|
1
|
Tao S, Pu Y, Yang EJ, Ren G, Shi C, Chen LJ, Chen L, Shim JS. Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer by blocking homologous recombination repair. Exp Mol Med 2025; 57:167-183. [PMID: 39762409 PMCID: PMC11799392 DOI: 10.1038/s12276-024-01374-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 09/06/2024] [Accepted: 10/06/2024] [Indexed: 02/07/2025] Open
Abstract
FHIT is a fragile site tumor suppressor that is primarily inactivated upon tobacco smoking. FHIT loss is frequently observed in lung cancer, making it an important biomarker for the development of targeted therapy for lung cancer. Here, we report that inhibitors of glycogen synthase kinase 3 beta (GSK3β) and the homologous recombination DNA repair (HRR) pathway are synthetic lethal with FHIT loss in lung cancer. Pharmacological inhibition or siRNA depletion of GSK3β selectively suppressed the growth of FHIT-deficient lung cancer tumors in vitro and in animal models. We further showed that FHIT inactivation leads to the activation of DNA damage repair pathways, including the HRR and NHEJ pathways, in lung cancer cells. Conversely, FHIT-deficient cells are highly dependent on HRR for survival under DNA damage stress. The inhibition of GSK3β in FHIT-deficient cells suppressed the ATR/BRCA1/RAD51 axis in HRR signaling via two distinct pathways and suppressed DNA double-strand break repair, leading to the accumulation of DNA damage and apoptosis. Small molecule inhibitors of HRR, but not NHEJ or PARP, induced synthetic lethality in FHIT-deficient lung cancer cells. The findings of this study suggest that the GSK3β and HRR pathways are potential drug targets in lung cancer patients with FHIT loss.
Collapse
Affiliation(s)
- Shishi Tao
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Yue Pu
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Eun Ju Yang
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Guowen Ren
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518055, Guangdong, China
| | - Changxiang Shi
- Nanjing Key Laboratory of Female Fertility Preservation and Restoration, Nanjing Women and Children's Healthcare Institute, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), Nanjing, 210004, China
| | - Li-Jie Chen
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Liang Chen
- Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Joong Sup Shim
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.
- MOE Frontiers Science Centre for Precision Oncology, University of Macau, Taipa, Macau SAR, China.
| |
Collapse
|
|
2
|
N. Kachouie N, Deebani W, Shutaywi M, Christiani DC. Lung cancer clustering by identification of similarities and discrepancies of DNA copy numbers using maximal information coefficient. PLoS One 2024; 19:e0301131. [PMID: 38739669 PMCID: PMC11090345 DOI: 10.1371/journal.pone.0301131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 03/11/2024] [Indexed: 05/16/2024] Open
Abstract
Lung cancer is the second most diagnosed cancer and the first cause of cancer related death for men and women in the United States. Early detection is essential as patient survival is not optimal and recurrence rate is high. Copy number (CN) changes in cancer populations have been broadly investigated to identify CN gains and deletions associated with the cancer. In this research, the similarities between cancer and paired peripheral blood samples are identified using maximal information coefficient (MIC) and the spatial locations with substantially high MIC scores in each chromosome are used for clustering analysis. The results showed that a sizable reduction of feature set can be obtained using only a subset of locations with high MIC values. The clustering performance was evaluated using both true rate and normalized mutual information (NMI). Clustering results using the reduced feature set outperformed the performance of clustering using entire feature set in several chromosomes that are highly associated with lung cancer with several identified oncogenes.
Collapse
Affiliation(s)
- Nezamoddin N. Kachouie
- Department of Mathematics and Systems Engineering, Florida Institute of Technology, Melbourne, FL, United States of America
| | - Wejdan Deebani
- Mathematics Department, College of Science and Arts, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Meshal Shutaywi
- Mathematics Department, College of Science and Arts, King Abdulaziz University, Jeddah, Saudi Arabia
| | - David C. Christiani
- Department of Environmental Health, Harvard School of Public Health, Boston, MA, United States of America
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States of America
| |
Collapse
|
|
3
|
Mohammad F, Pandith AA, Rasool SUA, Guru FR, Qasim I, Geelani S, Nisar S, Baba SM, Ganie FA, Kouser S, Rasool J. Significance and implications of FHIT gene expression and promoter hypermethylation in acute lymphoblastic leukemia (ALL). Discov Oncol 2024; 15:108. [PMID: 38587694 PMCID: PMC11001825 DOI: 10.1007/s12672-024-00971-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 04/04/2024] [Indexed: 04/09/2024] Open
Abstract
BACKGROUND Fragile histidine triad (FHIT) has been documented to play a vital role in various cancers including acute lymphoblastic leukemia (ALL). Keeping in view the plausible role of FHIT gene, we aimed to examine DNA promoter hypermethylation and mRNA expression in ALL cases in Kashmir (North India). METHODS A total of 66 cases of ALL were analyzed for FHIT mRNA expression and promoter methylation by qRT-PCR and Methylation Specific-PCR (MS-PCR) respectively. RESULTS FHIT mRNA expression showed significantly decreased expression in ALL cases with mean fold change of 9.24 ± 5.44 as compared to healthy controls (p = 0.01). The pattern of FHIT deregulation in ALL cases differed significantly between decreased and increased expression (p < 0.0001). A threefold decreased expression was observed in 75% of ALL cases than healthy controls (- 3.58 ± 2.32). ALL patients with FHIT gene promoter hypermethylation presented significantly higher in 80% (53/66) of cases (p = 0.0005). The association of FHIT gene hypermethylation and its subsequent expression showed FHIT mRNA expression as significantly lower in ALL cases with hypermethylation (p = 0.0008). B-ALL cases exhibited a highly significant association between the methylation pattern and its mRNA expression (p = 0.000). In low range WBC group, a significant association was found between increased expression (26%) of the cases and methylated (4%)/unmethylated group 86% (p = 0.0006). CONCLUSION The present study conclude that FHIT gene hypermethylation and its altered expression may be linked in the pathogenesis of ALL and provide an evidence for the role of FHIT in the development of ALL.
Collapse
Affiliation(s)
- Fozia Mohammad
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, 190011, India
- School of Life Sciences, Jaipur National University, Jaipur, Rajasthan, 302017, India
| | - Arshad A Pandith
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, 190011, India.
| | - Shayaq Ul Abeer Rasool
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, 190011, India
| | - Faisal R Guru
- Department of Medical Oncology, SKIMS, Srinagar, J&K,, 190011, India
| | - Iqbal Qasim
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, 190011, India
| | - Sajad Geelani
- Department of Hematology, SKIMS, Srinagar, 190011, J&K, India
| | - Syed Nisar
- Department of Medical Oncology, SKIMS, Srinagar, J&K,, 190011, India
| | - Shahid M Baba
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, 190011, India
- Department of Urology, SKIMS, Srinagar, 190011, J&K, India
| | | | - Safiya Kouser
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, 190011, India
| | - Javid Rasool
- Department of Hematology, SKIMS, Srinagar, 190011, J&K, India
| |
Collapse
|
|
4
|
Tanaka A, Ogawa M, Zhou Y, Namba K, Hendrickson RC, Miele MM, Li Z, Klimstra DS, Buckley PG, Gulcher J, Wang JY, Roehrl MHA. Proteogenomic characterization of primary colorectal cancer and metastatic progression identifies proteome-based subtypes and signatures. Cell Rep 2024; 43:113810. [PMID: 38377004 PMCID: PMC11288375 DOI: 10.1016/j.celrep.2024.113810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 10/26/2023] [Accepted: 02/01/2024] [Indexed: 02/22/2024] Open
Abstract
Metastatic progression of colorectal adenocarcinoma (CRC) remains poorly understood and poses significant challenges for treatment. To overcome these challenges, we performed multiomics analyses of primary CRC and liver metastases. Genomic alterations, such as structural variants or copy number alterations, were enriched in oncogenes and tumor suppressor genes and increased in metastases. Unsupervised mass spectrometry-based proteomics of 135 primary and 123 metastatic CRCs uncovered distinct proteomic subtypes, three each for primary and metastatic CRCs, respectively. Integrated analyses revealed that hypoxia, stemness, and immune signatures characterize these 6 subtypes. Hypoxic CRC harbors high epithelial-to-mesenchymal transition features and metabolic adaptation. CRC with a stemness signature shows high oncogenic pathway activation and alternative telomere lengthening (ALT) phenotype, especially in metastatic lesions. Tumor microenvironment analysis shows immune evasion via modulation of major histocompatibility complex (MHC) class I/II and antigen processing pathways. This study characterizes both primary and metastatic CRCs and provides a large proteogenomics dataset of metastatic progression.
Collapse
Affiliation(s)
- Atsushi Tanaka
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Makiko Ogawa
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yihua Zhou
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; ICU Department, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Kei Namba
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Ronald C Hendrickson
- Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Matthew M Miele
- Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zhuoning Li
- Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David S Klimstra
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Paige.AI, New York, NY, USA
| | | | | | | | - Michael H A Roehrl
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| |
Collapse
|
|
5
|
Herzog D, Jansen J, Mißun M, Diederichs K, Stengel F, Marx A. Chemical Proteomics of the Tumor Suppressor Fhit Covalently Bound to the Cofactor Ap 3A Elucidates Its Inhibitory Action on Translation. J Am Chem Soc 2022; 144:8613-8623. [PMID: 35522782 PMCID: PMC9121386 DOI: 10.1021/jacs.2c00815] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The tumor suppressor protein fragile histidine triad (Fhit) is known to be associated with genomic instability and apoptosis. The tumor-suppressive function of Fhit depends on the interaction with the alarmone diadenosine triphosphate (Ap3A), a noncanonical nucleotide whose concentration increases upon cellular stress. How the Fhit-Ap3A complex exerts its signaling function is unknown. Here, guided by a chemical proteomics approach employing a synthetic stable Fhit-Ap3A complex, we found that the Fhit-Ap3A complex, but not Fhit or Ap3A alone, impedes translation. Our findings provide a mechanistic model in which Fhit translocates from the nucleolus into the cytosol upon stress to form an Fhit-Ap3A complex. The Fhit-Ap3A complex impedes translation both in vitro and in vivo, resulting in reduced cell viability. Overall, our findings provide a mechanistic model by which the tumor suppressor Fhit collaborates with the alarmone Ap3A to regulate cellular proliferation.
