|
1
|
Perumal N, Gopalakrishnan P, Burkovetskaya M, Doss D, Dukkipati SS, Kanchan RK, Mahapatra S. Nuclear factor I/B: Duality in action in cancer pathophysiology. Cancer Lett 2025; 609:217349. [PMID: 39581218 DOI: 10.1016/j.canlet.2024.217349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 11/15/2024] [Accepted: 11/21/2024] [Indexed: 11/26/2024]
Abstract
The nuclear factor I (NFI) family of transcription factors plays a decisive role in organ development and maturation. Their deregulation has been linked with various diseases, most notably cancer. NFIB stands apart from the other NFI family members given its unique ability to drive both tumor suppressive and oncogenic programs. Thus, the ultimate impact of deregulated NFIB signaling is cancer-specific and strongly influenced by an intricate network of upstream regulators and downstream effectors. Deciphering the events that drive NFIB's paradoxical roles within these networks will enable us to not only understand how this critical transcription factor enacts its dual roles but also drive innovations to help us effectively target NFIB in different cancers. Here, we provide an in-depth review of NFIB. Starting with its defining role in the development of various organs, most notably the central nervous system, we highlight critical signaling pathways and the impact of deregulation on neoplastic transformation, contrasting it with the effect of silencing alone. We then provide examples of its dual roles in various cancers, identifying specific signaling networks associated with oncogenesis versus tumor suppression. We incorporate an example of a cancer type, osteosarcoma, wherein NFIB enacts its dual functions and explore which pathways influence each function. In this manner, we suggest plausible mechanisms for its role-switching from cancers sharing common triggering events in the setting of NFIB deregulation. We also review how NFIB enhances aggressiveness by driving metastasis, stemness, and chemoresistance. We conclude with a discussion on efficacious ways to target NFIB and pose some unanswered questions that may further help solidify our understanding of NFIB and facilitate clinical translation of NFIB targeting.
Collapse
Affiliation(s)
- Naveenkumar Perumal
- School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Prakadeeswari Gopalakrishnan
- Department of Ophthalmology, Center for Translational Vision Research, Gavin Herbert Eye Institute, University of California, Irvine, CA, USA
| | - Maria Burkovetskaya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - David Doss
- School of Medicine, Creighton University, Omaha, NE, USA
| | - S Shekar Dukkipati
- Department of Pediatrics, Columbia University Irving Medical Center, New York City, NY, USA
| | - Ranjana K Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA.
| |
Collapse
|
|
2
|
Pu J, Yan X, Zhang H. The potential of circular RNAs as biomarkers and therapeutic targets for gastric cancer: A comprehensive review. J Adv Res 2024:S2090-1232(24)00551-4. [PMID: 39617262 DOI: 10.1016/j.jare.2024.11.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 11/22/2024] [Accepted: 11/26/2024] [Indexed: 12/08/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is a global health concern, contributing significantly to cancer-related mortality rates. Early detection is vital for improving patient outcomes. Recently, circular RNAs (circRNAs) have emerged as crucial players in the development and progression of various cancers, including GC. AIM This comprehensive review underscores the promising potential of circRNAs as innovative biomarkers for the early diagnosis of GC, as well as their possible utility as therapeutic targets for this life-threatening disease. Specifically, the review focuses on recent findings, mechanistic insights, and clinical applications of circRNAs in GC. KEY SCIENTIFIC CONCEPTS OF REVIEW Dysregulation of circRNAs has been consistently observed in GC tissues, offering potential diagnostic value due to their stability in bodily fluids such as blood and urine. For instance, circPTPN22 and hsa_circ_000200. Furthermore, the expression levels of circRNAs such as circCUL2, hsa_circ_0000705 and circSHKBP1 have shown strong associations with critical clinical features of GC, including diagnosis, prognosis, tumor size, lymph node metastasis, tumor-node-metastasis (TNM) stage, and treatment response. Additionally, circRNAs such as circBGN, circLMO7, and circMAP7D1 have shown interactions with specific microRNAs (miRNAs), proteins, and other molecules that play key roles in development and progression of GC. This further highlighting their potential as therapeutic targets. Despite their potential, several challenges need to be addressed to effectively apply circRNAs as GC biomarkers. These include standardizing detection methods, establishing cutoff values for diagnostic accuracy, and validating findings in larger patient cohorts. Moreover, the functional mechanisms by which circRNAs contribute to GC pathogenesis and therapeutic resistance warrant further investigation. Advances in circRNAs research could provide valuable insights into the early detection and targeted treatment of GC, ultimately improving patient outcomes.
