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Zhao W, Liu Y, Hu Y, Zhang G. SOX4 accelerates intervertebral disc degeneration via EZH2/NRF2 pathway in response to mitochondrial ROS-dependent NLRP3 inflammasome activation in nucleus pulposus cells. J Transl Med 2025; 23:395. [PMID: 40181390 PMCID: PMC11969779 DOI: 10.1186/s12967-024-05913-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 11/22/2024] [Indexed: 04/05/2025] Open
Abstract
OBJECTIVE The transcription factor SRY-related HMG-box 4 (SOX4) has been implicated in intervertebral disc diseases. This study aimed to investigate the role of SOX4 in intervertebral disc degeneration (IDD) and explore the underlying molecular mechanisms. METHODS We established an IDD rat model via surgery and analyzed SOX4 expression using qRT-PCR and Western blotting. Histological evaluation, immunohistochemistry, and Safranin O staining assessed IDD progression. In vitro, an IDD cellular model was constructed using IL-1β-stimulated nucleus pulposus (NP) cells. SOX4 knockdown and overexpression experiments in NP cells examined SOX4 effects on ECM degradation, NLRP3-mediated pyroptosis, and mitochondrial ROS-dependent NLRP3 inflammasome activation. The involvement of the EZH2/NRF2 pathway in SOX4-mediated NLRP3 activation was also examined. RESULTS SOX4 expression was significantly increased in IDD rats and promoted IDD progression. Knockdown of SOX4 inhibited ECM degradation and NLRP3-mediated pyroptosis in NP cells. In vitro experiments showed that SOX4 promoted ECM degradation by upregulating MMPs and ADAMTS-5 expression, and suppressed collagen II and aggrecan synthesis. SOX4 knockdown inhibited NLRP3-mediated pyroptosis, while overexpression accelerated it in NP cells. Additionally, SOX4 was found to exacerbate mitochondrial ROS-dependent NLRP3 inflammasome activation in NP cells. Further investigation revealed that SOX4 enhanced NLRP3 inflammasome activation by upregulating EZH2 expression and modulating the EZH2/NRF2 pathway, with EZH2 inhibition attenuating SOX4-induced NLRP3 activation. CONCLUSION Our findings suggest that SOX4 accelerates IDD progression by promoting NLRP3 inflammasome activation via modulating the EZH2/NRF2 pathway, leading to NP cell pyroptosis and ECM degradation. Targeting SOX4 may represent a potential therapeutic strategy for treating IDD.
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Affiliation(s)
- Wenzhi Zhao
- Department of Traumatic Orthopedics, The Second Affiliated Hospital, Dalian Medical University, Dalian, 116011, China
| | - Yadong Liu
- Department of Spinal Surgery, Dalian Municipal Central Hospital, Dalian, 116033, China
| | - Yunxiang Hu
- Department of Spinal Surgery, Dalian Municipal Central Hospital, Dalian, 116033, China
| | - Guiqi Zhang
- Department of Spinal Surgery, Dalian Municipal Central Hospital, Dalian, 116033, China.
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Yao K, Yang M, Shu M, Wang T, Gao D, Zhou L, Wang G, Zhang Z, Tang J. SOX4 promotes vascular abnormality in glioblastoma and is a novel target to improve drug delivery. Transl Oncol 2024; 50:102120. [PMID: 39288695 PMCID: PMC11421337 DOI: 10.1016/j.tranon.2024.102120] [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: 05/31/2024] [Revised: 08/27/2024] [Accepted: 09/11/2024] [Indexed: 09/19/2024] Open
Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults with dismal prognosis. Vascular abnormality is a hallmark of GBM, and aggravates diseases progression by increasing hypoxia, inducing life-threaten edema and hindering drug delivery. Nonetheless, the intricate mechanism underlying vascular abnormality remains inadequately understood. Here, we revealed a key role of SOX4 on vascular abnormality in GBM. SOX4 expression was increased in endothelial cells (ECs) from human brain tumors compared with ECs from paired normal brain tissue. Knockdown of SOX4 in mouse brain ECs restrained cell migration and proliferation. Furthermore, in vitro suppression of SOX4 in brain ECs and in vivo conditional knockout of SOX4 in tumor ECs led to the downregulation of genes linked with vascular abnormality. Notably, specific depletion of SOX4 in ECs enhanced drug delivery and sensitive tumor to chemotherapeutic drugs in GBM. Taken together, these results demonstrated that SOX4 is a novel regulator for tumor angiogenesis and vascular abnormality in GBM. Our findings identify SOX4 as a potential vascular therapeutic target to improve drug delivery for GBM treatment.
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Affiliation(s)
- Kunhua Yao
- Department of Neurosurgery, First Affiliated Hospital of Hunan University of Medicine, Huaihua 418000, PR China
| | - Mingbiao Yang
- Department of Neurosurgery, First Affiliated Hospital of Hunan University of Medicine, Huaihua 418000, PR China
| | - Mi Shu
- Trauma Center, First Affiliated Hospital of Hunan University of Medicine, Huaihua 418000, PR China
| | - Tian Wang
- Department of Oncology, Xintai Hospital of Traditional Chinese Medicine, Tai'an, Shandong 271299,PR China
| | - Dan Gao
- Trauma Center, First Affiliated Hospital of Hunan University of Medicine, Huaihua 418000, PR China
| | - Liqi Zhou
- Trauma Center, First Affiliated Hospital of Hunan University of Medicine, Huaihua 418000, PR China
| | - Guangwei Wang
- Biomedical Research Center, Hunan University of Medicine, Huaihua 418000, PR China
| | - Zaiqi Zhang
- Hunan Provincial Key Laboratory of Dong Medicine, Hunan University of Medicine, Huaihua, Hunan 418000, PR China.
| | - Jiefu Tang
- Trauma Center, First Affiliated Hospital of Hunan University of Medicine, Huaihua 418000, PR China.
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Li Y, Kong M, Qiu T, Ji Y. Targeting ESM1 via SOX4 promotes the progression of infantile hemangioma through the PI3K/AKT signaling pathway. PRECISION CLINICAL MEDICINE 2024; 7:pbae026. [PMID: 39507292 PMCID: PMC11540160 DOI: 10.1093/pcmedi/pbae026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/22/2024] [Accepted: 10/07/2024] [Indexed: 11/08/2024] Open
Abstract
Background Infantile hemangioma (IH) is the most prevalent benign vascular tumor in children, yet its pathogenesis remains incompletely understood. Research has established a strong association between SOX4 and tumor blood vessel formation. The objective of this study was to investigate the function and underlying mechanism of SOX4 in IH development with the aim of identifying novel therapeutic targets. Methods We identified the transcription factor SOX4 associated with IH through RNA-seq screening of IH microtumors and validated it in IH tissues. The effect of SOX4 on the biological behavior of CD31+ hemangioma-derived endothelial cells (HemECs) was investigated via in vitro cell experiments. In addition, RNA-seq analysis was performed on CD31+ HemECs with low expression levels of SOX4, and the target genes of SOX4 were identified. Finally, the effect of SOX4 on tumor angiogenesis was further elucidated through 3D microtumor and animal experiments. Results SOX4 is highly expressed in IH tissues and promotes the proliferation, migration, and angiogenesis of CD31+ HemECs. In addition, SOX4 binds to the endothelial cell-specific molecule 1 (ESM1) promoter to promote the progression of the PI3K/AKT signaling pathway. Finally, through IH 3D microtumor and animal experiments, SOX4 and ESM1 are shown to be tumorigenic genes that independently promote tumor progression. Conclusions SOX4 plays a crucial role in the progression of IH, and the SOX4/ESM1 axis may serve as a novel biomarker and potential therapeutic target for IH.
