apoptosis and inhibiting cell invasion in human breast cancer.
Subject(s)
Apoptosis , Breast Neoplasms/pathology , Extracellular Signal-Regulated MAP Kinases/physiology , JNK Mitogen-Activated Protein Kinases/physiology , MAP Kinase Signaling System , Nuclear Proteins/physiology , Ubiquitin-Protein Ligases/physiology , Apoptosis Regulatory Proteins/physiology , Bcl-2-Like Protein 11 , Cell Line, Tumor , Female , Humans , Membrane Proteins/physiology , Neoplasm Invasiveness , Proto-Oncogene Proteins/physiologyABSTRACT
Serine threonine kinase 15 (STK15, also named BTAK, Aurora-A, aurora-2, or AIKI) is a type of mitotic kinase. The overexpression of STK15 is significantly associated with carcinogenesis in many tumors. The purpose of the present study was to investigate the expression of STK15 in lung squamous cell carcinoma and adenocarcinoma and analyze the correlation between STK15 expression and clinicopathological factors. The expression patterns of STK15 were examined by immunohistochemistry in 80 lung squamous cell carcinomas and adenocarcinomas and 20 normal lung tissues. The protein and mRNA expression of STK15 were evaluated by western blot and reverse transcription-polymerase chain reaction (RT-PCR) in 40 lung cancer samples and corresponding normal lung tissues. Immunohistochemically, the positivity of STK15 expression was 68.75% (55/80). The STK15 expression was significantly higher in poorly differentiated lung cancers than in well-differentiated or moderately differentiated lung cancers (P = 0.011). Western blot and RT-PCR showed that the protein and mRNA expression of STK15 were correlated (P = 0.044) and significantly higher in tumors than in corresponding normal lung tissues (P < 0.05). These results indicate that the overexpression of STK15 contributes to the carcinogenesis and de-differentiation of lung cancers.