Collapse
Affiliation(s)
- Junlin Pu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiuli Yan
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
| | - Hui Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| |
Collapse
|
|
3
|
Goh JY, Rueda P, Taylor J, Rathbone A, Scott D, Langmead CJ, Fone KC, Stewart GD, King MV. Transcriptomic analysis of rat prefrontal cortex following chronic stress induced by social isolation - Relevance to psychiatric and neurodevelopmental illness, and implications for treatment. Neurobiol Stress 2024; 33:100679. [PMID: 39502833 PMCID: PMC11536066 DOI: 10.1016/j.ynstr.2024.100679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/27/2024] [Accepted: 10/10/2024] [Indexed: 11/08/2024] Open
Abstract
Social isolation is an established risk factor for psychiatric illness, and became increasingly topical with the spread of SARS-CoV-2. We used RNA sequencing (RNA-Seq) to enable unbiased assessment of transcriptomic changes within the prefrontal cortex (PFC) of isolation-reared rats. To provide insight into the relevance of this manipulation for studying human illness, we compared differentially expressed genes (DEGs) and enriched biological functions against datasets involving post-mortem frontal cortical tissue from patients with psychiatric and neurodevelopmental illnesses. Sixteen male Sprague-Dawley rats were reared in groups of four or individually from weaning on postnatal day (PND) 22-24 until PFC tissue collection for RNA-Seq (PND64-66). We identified a total of 183 DEGs in isolates, of which 128 mirrored those in PFC tissue from patients with stress-related mental illnesses and/or neurodevelopmental conditions featuring social deficits. Seventy-one encode proteins classed as druggable by the gene-drug interaction database. Interestingly there are antagonists or inhibitors for the products of three of these up-regulated DEGs (Hrh3, Snca and Sod1) and agonists or activators for products of six of these down-regulated DEGs (Chrm4, Klf2, Lrrk2, Nr4a1, Nr4a3 and Prkca). Some have already undergone pre-clinical and clinical evaluation, and studies with the remainder may be warranted. Changes to Hrh3, Sod1, Chrm4, Lrrk2, Nr4a1 and Prkca were replicated in an independent cohort of sixteen male Sprague-Dawley rats via quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our findings support the continued use of post-weaning isolation rearing to investigate the neurobiology of stress-related disorders and evaluate therapeutic targets.
Collapse
Affiliation(s)
- Jen-Yin Goh
- Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Patricia Rueda
- Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Joy Taylor
- School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Alex Rathbone
- School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Daniel Scott
- School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Christopher J. Langmead
- Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Kevin C.F. Fone
- School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Gregory D. Stewart
- Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Madeleine V. King
- School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| |
Collapse
|
|
4
|
Cardus DF, Smith MT, Vernaza A, Smith JL, Del Buono B, Parajuli A, Lewis EG, Mesa-Diaz N, Du L. Systematic Analysis of miR-506-3p Target Genes Identified Key Mediators of Its Differentiation-Inducing Function. Genes (Basel) 2024; 15:1268. [PMID: 39457392 PMCID: PMC11507652 DOI: 10.3390/genes15101268] [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: 07/31/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: miR-506-3p has been demonstrated to be a strong inducer of neuroblastoma cell differentiation, highlighting the potential of applying miR-506-3p mimics to neuroblastoma differentiation therapy. However, the target genes of miR-506-3p that mediate its differentiation-inducing function have not been fully defined. This study aims to comprehensively investigate the targetome of miR-506-3p regarding its role in regulating neuroblastoma cell differentiation. Methods: We combined gene expression profiling and functional high-content screening (HCS) to identify miR-506-3p target genes that have differentiation-modulating functions. For evaluating the potential clinical relevance of the identified genes, we analyzed the correlations of gene expressions with neuroblastoma patient survival. Results: We identified a group of 19 target genes with their knockdown significantly inducing cell differentiation, suggesting that these genes play a key role in mediating the differentiation-inducing activity of miR-506-3p. We observed significant correlations of higher mRNA levels with lower patient survival with 13 of the 19 genes, suggesting that overexpression of these 13 genes plays important roles in promoting neuroblastoma development by disrupting the cell differentiation pathways. Conclusions: Through this study, we identified novel target genes of miR-506-3p that function as strong modulators of neuroblastoma cell differentiation. Our findings represent a significant advancement in understanding the mechanisms by which miR-506-3p induces neuroblastoma cell differentiation. Future investigations of the identified 13 genes are needed to fully define their functions and mechanisms in controlling neuroblastoma cell differentiation, the understanding of which may reveal additional targets for developing novel differentiation therapeutic agents.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Liqin Du
- Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA (M.T.S.); (A.V.); (J.L.S.); (B.D.B.); (A.P.); (E.G.L.)
