ABSTRACT
PIG3 is a target of the tumor suppressor p53 and is thought to be involved in p53-mediated cell apoptosis. Although PIG3 is similar to oxidoreductases involved in generating ROS, whether PIG3 would regulate HIF-1α was never characterized directly. Here we demonstrated that knockdown of PIG3 by transfecting with specific siRNA could increase the expression of HIF-1α in several human cancer cell lines, including CAKI, FTC-133 and A549. It indicates that PIG3 may be involved in the regulation of HIF-1α. Furthermore, we revealed that PIG3-siliencing increased HIF-1α protein level through promoting its protein biosynthesis via mTOR pathway. In addition, the effect of PIG3 on the production of HIF-1α was further related to VEGF secretion and cell migration. PIG3-downregulation increased the secretion of VEGF and promoted the migration of renal cancer cells obviously. Taken together, these data suggest that PIG3 was involved in HIF-1α regulation, and reveal a novel signaling pathway of PIG3/HIF-1α in the regulation of cell migration in renal cell carcinoma.
Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , A549 Cells , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cell Movement/genetics , Gene Expression Regulation, Neoplastic , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Immunoblotting , Intracellular Signaling Peptides and Proteins/genetics , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins/genetics , RNA Interference , Vascular Endothelial Growth Factor A/metabolismABSTRACT
BACKGROUND: The aim of this study was to detect the expression of hypoxia-inducible factor (HIF)-1α and HIF-2α in papillary thyroid carcinoma (PTC) compared with normal thyroid tissues. METHODS: The mRNA levels and protein levels of HIF-1α and HIF-2α were detected by real-time PCR and Western blot separately in 30 pairs of PTCs and normal thyroid cases. The protein levels were also detected by immunohistochemistry (IHC) using 92 samples of PTC group and 46 normal samples as control group for analyzing the biological and clinical significance of the expression of HIF-1α/HIF-2α. RESULTS: Real-time PCR results showed the mRNA level of HIF-1α and HIF-2α were significantly higher in PTC than normal group (P<0.001). Also, significantly higher positive rates (73%/65%) of HIF-1α and HIF-2α were observed in PTC compared with the control group (27%/35%) by IHC (P<0.01); the consistent results were gotten with Western blot. Although we did not find a significant correlation between the expression of HIF-1α and HIF-2α with gender, age, calcification, or Hashimoto's disease in the present study (P>0.05), both of their expressions were correlated to lymph node metastasis (P<0.05), capsular invasion (P<0.05), and TNM stage (P<0.05). CONCLUSIONS: Overexpression of HIF-1α and HIF-2α are associated with the carcinogenesis of PTC, served as potential biomarkers of PTC.