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Affiliation(s)
- Yanan Li
- Division of Oncology, Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Meng Kong
- Division of Oncology, Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
- Department of Pediatric Surgery, Children's Hospital Affiliated to Shandong University, Jinan 25002, China
| | - Tong Qiu
- Division of Oncology, Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yi Ji
- Division of Oncology, Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
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Sheridan M, Maqbool MA, Largeot A, Clayfield L, Xu J, Moncaut N, Sellers R, Whittle J, Paggetti J, Iqbal M, Aucagne R, Delva L, Baker SM, Lie-A-Ling M, Kouskoff V, Lacaud G. The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency. J Hematol Oncol 2024; 17:91. [PMID: 39380002 PMCID: PMC11462755 DOI: 10.1186/s13045-024-01610-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 09/20/2024] [Indexed: 10/10/2024] Open
Abstract
BACKGROUND The epigenetic factors KAT6A (MOZ/MYST3) and KMT2A (MLL/MLL1) interact in normal hematopoiesis to regulate progenitors' self-renewal. Both proteins are recurrently translocated in AML, leading to impairment of critical differentiation pathways in these malignant cells. We evaluated the potential of different KAT6A therapeutic targeting strategies to alter the growth of KAT6A and KMT2A rearranged AMLs. METHODS We investigated the action and potential mechanisms of the first-in-class KAT6A inhibitor, WM-1119 in KAT6A and KMT2A rearranged (KAT6Ar and KMT2Ar) AML using cellular (flow cytometry, colony assays, cell growth) and molecular (shRNA knock-down, CRISPR knock-out, bulk and single-cell RNA-seq, ChIP-seq) assays. We also used two novel genetic murine KAT6A models combined with the most common KMT2Ar AML, KMT2A::MLLT3 AML. In these murine models, the catalytic activity of KAT6A, or the whole protein, can be conditionally abrogated or deleted. These models allowed us to compare the effects of specific KAT6A KAT activity inhibition with the complete deletion of the whole protein. Finally, we also tested these therapeutic approaches on human AML cell lines and primary patient AMLs. RESULTS We found that WM-1119 completely abrogated the proliferative and clonogenic potential of KAT6Ar cells in vitro. WM-1119 treatment was associated with a dramatic increase in myeloid differentiation program. The treatment also decreased stemness and leukemia pathways at the transcriptome level and led to loss of binding of the fusion protein at critical regulators of these pathways. In contrast, our pharmacologic and genetic results indicate that the catalytic activity of KAT6A plays a more limited role in KMT2Ar leukemogenicity, while targeting the whole KAT6A protein dramatically affects leukemic potential in murine KMT2A::MLLT3 AML. CONCLUSION Our study indicates that inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients. In contrast, targeted degradation of KAT6A, and not just its catalytic activity, may represent a more appropriate therapeutic approach for KMT2Ar AMLs.
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Affiliation(s)
- Mathew Sheridan
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Muhammad Ahmad Maqbool
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
- GSK Medicines Research Centre, Stevenage, UK
| | - Anne Largeot
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
- Department of Cancer Research, Tumor Stroma Interactions, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Liam Clayfield
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Jingru Xu
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Natalia Moncaut
- Genome Editing and Mouse Models, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Robert Sellers
- Computational Biology Support, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Jessica Whittle
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Jerome Paggetti
- Department of Cancer Research, Tumor Stroma Interactions, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Mudassar Iqbal
- Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Romain Aucagne
- UFR des Sciences de Santé, Inserm U1231, Université de Bourgogne, Team Epi2THM, LipSTIC Labex, Dijon, France
| | - Laurent Delva
- UFR des Sciences de Santé, Inserm U1231, Université de Bourgogne, Team Epi2THM, LipSTIC Labex, Dijon, France
| | - Syed Murtuza Baker
- Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Michael Lie-A-Ling
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Valerie Kouskoff
- Division of Developmental Biology and Medicine, The University of Manchester, Manchester, UK
| | - Georges Lacaud
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.
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Zou W, Li Y, Zhang J, Yang R, Yan Y, Zhang X, Yan L, Zhang Z, Zhang X, Chen J. Cancer-associated fibroblast-derived circFARP1 modulates non-small cell lung cancer invasion and metastasis through the circFARP1/miR-338-3p/SOX4 axis. Clin Exp Pharmacol Physiol 2024; 51:e13914. [PMID: 39139001 DOI: 10.1111/1440-1681.13914] [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: 12/28/2023] [Revised: 05/13/2024] [Accepted: 05/31/2024] [Indexed: 08/15/2024]
Abstract
The pleiotropic effect of cancer-associated fibroblasts (CAFs) on tumour progression depends on the environment. circFARP1 is critical for CAFs-induced gemcitabine (GEM) resistance in pancreatic cancer. Its specific role and mechanism in non-small cell lung cancer (NSCLC) have not been reported yet. We prepared a cancer-associated fibroblasts-conditioned medium (CAF-CM) to incubate the A549 cells. Quantitative real-time polymerase chain reaction was used to detect RNA levels. We detected protein expression by immunohistochemistry, immunocytochemistry, western blot and immunofluorescence. We also detected the targeting impact between circFARP1, miR-338-3p and SRY-box transcription factor 4 (SOX4) by using dual-luciferase reporter and RNA pull-down assays. We determined cell proliferation, migration and invasion capabilities through Cell Counting Kit-8 and transwell assays. In addition, we measured tumour volume and weight in vivo by establishing a xenograft tumour model. CircFARP1 levels were remarkably high in the CAFs. The transfection experiments found that circFARP1 downregulation in CAFs caused migration, proliferation and invasion inhibition of CAFs and A549 cells, whereas inhibiting miR-38-3p or overexpressing SOX4 in CAFs could significantly reverse the inhibition. In vivo study in nude mice confirmed that CAFs could promote NSCLC tumour growth and knockdown of circFARP1 could inhibit tumour growth of NSCLC, whereas miR-38-3p downregulation or SOX4 overexpression could significantly reverse the inhibition. circFARP1 promotes NSCLC development by stimulating miR-338-3p/SOX4 signalling axis to regulate CAFs.