| |
Collapse
|
|
5
|
Yu H, Liu P, Chen T. CircIFFO1 suppresses tumor growth and metastasis of cutaneous squamous cell carcinoma by targeting the miR-424-5p/NFIB axis. Arch Dermatol Res 2023; 315:2585-2596. [PMID: 37405427 DOI: 10.1007/s00403-023-02659-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/14/2023] [Accepted: 06/18/2023] [Indexed: 07/06/2023]
Abstract
Cutaneous squamous cell carcinoma (CSCC) is a severe malignancy derived from the skin. Circular RNAs (circRNAs) play an important role in the pathological process of many malignant tumors. Moreover, circIFFO1 is reported to be down-regulated in CSCC tissues compared with non-lesional skin tissues. This study aimed to explore the specific role and potential mechanism of circIFFO1 in CSCC progression. Cell proliferation ability was analyzed by 3-(4, 5-dimethylthiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU) incorporation, and colony-formation assays. Cell cycle progression and apoptosis were detected by flow cytometry. Cell migration and invasion were examined by transwell assays. The interaction between microRNA-424-5p (miR-424-5p) and circIFFO1 or nuclear factor I/B (NFIB) was validated by dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation (RIP) assays. Xenograft tumor assay and immunohistochemistry (IHC) assay were employed to analyze the tumorigenesis in vivo. CircIFFO1 level was down-regulated in CSCC tissues and cell lines. CircIFFO1 overexpression suppressed the proliferation, migration, invasion, and promoted apoptosis of CSCC cells. CircIFFO1 acted as a molecular sponge for miR-424-5p. The anti-tumor effects mediated by circIFFO1 overexpression in CSCC cells could be reversed by miR-424-5p overexpression. miR-424-5p interacted with the 3' untranslated region (3'UTR) of Nuclear Factor I/B (NFIB). miR-424-5p knockdown suppressed the malignant behaviors of CSCC cells, and NFIB knockdown counteracted the anti-tumor effects of miR-424-5p absence in CSCC cells. Additionally, circIFFO1 overexpression restrained xenograft tumor growth in vivo. CircIFFO1 suppressed the malignant behaviors of CSCC by mediating the miR-424-5p/NFIB axis, which provided new insights into the pathogenesis of CSCC.
Collapse
Affiliation(s)
- Hui Yu
- Department of Pathology, Huangdao District Central Hospital, Qingdao, China
| | - Penglin Liu
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tianli Chen
- Department of Dermatology, Huangdao District Central Hospital, No. 9 Huangpujiang Road, Huangdao District, Qingdao City, 266555, Shandong Province, China.
| |
Collapse
|
|
6
|
Zhou L, Liu H, Chen Z, Chen S, Lu J, Liu C, Liao S, He S, Chen S, Zhou Z. Downregulation of miR-182-5p by NFIB promotes NAD+ salvage synthesis in colorectal cancer by targeting NAMPT. Commun Biol 2023; 6:775. [PMID: 37491379 PMCID: PMC10368701 DOI: 10.1038/s42003-023-05143-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 07/13/2023] [Indexed: 07/27/2023] Open
Abstract
Nuclear factor I B (NFIB) plays an important role in tumors. Our previous study found that NFIB can promote colorectal cancer (CRC) cell proliferation in acidic environments. However, its biological functions and the underlying mechanism in CRC are incompletely understood. Nicotinamide adenine dinucleotide (NAD+) effectively affects cancer cell proliferation. Nevertheless, the regulatory mechanism of NAD+ synthesis in cancer remains to be elucidated. Here we show NFIB promotes CRC proliferation in vitro and growth in vivo, and down-regulation of NFIB can reduce the level of NAD+. In addition, supplementation of NAD+ precursor NMN can recapture cell proliferation in CRC cells with NFIB knockdown. Mechanistically, we identified that NFIB promotes CRC cell proliferation by inhibiting miRNA-182-5p targeting and binding to NAMPT, the NAD+ salvage synthetic rate-limiting enzyme. Our results delineate a combination of high expression of NFIB and NAMPT predicted a clinical poorest prognosis. This work provides potential therapeutic targets for CRC treatment.