Collapse
|
|
6
|
Chae HJ, Seo JB, Kim SH, Jeon YJ, Suh SS. Fhit induces the reciprocal suppressions between Lin28/Let-7 and miR-17/92miR. Int J Med Sci 2021; 18:706-714. [PMID: 33437205 PMCID: PMC7797533 DOI: 10.7150/ijms.51429] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023] Open
Abstract
Objective: Fhit gene is known as a genome "caretaker" and frequently inactivated by deletion or hypermethylation on the promoter in several cancers. In spite of several lines of evidence, the exact mechanism underlying Fhit-induced biology is relatively less studied. This study will focus the role of Fhit in regulating Lin28 and microRNAs (miRNAs) loop. Material and Methods: To this end, we employed Fhit overexpressing isogenic cell lines to conduct miRNA nanostring array, and differentially expressed miRNAs were identified. Using real-time PCR and Western blot analysis, expression levels of Lin28b or miRNAs were investigated in response to the overexpression of Fhit gene in H1299 lung cancer cells. Results: A series of in vitro including gene nanostring analyses revealed that Lin28B protein was induced by Fhit gene overexpression, which consequently suppressed Let-7 miRNAs. Also, we found that miRNAs in miR-17/92 clusters are redundantly increased and there is an inverse correlation between Let-7 and miR-17/92 clusters in Fhit-expressing cells. Also, a series of in vitro experiments suggests that ELF-1- and/or STAT1-dependent Lin28b regulation is responsible for Let-7 induction in Fhit-expressing cancer cells. Conclusions: Based on the same experimental system proving that Fhit gene has a robust role in suppressing tumor progression and epithelial-mesenchymal transition, our data show that Fhit mediates the negative feedback between Lin28/Let-7 axis and miR-17/-92 miRNA although the physiological relevance of current interesting observation should be further investigated.
Collapse
Affiliation(s)
- Hae-Jung Chae
- Department of Biosciences, Mokpo National University, Joennam 58554, South Korea
| | - Jong Bae Seo
- Department of Biosciences, Mokpo National University, Joennam 58554, South Korea.,Department of Biomedicine, Health & Life Convergence Science, BK21 Four, Mokpo National University, Joennam 58554, South Korea
| | - Sung-Hak Kim
- Lab of Animal Molecular Biochemistry, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Young-Jun Jeon
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, South Korea
| | - Sung-Suk Suh
- Department of Biosciences, Mokpo National University, Joennam 58554, South Korea.,Department of Biomedicine, Health & Life Convergence Science, BK21 Four, Mokpo National University, Joennam 58554, South Korea
| |
Collapse
|
|
7
|
Isor A, O'Dea AT, Petroff JT, Skubic KN, Grady SF, Arnatt CK, McCulla RD. Synthesis of triphenylphosphonium dibenzothiophene S-oxide derivatives and their effect on cell cycle as photodeoxygenation-based cytotoxic agents. Bioorg Chem 2020; 105:104442. [DOI: 10.1016/j.bioorg.2020.104442] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 10/27/2020] [Indexed: 01/12/2023]
|
|
8
|
Zhu Q, Wu X, Huang Y, Tang M, Wu L. Upregulation of FHIT gene expression in endometrial carcinoma by RNA activation. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:1372-1380. [PMID: 32661472 PMCID: PMC7344018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 04/16/2020] [Indexed: 06/11/2023]
Abstract
Endometrial carcinoma is the most common malignant tumors of the reproductive system, and fragile histidine triad (FHIT) plays an important role in multiple tumors. The purpose of this study was to investigate the expression of FHIT gene in endometrial carcinoma, and its effect on proliferation, invasion, and metastasis after upregulation. In vitro, the endometrial carcinoma cell lines were cultured. The FHIT-saRNA expression vector was constructed. The endometrial carcinoma cell line that upregulated the expression of FHIT was established, and whether the saRNA had a direct targeting regulation on the FHIT was verified. A difference of expression of FHIT in normal endometrial and endometrial carcinoma was detected. We detected the proliferation of endometrial carcinoma cell lines before and after activating FHIT. The endometrial carcinoma cell lines were compared with the corresponding transiently transfected cell lines in their capabilities of cell migration and invasion. The results showed that the expression of FHIT in endometrial carcinoma was significantly decreased or even deficient compared with normal endometrium. Upregulating the expression of FHIT is related to inhibiting the proliferation, invasion and metastasis of endometrial carcinoma. The possible mechanism is related to the regulation of cell cycle regulation, and plays a role in inhibiting tumor proliferation. The research on molecular mechanism in the development and progression of endometrial carcinoma has important theoretical significance for improving the diagnosis, treatment and prognosis of clinical tumors.
Collapse
Affiliation(s)
- Qing Zhu
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical CollegeBengbu 233399, Anhui, China
- Department of Pathology, Bengbu Medical CollegeBengbu 233030, Anhui, China
| | - Xia Wu
- Class 2018, Clinical Pathology, The Graduate School, Bengbu Medical CollegeBengbu 233030, Anhui, China
| | - Yuanli Huang
- Class 2018, Clinical Pathology, The Graduate School, Bengbu Medical CollegeBengbu 233030, Anhui, China
| | - Mingyang Tang
- Class 2016, School of Clinical Medicine, Bengbu Medical CollegeBengbu 233030, Anhui, China
| | - Ligao Wu
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical CollegeBengbu 233399, Anhui, China
- Department of Pathology, Bengbu Medical CollegeBengbu 233030, Anhui, China
| |
Collapse
|
|
9
|
Khedri A, Khaghani S, Kheirollah A, Babaahmadi-Rezaei H, Shadboorestan A, Zangooei M, Afra HS, Meshkani R, Ghahremani MH. Signaling Crosstalk of FHIT, p53, and p38 in etoposide-induced apoptosis in MCF-7 cells. J Cell Biochem 2019; 120:9125-9137. [PMID: 30614034 DOI: 10.1002/jcb.28188] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 11/12/2018] [Indexed: 12/13/2022]
Abstract
Fragile histidine trail (FHIT) is a tumor suppressor in response to DNA damage which has been deleted in various tumors. However, the signaling mechanisms and interactions of FHIT with regard to apoptotic proteins including p53 and p38 in the DNA damage-induced apoptosis are not well described. In the present study, we used etoposide-induced DNA damage in MCF-7 as a model to address these crosstalks. The time course study showed that the expression of FHIT, p53, and p38MAPK started after 1 hour following etoposide treatment. FHIT overexpression led to increase p53 expression, p38 activation, and augmented apoptosis following etoposide-induced DNA damage compared to wild-type cells. However, FHIT knockdown blocked p53 expression, delayed p38 activation, and completely inhibited etoposide-induced apoptosis. Inhibition of p38 activity prevented induction of p53, FHIT, and apoptosis in this model. Thus, activation of p38 upon etoposide treatment leads to increase in FHIT and p53 expression. In p53 knockdown MCF-7, the FHIT induction was hampered but p38 activation was induced in lower doses of etoposide. In p53 knockdown cells, inhibition of p38 induced FHIT expression and apoptosis. Our data demonstrated that the exposure of MCF-7 cells to etoposide increases apoptosis through a mechanism involving the activation of the p38-FHIT-p53 pathway. Moreover, our findings suggest signaling interaction for these pathways may represent a promising therapy for breast cancer.
Collapse
Affiliation(s)
- Azam Khedri
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahnaz Khaghani
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Kheirollah
- Cellular and Molecular Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hossein Babaahmadi-Rezaei
- Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Amir Shadboorestan
- Department of Toxicology Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Zangooei
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hajar Shokri Afra
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Meshkani
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Ghahremani
- Department of Toxicology Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
10
|
Xu Z, Wu J, Cai P, Zhou X, Yi C, Wang B. Effects of FHIT gene on proliferation and apoptosis of osteosarcoma cells. Oncol Lett 2018; 17:877-882. [PMID: 30655842 PMCID: PMC6312956 DOI: 10.3892/ol.2018.9696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 10/10/2018] [Indexed: 01/13/2023] Open
Abstract
Regulatory effects of fragile histidine triad (FHIT) gene on proliferation and apoptosis of osteosarcoma cells were studied. The hFOB1.19 and Saos2 cells were routinely cultured, pcDNA3.1-FHIT overexpression vectors carrying FHIT gene fragments and blank pcDNA3.1 vectors were transfected into Saos2 cells, respectively, and the cells were divided into hFOB, Saos2, transfection and no-load transfection groups. After transfection for 48 h, the cells were collected and analyzed. The expression of FHIT messenger ribonucleic acid (mRNA) was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression of FHIT protein was detected by western blot analysis. Cell Counting Kit 8 (CCK8) was used to detect cell proliferation, and flow cytometry was used to detect apoptosis. The expression of FHIT mRNA was significantly decreased in Saos2 group compared with that in hFOB group, and the difference was statistically significant (P<0.05). The expression of FHIT mRNA was significantly increased in transfection group compared with that in Saos2 group, and the difference was statistically significant (P<0.05). The expression of FHIT protein was obviously decreased in Saos2 group compared with that in hFOB group, and there was a statistically significant difference (P<0.05). The expression of FHIT protein was obviously increased in transfection group compared with that in Saos2 group, and the difference was statistically significant (P<0.05). Compared with that in the hFOB group, the cell proliferation rate was remarkably increased in Saos2 group, while the apoptosis rate was remarkably decreased, showing statistically significant differences (P<0.05). Compared with those in Saos2 group, the cell proliferation rate was significantly decreased in transfection group, while the apoptosis rate was significantly increased, and the differences were statistically significant (P<0.05). In conclusion, FHIT gene regulates the proliferation and apoptosis of Saos2 osteosarcoma cells, inhibits the proliferation and promotes apoptosis of Saos2 osteosarcoma cells.
Collapse
Affiliation(s)
- Zhengfeng Xu
- Department of Orthopedics, Zhoupu Hospital Affiliated to Shanghai University of Medicine and Health Science, Shanghai 201318, P.R. China
| | - Jiajun Wu
- Department of Orthopedics, Zhoupu Hospital Affiliated to Shanghai University of Medicine and Health Science, Shanghai 201318, P.R. China
| | - Pan Cai
- Department of Orthopedics, Zhoupu Hospital Affiliated to Shanghai University of Medicine and Health Science, Shanghai 201318, P.R. China
| | - Xiaoxiao Zhou
- Department of Orthopedics, Zhoupu Hospital Affiliated to Shanghai University of Medicine and Health Science, Shanghai 201318, P.R. China
| | - Cunguo Yi
- Department of Orthopedics, Zhoupu Hospital Affiliated to Shanghai University of Medicine and Health Science, Shanghai 201318, P.R. China
| | - Bin Wang
- Department of Orthopedics, Zhoupu Hospital Affiliated to Shanghai University of Medicine and Health Science, Shanghai 201318, P.R. China
| |
Collapse
|
|
11
|
Lee TG, Jeong EH, Kim SY, Kim HR, Kim H, Kim CH. Fhit, a tumor suppressor protein, induces autophagy via 14-3-3τ in non-small cell lung cancer cells. Oncotarget 2018; 8:31923-31937. [PMID: 28404875 PMCID: PMC5458259 DOI: 10.18632/oncotarget.16652] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 03/16/2017] [Indexed: 12/14/2022] Open
Abstract
Inactivation of the fragile histidine triad (Fhit) gene has been reported in the majority of human cancers, particularly in lung cancer. The role of Fhit as a tumor suppressor gene has been well documented, and restoration of Fhit expression suppresses tumorigenicity in tumor cell lines and in mouse models by inducing apoptosis and inhibiting proliferation of tumor cells. Autophagy is a catabolic pathway, whereby cytoplasmic proteins and organelles are sequestered in vacuoles and delivered to lysosomes for degradation and recycling. Although autophagy is necessary for cell survival under stress conditions, recent studies have shown that autophagy can also promote cell death. Due to the fact that both autophagy induction and Fhit expression are commonly associated with nutrient starvation, we hypothesized that Fhit expression may be related to autophagy induction. In the present study, we assessed whether Fhit overexpression by gene transfer induces autophagy in Fhit-deficient non-small cell lung cancer (NSCLC) cells. The results of our study indicate that Fhit protein induces autophagy in NSCLC cells, and that this autophagy prevents apoptotic cell death in vivo and in vitro in a 14-3-3τ protein-dependent manner. To the best of our knowledge, this is the first report to describe Fhit-induced autophagy. Suppressing autophagy might be a promising therapeutic option to enhance the efficacy of Fhit gene therapy in NSCLC.
