Abstract
Krüppel-like factor 4 (KLF4) is a transcription factor that can have divergent functions in different malignancies. The expression and role of KLF4 in renal cell cancer remain unclear. The purpose of this study is to determine epigenetic alterations and possible roles of KLF4 in renal cell carcinoma. The KLF4 expression in primary renal cell cancer tissues and case-matched normal renal tissues was determined by protein and messenger RNA analyses. The epigenetic alterations were detected by methylation-specific PCR and Sequenom MassARRAY. Kaplan-Meier curves and the log-rank test were used for the survival analysis. The effects of KLF4 on cell growth and epithelial-to-mesenchymal transition (EMT) were determined in renal cancer cell lines after viral-based and RNA activation-mediated overexpression of KLF4. In vivo antitumor activity of KLF4 was evaluated by using stably KLF4-transfected renal cancer cells. KLF4 expression was dramatically decreased in various pathological types of renal cancer and associated with poor survival after nephrectomy. Hypermethylation of KLF4 promoter mainly contributed to its expression suppression. In vitro assays indicated that KLF4 overexpression inhibited renal cancer cell growth and survival. KLF4 overexpression also suppressed renal cancer cell migration and invasion by altering the EMT-related factors. In vivo assay showed that ectopic expression of KLF4 also inhibited tumorigenicity and metastasis of renal cancer. Our results suggest that KLF4 is a putative tumor suppressor gene epigenetically silenced in renal cell cancers by promoter CpG methylation and that it has prognostic value for renal cell progression.
Highlights
Renal cell carcinoma (RCC) is a common urologic tumor and accounts for about 3% of all human malignancies in adults
Krüppel-like factor 4 (KLF4) is downregulated in various types of RCC and renal cancer cell lines
To determine the effect of KLF4 expression on renal cancer development and progression, we did immunohistochemistry staining of tissue microarrays, which contained 243 renal cancer and normal renal tissue specimens, 230 of them were confirmed qualified and contained enough cancer tissue for immunohistochemistry staining by pathologist, and tissue specimens from 12 cancer adjacent normal renal tissues, 16 renal clear cell cancer with lymph node metastasis, 19 renal clear cell cancer with vena cava tumor thrombus and 149 primary renal cancer specimens were obtained from Department of Urology, Tongji Hospital, which were involved in further survival assay
Summary
Renal cell carcinoma (RCC) is a common urologic tumor and accounts for about 3% of all human malignancies in adults. It is the third most common urological cancer after prostate and bladder cancer, but it has the highest mortality rate at over 40% and significant increase in its incidence during the last decades [1,2]. Clear cell carcinoma is the most common subtype of RCC and accounts for approximately 75–80% of these tumors [3]. Apart from surgery, it is both chemotherapy and radiotherapy resistant.
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