Collapse
Affiliation(s)
- Li Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Hongtao Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Zhiji Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Siyuan Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Junyu Lu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Cao Liu
- Department of Emergency, The General Hospital of Xinjiang Military Command, Urumqi, 830000, China
| | - Siqi Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Song He
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Shu Chen
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
| | - Zhihang Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
| |
Collapse
|
|
7
|
Zhou L, Mao LH, Li X, Wang QL, Chen SY, Chen ZJ, Lei J, Liu HT, Liao SQ, Ran T, Li XQ, Zhou ZH, He S. Transcriptional regulation of NDUFA4L2 by NFIB induces sorafenib resistance by decreasing reactive oxygen species in hepatocellular carcinoma. Cancer Sci 2023; 114:793-805. [PMID: 36369883 PMCID: PMC9986074 DOI: 10.1111/cas.15648] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 11/02/2022] [Indexed: 11/15/2022] Open
Abstract
Sorafenib is one a first-line therapeutic drugs for advanced hepatocellular carcinoma (HCC). However, only 30% of patients benefit from sorafenib due to drug resistance. We and other groups have revealed that nuclear factor I B (NFIB) regulates liver regeneration and carcinogenesis, but its role in drug resistance is poorly known. We found that NFIB was more upregulated in sorafenib-resistant SMMC-7721 cells compared to parental cells. NFIB knockdown not only sensitized drug-resistant cells to sorafenib but also inhibited the proliferation and invasion of these cells. Meanwhile, NFIB promoted the proliferation and invasion of HCC cells in vitro and facilitated tumor growth and metastasis in vivo. Knocking down NFIB synergetically inhibited tumor growth with sorafenib. Mechanically, gene expression profiling and subsequent verification experiments proved that NFIB could bind with the promoter region of a complex I inhibitor NDUFA4L2 and promote its transcription. Transcriptional upregulation of NDUFA4L2 by NFIB could thus inhibit the sorafenib-induced reactive oxygen species accumulation. Finally, we found that NFIB was highly expressed in HCC tissues, and high NFIB expression level was associated with macrovascular invasion, advanced tumor stage, and poor prognosis of HCC patients (n = 156). In summary, we demonstrated that NFIB could transcriptionally upregulate NDUFA4L2 to enhance both intrinsic and acquired sorafenib resistance of HCC cells by reducing reactive oxygen species induction.
Collapse
Affiliation(s)
- Li Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin-Hong Mao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Gastroenterology, Chengdu Second People's Hospital, Sichuan, China
| | - Xia Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qing-Liang Wang
- Department of Pathology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Si-Yuan Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Ji Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Lei
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hong-Tao Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Si-Qi Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tao Ran
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiao-Qin Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Hang Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Song He
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
8
|
Chen Y, Zhang Y. CircDLG1 promotes malignant development of non-small cell lung cancer through regulation of the miR-630/CENPF axis. Strahlenther Onkol 2023; 199:169-181. [PMID: 35748916 DOI: 10.1007/s00066-022-01965-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 05/22/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND Circular RNAs (circRNAs) have been reported to be crucial modulatory molecules in the etiology of non-small cell lung cancer (NSCLC). This study aimed to probe the precise role and mechanism of circRNA discs large MAGUK scaffold protein 1 (circDLG1) in the malignant progression of NSCLC. METHODS The abundances of circDLG1, miR-630, and centromere protein F (CENPF) mRNAs were gauged by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was tested in 3‑(4, 5‑dimethylthiazol-2-yl)-2, 5‑diphenyltetrazolium bromide (MTT) assay and 5‑ethynyl-2'-deoxyuridine (EdU)-incorporation assay. Cell apoptosis was analyzed by flow cytometry. Cell migration and invasion were assessed by transwell assay. Western blot was exploited to examine the levels of all proteins. The interaction between miR-630 and circDLG1 or CENPF was verified by dual-luciferase reporter, RNA pull-down, and/or RNA immunoprecipitation assays. Tumor xenograft assay and immunohistochemistry (IHC) were executed for the role of circDLG1 in tumor growth in vivo. RESULTS CircDLG1 and CENPF were highly expressed in NSCLC, while miR-630 was downregulated. CircDLG1 silencing repressed proliferation, migration, and invasion, and expedited apoptosis of NSCLC cells in vitro. Mechanistically, circDLG1 deficiency modulated NSCLC cell malignant development through interacting with miR-630. Furthermore, CENPF was targeted by miR-630, and circDLG1 could positively control CENPF expression through acting as an miR-630 sponge. Furthermore, CENPF overexpression reversed the repressive impacts of circDLG1 inhibition in the malignant behaviors of NSCLC cells. Besides, circDLG1 interference hindered tumor growth in vivo. CONCLUSION CircDLG1 knockdown could impede NSCLC advancement through modulating the miR-630/CENPF axis, manifesting as a promising molecular target for NSCLC treatment.