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Affiliation(s)
- Wailong Zou
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Beijing, China
| | - Yulin Li
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Beijing, China
| | - Jia Zhang
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Beijing, China
| | - Rui Yang
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Beijing, China
| | - Yaxin Yan
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Beijing, China
| | - Xin Zhang
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Beijing, China
| | - Lei Yan
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Beijing, China
| | - Zhe Zhang
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Beijing, China
| | - Xinjun Zhang
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Beijing, China
| | - Jichao Chen
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Beijing, China
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Baldan J, Camacho-Roda J, Ballester M, Høj K, Kurilla A, Maurer HC, Arcila-Barrera S, Lin X, Pan Z, Castro JL, Mayorca-Guiliani AE, Rift CV, Hasselby J, Bouwens L, Lefebvre V, David CJ, Parnas O, DelGiorno KE, Erler JT, Rooman I, Arnes L. Resolution of Acinar Dedifferentiation Regulates Tissue Remodeling in Pancreatic Injury and Cancer Initiation. Gastroenterology 2024; 167:718-732.e18. [PMID: 38729450 DOI: 10.1053/j.gastro.2024.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 04/02/2024] [Accepted: 04/29/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND & AIMS Acinar-to-ductal metaplasia (ADM) is crucial in the development of pancreatic ductal adenocarcinoma. However, our understanding of the induction and resolution of ADM remains limited. We conducted comparative transcriptome analyses to identify conserved mechanisms of ADM in mouse and human. METHODS We identified Sox4 among the top up-regulated genes. We validated the analysis by RNA in situ hybridization. We performed experiments in mice with acinar-specific deletion of Sox4 (Ptf1a: CreER; Rosa26-LSL-YFPLSL-YFP; Sox4fl/fl) with and without an activating mutation in Kras (KrasLSL-G12D/+). Mice were given caerulein to induce pancreatitis. We performed phenotypic analysis by immunohistochemistry, tissue decellularization, and single-cell RNA sequencing. RESULTS We demonstrated that Sox4 is reactivated in ADM and pancreatic intraepithelial neoplasias. Contrary to findings in other tissues, Sox4 actually counteracts cellular dedifferentiation and helps maintain tissue homeostasis. Moreover, our investigations unveiled the indispensable role of Sox4 in the specification of mucin-producing cells and tuft-like cells from acinar cells. We identified Sox4-dependent non-cell-autonomous mechanisms regulating the stromal reaction during disease progression. Notably, Sox4-inferred targets are activated upon KRAS inactivation and tumor regression. CONCLUSIONS Our results indicate that our transcriptome analysis can be used to investigate conserved mechanisms of tissue injury. We demonstrate that Sox4 restrains acinar dedifferentiation and is necessary for the specification of acinar-derived metaplastic cells in pancreatic injury and cancer initiation and is activated upon Kras ablation and tumor regression in mice. By uncovering novel potential strategies to promote tissue homeostasis, our findings offer new avenues for preventing the development of pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Jonathan Baldan
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark; Translational Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
| | - Juan Camacho-Roda
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Marta Ballester
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Kristina Høj
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Anita Kurilla
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - H Carlo Maurer
- Department of Internal Medicine II, Technical University of Munich, Munich, Germany
| | - Sebastian Arcila-Barrera
- The Lautenberg Center for Immunology and Cancer Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Xinyi Lin
- Tsinghua University School of Medicine, Beijing, China; Peking University-Tsinghua Center for Life Sciences, Beijing, China
| | - Zhaolong Pan
- Translational Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Joana Leitão Castro
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | | | - Charlotte Vestrup Rift
- Department of Pathology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Jane Hasselby
- Department of Pathology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Luc Bouwens
- Cell Differentiation Lab, Vrije Universiteit Brussel, Brussels, Belgium
| | - Véronique Lefebvre
- Department of Surgery/Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Charles J David
- Tsinghua University School of Medicine, Beijing, China; Peking University-Tsinghua Center for Life Sciences, Beijing, China
| | - Oren Parnas
- The Lautenberg Center for Immunology and Cancer Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | | | - Janine Terra Erler
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Ilse Rooman
- Translational Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Luis Arnes
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
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Figueira MI, Carvalho TMA, Macário-Monteiro J, Cardoso HJ, Correia S, Vaz CV, Duarte AP, Socorro S. The Pros and Cons of Estrogens in Prostate Cancer: An Update with a Focus on Phytoestrogens. Biomedicines 2024; 12:1636. [PMID: 39200101 PMCID: PMC11351860 DOI: 10.3390/biomedicines12081636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/14/2024] [Accepted: 07/20/2024] [Indexed: 09/01/2024] Open
Abstract
The role of estrogens in prostate cancer (PCa) is shrouded in mystery, with its actions going from angelic to devilish. The findings by Huggins and Hodges establishing PCa as a hormone-sensitive cancer have provided the basis for using estrogens in therapy. However, despite the clinical efficacy in suppressing tumor growth and the panoply of experimental evidence describing its anticarcinogenic effects, estrogens were abolished from PCa treatment because of the adverse secondary effects. Notwithstanding, research work over the years has continued investigating the effects of estrogens, reporting their pros and cons in prostate carcinogenesis. In contrast with the beneficial therapeutic effects, many reports have implicated estrogens in the disruption of prostate cell fate and tissue homeostasis. On the other hand, epidemiological data demonstrating the lower incidence of PCa in Eastern countries associated with a higher consumption of phytoestrogens support the beneficial role of estrogens in counteracting cancer development. Many studies have investigated the effects of phytoestrogens and the underlying mechanisms of action, which may contribute to developing safe estrogen-based anti-PCa therapies. This review compiles the existing data on the anti- and protumorigenic actions of estrogens and summarizes the anticancer effects of several phytoestrogens, highlighting their promising features in PCa treatment.
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Affiliation(s)
| | | | | | | | | | | | | | - Sílvia Socorro
- CICS-UBI, Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6200-506 Covilhã, Portugal; (M.I.F.)
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He X, Zhang Y, Fang Q, Sun Y, Zheng X, Fu Y, Fan W, Yang L, Hong Y, Du Y, Wang Z, Chen L. Unraveling the role of CD24 in Hepatocellular carcinoma: Involvement of inactivated Hippo signaling and SOX4-mediated regulation. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167117. [PMID: 38462024 DOI: 10.1016/j.bbadis.2024.167117] [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: 07/12/2023] [Revised: 03/03/2024] [Accepted: 03/05/2024] [Indexed: 03/12/2024]
Abstract
Hepatocellular carcinoma (HCC) is a prevalent type of liver cancer, and CD24 gene is reportedly involved in HCC progression. However, the precise regulatory mechanisms of CD24 in HCC remain unclear. In this study, we established a primary HCC mouse model and observed that CD24, induced by inactivation of the Hippo pathway, was highly expressed in HCC. Using a systematic molecular and genomic approach, we identified the Hippo-YAP1-SOX4 pathway as the mechanism through which YAP1 induces CD24 upregulation in HCC cells. CD24 knockdown significantly attenuated YAP1 activation-induced HCC. These findings shed light on the link between CD24 and HCC progression, particularly in the Hippo-inactivated subclass of HCC. Therefore, CD24 may serve as a potential target for specific treatment of this HCC subclass.
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Affiliation(s)
- Xiaobai He
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China; Zhejiang Provincial Engineering Research Centre for Key Technology of Diagnostic Testing, Hangzhou, China; Zhejiang Provincial Key Laboratory of Biomarkers and In Vitro Diagnostics Translation, Hangzhou, China
| | - Yangyang Zhang
- Department of Clinical Laboratory, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Quan Fang
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Yue Sun
- Blood Transfusion Department, Grand Hospital of Shuozhou, Shuozhou, China
| | - Xiaoguang Zheng
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Yu Fu
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Weijiao Fan
- Institute of Clinical Medicine Research, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Leixiang Yang
- Department of Genetic and Genomic Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Yeting Hong
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Yaoqiang Du
- Allergy Center, Department of Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
| | - Zhen Wang
- Zhejiang Provincial Engineering Research Centre for Key Technology of Diagnostic Testing, Hangzhou, China; Allergy Center, Department of Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
| | - Linjie Chen
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China; Zhejiang Provincial Engineering Research Centre for Key Technology of Diagnostic Testing, Hangzhou, China; Zhejiang Provincial Key Laboratory of Biomarkers and In Vitro Diagnostics Translation, Hangzhou, China.
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9
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Abduh MS, Alwassil OI, Aldaqal SM, Alfwuaires MA, Farhan M, Hanieh H. A pyrazolopyridine as a novel AhR signaling activator with anti-breast cancer properties in vitro and in vivo. Biochem Pharmacol 2024; 222:116079. [PMID: 38402910 DOI: 10.1016/j.bcp.2024.116079] [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: 10/06/2023] [Revised: 01/29/2024] [Accepted: 02/22/2024] [Indexed: 02/27/2024]
Abstract
Breast cancer is one of the main causes of malignancy-related deaths globally and has a significant impact on women's quality of life. Despite significant therapeutic advances, there is a medical need for targeted therapies in breast cancer. Aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor mediates responses to environment stimuli, is emerging as a unique pleiotropic target. Herein, a combined molecular simulation and in vitro investigations identified 3-(3-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine (3FPP) as a novel AhR ligand in T47D and MDA-MB-231 breast cancer cells. Its agonistic effects induced formation of the AhR-AhR nuclear translocator (Arnt) heterodimer and prompted its binding to the penta-nucleotide sequence, called xenobiotic-responsive element (XRE) motif. Moreover, 3FPP augmented the promoter-driven luciferase activities and expression of AhR-regulated genes encoding cytochrome P450 1A1 (CYP1A1) and microRNA (miR)-212/132 cluster. It reduced cell viability, migration, and invasion of both cell lines through AhR signaling. These anticancer properties were concomitant with reduced levels of B-cell lymphoma 2 (BCL-2), SRY-related HMG-box4 (SOX4), snail family zinc finger 2 (SNAI2), and cadherin 2 (CDH2). In vivo, 3FPP suppressed tumor growth and activated AhR signaling in an orthotopic mouse model. In conclusion, our results introduce the fused pyrazolopyridine 3FPP as a novel AhR agonist with AhR-specific anti-breast cancer potential in vitro and in vivo.