Collapse
Affiliation(s)
- Tae-Gul Lee
- Division of Pulmonology, Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea.,School of Life Sciences and Biotechnology, Korea University, Seoul, Korea
| | - Eun-Hui Jeong
- Division of Pulmonology, Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea
| | - Seo Yun Kim
- Division of Pulmonology, Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea
| | - Hye-Ryoun Kim
- Division of Pulmonology, Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea
| | - Hyunggee Kim
- School of Life Sciences and Biotechnology, Korea University, Seoul, Korea
| | - Cheol-Hyeon Kim
- Division of Pulmonology, Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea
| |
Collapse
|
|
12
|
Lin C, Zhang J, Lu Y, Li X, Zhang W, Zhang W, Lin W, Zheng L, Li X. NIT1 suppresses tumour proliferation by activating the TGFβ1-Smad2/3 signalling pathway in colorectal cancer. Cell Death Dis 2018; 9:263. [PMID: 29449642 PMCID: PMC5833788 DOI: 10.1038/s41419-018-0333-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 01/18/2018] [Accepted: 01/19/2018] [Indexed: 12/19/2022]
Abstract
NIT1 protein has been reported to be a potential tumour suppressor in tumour progression. However, little is known about the specific role of NIT1 in tumour development and progression. In this study, we confirmed the specific effects of NIT1 in the regulation of colorectal carcinoma cell proliferation. Here, we showed that NIT1 was significantly downregulated in colorectal cancer tissues compared with that in adjacent normal tissues. The decreased expression of NIT1 was significantly correlated with poor differentiation and more serosal invasion. Functional experiments showed that NIT1 inhibited CRC cell growth both in vitro and in vivo. NIT1 induced cell cycle arrest and apoptosis. Furthermore, NIT1 recruited Smad2/3 to the TGFβ receptor and activated the TGFβ–Smad2/3 pathway by interacting with SARA and SMAD2/3 in CRC. Further study has shown that SMAD3 directly binds to the promoter regions of NIT1 and enhances the transcription of NIT1. Together, our findings indicate that NIT1 suppresses CRC proliferation through a positive feedback loop between NIT1 and activation of the TGFβ–Smad signalling pathway. This study might provide a new promising strategy for CRC.
Collapse
Affiliation(s)
- Chun Lin
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jianming Zhang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanxia Lu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaomin Li
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Wenjuan Zhang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Wei Zhang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Weihao Lin
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Lin Zheng
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xuenong Li
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
| |
Collapse
|
|
13
|
Kiss DL, Baez W, Huebner K, Bundschuh R, Schoenberg DR. Impact of FHIT loss on the translation of cancer-associated mRNAs. Mol Cancer 2017; 16:179. [PMID: 29282095 PMCID: PMC5745650 DOI: 10.1186/s12943-017-0749-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 12/10/2017] [Indexed: 11/30/2022] Open
Abstract
Background FHIT is a genome caretaker/tumor suppressor that is silenced in >50% of cancers. Although it was identified more than 20 years ago, questions remain as to how FHIT loss contributes to cancer, and conversely, how FHIT acts to maintain genome integrity and suppress malignancy. Fhit belongs to the histidine triad family of enzymes that catalyze the degradation of nucleoside 5′,5′-triphosphates, including the m7GpppN ‘caps’ that are generated when mRNAs undergo 3′-5′ decay. This raised the possibility that Fhit loss might affect changes in the translation of cancer-associated mRNAs, possibly as a consequence of increased intracellular concentrations of these molecules. Results Ribosome profiling identified several hundred mRNAs for which coding region ribosome occupancy changed as a function of Fhit expression. While many of these changes could be explained by changes in mRNA steady-state, a subset of these showed changes in translation efficiency as a function of Fhit expression. The onset of malignancy has been linked to changes in 5’-UTR ribosome occupancy and this analysis also identified ribosome binding to 5′-untranslated regions (UTRs) of a number of cancer-associated mRNAs. 5’-UTR ribosome occupancy of these mRNAs differed between Fhit-negative and Fhit-positive cells, and in some cases these differences correlated with differences in coding region ribosome occupancy. Conclusions In summary, these findings show Fhit expression impacts the translation of a number of cancer associated genes, and they support the hypothesis that Fhit’s genome protective/tumor suppressor function is associated with post-transcriptional changes in expression of genes whose dysregulation contributes to malignancy. Electronic supplementary material The online version of this article (10.1186/s12943-017-0749-x) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Daniel L Kiss
- Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA.,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.,Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, 43210, USA.,Biomarker Research Program, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - William Baez
- Department of Physics, The Ohio State University, Columbus, OH, 43210, USA
| | - Kay Huebner
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.,Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, 43210, USA
| | - Ralf Bundschuh
- Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA.,Department of Physics, The Ohio State University, Columbus, OH, 43210, USA.,Department of Chemistry & Biochemistry, The Ohio State University, Columbus, OH, 43210, USA.,Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Daniel R Schoenberg
- Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA. .,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. .,Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, 43210, USA.
| |
Collapse
|
|
14
|
Lin S, Huang G, Xiao Y, Sun W, Jiang Y, Deng Q, Peng M, Wei X, Ye W, Li B, Lin S, Wang S, Wu Q, Liang Q, Li Y, Zhang X, Wu Y, Liu P, Pei D, Yu F, Wen Z, Yao Y, Wu D, Li P. CD215+ Myeloid Cells Respond to Interleukin 15 Stimulation and Promote Tumor Progression. Front Immunol 2017; 8:1713. [PMID: 29255466 PMCID: PMC5722806 DOI: 10.3389/fimmu.2017.01713] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Accepted: 11/20/2017] [Indexed: 12/16/2022] Open
Abstract
Interleukin 15 (IL-15) regulates the development, survival, and functions of multiple innate and adaptive immune cells and plays a dual role in promoting both tumor cell growth and antitumor immunity. Here, we demonstrated that the in vivo injection of recombinant human IL-15 (200 µg/kg) or murine IL-15 (3 µg/kg) to tumor-bearing NOD-SCID-IL2Rg−/− (NSI) mice resulted in increased tumor progression and CD45+ CD11b+ Gr-1+ CD215+ cell expansion in the tumors and spleen. In B16F10-bearing C57BL/6 mice model, we found that murine IL-15 has antitumoral effect since the activation and expansion of CD8+ T cells with murine IL-15 treatment. But no enhanced or reduced tumor growth was observed in mice when human IL-15 was used. However, both murine and human IL-15 promote CD45+ CD11b+ Gr-1+ CD215+ cells expansion. In xenograft tumor models, CD215+ myeloid cells, but not CD215− cells, responded to human IL-15 stimulation and promoted tumor growth. Furthermore, we found that human IL-15 mediated insulin-like growth factor-1 production in CD215+ myeloid cells and blocking IGF-1 reduced the tumor-promoting effect of IL-15. Finally, we observed that higher IGF-1 expression is an indicator of poor prognosis among lung adenocarcinoma patients. These findings provide evidence that IL-15 may promote tumor cell progression via CD215+ myeloid cells, and IGF-1 may be an important candidate that IL-15 facilitates tumor growth.
Collapse
Affiliation(s)
- Shouheng Lin
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Guohua Huang
- Department of Respiratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yiren Xiao
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Wei Sun
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yuchuan Jiang
- Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qiuhua Deng
- Department of Respiratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Muyun Peng
- Department of Thoracic Oncology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xinru Wei
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Wei Ye
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Baiheng Li
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Simiao Lin
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Suna Wang
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Qiting Wu
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Qiubin Liang
- Guangdong Zhaotai InVivo Biomedicine Co. Ltd., Guangzhou, China
| | - Yangqiu Li
- Medical College, Institute of Hematology, Jinan University, Guangzhou, China
| | - Xuchao Zhang
- Guangdong Lung Cancer Institute, Medical Research Center, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yilong Wu
- Guangdong Lung Cancer Institute, Medical Research Center, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Pentao Liu
- Wellcome Trust Sanger Institute, Hinxton, United Kingdom
| | - Duanqing Pei
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Fenglei Yu
- Department of Thoracic Oncology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhesheng Wen
- Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yao Yao
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Donghai Wu
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Peng Li
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| |
Collapse
|
|
15
|
Bahari G, Hashemi M, Naderi M, Sadeghi-Bojd S, Taheri M. FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia. Oncol Lett 2017; 14:5034-5038. [PMID: 29085517 DOI: 10.3892/ol.2017.6796] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 06/16/2017] [Indexed: 12/27/2022] Open
Abstract
Fragile histidine triad (FHIT) is a tumor suppressor gene, which is involved in several malignancies. Epigenetic alterations in FHIT have been hypothesized to contribute to tumorigenesis. The present study aimed to examine DNA promoter methylation and gene expression levels of FHIT in childhood acute lymphoblastic leukemia (ALL), in a sample of Iranian patients. The promoter methylation status of FHIT was analyzed in 100 patients diagnosed with ALL and 120 healthy control patients. mRNA expression levels were assessed in 30 new cases of ALL compared with 32 healthy controls. Hypermethylation of the FHIT promoter was significantly more frequent in patients with ALL than in healthy controls (OR=3.83, 95% CI=1.51-9.75, P=0.007). Furthermore, FHIT mRNA expression levels were significantly reduced in childhood ALL patients compared with healthy controls (P=0.032). The results of the present study revealed that dysregulation of the FHIT gene may contribute to the pathogenesis of childhood ALL. Future studies investigating a larger sample population with greater ethnic diversity would be beneficial, to confirm the results from the present study.