Collapse
Affiliation(s)
- Yingying Chen
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Ying Zhang
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, No. 39 Huaxiang Road, 110022, Tiexi District, Shenyang, Liaoning Province, China.
| |
Collapse
|
|
9
|
Ingelman-Sundberg M. Cytochrome P450 polymorphism: From evolution to clinical use. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2022; 95:393-416. [PMID: 35953162 DOI: 10.1016/bs.apha.2022.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
The cytochromes P450s can be divided in two groups, those of high importance for endogenous functions being evolutionary quite stable and those participating in detoxification of drugs and other xenobiotics having less important endogenous functions. In the latter group extensive genetic diversity has been allowed and in addition this is of high importance for survival in different environments. The genetic polymorphisms in these genes have evolved to some extent based on dietary restrictions and environmental factors and have not been subject of conservation due to less importance for survival. In cases of high dietary selection events, gene multiplication and amplification events have been seen. The different variants in genes encoding drug metabolizing enzymes can be used as genetic biomarkers (pharmacogenomic labels) for adjustment of drug treatment leading to less adverse drug reactions and better response. Indeed, this has improved the use of personalized medicine, although the missing heredity seen based on twin studies indicates that there are indeed many more genetic variants to be discovered before one can achieve a satisfactory relationship between genotype and phenotype with respect to drug metabolism and toxicity.
Collapse
Affiliation(s)
- Magnus Ingelman-Sundberg
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institute, Stockholm, Sweden.
| |
Collapse
|
|
10
|
Zhou L, Wang QL, Mao LH, Chen SY, Yang ZH, Liu X, Gao YH, Li XQ, Zhou ZH, He S. Hepatocyte-Specific Knock-Out of Nfib Aggravates Hepatocellular Tumorigenesis via Enhancing Urea Cycle. Front Mol Biosci 2022; 9:875324. [PMID: 35655758 PMCID: PMC9152321 DOI: 10.3389/fmolb.2022.875324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 03/28/2022] [Indexed: 12/23/2022] Open
Abstract
Nuclear Factor I B (NFIB) has been reported to promote tumor growth, metastasis, and liver regeneration, but its mechanism in liver cancer is not fully elucidated. The present study aims to reveal the role of NFIB in hepatocellular carcinogenesis. In our study, we constructed hepatocyte-specific NFIB gene knockout mice with CRISPR/Cas9 technology (Nfib-/-; Alb-cre), and induced liver cancer mouse model by intraperitoneal injection of DEN/CCl4. First, we found that Nfib-/- mice developed more tumor nodules and had heavier livers than wild-type mice. H&E staining indicated that the liver histological severity of Nfib-/- group was more serious than that of WT group. Then we found that the differentially expressed genes in the tumor tissue between Nfib-/- mice and wild type mice were enriched in urea cycle. Furthermore, ASS1 and CPS1, the core enzymes of the urea cycle, were significantly upregulated in Nfib-/- tumors. Subsequently, we validated that the expression of ASS1 and CPS1 increased after knockdown of NFIB by lentivirus in normal hepatocytes and also promoted cell proliferation in vitro. In addition, ChIP assay confirmed that NFIB can bind with promoter region of both ASS1 and CPS1 gene. Our study reveals for the first time that hepatocyte-specific knock-out of Nfib aggravates hepatocellular tumor development by enhancing the urea cycle.