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Affiliation(s)
- Maisa S Abduh
- Immune Responses in Different Diseases Research Group, Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Osama I Alwassil
- Department of Pharmaceutical Sciences, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh 11451, Saudi Arabia.
| | - Saleh M Aldaqal
- Immune Responses in Different Diseases Research Group, Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Manal A Alfwuaires
- Department of Biological Sciences, College of Science, King Faisal University, Hofuf 31982, Saudi Arabia.
| | - Mahdi Farhan
- International Medical Research Center (iMReC), Aqaba 77110, Jordan; Drug Development Department, UniTechPharma, Fribourg 1700, Switzerland.
| | - Hamza Hanieh
- International Medical Research Center (iMReC), Aqaba 77110, Jordan; Basic Medical Sciences Department, Faculty of Medicine, Aqaba Medical Sciences University, Aqaba 77110, Jordan.
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10
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Hu M, Li J, Fu Y, Xu E, Li D, Huang S, Tong D, Jin S, Guan T, Liu Y. Establishment and characterization of cisplatin-resistant cell lines from canine mammary gland tumors. Theriogenology 2024; 217:103-112. [PMID: 38271764 DOI: 10.1016/j.theriogenology.2024.01.017] [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: 10/06/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 01/27/2024]
Abstract
The development of cisplatin resistance is one of the major causes of mammary cancer treatment failure, and is associated with changes in Sox4 gene expression. To investigate the characteristic changes that occur in canine mammary gland tumor (CMGT) cells following the development of acquired cisplatin resistance, along with the relationship between these changes and the Sox4 gene. We constructed cisplatin-resistant cell line, CHMpCIS, from the cell line CHMp, which was isolated from the primary lesion of a malignant CMGT. The biological characteristics of these cells were examined by Western blot analysis, Transwell assays, and mammosphere formation assays. Compared to CHMp cells, CHMpCIS cells exhibited elevated cisplatin resistance, apoptotic escape ability, enhanced epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) features, in addition to over-activation of the Wnt/β-catenin signaling pathway and increased Sox4 protein. In CMGT cases, CMGT tissues (CMGTT) expressed higher levels of Sox4 protein and mRNA compared to adjacent tissues (CAMGTT). We found that these changes were inhibited by silencing of Sox4 expression in CHMpCIS cells. Furthermore, activation of the Wnt/β-catenin signaling pathway increased Sox4 expression levels through a positive feedback loop. These results suggested that CHMpCIS cells circumvented the damage caused by cisplatin through altering the expression of the Sox4 gene and activating the Wnt/β-catenin pathway, thereby changing the cellular biological characteristics.
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Affiliation(s)
- Mengxin Hu
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China; Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Jie Li
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Yunwei Fu
- University Hospital, Northeast Agricultural University, Harbin, 150030, China
| | - Enshuang Xu
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China; Department of Veterinary Surgery, College of Veterinary Medicine, Heilongjiang Bayi Land Reclamation University, Daqing, 163000, China
| | - Ding Li
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Siqi Huang
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Danning Tong
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Shengzi Jin
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Tongxu Guan
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Yun Liu
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China.
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11
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Bahmad HF, Thiravialingam A, Sriganeshan K, Gonzalez J, Alvarez V, Ocejo S, Abreu AR, Avellan R, Arzola AH, Hachem S, Poppiti R. Clinical Significance of SOX10 Expression in Human Pathology. Curr Issues Mol Biol 2023; 45:10131-10158. [PMID: 38132479 PMCID: PMC10742133 DOI: 10.3390/cimb45120633] [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: 11/20/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023] Open
Abstract
The embryonic development of neural crest cells and subsequent tissue differentiation are intricately regulated by specific transcription factors. Among these, SOX10, a member of the SOX gene family, stands out. Located on chromosome 22q13, the SOX10 gene encodes a transcription factor crucial for the differentiation, migration, and maintenance of tissues derived from neural crest cells. It plays a pivotal role in developing various tissues, including the central and peripheral nervous systems, melanocytes, chondrocytes, and odontoblasts. Mutations in SOX10 have been associated with congenital disorders such as Waardenburg-Shah Syndrome, PCWH syndrome, and Kallman syndrome, underscoring its clinical significance. Furthermore, SOX10 is implicated in neural and neuroectodermal tumors, such as melanoma, malignant peripheral nerve sheath tumors (MPNSTs), and schwannomas, influencing processes like proliferation, migration, and differentiation. In mesenchymal tumors, SOX10 expression serves as a valuable marker for distinguishing between different tumor types. Additionally, SOX10 has been identified in various epithelial neoplasms, including breast, ovarian, salivary gland, nasopharyngeal, and bladder cancers, presenting itself as a potential diagnostic and prognostic marker. However, despite these associations, further research is imperative to elucidate its precise role in these malignancies.
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Affiliation(s)
- Hisham F. Bahmad
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA;
| | - Aran Thiravialingam
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (A.T.); (K.S.); (J.G.); (S.O.); (A.R.A.); (R.A.); (A.H.A.)
| | - Karthik Sriganeshan
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (A.T.); (K.S.); (J.G.); (S.O.); (A.R.A.); (R.A.); (A.H.A.)
| | - Jeffrey Gonzalez
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (A.T.); (K.S.); (J.G.); (S.O.); (A.R.A.); (R.A.); (A.H.A.)
| | - Veronica Alvarez
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (A.T.); (K.S.); (J.G.); (S.O.); (A.R.A.); (R.A.); (A.H.A.)
| | - Stephanie Ocejo
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (A.T.); (K.S.); (J.G.); (S.O.); (A.R.A.); (R.A.); (A.H.A.)
| | - Alvaro R. Abreu
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (A.T.); (K.S.); (J.G.); (S.O.); (A.R.A.); (R.A.); (A.H.A.)
| | - Rima Avellan
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (A.T.); (K.S.); (J.G.); (S.O.); (A.R.A.); (R.A.); (A.H.A.)
| | - Alejandro H. Arzola
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (A.T.); (K.S.); (J.G.); (S.O.); (A.R.A.); (R.A.); (A.H.A.)
| | - Sana Hachem
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon;
| | - Robert Poppiti
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA;
- Department of Pathology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
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12
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Kuo CY, Hsu YC, Liu CL, Li YS, Chang SC, Cheng SP. SOX4 is a pivotal regulator of tumorigenesis in differentiated thyroid cancer. Mol Cell Endocrinol 2023; 578:112062. [PMID: 37673293 DOI: 10.1016/j.mce.2023.112062] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/30/2023] [Accepted: 09/02/2023] [Indexed: 09/08/2023]
Abstract
The SOX family consists of about 20 transcription factors involved in embryonic development, reprogramming, and cell fate determination. In this study, we demonstrated that SOX4 was significantly upregulated in differentiated thyroid cancer. Immunohistochemical analysis revealed that high SOX4 expression was associated with papillary histology, extrathyroidal extension, lymph node metastasis, and advanced disease stage. Patients whose tumors exhibited high SOX4 expression had a shorter recurrence-free survival, though significance was lost in multivariate Cox regression analysis. SOX4 silencing in thyroid cancer cells slowed cell growth, attenuated clonogenicity, and suppressed anoikis resistance. Additionally, SOX4 knockdown impeded xenograft tumor growth in nude mice. Knockdown of SOX4 expression was accompanied by reduced phosphorylation of AKT and ERK. Furthermore, CRABP2 expression correlated with SOX4 expression, and SOX4 silencing decreased CRABP2 expression and its downstream effectors such as integrin β1 and β4. These results indicate that SOX4 has both prognostic and therapeutic implications in differentiated thyroid cancer, and targeting SOX4 may modulate tumorigenic processes in the thyroid.