Collapse
Affiliation(s)
- Gholamreza Bahari
- Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan 98167-43181, Iran.,Department of Clinical Biochemistry, Zahedan University of Medical Sciences, Zahedan 98167-43181, Iran
| | - Mohammad Hashemi
- Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan 98167-43181, Iran.,Department of Clinical Biochemistry, Zahedan University of Medical Sciences, Zahedan 98167-43181, Iran
| | - Majid Naderi
- Department of Pediatrics, Zahedan University of Medical Sciences, Zahedan 98167-43181, Iran
| | - Simin Sadeghi-Bojd
- Department of Pediatrics, Zahedan University of Medical Sciences, Zahedan 98167-43181, Iran
| | - Mohsen Taheri
- Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan 98167-43181, Iran
| |
Collapse
|
|
16
|
Krakowiak A, Kocoń-Rębowska B, Dolot R, Piotrzkowska D. New interactions between tumor suppressor Fhit protein and a nonhydrolyzable analog of its A P4 A substrate. FEBS Lett 2017; 591:548-559. [PMID: 28094435 DOI: 10.1002/1873-3468.12560] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 10/14/2016] [Accepted: 01/10/2017] [Indexed: 11/06/2022]
Abstract
Fragile histidine triad protein (Fhit) is a protein which primarily hydrolyses dinucleoside polyphosphates. To investigate possible interactions between the protein and a substrate, we used a nonhydrolyzable phosphorothioate analog of Ap4 A, containing 5-bromo-2'-deoxyuridine instead of one adenosine residue. Photocrosslinking, followed by LC-MS experiments, determined a complex in which the probe was covalently linked to the NDSIYEELQK peptide (residues 110-119). The peptide was located within the 'disordered' region, which is invisible in the known crystal structures of Fhit. This invisible and flexible part seems to play a role in the stabilization of the Fhit-substrate complex, which may be important for its tumor suppressor activity.
Collapse
Affiliation(s)
- Agnieszka Krakowiak
- Department of Bioorganic Chemistry, Polish Academy of Sciences, Centre of Molecular and Macromolecular Studies, Lodz, Poland
| | - Beata Kocoń-Rębowska
- Department of Bioorganic Chemistry, Polish Academy of Sciences, Centre of Molecular and Macromolecular Studies, Lodz, Poland
| | - Rafał Dolot
- Department of Bioorganic Chemistry, Polish Academy of Sciences, Centre of Molecular and Macromolecular Studies, Lodz, Poland
| | - Danuta Piotrzkowska
- Department of Bioorganic Chemistry, Polish Academy of Sciences, Centre of Molecular and Macromolecular Studies, Lodz, Poland
| |
Collapse
|
|
17
|
Canisius S, Martens JWM, Wessels LFA. A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains most co-occurrence. Genome Biol 2016; 17:261. [PMID: 27986087 PMCID: PMC5162102 DOI: 10.1186/s13059-016-1114-x] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 11/21/2016] [Indexed: 01/08/2023] Open
Abstract
In cancer, mutually exclusive or co-occurring somatic alterations across genes can suggest functional interactions. Existing tests for such patterns make the unrealistic assumption of identical gene alteration probabilities across tumors. We present Discrete Independence Statistic Controlling for Observations with Varying Event Rates (DISCOVER), a novel test that is more sensitive than other methods and controls its false positive rate. A pan-cancer analysis using DISCOVER finds no evidence for widespread co-occurrence, and most co-occurrences previously detected do not exceed expectation by chance. Many mutual exclusivities are identified involving well-known genes related to cell cycle and growth factor signaling, as well as lesser known regulators of Hedgehog signaling.
Collapse
Affiliation(s)
- Sander Canisius
- Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands
| | - John W M Martens
- Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Lodewyk F A Wessels
- Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands. .,Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands. .,Cancer Genomics Netherlands, Amsterdam, The Netherlands.
| |
Collapse
|
|
18
|
Karras JR, Schrock MS, Batar B, Zhang J, La Perle K, Druck T, Huebner K. Fhit loss-associated initiation and progression of neoplasia in vitro. Cancer Sci 2016; 107:1590-1598. [PMID: 27513973 PMCID: PMC5132276 DOI: 10.1111/cas.13032] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 08/05/2016] [Accepted: 08/09/2016] [Indexed: 12/28/2022] Open
Abstract
The FHIT gene, encompassing an active common fragile site, FRA3B, is frequently silenced in preneoplasia and cancer, through gene rearrangement or methylation of regulatory sequences. Silencing of Fhit protein expression causes thymidine kinase 1 downregulation, resulting in dNTP imbalance, and spontaneous replication stress that leads to chromosomal aberrations, allele copy number variations, insertions/deletions, and single-base substitutions. Thus, Fhit, which is reduced in expression in the majority of human cancers, is a genome "caretaker" whose loss initiates genome instability in preneoplastic lesions. To follow the early genetic alterations and functional changes induced by Fhit loss that may recapitulate the neoplastic process in vitro, we established epithelial cell lines from kidney tissues of Fhit-/- and +/+ mouse pups early after weaning, and subjected cell cultures to nutritional and carcinogen stress, which +/+ cells did not survive. Through transcriptome profiling and protein expression analysis, we observed changes in the Trp53/p21 and survivin apoptotic pathways in -/- cells, and in expression of proteins involved in epithelial-mesenchymal transition. Some Fhit-deficient cell lines showed anchorage-independent colony formation and increased invasive capacity in vitro. Furthermore, cells of stressed Fhit-/- cell lines formed s.c. and metastatic tumors in nude mice. Collectively, we show that Fhit loss and subsequent thymidine kinase 1 inactivation, combined with selective pressures, leads to neoplasia-associated alterations in genes and gene expression patterns in vitro and in vivo.
Collapse
Affiliation(s)
- Jenna R. Karras
- Department of Cancer Biology and GeneticsOhio State University Wexner Medical CenterColumbusOhioUSA
| | - Morgan S. Schrock
- Department of Cancer Biology and GeneticsOhio State University Wexner Medical CenterColumbusOhioUSA
| | - Bahadir Batar
- Department of Cancer Biology and GeneticsOhio State University Wexner Medical CenterColumbusOhioUSA
| | - Jie Zhang
- Department of Biomedical InformaticsOhio State University Wexner Medical CenterColumbusOhioUSA
| | - Krista La Perle
- Department of Veterinary BiosciencesCollege of Veterinary MedicineOhio State UniversityColumbusOhioUSA
| | - Teresa Druck
- Department of Cancer Biology and GeneticsOhio State University Wexner Medical CenterColumbusOhioUSA
| | - Kay Huebner
- Department of Cancer Biology and GeneticsOhio State University Wexner Medical CenterColumbusOhioUSA
| |
Collapse
|
|
19
|
Kaczmarek R, Krakowiak A, Korczyński D, Baraniak J, Nawrot B. Phosphorothioate analogs of P1,P3-di(nucleosid-5′-yl) triphosphates: Synthesis, assignment of the absolute configuration at P-atoms and P-stereodependent recognition by Fhit hydrolase. Bioorg Med Chem 2016; 24:5068-5075. [DOI: 10.1016/j.bmc.2016.08.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 08/03/2016] [Accepted: 08/18/2016] [Indexed: 11/25/2022]
|
|
20
|
Paquette AG, Houseman EA, Green BB, Lesseur C, Armstrong DA, Lester B, Marsit CJ. Regions of variable DNA methylation in human placenta associated with newborn neurobehavior. Epigenetics 2016; 11:603-13. [PMID: 27366929 DOI: 10.1080/15592294.2016.1195534] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
The placenta regulates the in utero environment and functionally impacts fetal development. Candidate gene studies identified variation in placental DNA methylation is associated with newborn neurologic and behavioral outcomes including movement quality, lethargic behavior, attention, and arousal. We sought to identify novel regions of variable DNA methylation associated with newborn attention, lethargy, quality of movement, and arousal by performing an epigenome-wide association study in 335 infants from a US birth cohort. Methylation status was quantified using the Illumina HumanMethylation450 BeadChip array and associations to newborn outcomes assessed by the NICU Network Neurobehavioral Scales (NNNS) were identified while incorporating established bioinformatics algorithms to control for confounding by cell type composition. Methylation of CpGs within FHIT (cg15970800) and ANKRD11 (cg16710656) demonstrated genome-wide significance (P < 1.8 × 10(-7)) in specific associations with infant attention. CpGs whose differential methylation was associated with all 4 neurobehavioral outcomes were common to 50 genes involved in biological processes relating to cellular adhesion and nervous system development. Comprehensive methylation profiling identified relationships between methylation of FHIT and ANKRD11, which have been previously linked to neurodevelopment and behavioral outcomes in genetic association studies. Subtle changes in DNA methylation of these genes within the placenta may impact normal variation of a newborn's ability to alter and track visual and auditory stimuli. Gene ontology analysis suggested that those genes with variable methylation related to these outcomes are over-represented in biological pathways involved in brain development and placental physiology, supportive of our hypothesis for a key role of the placenta in neurobehavioral outcomes.
Collapse
Affiliation(s)
- Alison G Paquette
- a Department of Pharmacology and Toxicology , Geisel School of Medicine at Dartmouth College , Hanover , NH , USA
| | - E Andres Houseman
- b School of Biological and Population Health Sciences , College of Public Health and Human Sciences, Oregon State University , Corvallis , OR , USA
| | - Benjamin B Green
- a Department of Pharmacology and Toxicology , Geisel School of Medicine at Dartmouth College , Hanover , NH , USA
| | - Corina Lesseur
- a Department of Pharmacology and Toxicology , Geisel School of Medicine at Dartmouth College , Hanover , NH , USA
| | - David A Armstrong
- a Department of Pharmacology and Toxicology , Geisel School of Medicine at Dartmouth College , Hanover , NH , USA
| | - Barry Lester
- c Department of Pediatrics , Center for the Study of Children at Risk, Women and Infants Hospital, Warren Alpert Medical School of Brown University , Providence , RI , USA
| | - Carmen J Marsit
- a Department of Pharmacology and Toxicology , Geisel School of Medicine at Dartmouth College , Hanover , NH , USA.,d Department of Epidemiology , Geisel School of Medicine at Dartmouth College , Lebanon , NH , USA
| |
Collapse
|
|
21
|
Kujan O, Abuderman A, Al-Shawaf AZ. Immunohistochemical characterization of FHIT expression in normal human tissues. Interv Med Appl Sci 2016; 8:7-13. [PMID: 28250975 DOI: 10.1556/1646.8.2016.1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Fragile histidine triad (FHIT) is a tumor suppressor gene that is commonly inactivated in human tumors. Interestingly, the normal pattern of FHIT expression is largely unknown. AIM This study is aimed to characterize the expression of FHIT protein in normal human tissues. MATERIALS AND METHODS A total of 119 normal human tissue specimens were analyzed for the FHIT expression using immunohistochemistry technique. The inclusion criteria included: normal/inflammatory tissue with no evidence of cellular atypia. RESULTS All studied specimens were stained positively with FHIT and showed either nuclear or cytoplasmic expression. Interestingly, the pattern of FHIT staining was similar among different specimens from each organ. FHIT is located predominantly in the nucleus, although cytoplasmic staining is also present in some cell types. Oral squamous epithelium, breast ductal epithelium, squamous and tubal metaplastic epithelium of the uterine cervix, esophageal squamous epithelium, salivary glands, and bronchial epithelia all strongly expressed the nuclear protein. In connective tissue, FHIT has shown strong cytoplasmic expression in histocytes including macrophages and dendritic cells, fibroblasts, and myofibroblasts. CONCLUSION Documentation of the pattern of FHIT expression in normal tissues will contribute to our understanding of the normal function of this protein and to interpretation of potentially altered FHIT expression in human tumors.
