ABSTRACT
BACKGROUND: Details of mechanisms regulating telomere length are poorly understood in human hematopoietic cells. MATERIALS AND METHODS: Gene expression for TRFs and TIN2 was studied in hematopoietic cell lines, blood or bone marrow cells from acute leukemia and in normal leukocyte fractions. RESULTS: The telomeres were longest in normal leukocytes, shorter in patient samples and still shorter in malignant hematopoietic cell lines. TRF1 mRNA, TRF2 mRNA and TIN2 mRNA in three myeloblastic cell lines and six lymphoblastic cell lines were significantly less abundant than in the corresponding normal cell types. In patients with acute myeloid leukemia, expression of these gene was also less than in normal cells. In additional studies in culture, HL-60 cells with initially high telomerase activity and low expression of TRF mRNA and TIN2 mRNA differentiated into granulocytic and monocytic cells with low telomerase activity and high expression of these mRNAs. CONCLUSION: In hematopoietic carcinogenesis, gene expression for suppressors of telomerase activity, such as TRF and TIN2, is decreased. These genes might hold promise for gene therapy against cancer.
Subject(s)
DNA-Binding Proteins/biosynthesis , Hematologic Neoplasms/metabolism , Hematopoietic Stem Cells/physiology , Telomere-Binding Proteins , Adolescent , Adult , Cell Differentiation/physiology , DNA-Binding Proteins/genetics , Female , Gene Expression , HL-60 Cells , Hematologic Neoplasms/genetics , Hematologic Neoplasms/pathology , Hematopoietic Stem Cells/metabolism , Humans , Jurkat Cells , K562 Cells , Male , Middle Aged , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Telomerase/metabolism , Telomere/genetics , Telomere/metabolism , Telomere/physiology , Telomeric Repeat Binding Protein 1 , Tretinoin/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , U937 CellsABSTRACT
BACKGROUND: The maintenance of telomeres may be required for long-term proliferation of tumors. Activity of telomerase, a ribonucleoprotein complex that elongates telomeres, has been found in almost all human tumors but not in adjacent normal cells. Several factors which regulate telomere length, TRF1 and 2, TIN2, tankyrase and Rap1, have been identified. TRF1, TRF2 and TIN2 are negative regulators of telomere length, while tankyrase and Rap1 act as positive regulators. In this study, we quantitated the mRNA of these five genes in gastric cancers to clarify the mechanism by which cancer cells maintain telomere length. MATERIALS AND METHODS: The expression of these five genes transcription was determined using a quantitative RT-PCR. RESULTS: TRF1, TRF2 and TIN2 mRNAs were significantly down-regulated in cancers compared to non-cancerous mucosa. Neither tankyrase nor Rap1 was upregulated in cancers. CONCLUSION: Down-regulation of TRF1, TRF2 and TIN2 gene expression may be important to maintain telomeres in gastric cancer.
Subject(s)
DNA, Neoplasm/genetics , Stomach Neoplasms/genetics , Telomere-Binding Proteins/genetics , Telomere/genetics , Telomeric Repeat Binding Protein 1/genetics , Telomeric Repeat Binding Protein 2/genetics , DNA, Neoplasm/metabolism , Down-Regulation , Gene Expression Regulation, Neoplastic , Humans , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Shelterin Complex , Stomach Neoplasms/metabolism , Tankyrases/biosynthesis , Tankyrases/genetics , Telomere/metabolism , Telomere-Binding Proteins/biosynthesis , Telomeric Repeat Binding Protein 1/biosynthesis , Telomeric Repeat Binding Protein 2/biosynthesis , Tumor Cells, CulturedABSTRACT
BACKGROUND: To investigate the potential role of a nuclear transcription factor, early growth response-1 (Egr-1), in formation and progression of gastric cancer, we compared its expression in gastric cancers with that in non-cancerous tissues. MATERIALS AND METHODS: Egr-1 mRNA expression was measured using TaqMan RT-PCR. The corresponding protein expression was examined immunohistochemically. RESULTS: Egr-1 mRNA expression was significantly higher in gastric cancer tissues than in normal mucosa (p < 0.0005). These differences were also reflected by protein product expression. Moreover, Egr-1 mRNA expression was higher in cases with metastasis to lymph nodes or remote organs. In cultured gastric cancer cells known to have a high metastatic potential, expression of this mRNA was higher than that of parental cells. CONCLUSION: It was suggested that Egr-1 has a significant role in carcinogenesis and in cancer progression, especially metastasis. Measurement of this mRNA should be useful for evaluation of the metastatic potential of gastric cancer.