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Affiliation(s)
- Chi-Yu Kuo
- Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medicine, School of Medicine, MacKay Medical College, New Taipei City, Taiwan
| | - Yi-Chiung Hsu
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan City, Taiwan
| | - Chien-Liang Liu
- Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medicine, School of Medicine, MacKay Medical College, New Taipei City, Taiwan
| | - Ying-Syuan Li
- Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
| | - Shao-Chiang Chang
- Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
| | - Shih-Ping Cheng
- Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medicine, School of Medicine, MacKay Medical College, New Taipei City, Taiwan; Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan; Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan; Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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13
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Pinzaru AM, Tavazoie SF. Transfer RNAs as dynamic and critical regulators of cancer progression. Nat Rev Cancer 2023; 23:746-761. [PMID: 37814109 DOI: 10.1038/s41568-023-00611-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/28/2023] [Indexed: 10/11/2023]
Abstract
Transfer RNAs (tRNAs) have been historically viewed as non-dynamic adaptors that decode the genetic code into proteins. Recent work has uncovered dynamic regulatory roles for these fascinating molecules. Advances in tRNA detection methods have revealed that specific tRNAs can become modulated upon DNA copy number and chromatin alterations and can also be perturbed by oncogenic signalling and transcriptional regulators in cancer cells or the tumour microenvironment. Such alterations in the levels of specific tRNAs have been shown to causally impact cancer progression, including metastasis. Moreover, sequencing methods have identified tRNA-derived small RNAs that influence various aspects of cancer progression, such as cell proliferation and invasion, and could serve as diagnostic and prognostic biomarkers or putative therapeutic targets in various cancers. Finally, there is accumulating evidence, including from genetic models, that specific tRNA synthetases - the enzymes responsible for charging tRNAs with amino acids - can either promote or suppress tumour formation. In this Review, we provide an overview of how deregulation of tRNAs influences cancer formation and progression.
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Affiliation(s)
- Alexandra M Pinzaru
- Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA.
| | - Sohail F Tavazoie
- Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA.
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14
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Liang J, Bao D, Ye Z, Cao B, Jin G, Lu Z, Chen J. miR-3195 suppresses the malignant progression of osteosarcoma cells via targeting SOX4. J Orthop Surg Res 2023; 18:809. [PMID: 37904207 PMCID: PMC10614315 DOI: 10.1186/s13018-023-04321-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/25/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND Osteosarcoma (OS) is a highly invasive primary malignancy of the bone that is common in children and adolescents. MicroRNAs (miRNAs) are novel diagnostic and predictive biomarkers for cancers. The miRNA miR-3195 is aberrantly expressed in multiple types of tumors. However, the expression levels and biological functions of miR-3195 in OS remain unclear. METHODS Two Gene Expression Omnibus (GEO) datasets (GSE69470 and GSE16088) were used to analyze differentially expressed miRNAs and mRNAs in osteosarcoma cell lines and OS tissues. Quantitative RT-PCR was used to detect the expression levels of miR-3195 and the SRY-box transcription factor 4 (SOX4) mRNA in OS tissues and cell lines. The relationship between miR-3195 and the 3'-upstream region (3'-UTR) in the SOX4 mRNA (predicted through bioinformatics) was analyzed using Pearson's correlation analysis and confirmed by a dual-luciferase reporter gene experiment. Cell counting kit-8 assays, colony formation assays, flow cytometry, wound healing assays, transwell assays, and western blotting were performed to explore the effects of miR-3195 levels on SOX4 affected OS cell biological behavior. RESULTS Our results revealed that miR-3195 was the most down-regulated miRNA and SOX4 was the most up-regulated mRNA by Bioinformatic analysis. It was further confirmed miR-3195 had low expression, and SOX4 had high expression levels in clinical OS tissue samples; the expression levels of both genes were negatively correlated with each other in OS tissues. Overexpression of miR-3195 in OS cell lines significantly inhibited cell proliferation, migration, and invasiveness, while promoting apoptosis; all these effects were reversed by increasing SOX4 expression levels. We also found that miR-3195 could directly bind with the SOX4 gene and down-regulate SOX4 expression. CONCLUSIONS miR-3195 can modulate proliferation, migration, invasiveness, and apoptosis in OS cells by regulating the SOX4 gene. Thus, the miR-3195/SOX4 signaling may be a novel therapeutic target in OS treatment.
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Affiliation(s)
- Jianwei Liang
- Department of Orthopedics, The First People's Hospital of Taizhou, No.218 Hengjie Road, Huangyan District, Taizhou City, 318020, Zhejiang Province, China
| | - Dandan Bao
- Department of Pharmacy, The First People's Hospital of Taizhou, No.218 Hengjie Road, Huangyan District, Taizhou City, 318020, Zhejiang Province, China
| | - Zhan Ye
- Department of Orthopedics, The First People's Hospital of Taizhou, No.218 Hengjie Road, Huangyan District, Taizhou City, 318020, Zhejiang Province, China
| | - Binhao Cao
- Department of Orthopedics, The First People's Hospital of Taizhou, No.218 Hengjie Road, Huangyan District, Taizhou City, 318020, Zhejiang Province, China
| | - Guojun Jin
- Department of Orthopedics, The First People's Hospital of Taizhou, No.218 Hengjie Road, Huangyan District, Taizhou City, 318020, Zhejiang Province, China
| | - Zhenyu Lu
- Department of Orthopedics, The First People's Hospital of Taizhou, No.218 Hengjie Road, Huangyan District, Taizhou City, 318020, Zhejiang Province, China
| | - Jianjun Chen
- Department of Orthopedics, The First People's Hospital of Taizhou, No.218 Hengjie Road, Huangyan District, Taizhou City, 318020, Zhejiang Province, China.
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15
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AbdelHafez FF, Klausen C, Zhu H, Yi Y, Leung PCK. Growth differentiation factor myostatin regulates epithelial-mesenchymal transition genes and enhances invasion by increasing serine protease inhibitors E1 and E2 in human trophoblast cells. FASEB J 2023; 37:e23204. [PMID: 37738042 DOI: 10.1096/fj.202300740r] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/21/2023] [Accepted: 09/05/2023] [Indexed: 09/23/2023]
Abstract
Placental insufficiency disorders, including preeclampsia and intrauterine growth restriction, are major obstetric complications that can have devastating effects on both the mother and the fetus. These syndromes have underlying poor placental trophoblast cell invasion into uterine tissues. Placental invasion is controlled by many hormones and growth factors. Myostatin (MSTN) is a transforming growth factor-β superfamily member recognized for its important role in muscle growth control. MSTN has also been shown to be secreted and functioning in the placenta, and its serum and/or placental levels were found to be upregulated in preeclampsia and intrauterine growth restriction. Considering that the mechanistic role of MSTN in placentation remains poorly understood, we hypothesized that MSTN uses ALK4/5-SMAD2/3/4 signaling to increase human trophoblast invasion through a group of epithelial-mesenchymal transition genes including SERPINE2, PAI-1, and SOX4. mRNA sequencing of control and MSTN-treated primary human trophoblast cells (n = 5) yielded a total of 610 differentially expressed genes (false discovery rate <0.05) of which 380 genes were upregulated and 230 were downregulated. These differentially expressed genes were highly enriched in epithelial-mesenchymal transition genes, and a subset including SERPINE2, PAI-1, and SOX4 was investigated for its role in MSTN-induced trophoblast cell invasion. We found that MSTN induced upregulation of SERPINE2 via ALK4/5-SMAD2/3/4 signaling; however, SMAD2 was not involved in MSTN-induced PAI-1 upregulation. SOX4 was involved in MSTN-induced upregulation of SERPINE2, but not PAI-1. Collectively, this study discovers novel molecular mechanisms of MSTN-induced human trophoblast cell invasion and provides insight into the functional consequences of its dysregulation in placental insufficiency disorders.