Collapse
Affiliation(s)
- Omar Kujan
- Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, Al-Farabi Colleges, Riyadh, Saudi Arabia; Department of Oral Pathology, Faculty of Dentistry, Hama University, Hama, Syria
| | - Abdulwahab Abuderman
- College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia; Al-Farabi College of Medicine, Al-Farabi Colleges, Riyadh, Saudi Arabia
| | - Ahmad Zahi Al-Shawaf
- Department of Pathology, Faculty of Medicine, Al-Baath University , Homs , Syria
| |
Collapse
|
|
22
|
Xu XJ, Gao S, Wang M, Qian H, Gu GY, Zhang K, Xu WR. Methylation status of the FHIT gene in the transformed human mesenchymal F6 stem cell line. Oncol Lett 2015; 9:2661-2666. [PMID: 26137124 DOI: 10.3892/ol.2015.3092] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 03/11/2015] [Indexed: 02/06/2023] Open
Abstract
The fragile histidine triad (FHIT) gene is known to be a tumor suppressor gene and the abnormal methylation of FHIT has been identified in leukemia and several solid tumors. The transformation of the tumor F6 cell line from human fetal mesenchymal stem cells (FMSCs) was first reported in a previous study that also identified the presence of a population of cancer stem cells in the F6 cell line. However, the existence of the epigenetic changes during the transformation process have yet to be elucidated. To confirm the role of the FHIT gene in the transformation process of FMSC, the expression level and methylation status of the FHIT gene was examined in F6 tumor cells and FMSCs. Additionally, the alteration in cell morphology, the cell cycle and apoptosis in F6 cells following 5-Aza-CdR treatment was assessed. It was found that the FHIT gene was expressed in FMSCs, but not in F6 cells. The methylation-specific PCR results demonstrated that the promoter methylation of FHIT genes existed in the F6 cell line. Subsequent to treatment with 5-Aza-CdR the expression of FHIT genes was restored in F6 cells. In addition, the morphology of F6 cells was altered, and the cell cycle was arrested in the G2 phase, with the initiation of apoptosis. Overall, the present findings demonstrated that the FHIT gene was methylated in F6 cells and demethylation treatment lead to changes in the biological characteristics, thereby promoting the apoptosis of F6 cells. FHIT gene methylation may be one of the molecular events involved in the development and transformation of FMSCs into F6 tumor cells.
Collapse
Affiliation(s)
- Xue-Jing Xu
- Department of Laboratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Shuo Gao
- Department of Laboratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Mei Wang
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Hui Qian
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Guang-Yu Gu
- Department of Laboratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Kui Zhang
- Department of Laboratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Wen-Rong Xu
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| |
Collapse
|
|
23
|
Liao J, Wen S, Cao L, Zhou Y, Feng Z. Effect of eradication of Helicobacter pylori on expression levels of FHIT, IL-8 and P73 in gastric mucosa of first-degree relatives of gastric cancer patients. PLoS One 2015; 10:e0124576. [PMID: 25875960 PMCID: PMC4397018 DOI: 10.1371/journal.pone.0124576] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 03/06/2015] [Indexed: 12/19/2022] Open
Abstract
Objectives Helicobacter pylori (H. pylori) infection plays an important role in the carcinogenesis and development of gastric cancer. Eradication of H. pylori can effectively reduce the risk of gastric cancer, but the underlying mechanisms are not fully understood. This study aimed to investigate the effect of eradication of H. pylori on the expression levels of FHIT, IL-8 and P73 in the gastric mucosa of first-degree relatives of gastric cancer patients. Methods One hundred and thirty-two patients with functional dyspepsia having first-degree relatives with gastric cancer were prospectively recruited in this study. Nine patients presented with H. pylori infection and family histories of gastric cancer, 61 with H. pylori infection and without family histories of gastric cancer, 6 without H. pylori infection and with family histories of gastric cancer, and 56 without H. pylori infection and family histories of gastric cancer. The protein and mRNA expression levels of FHIT, IL-8 and P73 in gastric mucosa of the subjects were detected by immunohistochemical staining and polymerase chain reaction, respectively. Results Compared with the patients without H. pylori infection and family histories of gastric cancer, both the protein and mRNA levels of FIHT significantly decreased in patients with H. pylori infection and/or family histories of gastric cancer, and both the protein and mRNA levels of IL-8 significantly increased. After eradication of H. pylori, both the protein and mRNA levels of FHIT were significantly higher, and both the protein and mRNA levels of IL-8 were significantly lower. However, H. pylori infection and family histories of gastric cancer had no major effect on P73 expression. Conclusions Down-regulation of FHIT and up-regulation of IL-8 may be involved in the pathogenesis of H. pylori infection in the first-degree relatives of gastric cancer patients.
Collapse
Affiliation(s)
- Juan Liao
- Department of Gastroenterology, The Affiliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong 637000, Sichuan Province, China
| | - Shichao Wen
- Department of Gastroenterology, The Affiliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong 637000, Sichuan Province, China
| | - Lipeng Cao
- Department of Gastroenterology, The Affiliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong 637000, Sichuan Province, China
| | - Yunfeng Zhou
- Department of Gastroenterology, The Affiliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong 637000, Sichuan Province, China
| | - Zhisong Feng
- Department of Gastroenterology, The Affiliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong 637000, Sichuan Province, China
- * E-mail:
| |
Collapse
|
|
24
|
Adduri R, Kotapalli V, Gupta NA, Gowrishankar S, Srinivasulu M, Ali MM, Rao S, Uppin SG, Nayak UK, Dhagam S, Chigurupati MV, Bashyam MD. P53 nuclear stabilization is associated with FHIT loss and younger age of onset in squamous cell carcinoma of oral tongue. BMC Clin Pathol 2014; 14:37. [PMID: 25152695 PMCID: PMC4141988 DOI: 10.1186/1472-6890-14-37] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 07/29/2014] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Squamous cell carcinoma of tongue (SCCT) is expected to harbor unique clinico-pathological and molecular genetic features since a significant proportion of patients are young and exhibit no association with tobacco or alcohol. METHODS We determined P53, epidermal growth factor receptor, microsatellite instability, human papilloma virus infection and loss of heterozygosity status at several tumor suppressor loci in one hundred and twenty one oral SCCT (SSCOT) samples and analyzed their association with clinico-pathological features and patient survival. RESULTS Our results revealed a significantly higher incidence of p53 nuclear stabilization in early (as against late) onset SCCOT. FHIT loss was significantly associated with p53 nuclear stabilization and the association was stronger in patients with no history of tobacco use. Samples harboring mutation in p53 DNA binding domain or exhibiting p53 nuclear stabilization, were significantly associated with poor survival. CONCLUSION Our study has therefore identified distinct features in SCCOT tumorigenesis with respect to age and tobacco exposure and revealed possible prognostic utility of p53.
Collapse
Affiliation(s)
- Raju Adduri
- Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500001, India
| | - Viswakalyan Kotapalli
- Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500001, India
| | - Neha A Gupta
- Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500001, India ; Currently at National Centre for Cell Science, Ganeshkhind, Pune, India
| | | | - Mukta Srinivasulu
- MNJ Institute of Oncology & Regional Cancer Centre, Red Hills, Hyderabad India
| | | | - Subramanyeshwar Rao
- MNJ Institute of Oncology & Regional Cancer Centre, Red Hills, Hyderabad India ; Currently at Basavatarakam Indo American Cancer Hospital & Research Institute, Hyderabad, India
| | | | | | | | | | - Murali Dharan Bashyam
- Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500001, India
| |
Collapse
|
|
25
|
Cherneva R, Georgiev O, Petrova D. Early Detection of Lung Cancer: A Call for Novel Biomarkers-Review. BIOTECHNOL BIOTEC EQ 2014. [DOI: 10.1080/13102818.2007.10817435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
|
|
26
|
Christensen CL, Zandi R, Gjetting T, Cramer F, Poulsen HS. Specifically targeted gene therapy for small-cell lung cancer. Expert Rev Anticancer Ther 2014; 9:437-52. [DOI: 10.1586/era.09.10] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
|
|
27
|
Pyne NJ, Ohotski J, Bittman R, Pyne S. The role of sphingosine 1-phosphate in inflammation and cancer. Adv Biol Regul 2014; 54:121-129. [PMID: 24070975 DOI: 10.1016/j.jbior.2013.08.005] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 08/31/2013] [Accepted: 08/31/2013] [Indexed: 06/02/2023]
Abstract
The enzymes that catalyze formation of the bioactive sphingolipid, sphingosine 1-phosphate, sphingosine kinase 1 and 2, are predictive markers in inflammatory diseases and cancer as evidenced by data from patients, knockout mice and the use of available molecular and chemical inhibitors. Thus, there is a compelling case for therapeutic targeting of sphingosine kinase. In addition, there are several examples of functional interaction between sphingosine 1-phosphate receptors and sphingosine kinase 1 that can drive malicious amplification loops that promote cancer cell growth. These novel aspects of sphingosine 1-phosphate pathobiology are reviewed herein.
Collapse
Affiliation(s)
- Nigel J Pyne
- Cell Biology Research Group, Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
| | - Jan Ohotski
- Cell Biology Research Group, Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Robert Bittman
- Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, New York 11367-1597, USA
| | - Susan Pyne
- Cell Biology Research Group, Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| |
Collapse
|
|
28
|
Miuma S, Saldivar JC, Karras JR, Waters CE, Paisie CA, Wang Y, Jin V, Sun J, Druck T, Zhang J, Huebner K. Fhit deficiency-induced global genome instability promotes mutation and clonal expansion. PLoS One 2013; 8:e80730. [PMID: 24244712 PMCID: PMC3828255 DOI: 10.1371/journal.pone.0080730] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Accepted: 10/07/2013] [Indexed: 01/25/2023] Open
Abstract
Loss of Fhit expression, encoded at chromosome fragile site FRA3B, leads to increased replication stress, genome instability and accumulation of genetic alterations. We have proposed that Fhit is a genome ‘caretaker’ whose loss initiates genome instability in preneoplastic lesions. We have characterized allele copy number alterations and expression changes observed in Fhit-deficient cells in conjunction with alterations in cellular proliferation and exome mutations, using cells from mouse embryo fibroblasts (MEFs), mouse kidney, early and late after establishment in culture, and in response to carcinogen treatment. Fhit-/- MEFs escape senescence to become immortal more rapidly than Fhit+/+ MEFs; -/- MEFs and kidney cultures show allele losses and gains, while +/+ derived cells show few genomic alterations. Striking alterations in expression of p53, p21, Mcl1 and active caspase 3 occurred in mouse kidney -/- cells during progressive tissue culture passage. To define genomic changes associated with preneoplastic changes in vivo, exome DNAs were sequenced for +/+ and -/- liver tissue after treatment of mice with the carcinogen, 7,12-dimethylbenz[a]anthracene, and for +/+ and -/- kidney cells treated in vitro with this carcinogen. The -/- exome DNAs, in comparison with +/+ DNA, showed small insertions, deletions and point mutations in more genes, some likely related to preneoplastic changes. Thus, Fhit loss provides a ‘mutator’ phenotype, a cellular environment in which mild genome instability permits clonal expansion, through proliferative advantage and escape from apoptosis, in response to pressures to survive.
