Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, reflecting incomplete characterization of underlying mechanisms and lack of early detection. Kruppel like factor 6 (KLF6) is a ubiquitously ...Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, reflecting incomplete characterization of underlying mechanisms and lack of early detection. Kruppel like factor 6 (KLF6) is a ubiquitously expressed zinc finger transcription factor that is deregulated in multiple cancers through loss of heterozygosity (LOH) and/or inactivating somatic mutation. We analyzed the potential role of the KLF6 tumor suppressor gene in 41 patients who had HCC associated with hepatitis C virus (16 patients), hepatitis B virus (12 patients, one of whom was coinfected with hepatitis C virus), and other etiologies (14 patients) by determining the presence of LOH and mutations. Overall, LOH and/or mutations were present in 20 (49%) of 41 tumors. LOH of the KLF6 gene locus was present in 39%of primary HCCs, and the mutational frequency was 15%. LOH and/or mutations were distributed across all etiologies of HCC evaluated, including patients who did not have cirrhosis. Functionally, wild type KLF6 decreased cellular proliferation of HepG2 cells, while patient derived mutants did not. In conclusion, we propose that KLF6 is deregulated by loss and/or mutation in HCC, and its inactivation may contribute to pathogenesis in a significant number of these tumors.展开更多
N^(6)-甲基腺苷(N^(6)-methyladenosine,m^(6)A)是RNA最常见的内部修饰,在RNA的加工、转运、翻译及稳定性方面发挥重要作用。脂肪量和肥胖相关基因(fat mass and obesity-associated,FTO)作为第一个被发现的mRNA m^(6)A去甲基化酶,参与...N^(6)-甲基腺苷(N^(6)-methyladenosine,m^(6)A)是RNA最常见的内部修饰,在RNA的加工、转运、翻译及稳定性方面发挥重要作用。脂肪量和肥胖相关基因(fat mass and obesity-associated,FTO)作为第一个被发现的mRNA m^(6)A去甲基化酶,参与多种肿瘤的发生、发展及治疗抵抗,调节肿瘤干细胞自我更新、肿瘤代谢及肿瘤微环境。作为肿瘤治疗有希望的靶点,越来越多的FTO抑制剂被研发出来并在临床前研究中取得了良好的治疗效果。本研究就FTO在肿瘤发生、肿瘤干细胞自我更新、肿瘤免疫和代谢及治疗抵抗等方面的功能和潜在分子机制的研究进展作一综述,并讨论靶向FTO在肿瘤治疗中的应用前景。展开更多
Background and aim: The Krüppel-like transcription factor KLF6 is a novel tumor-suppressor gene. It was inactivated in human prostate cancer and other tumors tissue, as the result of frequent mutation and loss of...Background and aim: The Krüppel-like transcription factor KLF6 is a novel tumor-suppressor gene. It was inactivated in human prostate cancer and other tumors tissue, as the result of frequent mutation and loss of heterozygosity (LOH). However, there is no data reporting the levels of KLF6 both mRNA and protein in hepatocellular carcinomas (HCCs). We therefore detected mutations and expression of KLF6 in HCC tissues and further observed the effect of it on cell growth in HCC cell lines. Methods: We analyzed the exon-2 of KLF6 gene by direct DNA sequencing, and detected the expression of KLF6 by RT-PCR and Western blot in 23 HCC tissues and corresponding nontumorous tissues. Loss of growth suppressive effect of the HCC-derived KLF6 mutant was characterized by in vitro growth curves plotted, flow cytometry and Western blotting. Results: KLF6 mutations were found in 2 of 23 HCC tissues and one of mutations was missense. Expression of KLF6 mRNA or protein was down-regulated in 8 (34.7%) or 9 (39.1%) of 23 HCC tissues. Wild-type KLF6 (wtKLF6) inhibited cellular proliferation and prolonged G1-S transition by inducing the expression of p21WAF1 following stable transfection into cultured HepG2 cells, but tumor-derived KLF6 mutant (mKLF6) had no effects. Conclusion: Our findings suggest that KLF6 may be involved in pathogenesis of HCC.展开更多
文摘Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, reflecting incomplete characterization of underlying mechanisms and lack of early detection. Kruppel like factor 6 (KLF6) is a ubiquitously expressed zinc finger transcription factor that is deregulated in multiple cancers through loss of heterozygosity (LOH) and/or inactivating somatic mutation. We analyzed the potential role of the KLF6 tumor suppressor gene in 41 patients who had HCC associated with hepatitis C virus (16 patients), hepatitis B virus (12 patients, one of whom was coinfected with hepatitis C virus), and other etiologies (14 patients) by determining the presence of LOH and mutations. Overall, LOH and/or mutations were present in 20 (49%) of 41 tumors. LOH of the KLF6 gene locus was present in 39%of primary HCCs, and the mutational frequency was 15%. LOH and/or mutations were distributed across all etiologies of HCC evaluated, including patients who did not have cirrhosis. Functionally, wild type KLF6 decreased cellular proliferation of HepG2 cells, while patient derived mutants did not. In conclusion, we propose that KLF6 is deregulated by loss and/or mutation in HCC, and its inactivation may contribute to pathogenesis in a significant number of these tumors.
文摘N^(6)-甲基腺苷(N^(6)-methyladenosine,m^(6)A)是RNA最常见的内部修饰,在RNA的加工、转运、翻译及稳定性方面发挥重要作用。脂肪量和肥胖相关基因(fat mass and obesity-associated,FTO)作为第一个被发现的mRNA m^(6)A去甲基化酶,参与多种肿瘤的发生、发展及治疗抵抗,调节肿瘤干细胞自我更新、肿瘤代谢及肿瘤微环境。作为肿瘤治疗有希望的靶点,越来越多的FTO抑制剂被研发出来并在临床前研究中取得了良好的治疗效果。本研究就FTO在肿瘤发生、肿瘤干细胞自我更新、肿瘤免疫和代谢及治疗抵抗等方面的功能和潜在分子机制的研究进展作一综述,并讨论靶向FTO在肿瘤治疗中的应用前景。
文摘Background and aim: The Krüppel-like transcription factor KLF6 is a novel tumor-suppressor gene. It was inactivated in human prostate cancer and other tumors tissue, as the result of frequent mutation and loss of heterozygosity (LOH). However, there is no data reporting the levels of KLF6 both mRNA and protein in hepatocellular carcinomas (HCCs). We therefore detected mutations and expression of KLF6 in HCC tissues and further observed the effect of it on cell growth in HCC cell lines. Methods: We analyzed the exon-2 of KLF6 gene by direct DNA sequencing, and detected the expression of KLF6 by RT-PCR and Western blot in 23 HCC tissues and corresponding nontumorous tissues. Loss of growth suppressive effect of the HCC-derived KLF6 mutant was characterized by in vitro growth curves plotted, flow cytometry and Western blotting. Results: KLF6 mutations were found in 2 of 23 HCC tissues and one of mutations was missense. Expression of KLF6 mRNA or protein was down-regulated in 8 (34.7%) or 9 (39.1%) of 23 HCC tissues. Wild-type KLF6 (wtKLF6) inhibited cellular proliferation and prolonged G1-S transition by inducing the expression of p21WAF1 following stable transfection into cultured HepG2 cells, but tumor-derived KLF6 mutant (mKLF6) had no effects. Conclusion: Our findings suggest that KLF6 may be involved in pathogenesis of HCC.