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Affiliation(s)
- Faten F AbdelHafez
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Obstetrics and Gynecology, Assiut School of Medicine, Assiut, Egypt
| | - Christian Klausen
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hua Zhu
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Yuyin Yi
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Peter C K Leung
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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16
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Khanna P, Mehta R, Mehta GA, Bhatt V, Guo JY, Gatza ML. SOX4-SMARCA4 complex promotes glycolysis-dependent TNBC cell growth through transcriptional regulation of Hexokinase 2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.10.557071. [PMID: 37745600 PMCID: PMC10515838 DOI: 10.1101/2023.09.10.557071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Tumor cells rely on increased glycolytic capacity to promote cell growth and progression. While glycolysis is known to be upregulated in the majority of triple negative (TNBC) or basal-like subtype breast cancers, the mechanism remains unclear. Here, we used integrative genomic analyses to identify a subset of basal-like tumors characterized by increased expression of the oncogenic transcription factor SOX4 and its co-factor the SWI/SNF ATPase SMARCA4. These tumors are defined by unique gene expression programs that correspond with increased tumor proliferation and activation of key metabolic pathways, including glycolysis. Mechanistically, we demonstrate that the SOX4-SMARCA4 complex mediates glycolysis through direct transcriptional regulation of Hexokinase 2 (HK2) and that aberrant HK2 expression and altered glycolytic capacity are required to mediate SOX4-SMARCA4-dependent cell growth. Collectively, we have defined the SOX4-SMARCA4-HK2 signaling axis in basal-like breast tumors and established that this axis promotes metabolic reprogramming which is required to maintain tumor cell growth.
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Affiliation(s)
- Pooja Khanna
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Rushabh Mehta
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Gaurav A. Mehta
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Vrushank Bhatt
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901
- Department of Chemical Biology, Rutgers Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854
| | - Jessie Y. Guo
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901
- Department of Chemical Biology, Rutgers Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854
| | - Michael L. Gatza
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
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17
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Chuang TD, Ton N, Rysling S, Quintanilla D, Boos D, Gao J, McSwiggin H, Yan W, Khorram O. The Influence of Race/Ethnicity on the Transcriptomic Landscape of Uterine Fibroids. Int J Mol Sci 2023; 24:13441. [PMID: 37686244 PMCID: PMC10487975 DOI: 10.3390/ijms241713441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/26/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
The objective of this study was to determine if the aberrant expression of select genes could form the basis for the racial disparity in fibroid characteristics. The next-generation RNA sequencing results were analyzed as fold change [leiomyomas/paired myometrium, also known as differential expression (DF)], comparing specimens from White (n = 7) and Black (n = 12) patients. The analysis indicated that 95 genes were minimally changed in tumors from White (DF ≈ 1) but were significantly altered by more than 1.5-fold (up or down) in Black patients. Twenty-one novel genes were selected for confirmation in 69 paired fibroids by qRT-PCR. Among these 21, coding of transcripts for the differential expression of FRAT2, SOX4, TNFRSF19, ACP7, GRIP1, IRS4, PLEKHG4B, PGR, COL24A1, KRT17, MMP17, SLN, CCDC177, FUT2, MYO5B, MYOG, ZNF703, CDC25A, and CDCA7 was significantly higher, while the expression of DAB2 and CAV2 was significantly lower in tumors from Black or Hispanic patients compared with tumors from White patients. Western blot analysis revealed a greater differential expression of PGR-A and total progesterone (PGR-A and PGR-B) in tumors from Black compared with tumors from White patients. Collectively, we identified a set of genes uniquely expressed in a race/ethnicity-dependent manner, which could form the underlying mechanisms for the racial disparity in fibroids and their associated symptoms.
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Affiliation(s)
- Tsai-Der Chuang
- Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Torrance, CA 90502, USA;
- The Lundquist Institute for Biomedical Innovation, Torrance, CA 90502, USA; (N.T.); (S.R.); (D.Q.); (D.B.); (J.G.); (H.M.); (W.Y.)
| | - Nhu Ton
- The Lundquist Institute for Biomedical Innovation, Torrance, CA 90502, USA; (N.T.); (S.R.); (D.Q.); (D.B.); (J.G.); (H.M.); (W.Y.)
| | - Shawn Rysling
- The Lundquist Institute for Biomedical Innovation, Torrance, CA 90502, USA; (N.T.); (S.R.); (D.Q.); (D.B.); (J.G.); (H.M.); (W.Y.)
| | - Derek Quintanilla
- The Lundquist Institute for Biomedical Innovation, Torrance, CA 90502, USA; (N.T.); (S.R.); (D.Q.); (D.B.); (J.G.); (H.M.); (W.Y.)
| | - Drake Boos
- The Lundquist Institute for Biomedical Innovation, Torrance, CA 90502, USA; (N.T.); (S.R.); (D.Q.); (D.B.); (J.G.); (H.M.); (W.Y.)
| | - Jianjun Gao
- The Lundquist Institute for Biomedical Innovation, Torrance, CA 90502, USA; (N.T.); (S.R.); (D.Q.); (D.B.); (J.G.); (H.M.); (W.Y.)
| | - Hayden McSwiggin
- The Lundquist Institute for Biomedical Innovation, Torrance, CA 90502, USA; (N.T.); (S.R.); (D.Q.); (D.B.); (J.G.); (H.M.); (W.Y.)
| | - Wei Yan
- The Lundquist Institute for Biomedical Innovation, Torrance, CA 90502, USA; (N.T.); (S.R.); (D.Q.); (D.B.); (J.G.); (H.M.); (W.Y.)
- Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA
| | - Omid Khorram
- Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Torrance, CA 90502, USA;
- The Lundquist Institute for Biomedical Innovation, Torrance, CA 90502, USA; (N.T.); (S.R.); (D.Q.); (D.B.); (J.G.); (H.M.); (W.Y.)
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA
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18
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Elshafie NO, Gribskov M, Lichti NI, Sayedahmed EE, Childress MO, dos Santos AP. miRNome expression analysis in canine diffuse large B-cell lymphoma. Front Oncol 2023; 13:1238613. [PMID: 37711209 PMCID: PMC10499539 DOI: 10.3389/fonc.2023.1238613] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/04/2023] [Indexed: 09/16/2023] Open
Abstract
Introduction Lymphoma is a common canine cancer with translational relevance to human disease. Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype, contributing to almost fifty percent of clinically recognized lymphoma cases. Identifying new biomarkers capable of early diagnosis and monitoring DLBCL is crucial for enhancing remission rates. This research seeks to advance our knowledge of the molecular biology of DLBCL by analyzing the expression of microRNAs, which regulate gene expression by negatively impacting gene expression via targeted RNA degradation or translational repression. The stability and accessibility of microRNAs make them appropriate biomarkers for the diagnosis, prognosis, and monitoring of diseases. Methods We extracted and sequenced microRNAs from ten fresh-frozen lymph node tissue samples (six DLBCL and four non-neoplastic). Results Small RNA sequencing data analysis revealed 35 differently expressed miRNAs (DEMs) compared to controls. RT-qPCR confirmed that 23/35 DEMs in DLBCL were significantly upregulated (n = 14) or downregulated (n = 9). Statistical significance was determined by comparing each miRNA's average expression fold-change (2-Cq) between the DLCBL and healthy groups by applying the unpaired parametric Welch's 2-sample t-test and false discovery rate (FDR). The predicted target genes of the DEMs were mainly enriched in the PI3K-Akt-MAPK pathway. Discussion Our data point to the potential value of miRNA signatures as diagnostic biomarkers and serve as a guideline for subsequent experimental studies to determine the targets and functions of these altered miRNAs in canine DLBCL.