Collapse
Affiliation(s)
- Satoshi Miuma
- Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Joshua C. Saldivar
- Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Jenna R. Karras
- Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Catherine E. Waters
- Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Carolyn A. Paisie
- Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Yao Wang
- Department of Biomedical Informatics, Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Victor Jin
- Department of Biomedical Informatics, Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Jin Sun
- Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Teresa Druck
- Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Jie Zhang
- Department of Biomedical Informatics, Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Kay Huebner
- Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
- * E-mail:
| |
Collapse
|
|
29
|
Taylor F, Teare MD, Cox A, Woll PJ. Circulating cell-free DNA: a potential biomarker in lung cancer. Lung Cancer Manag 2013. [DOI: 10.2217/lmt.13.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
SUMMARY Cell-free DNA (cfDNA) is a promising, noninvasive tumor ‘liquid biopsy’ with quantitative and qualitative significance. Circulating cfDNA levels are raised in cancer patients and cfDNA exhibits genetic and epigenetic changes found in the underlying tumor. In lung cancer patients, cfDNA levels and tumor-associated genetic and epigenetic changes have been assessed as diagnostic, prognostic and predictive biomarkers. To date, many small studies have been reported with contradictory results. Their interpretation is hampered by differences in methodology and the selection of patients and controls. The treatment of lung cancer is increasingly guided by molecular subtyping, but access to tumor tissue is limited and cfDNA represents an attractive alternative. Moreover, repeated sampling of cfDNA is feasible and cfDNA may be more representative of tumor heterogeneity than a small biopsy sample. However, the establishment of robust and standardized protocols for blood sampling, processing, storage, DNA extraction and analysis are required before cfDNA biomarkers can be utilized in clinical practice.
Collapse
Affiliation(s)
- Fiona Taylor
- Academic Unit of Oncology, CR-UK/YCR Sheffield Cancer Research Centre, Weston Park Hospital, Whitham Road, Sheffield, S10 2SJ, UK
| | - M Dawn Teare
- School of Health & Related Research (ScHARR), University of Sheffield, Sheffield, S1 4DA, UK
| | - Angela Cox
- Academic Unit of Molecular Oncology, The Medical School, University of Sheffield, Sheffield, S10 2RX, UK
| | - Penella J Woll
- Academic Unit of Oncology, CR-UK/YCR Sheffield Cancer Research Centre, Weston Park Hospital, Whitham Road, Sheffield, S10 2SJ, UK
| |
Collapse
|
|
30
|
Watson DG, Tonelli F, Osaimi MA, Williamson L, Chan E, Gorshkova I, Berdyshev E, Bittman R, Pyne NJ, Pyne S. The roles of sphingosine kinases 1 and 2 in regulating the Warburg effect in prostate cancer cells. Cell Signal 2013; 25:1011-7. [PMID: 23314175 PMCID: PMC3595369 DOI: 10.1016/j.cellsig.2013.01.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 01/06/2013] [Indexed: 12/30/2022]
Abstract
Two isoforms of sphingosine kinase, SK1 and SK2, catalyze the formation of the bioactive lipid sphingosine 1-phosphate (S1P) in mammalian cells. We have previously shown that treatment of androgen-sensitive LNCaP prostate cancer cells with a non-selective SK isoform inhibitor, 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SKi), induces the proteasomal degradation of SK1. This is concomitant with a significant increase in C22:0-ceramide and sphingosine levels and a reduction in S1P levels, resulting in the apoptosis of LNCaP cells. In contrast, we show here that a SK2-selective inhibitor, (R)-FTY720 methyl ether (ROME), increases sphingosine and decreases S1P levels but has no effect on ceramide levels and does not induce apoptosis in LNCaP cells. We also show that several glycolytic metabolites and (R)-S-lactoylglutathione are increased upon treatment of LNCaP cells with SKi, which induces the proteasomal degradation of c-Myc. These changes reflect an indirect antagonism of the Warburg effect. LNCaP cells also respond to SKi by diverting glucose 6-phosphate into the pentose phosphate pathway to provide NADPH, which serves as an antioxidant to counter an oxidative stress response. SKi also promotes the formation of a novel pro-apoptotic molecule called diadenosine 5',5'''-P(1),P(3)-triphosphate (Ap3A), which binds to the tumor suppressor fragile histidine triad protein (FHIT). In contrast, the SK2-selective inhibitor, ROME, induces a reduction in some glycolytic metabolites and does not affect oxidative stress. We conclude that SK1 functions to increase the stability of c-Myc and suppresses Ap3A formation, which might maintain the Warburg effect and cell survival, while SK2 exhibits a non-overlapping function.
Collapse
Affiliation(s)
| | | | | | | | | | - Irina Gorshkova
- The University of Illinois at Chicago Section of Pulmonary, Critical Care, Sleep, and Allergy, 909 S. Wolcott Ave., Chicago, IL 60612, USA
| | - Evgeny Berdyshev
- The University of Illinois at Chicago Section of Pulmonary, Critical Care, Sleep, and Allergy, 909 S. Wolcott Ave., Chicago, IL 60612, USA
| | - Robert Bittman
- Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, New York 11367-1597, USA
| | | | - Susan Pyne
- To whom correspondence should be addressed (Tel: 441415482012; Fax: 441415522562; )
| |
Collapse
|
|
31
|
Inactivation of both FHIT and p53 cooperate in deregulating proliferation-related pathways in lung cancer. J Thorac Oncol 2012; 7:631-42. [PMID: 22425911 DOI: 10.1097/jto.0b013e318244aed0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION FHIT and p53 are the two most commonly altered tumor suppressor genes in lung cancer, and their molecular status regulates sensitivity to anticancer drugs. Although their functions are independent, there is evidence that their pathways might be interconnected, but little is known at the molecular level. METHODS Microarray profiling of FHIT-transduced lung cancer cells and modulation of FHIT levels by RNA interference in human bronchial cells were used to generate a signature of FHIT-regulated transcripts. Expression of these genes was evaluated by real-time polymerase chain reaction in 55 primary lung cancer samples characterized for FHIT and p53 expression by immunehistochemistry. RESULTS A signature of FHIT-transcripts, particularly enriched in genes involved in cell cycle control, was identified. This signature showed overlap with p53-regulated genes, indicating possible crosstalk between these proteins. Consistently, transcriptional deregulation after FHIT modulation was higher in p53-negative cells. In primary lung cancers, inactivation of either gene was detected in 48 of 55 cases (87%) and both genes in 23 of 55 (42%) cases, confirming the central role of these pathways. Primary tumors with inactivation of both FHIT and p53 displayed the strongest deregulation of growth-related pathways with high levels of expression of CCNB1, BUB1, CDC6, TOP2A, MCM6, and CENPF. CONCLUSIONS FHIT and p53 seem to rely on common mediators, and inactivation of both genes results in prominent deregulation of growth-related pathways in lung cancer cell lines and primary tumors. This reveals crosstalk between these proteins and suggests a possible distinctive phenotype for tumors with inactivation of both genes.
Collapse
|
|
32
|
Romero I, Martinez M, Garrido C, Collado A, Algarra I, Garrido F, Garcia-Lora AM. The tumour suppressor Fhit positively regulates MHC class I expression on cancer cells. J Pathol 2012; 227:367-79. [PMID: 22451343 DOI: 10.1002/path.4029] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2011] [Revised: 03/12/2012] [Accepted: 03/20/2012] [Indexed: 12/12/2022]
Abstract
MHC class I (MHC-I) molecules are ubiquitously expressed on the cells of an organism. Study of the regulation of these molecules in normal and disease conditions is important. In tumour cells, the expression of MHC-I molecules is very frequently lost, allowing these cells to evade the immune response. Cancers of different histology have shown total loss of MHC-I molecule expression, due to a coordinated transcriptional down-regulation of various antigen-processing machinery (APM) components and/or MHC-I heavy chains. The mechanisms responsible for these alterations remain unclear. We determined the possible genes involved by comparing MHC-I-positive with MHC-I-negative murine metastases derived from the same fibrosarcoma tumour clone. MHC-I-negative metastases showed transcriptional down-regulation of APM and MHC-I heavy chains. The use of microarrays and subtraction cDNA libraries revealed four candidate genes responsible for this alteration, but two of them were ruled out by real-time RT-PCR analyses. The other two genes, AP-2α and Fhit tumour suppressors, were studied by using siRNA to silence their expression in a MHC-I-positive metastatic cell line. AP-2α inhibition did not modify transcriptional expression of APM components or MHC-I heavy chains or surface expression of MHC-I. In contrast, silencing of the Fhit gene produced the transcriptional down-regulation of APM components and MHC-I heavy chains and decreased MHC-I surface expression. Moreover, transfection of Fhit in MHC-I-negative tumour cell lines restored MHC-I cell surface expression. These data indicate that defects in Fhit expression may promote MHC-I down-regulation in cancer cells and allow escape from immunosurveillance(#).
Collapse
Affiliation(s)
- Irene Romero
- Servicio de Análisis Clínicos & Inmunología, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Yang M, Park JY. DNA methylation in promoter region as biomarkers in prostate cancer. Methods Mol Biol 2012; 863:67-109. [PMID: 22359288 DOI: 10.1007/978-1-61779-612-8_5] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The prostate gland is the most common site of cancer and the second leading cause of cancer death in American men. Recent emerging molecular biological technologies help us to know that epigenetic alterations such as DNA methylation within the regulatory (promoter) regions of genes are associated with transcriptional silencing in cancer. Promoter hypermethylation of critical pathway genes could be potential biomarkers and therapeutic targets for prostate cancer. In this chapter, we updated current information on methylated genes associated with the development and progression of prostate cancer. Over 40 genes have been investigated for methylation in promoter region in prostate cancer. These methylated genes are involved in critical pathways, such as DNA repair, metabolism, and invasion/metastasis. The role of hypermethylated genes in regulation of critical pathways in prostate cancer is discussed. These findings may provide new information of the pathogenesis, the exciting potential to be predictive and to provide personalized treatment of prostate cancer. Indeed, some epigenetic alterations in prostate tumors are being translated into clinical practice for therapeutic use.