Collapse
Affiliation(s)
- Li Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qing-Liang Wang
- Department of Pathology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin-Hong Mao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Gastroenterology, Chengdu Second People's Hospital, Sichuan, China
| | - Si-Yuan Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zi-Han Yang
- Department of Biomedical Science, City University of Hong Kong, Hong Kong, China
| | - Xue Liu
- Department of Pathology, College of Basic Medicine, Jining Medical University, Jining, China
| | - Yu-Hua Gao
- Key Laboratory of Precision Oncology in Universities of Shandong, Institute of Precision Medicine, Jining Medical University, Jining, China
| | - Xiao-Qin Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Hang Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Song He
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
11
|
Ingelman-Sundberg M. The missing heritability in pharmacogenomics: role of NFIB and other factors. Pharmacogenomics 2022; 23:453-455. [PMID: 35546341 DOI: 10.2217/pgs-2022-0054] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Magnus Ingelman-Sundberg
- Department of Physiology & Pharmacology, Section of Pharmacogenetics, Biomedicum 5B, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| |
Collapse
|
|
12
|
Lenk HÇ, Klöditz K, Johansson I, Smith RL, Jukić MM, Molden E, Ingelman-Sundberg M. The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients. Clin Pharmacol Ther 2022; 111:1165-1174. [PMID: 35253216 PMCID: PMC9314634 DOI: 10.1002/cpt.2571] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/21/2022] [Indexed: 12/02/2022]
Abstract
The genetic background for interindividual variability of the polymorphic CYP2D6 enzyme activity remains incompletely understood and the role of NFIB genetic polymorphism for this variability was evaluated in this translational study. We investigated the effect of NFIB expression in vitro using 3D liver spheroids, Huh7 cells, and the influence of the NFIB polymorphism on metabolism of risperidone in patients in vivo. We found that NFIB regulates several important pharmacogenes, including CYP2D6. NFIB inhibited CYP2D6 gene expression in Huh7 cells and NFIB expression in livers was predominantly nuclear and reduced at the mRNA and protein level in carriers of the NFIB rs28379954 T>C allele. Based on 604 risperidone treated patients genotyped for CYP2D6 and NFIB, we found that the rate of risperidone hydroxylation was elevated in NFIB rs28379954 T>C carriers among CYP2D6 normal metabolizers, resulting in a similar rate of drug metabolism to what is observed in CYP2D6 ultrarapid metabolizers, with no such effect observed in CYP2D6 poor metabolizers lacking functional enzyme. The results indicate that NFIB constitutes a novel nuclear factor in the regulation of cytochrome P450 genes, and that its polymorphism is a predictor for the rate of CYP2D6 dependent drug metabolism in vivo.
Collapse
Affiliation(s)
- Hasan Çağın Lenk
- Center for Psychopharmacology, Diakonhjemmet Hospital, Vinderen, Oslo, Norway.,Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Katharina Klöditz
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden
| | - Inger Johansson
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden
| | - Robert Løvsletten Smith
- Center for Psychopharmacology, Diakonhjemmet Hospital, Vinderen, Oslo, Norway.,NORMENT, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Marin M Jukić
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.,Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Espen Molden
- Center for Psychopharmacology, Diakonhjemmet Hospital, Vinderen, Oslo, Norway.,Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Magnus Ingelman-Sundberg
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
13
|
Tang SY, Zhou PJ, Meng Y, Zeng FR, Deng GT. Gastric cancer: An epigenetic view. World J Gastrointest Oncol 2022; 14:90-109. [PMID: 35116105 PMCID: PMC8790429 DOI: 10.4251/wjgo.v14.i1.90] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/17/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) poses a serious threat worldwide with unfavorable prognosis mainly due to late diagnosis and limited therapies. Therefore, precise molecular classification and search for potential targets are required for diagnosis and treatment, as GC is complicated and heterogeneous in nature. Accumulating evidence indicates that epigenetics plays a vital role in gastric carcinogenesis and progression, including histone modifications, DNA methylation and non-coding RNAs. Epigenetic biomarkers and drugs are currently under intensive evaluations to ensure efficient clinical utility in GC. In this review, key epigenetic alterations and related functions and mechanisms are summarized in GC. We focus on integration of existing epigenetic findings in GC for the bench-to-bedside translation of some pivotal epigenetic alterations into clinical practice and also describe the vacant field waiting for investigation.
Collapse
Affiliation(s)
- Si-Yuan Tang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Pei-Jun Zhou
- Cancer Research Institute, School of Basic Medicine Science, Central South University, School of Basic Medicine Science, Central South University 410008, Hunan Province, China
| | - Yu Meng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Fu-Rong Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Guang-Tong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| |
Collapse
|