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Affiliation(s)
- Nelly O. Elshafie
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
| | - Michael Gribskov
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
| | - Nathanael I. Lichti
- Bindley Bioscience Center, Purdue University, West Lafayette, IN, United States
| | - Ekramy. E. Sayedahmed
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
| | - Michael O. Childress
- Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, United States
| | - Andrea P. dos Santos
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
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19
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Tang P, Sun D, Xu W, Li H, Chen L. Long non‑coding RNAs as potential therapeutic targets in non‑small cell lung cancer (Review). Int J Mol Med 2023; 52:68. [PMID: 37350412 PMCID: PMC10413047 DOI: 10.3892/ijmm.2023.5271] [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: 12/17/2022] [Accepted: 05/02/2023] [Indexed: 06/24/2023] Open
Abstract
Non‑small cell lung cancer (NSCLC) is one of the most common malignancies with a high morbidity and mortality rate. Long non‑coding RNAs (lncRNAs) have been reported to be closely associated with the occurrence and progression of NSCLC. In addition, lncRNAs have been documented to participate in the development of drug resistance and radiation sensitivity in patients with NSCLC. Due to their extensive functional characterization, high tissue specificity and sex specificity, lncRNAs have been proposed to be novel biomarkers and therapeutic targets for NSCLC. Therefore, in the current review, the functional classification of lncRNAs were presented, whilst the potential roles of lncRNAs in NSCLC were also summarized. Various physiological aspects, including proliferation, invasion and drug resistance, were all discussed. It is anticipated that the present review will provide a perspective on lncRNAs as potential diagnostic molecular biomarkers and therapeutic targets for NSCLC.
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Affiliation(s)
- Peiyu Tang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016
| | - Dejuan Sun
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016
| | - Wei Xu
- Institute of Structural Pharmacology and TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Hua Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016
- Institute of Structural Pharmacology and TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Lixia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016
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20
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Fang J, Singh S, Cheng C, Natarajan S, Sheppard H, Abu-Zaid A, Durbin AD, Lee HW, Wu Q, Steele J, Connelly JP, Jin H, Chen W, Fan Y, Pruett-Miller SM, Rehg JE, Koo SC, Santiago T, Emmons J, Cairo S, Wang R, Glazer ES, Murphy AJ, Chen T, Davidoff AM, Armengol C, Easton J, Chen X, Yang J. Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma. Nat Commun 2023; 14:4003. [PMID: 37414763 PMCID: PMC10326052 DOI: 10.1038/s41467-023-39717-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/27/2023] [Indexed: 07/08/2023] Open
Abstract
A lack of relevant genetic models and cell lines hampers our understanding of hepatoblastoma pathogenesis and the development of new therapies for this neoplasm. Here, we report an improved MYC-driven hepatoblastoma-like murine model that recapitulates the pathological features of embryonal type of hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of the human disease. Single-cell RNA-sequencing and spatial transcriptomics identify distinct subpopulations of hepatoblastoma cells. After deriving cell lines from the mouse model, we map cancer dependency genes using CRISPR-Cas9 screening and identify druggable targets shared with human hepatoblastoma (e.g., CDK7, CDK9, PRMT1, PRMT5). Our screen also reveals oncogenes and tumor suppressor genes in hepatoblastoma that engage multiple, druggable cancer signaling pathways. Chemotherapy is critical for human hepatoblastoma treatment. A genetic mapping of doxorubicin response by CRISPR-Cas9 screening identifies modifiers whose loss-of-function synergizes with (e.g., PRKDC) or antagonizes (e.g., apoptosis genes) the effect of chemotherapy. The combination of PRKDC inhibition and doxorubicin-based chemotherapy greatly enhances therapeutic efficacy. These studies provide a set of resources including disease models suitable for identifying and validating potential therapeutic targets in human high-risk hepatoblastoma.
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Affiliation(s)
- Jie Fang
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Shivendra Singh
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Changde Cheng
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Sivaraman Natarajan
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Heather Sheppard
- Comparative Pathology Core, St. Jude Children's Research Hospital, Memphis, TN, USA
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Ahmed Abu-Zaid
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Adam D Durbin
- Division of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Ha Won Lee
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Qiong Wu
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Jacob Steele
- Center for Advanced Genome Engineering (CAGE), St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Jon P Connelly
- Center for Advanced Genome Engineering (CAGE), St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Hongjian Jin
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Wenan Chen
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Yiping Fan
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Shondra M Pruett-Miller
- Center for Advanced Genome Engineering (CAGE), St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Jerold E Rehg
- Comparative Pathology Core, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Selene C Koo
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Teresa Santiago
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Joseph Emmons
- VPC Diagnostic Laboratory, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Stefano Cairo
- Champions Oncology, 1330 Piccard dr, Rockville, MD, USA
| | - Ruoning Wang
- Center for Childhood Cancer and Blood Disease, Hematology/Oncology & BMT, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
| | - Evan S Glazer
- Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, 910 Madison Ave., Suite 325, Memphis, TN, USA
| | - Andrew J Murphy
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
- Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, 910 Madison Ave., Suite 325, Memphis, TN, USA
| | - Taosheng Chen
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Andrew M Davidoff
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
- Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, 910 Madison Ave., Suite 325, Memphis, TN, USA
- St Jude Graduate School of Biomedical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA
- Department of Pathology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Carolina Armengol
- Childhood Liver Oncology Group, Germans Trias i Pujol Research Institute (IGTP), Translational Program in Cancer Research (CARE), Badalona, Spain
- CIBER, Hepatic and Digestive Diseases, Barcelona, Spain
- CIBERehd, Madrid, Spain
| | - John Easton
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Xiang Chen
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
- St Jude Graduate School of Biomedical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
| | - Jun Yang
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA.
- St Jude Graduate School of Biomedical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
- Department of Pathology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA.
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21
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He T, Wang S, Li S, Shen H, Hou L, Liu Y, Wei Y, Xie F, Zhang Z, Zhao Z, Mo C, Guo H, Huang Q, Zhang R, Shen D, Li B. Suppression of preadipocyte determination by SOX4 limits white adipocyte hyperplasia in obesity. iScience 2023; 26:106289. [PMID: 36968079 PMCID: PMC10030912 DOI: 10.1016/j.isci.2023.106289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/03/2023] [Accepted: 02/20/2023] [Indexed: 03/18/2023] Open
Abstract
Preadipocyte determination expanding the pool of preadipocytes is a vital process in adipocyte hyperplasia, but the molecular mechanisms underlying this process are yet to be elucidated. Herein, SRY-related HMG box transcription factor 4 (SOX4) was identified as a critical target in response to BMP4- and TGFβ-regulated preadipocyte determination. SOX4 deficiency is sufficient to promote preadipocyte determination in mesenchymal stem cells (MSCs) and acquisition of preadipocyte properties in nonadipogenic lineages, while its overexpression impairs the adipogenic capacity of preadipocytes and converts them into nonadipogenic lineages. Mechanism studies indicated that SOX4 activates and cooperates with LEF1 to retain the nuclear localization of β-catenin, thus mediating the crosstalk between TGFβ/BMP4 signaling pathway and Wnt signaling pathway to regulate the preadipocyte determination. In vivo studies demonstrated that SOX4 promotes the adipogenic-nonadipogenic conversion and suppresses the adipocyte hyperplasia. Together, our findings highlight the importance of SOX4 in regulating the adipocyte hyperplasia in obesity.