Collapse
Affiliation(s)
- Mihi Yang
- Division of Cancer Prevention and Controls, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | | |
Collapse
|
|
34
|
Krakowiak A, Pęcherzewska R, Kaczmarek R, Tomaszewska A, Nawrot B, Stec WJ. Evaluation of influence of Ap4A analogues on Fhit-positive HEK293T cells; cytotoxicity and ability to induce apoptosis. Bioorg Med Chem 2011; 19:5053-60. [PMID: 21757356 DOI: 10.1016/j.bmc.2011.06.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Revised: 06/02/2011] [Accepted: 06/08/2011] [Indexed: 01/06/2023]
Abstract
Fragile histidine triad (Fhit) protein encoded by tumour suppressor FHIT gene is a proapoptotic protein with diadenosine polyphosphate (Ap(n)A, n=2-6) hydrolase activity. It has been hypothesised that formation of Fhit-substrate complex results in an apoptosis initiation signal while subsequent hydrolysis of Ap(n)A terminates this action. A series of Ap(n)A analogues have been identified in vitro as strong Fhit ligands [Varnum, J. M.; Baraniak, J.; Kaczmarek, R.; Stec, W. J.; Brenner, C. BMC Chem. Biol.2001, 1, 3]. We assumed that in Fhit-positive cells these compounds might preferentially bind to Fhit and inhibit its hydrolytic activity what would prolong the lifetime of apoptosis initiation signalling complex. Therefore, several Fhit inhibitors were tested for their cytotoxicity and ability to induce apoptosis in Fhit-positive HEK293T cells. These experiments have shown that Ap(4)A analogue, containing a glycerol residue instead of the central pyrophosphate and two terminal phosphorothioates [A(PS)-CH(2)CH(OH)CH(2)-(PS)A (1)], is the most cytotoxic among test compounds (IC(50)=17.5±4.2 μM) and triggers caspase-dependent cell apoptosis. The Fhit-negative HEK293T cells (in which Fhit was silenced by RNAi) were not sensitive to compound 1. These results indicate that the Ap(4)A analogue 1 induces Fhit-dependent apoptosis and therefore, it can be considered as a drug candidate for anticancer therapy in Fhit-positive cancer cells and in Fhit-negative cancer cells, in which re-expression of Fhit was accomplished by gene therapy.
Collapse
Affiliation(s)
- Agnieszka Krakowiak
- Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Bioorganic Chemistry, Sienkiewicza 112, 90-363 Lodz, Poland.
| | | | | | | | | | | |
Collapse
|
|
35
|
Wang H, Wu J, Meng X, Ying X, Zuo Y, Liu R, Pan Z, Kang T, Huang W. MicroRNA-342 inhibits colorectal cancer cell proliferation and invasion by directly targeting DNA methyltransferase 1. Carcinogenesis 2011; 32:1033-42. [PMID: 21565830 DOI: 10.1093/carcin/bgr081] [Citation(s) in RCA: 143] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Overexpressed DNA methyltransferase 1 (DNMT1) strongly contributes to tumor suppressor gene silencing in colorectal cancer (CRC). However, the underlying mechanism of DNMT1 overexpression is still unclear. MicroRNAs (miRNA) have been implicated as gene regulators controlling diverse biological processes, including carcinogenesis. In this study, we investigated whether some miRNA is involved in the regulation of DNMT1 and thus play a functional role in CRC. Our results showed that miR-342 was downregulated in CRC tissues and cell lines. Restoration of miR-342 resulted in a dramatic reduction of the expression of DNMT1 at both messenger RNA and protein levels by directly targeting its 3' untranslated region. This in turn reactivated ADAM23, Hint1, RASSF1A and RECK genes via promoter demethylation. Furthermore, the enhanced expression of miR-342 could significantly inhibit SW480 cell proliferation in vitro (P = 0.006). Further investigation demonstrated G(0)/G(1) cell cycle arrest in SW480 cells, which was associated with an upregulation of p21 and downregulation of cyclinE and CDK2. Overexpression of miR-342 also inhibited SW480 cell invasion. The in vivo antitumor effect was evaluated in SW480 cells with lentivirus-mediated expression of miR-342. Results showed that overexpression of miR-342 significantly inhibited tumor growth and lung metastasis in nude mice (P = 0.034). Our findings describe a new mechanism for the regulation of DNMT1 and aberrant DNA hypermethylation in CRC. This is also the first report to demonstrate that miR-342 may act as a tumor suppressor gene in CRC development. The newly identified miR-342/DNMT1 link provides a new, potential therapeutic target for the treatment of CRC.
Collapse
Affiliation(s)
- Hui Wang
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road, East, Guangzhou 510060, People's Republic of China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Martin J, St-Pierre MV, Dufour JF. Hit proteins, mitochondria and cancer. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2011; 1807:626-32. [PMID: 21316334 DOI: 10.1016/j.bbabio.2011.02.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Revised: 02/02/2011] [Accepted: 02/02/2011] [Indexed: 11/30/2022]
Abstract
The histidine triad (HIT) superfamily comprises proteins that share the histidine triad motif, His-ϕ-His-ϕ-His-ϕ-ϕ, where ϕ is a hydrophobic amino acid. HIT proteins are ubiquitous in prokaryotes and eukaryotes. HIT proteins bind nucleotides and exert dinucleotidyl hydrolase, nucleotidylyl transferase or phosphoramidate hydrolase enzymatic activity. In humans, 5 families of HIT proteins are recognized. The accumulated epidemiological and experimental evidence indicates that two branches of the superfamily, the HINT (Histidine Triad Nucleotide Binding) members and FHIT (Fragile Histidine Triad), have tumor suppressor properties but a conclusive physiological role can still not be assigned to these proteins. Aprataxin forms another discrete branch of the HIT superfamily, is implicated in DNA repair mechanisms and unlike the HINT and FHIT members, a defective protein can be conclusively linked to a disease, ataxia with oculomotor apraxia type 1. The scavenger mRNA decapping enzyme, DcpS, forms a fourth branch of the HIT superfamily. Finally, the GalT enzymes, which exert specific nucleoside monophosphate transferase activity, form a fifth branch that is not implicated in tumorigenesis. The molecular mechanisms by which the HINT and FHIT proteins participate in bioenergetics of cancer are just beginning to be unraveled. Their purported actions as tumor suppressors are highlighted in this review.
Collapse
Affiliation(s)
- Juliette Martin
- Institute of Clinical Pharmacology and Visceral Research, University of Bern, Switzerland
| | | | | |
Collapse
|
|
37
|
D'Angelo SP, Pietanza MC. [The molecular pathogenesis of small cell lung cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2010; 13:C46-57. [PMID: 21081036 PMCID: PMC6134416 DOI: 10.3779/j.issn.1009-3419.2010.11.18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Sandra P D'Angelo
- Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, NY, USA
| | | |
Collapse
|
|
38
|
Song X, Tian Z, Wang S, Peng Z, Feng J. Restoration of fragile histidine triad (FHIT) expression inhibits cell growth and induces apoptosis in cutaneous T-cell lymphoma cell line. Cancer Invest 2010; 28:1019-23. [PMID: 20690795 DOI: 10.3109/07357900902849608] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
To investigate the effects of fragile histidine triad (FHIT) restoration on cell proliferation and apoptosis in human cutaneous T-cell lymphoma cell line, Hut-78, in vitro and in nude mouse. Wild-type FHIT gene was transfected by liposome into the Hut-78 cells. The alteration of cell growth curve and soft agar colony formation was studied in vitro and in nude mice. The FHIT gene was stably expressed in Hut-78 cells after the transfection. Compared with the controls, restoration of FHIT expression inhibited cell growth and induced apoptosis. Tumor formation in vivo was strongly suppressed by FHIT gene restoration. Our data demonstrate restoration of FHIT gene expression inhibit the tumor cell growth and provide an option for the treatment.
Collapse
Affiliation(s)
- Xiangfeng Song
- Department of Immunology, Xinxiang Medical University, Xingxiang, China
| | | | | | | | | |
Collapse
|
|
39
|
Hassan MI, Naiyer A, Ahmad F. Fragile histidine triad protein: structure, function, and its association with tumorogenesis. J Cancer Res Clin Oncol 2010; 136:333-50. [PMID: 20033706 DOI: 10.1007/s00432-009-0751-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Accepted: 12/09/2009] [Indexed: 01/31/2023]
Abstract
BACKGROUND The human fragile histidine triad (FHIT) gene is a putative tumor suppressor gene, which is located at chromosome region 3p14.2. It was suggested that the loss of heterozygosity (LOH), homozygous deletions, and abnormal expression of the FHIT gene were involved in several types of human malignancies. MATERIALS AND METHODS To determine the role of FHIT in various cancers, we have performed structural and functional analysis of FHIT in detail. RESULTS AND DISCUSSION The protein FHIT catalyzes the Mg(2+) dependent hydrolysis of P1-5 cent-O-adenosine-P3-5 cent-O-adenosine triphosphate, Ap3A, to AMP, and ADP. The reaction is thought to follow a two-step mechanism. Histidine triad proteins, named for a motif related to the sequence H-cent-H-cent-H-cent-cent- (cent, a hydrophobic amino acid), belong to superfamily of nucleotide hydrolases and transferases. This enzyme acts on the R-phosphate of ribonucleotides, and contain a approximately 30-kDa domain that is typically a homodimer of approximately 15 kDa polypeptides with catalytic site. CONCLUSION Here we have gathered information is known about biological activities of FHIT, the structural and biochemical bases for their functions. Our approach may provide a comparative framework for further investigation of FHIT.
Collapse
Affiliation(s)
- Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | | | | |
Collapse
|
|
40
|
The DNA unwinding element binding protein DUE-B interacts with Cdc45 in preinitiation complex formation. Mol Cell Biol 2010; 30:1495-507. [PMID: 20065034 DOI: 10.1128/mcb.00710-09] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Template unwinding during DNA replication initiation requires the loading of the MCM helicase activator Cdc45 at replication origins. We show that Cdc45 interacts with the DNA unwinding element (DUE) binding protein DUE-B and that these proteins localize to the DUEs of active replication origins. DUE-B and Cdc45 are not bound at the inactive c-myc replicator in the absence of a functional DUE or at the recently identified ataxin 10 (ATX10) origin, which is silent before disease-related (ATTCT)(n) repeat length expansion of its DUE sequence, despite the presence of the origin recognition complex (ORC) and MCM proteins at these origins. Addition of a heterologous DUE to the ectopic c-myc origin, or expansion of the ATX10 DUE, leads to origin activation, DUE-B binding, and Cdc45 binding. DUE-B, Cdc45, and topoisomerase IIbeta binding protein 1 (TopBP1) form complexes in cell extracts and when expressed from baculovirus vectors. During replication in Xenopus egg extracts, DUE-B and Cdc45 bind to chromatin with similar kinetics, and DUE-B immunodepletion blocks replication and the loading of Cdc45 and a fraction of TopBP1. The coordinated binding of DUE-B and Cdc45 to origins and the physical interactions of DUE-B, Cdc45, and TopBP1 suggest that complexes of these proteins are necessary for replication initiation.
Collapse
|
|
41
|
Abstract
Lung cancer is a complex spectrum of diseases characterized by extensive genomic instability, which can be detected among both histological subtypes and different foci within a tumor. Conventional and cutting edge investigative technologies have uncovered scores of genomic changes in individual specimens that have been used to characterize specific molecular subtypes. Oncogenes with predominant roles in lung cancer include EGFR, MYC and RAS family members, PIK3CA, NKX2-1 and ALK; tumor suppressor genes include TP53, RB1, CDKN2, and a cluster of genes mapped at 3p. MicroRNA regulators also have been linked to lung cancer. The functional role of the recurrent genomic changes in lung tumors has been explored, which has led to a better understanding of cell growth, differentiation and apoptotic pathways. Additionally, this knowledge has supported the development of novel therapeutics and translational tools for selection of patients for personalized therapy.
Collapse
Affiliation(s)
- Marileila Varella-Garcia
- Departments of Medicine and Pathology, University of Colorado Denver, Anschutz Medical Center, University of Colorado Cancer Center, Aurora, CO, USA.
| |
Collapse
|
|
42
|
Xie F, Huang Q. FHIT gene transfection inhibits the proliferation and invasiveness of human cholangiocarcinoma QBC939 cells. Shijie Huaren Xiaohua Zazhi 2009; 17:3437-3440. [DOI: 10.11569/wcjd.v17.i33.3437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the impact of fragile histidine triad (FHIT) gene transfection on the proliferation and invasiveness of human cholangiocarcinoma QBC939 cells.
METHODS: The recombinant FHIT eukaryotic expression plasmid was introduced into QBC939 cells by liposome-mediated transfection. Cell proliferation was tested by methyl thiazolyl tetrazolium (MTT) assay. Cell invasion was determined by Transwell chamber assay.
RESULTS: MTT assay showed that FHIT gene transfection significantly decreased the proliferation of QBC939 cells (P < 0.05). Transwell chamber assay showed that the number of transfected cells that passed the Transwell membrane was significantly less than those of blank control and normal control cells (48 ± 7 vs 109 ± 14 and 104 ± 12, respectively; both P < 0.01).
CONCLUSION: FHIT gene can inhibit the proliferation and invasiveness of human cholangiocarcinoma QBC939 cells.
Collapse
|
|
43
|
Enlightened protein: Fhit tumor suppressor protein structure and function and its role in the toxicity of protoporphyrin IX-mediated photodynamic reaction. Toxicol Appl Pharmacol 2009; 241:246-52. [PMID: 19716840 DOI: 10.1016/j.taap.2009.08.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2009] [Revised: 08/18/2009] [Accepted: 08/20/2009] [Indexed: 12/12/2022]
Abstract
The Fhit tumor suppressor protein possesses Ap(3)A (diadenosine triphosphate - ApppA) hydrolytic activity in vitro and its gene is found inactive in many pre-malignant states due to gene inactivation. For several years Fhit has been a widely investigated protein as its cellular function still remains largely unsolved. Fhit was shown to act as a molecular 'switch' of cell death via cascade operating on the influence of ATR-Chk1 pathway but also through the mitochondrial apoptotic pathway. Notably, Fhit was reported by our group to enhance the overall eradication effect of porphyrin-mediated photodynamic treatment (PDT). In this review the up-to-date findings on Fhit protein as a tumor suppressor and its role in PDT are presented.
Collapse
|
|
44
|
Mirandola P, Gobbi G, Sponzilli I, Malinverno C, Cavazzoni A, Alfieri R, Petronini PG, Vitale M. TRAIL-induced apoptosis of FHIT-negative lung cancer cells is inhibited by FHIT re-expression. J Cell Physiol 2009; 220:492-8. [DOI: 10.1002/jcp.21801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
|
|
45
|
Okumura H, Ishii H, Pichiorri F, Croce CM, Mori M, Huebner K. Fragile gene product, Fhit, in oxidative and replicative stress responses. Cancer Sci 2009; 100:1145-50. [PMID: 19486340 PMCID: PMC11159339 DOI: 10.1111/j.1349-7006.2009.01168.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2009] [Revised: 03/12/2009] [Accepted: 03/15/2009] [Indexed: 10/21/2022] Open
Abstract
Though the fragile histidine triad gene product, Fhit, was discovered and characterized as a tumor suppressor 13 years ago, its sequence, structure, and cellular location did not provide clues to aid discovery of its mechanisms of suppression. Recently, using chemical cross-linkers and immunoprecipitation, a Fhit protein complex was identified that includes Hsp60 and Hsp10 which may mediate Fhit stability and mitochondrial localization, where Fhit binds and stabilizes ferredoxin reductase (Fdxr); when Fdxr is overexpressed, it can lead to production of reactive oxygen species (ROS) that induce apoptosis. Cancer cells expressing endogenous or exogenous Fhit, when exposed to H(2)O(2), an oxidative stress, produce higher levels of apoptosis-inducing ROS than matched, Fhit-negative cells; the Fhit-negative cancer cells survive, carrying DNA damage. In addition to this mitochondrial function, Fhit-overexpression in cancer cells exposed to replicative stress-inducing agents leads to enhanced caspase 3 activation and apoptosis, due to defective Chk1 activation. Thus, damage to the fragile FHIT locus leads to reduced expression of Fhit protein, and makes a two-pronged contribution to development of preneoplastic clonal expansion: (1) absence or reduction of Fhit leads to reduced expression of Fdxr and reduced ROS-induced apoptosis; (2) cells that escape ROS- or replicative stress-induced apoptosis can carry misrepaired DNA damage. The aberrant DNA damage response checkpoint in Fhit-deficient preneoplasias and cancers may make these lesions targets for inhibitors of proteins such as Parp1 and Chk1 with important roles in checkpoint responses, as observed for BRCA1-deficient cancer cells that also exhibit DNA damage repair deficiencies.
Collapse
Affiliation(s)
- Hiroshi Okumura
- Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | | | | | | | | | | |
Collapse
|
|
46
|
Mimori K, Ishii H, Inoue H, Barnard GF, Mori M. Identification of the expression profile of apoptotic esophageal cancer cells by adenoviral-fragile histidine triad treatment. J Gastroenterol Hepatol 2008; 23 Suppl 2:S205-9. [PMID: 19120899 DOI: 10.1111/j.1440-1746.2008.05439.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The fragile histidine triad (FHIT) functions as a tumor suppressor, and giving adenoviral-FHIT (Ad-FHIT) is thus expected to be clinically beneficial. Much attention has recently been focused on which genes are commonly regulated by Ad-FHIT, and which genes are dominant in Ad-FHIT-induced apoptotic cells. METHODS Ad-FHIT apoptosis-induced cells (H1299 and TE4) and non-apoptosis-induced cells (TE2) were used in the current experiments. The total RNA extracted from Ad-FHIT or control was labeled with Cy3-dCTP or Cy5-dCTP and hybridized with 19,192 genes on a chip. A microarray analysis for each gene was carried out with high reproducibility provided by seven independent experiments and duplicated oligos on a chip. RESULTS We listed the upregulated genes based on the TE4:TE2 expression ratio, such as c-Src, Jak-1, and sialyltransferase, which are expected to be target pathways as well as the downregulated genes, including CASP8 and CASP10, after Ad-FHIT treatment in esophageal cancer. CONCLUSIONS The current microarray analysis indicated that the apoptosis of esophageal cancer observed after giving Ad-FHIT was possibly induced by activation of the c-Src gene and inactivation of the CASP8 gene.
Collapse
Affiliation(s)
- Koshi Mimori
- Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
| | | | | | | | | |
Collapse
|
|
47
|
Liu F, Wu JZ, Li F, Li Y, Li J. Effect of fragile histidine triad gene on biologic properties of muco-epidermoid carcinoma cells. Cytotherapy 2008; 10:753-8. [PMID: 18985481 DOI: 10.1080/14653240802357049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND The fragile histidine triad (FHIT) gene is abnormally expressed in many kinds of tumors and plays an important role in tumor development. However, the function of the FHIT gene in muco-epidermoid carcinoma (MEC) is still unknown. This study aimed to investigate the effect of exogenous FHIT gene on the biologic properties of MEC cells. METHODS Wild-type FHIT gene was transferred into MEC-1 cells. The in vitro proliferation, clone formation ability and apoptosis of FHIT-transfected MEC-1 cells (MEC-FHITc4) were examined by cell counting, clonal forming assay, immunochemical staining, histochemical staining, flow cytometry analysis and transmission electron microscopy. The tumorigenicity of MEC-FHITc4 cells was observed by in vivo study in nude mice. RESULTS In vitro study showed that the population doubling times of MEC-1 and MEC-FHITc4 cells were 21.03 h and 26.86 h, respectively. FHIT gene transfer reduced the percentage of cells in cell cycle S phase (3.8%) and kept more cells in the G(1) phase (62.4%). Additionally, the clonal forming rates of MEC-1 and MEC-FHITc4 were 17.9+/-0.87% and 12.3+/-0.02%, respectively. In a 4-week tumor growth study in nude mice, FHIT transfection suppressed the tumor growth by 70.1+/-0.38%. Interestingly, MEC-FHITc4 cells were stained more strongly with Alician Blue and Periodic Schiffs than control cells. DISCUSSION The FHIT gene might function to inhibit the proliferation and tumorigenicity of MEC-1 cells, and to induce the differentiation of MEC-1 cells, in vitro and in vivo.
Collapse
Affiliation(s)
- F Liu
- Department of Oral Biology, College of Stomatology, Fourth Military Medical University, Xi'an,Shaanxi Province, China.
| | | | | | | | | |
Collapse
|
|
48
|
Gray SE, Kay E, Leader M, Mabruk M. Analysis ofFHITallelic imbalance/loss of heterozygosity and FHIT expression in cutaneous squamous cell carcinomas. J Cutan Pathol 2008; 35:816-25. [DOI: 10.1111/j.1600-0560.2007.00913.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
|
49
|
Abstract
Lung cancer is the leading cause of cancer-related death and thus a major health problem. The efficiency of current treatment modalities for lung cancer depends strongly on the time of diagnosis, with better chances of survival if a tumor has been detected at an early stage. Thus, there is an urgent need for rapid and efficient early detection methods. Biomarkers represent a possible alternative to current, rather expensive, screening tools such as spiral computer tomography (CT), or may allow the identification of high risk groups for whom screening would be cost efficient. Although most lung cancers are the consequence of smoking, a substantial fraction of molecular-epidemiological studies point to high-prevalence, low-penetrance genetic polymorphisms as modifiers of environmental lung cancer risk. In the past the genomics field has also made significant advances in identifying genetic lesions that can now be harvested with the goal of identifying novel biomarkers for lung cancer. Furthermore, the importance of epigenetic changes that occur during lung cancer development has been reported, but has been underestimated in the past. Novel high-throughput, quantitative assays for the detection of DNA methylation or histone tail modifications are now applied, to search for alterations in the lung cancer genome and will identify novel cancer-related genes that may become attractive targets for treatment, provide new insight into the biology of lung cancers, and could also become useful biomarkers for the early detection of lung cancer in sputum, or may be used as prognostic markers. Thus, an integrative approach in lung cancer research combining epidemiological, genetic and epigenetic information becomes an important concept for the future.
Collapse
Affiliation(s)
- Angela Risch
- German Cancer Research Center, Division of Epigenomics and Cancer Risk Factors, Heidelberg, Germany
| | | |
Collapse
|
|
50
|
Abstract
A few signaling pathways are driving the growth of hepatocellular carcinoma. Each of these pathways possesses negative regulators. These enzymes, which normally suppress unchecked cell proliferation, are circumvented in the oncogenic process, either the over-activity of oncogenes is sufficient to annihilate the activity of tumor suppressors or tumor suppressors have been rendered ineffective. The loss of several key tumor suppressors has been described in hepatocellular carcinoma. Here, we systematically review the evidence implicating tumor suppressors in the development of hepatocellular carcinoma.
Collapse
|