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Affiliation(s)
- Ting He
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of The Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China
| | - Shuai Wang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of The Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China
| | - Shengnan Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of The Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China
- School of Medicine, Henan Polytechnic University, Jiaozuo, Henan 454000, China
| | - Huanming Shen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of The Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China
| | - Lingfeng Hou
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of The Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China
| | - Yunjia Liu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of The Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China
| | - Yixin Wei
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of The Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China
| | - Fuan Xie
- Xiamen University Research Center of Retroperitoneal, Tumor Committee of Oncology Society of Chinese Medical Association, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Zhiming Zhang
- Xiamen Cell Therapy Research Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361003, China
| | - Zehang Zhao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of The Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China
| | - Chunli Mo
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of The Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China
| | - Huiling Guo
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of The Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China
| | - Qingsong Huang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of The Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China
| | - Rui Zhang
- Xiamen Cell Therapy Research Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361003, China
- Corresponding author
| | - Dongyan Shen
- Xiamen Cell Therapy Research Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361003, China
- Corresponding author
| | - Boan Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of The Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China
- Corresponding author
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22
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Hao F, Wang N, Zhang Y, Xu W, Chen Y, Fei X, Wang J. E2F7 enhances hepatocellular carcinoma growth by preserving the SP1/SOX4/Anillin axis via repressing miRNA-383-5p transcription. Mol Carcinog 2022; 61:975-988. [PMID: 35924788 PMCID: PMC9804269 DOI: 10.1002/mc.23454] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/20/2022] [Accepted: 07/22/2022] [Indexed: 01/05/2023]
Abstract
E2F family participates in most human malignancies by activating the transcription of the cell cycle-related genes. Whereas, as a specifical atypical member of this family, E2F7 was described as a repressor against its downstream genes and exerted oscillatory and controversial functions in cancers. Our previous study identified a molecular interaction promoting hepatocellular carcinoma (HCC) growth induced by SOX4 and Anillin. Meanwhile, we preliminarily identified SP1 as the upstream activator of SOX4. Intriguingly, we observed that the repressive E2F7 presents a remarkable high expression in HCC, and is positively correlated and involved in the same pathway with the potentially SP1/SOX4/Anillin axis. However, their exact interaction or mechanism controlling tumor progress between these genes has not been illustrated. Thus, we focused on this point in this study and attempted to improve the potential regulating axis in HCC cell proliferation and tumor growth for promoting tumor prevention and control. The expression profile of E2F7 in HCC tissues and tumor cells was detected along with the related candidate genes, through real-time quantitative polymerase chain reaction assay, the Western blot analysis, and the immunohistochemistry assay, combined with bioinformatics analysis of the HCC information from the the Cancer Genome Altas and Gene Expression Omnibus data sets. The correlation between E2F7 and HCC patients' clinicopathologic features was explored. Gain-of and loss-of-function assays were conducted both in vitro and in vivo along with the rescue experiment, for revealing the relative genes' functions in HCC progress. The ChIP and the dual-luciferase reporter assays were performed to verify the transcriptional regulating profile between E2F7 and SP1/SOX4/Anillin axis. E2F7 was upregulated in HCC and significantly correlated with SP1/SOX4/Anillin axis. High E2F7 expression is associated with dismal clinicopathologic features and poor survival of the patients. E2F7 depletion potently impaired SP1/SOX4/Anillin expression and significantly inhibited HCC growth. Furthermore, intensive exploration demonstrated that E2F7 preserves high SP1 levels by abrogating miR-383-5p in a transcriptional way. Atypical E2F7 is an important repressive transcription factor commonly upregulated in the HCC environment. E2F7 facilitates HCC growth by repressing miR-383-5p transcription and sequentially promoting SP1/SOX4/Anillin axis. Our findings provide us with probable targets for HCC prevention and therapeutic treatment.
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Affiliation(s)
- Fengjie Hao
- Department of General SurgeryRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Nan Wang
- Department of General SurgeryRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Yifan Zhang
- Department of General SurgeryRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Wen Xu
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of PharmacyEast China University of Science and TechnologyShanghaiP.R. China
| | - Yongjun Chen
- Department of General SurgeryRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Xiaochun Fei
- Department of PathologyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Junqing Wang
- Department of General SurgeryRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiP.R. China
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23
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Ramšak B, Kück U. The Penicillium chrysogenum tom1 Gene a Major Target of Transcription Factor MAT1-1-1 Encodes a Nuclear Protein Involved in Sporulation. FRONTIERS IN FUNGAL BIOLOGY 2022; 3:937023. [PMID: 37746180 PMCID: PMC10512297 DOI: 10.3389/ffunb.2022.937023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/13/2022] [Indexed: 09/26/2023]
Abstract
Fungal mating-type loci (MAT) encode transcription factors (TFs) MAT1-1-1 and MAT1-2-1, which govern sexual reproduction as well as other developmental processes. In Penicillium chrysogenum, the major producer of the beta-lactam antibiotic penicillin, a recent chromatin immunoprecipitation followed by sequencing (ChIP-seq) analysis identified 254 genes as direct targets of MAT1-1-1, many of which encode thus far uncharacterized proteins. Here, we characterized one of the major targets of MAT1-1-1, the tom1 gene, which encodes a protein highly conserved within the group of Eurotiomycetes fungi. Using fluorescence microscopy, we demonstrated binding of MAT1-1-1 to the tom1 promoter by reporter gene analysis. Extensive electrophoretic mobility shift assays (EMSAs) further showed that the promoter sequence of tom1 is bound in vitro by both MAT1-1-1 and MAT1-2-1. This indicated an interaction between the two TFs, which was verified by yeast two-hybrid analysis. The sequence of tom1 carries a nuclear localization sequence, and indeed its nuclear localization was verified by fluorescence microscopy. The in vivo function of tom1 was investigated using tom1 deletion strains, as well as a complementing strain where the wild-type tom1 gene was reintroduced. We found a clear sporulation defect in the deletion strain, which became more evident when the fungi were grown at an elevated temperature of 31°C.
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Affiliation(s)
| | - Ulrich Kück
- Allgemeine und Molekulare Botanik, Ruhr-Universität Bochum, Fakultät für Biologie und Biotechnologie, Bochum, Germany
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24
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Guan Y, Jiang SR, Liu JG, Shi JR, Liu ZB. USP20 regulates the stability of EMT transcription factor SOX4 and influences colorectal cancer metastasis. Pathol Res Pract 2022; 233:153879. [PMID: 35405623 DOI: 10.1016/j.prp.2022.153879] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/28/2021] [Accepted: 04/01/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is a familiar malignancy accompanied by higher morbidity and mortality. The deubiquitination enzyme USP20 has been discovered to be one key factor in several cancers progression. SOX4 is a critical transcription factor to regulate the expression of various genes, and participates into the occurrence and progression of cancers. In this study, it was aimed to illustrate the role of USP20 and the regulatory relationship between USP20 and SOX4 in CRC. METHODS The protein expressions of USP20, SOX4, E-cadherin, N-cadherin, Snail and slug were tested through western blot. The cell proliferation ability was verified through CCK-8 assay. The migration and invasion abilities were detected through Transwell assay. The mRNA expression of SOX4 was confirmed through RT-qPCR. The interaction between USP20 and SOX4 was notarized through Co-IP assay. RESULT Our study demonstrated that USP20 displayed higher expression, and facilitated CRC progression through regulating cell proliferation, migration, invasion and EMT process markers. USP20 was found to modulate SOX4 protein expression. Next, it was verified that USP20 regulated SOX4 degradation through deubiquitination. Finally, through rescue assays, we revealed that USP20 mediated SOX4 expression to accelerate CRC progression. CONCLUSIONS In this study, USP20 regulated the stability of EMT transcription factor SOX4 and aggravated colorectal cancer metastasis. This finding might highlight the function of USP20 in the treatment of CRC.
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Affiliation(s)
- Yu Guan
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Shi-Ru Jiang
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Jun-Guang Liu
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Ji-Rong Shi
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Zhan-Bing Liu
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China.
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25
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Man L, Lustgarten Guahmich N, Kallinos E, Caiazza B, Khan M, Liu ZY, Patel R, Torres C, Pepin D, Yang HS, Bodine R, Zaninovic N, Schattman G, Rosenwaks Z, James D. Chronic superphysiologic AMH promotes premature luteinization of antral follicles in human ovarian xenografts. SCIENCE ADVANCES 2022; 8:eabi7315. [PMID: 35263130 PMCID: PMC8906729 DOI: 10.1126/sciadv.abi7315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 01/14/2022] [Indexed: 05/19/2023]
Abstract
Anti-Müllerian hormone (AMH) is produced by growing ovarian follicles and provides a diagnostic measure of reproductive reserve in women; however, the impact of AMH on folliculogenesis is poorly understood. We cotransplanted human ovarian cortex with control or AMH-expressing endothelial cells in immunocompromised mice and recovered antral follicles for purification and downstream single-cell RNA sequencing of granulosa and theca/stroma cell fractions. A total of 38 antral follicles were observed (19 control and 19 AMH) at long-term intervals (>10 weeks). In the context of exogenous AMH, follicles exhibited a decreased ratio of primordial to growing follicles and antral follicles of increased diameter. Transcriptomic analysis and immunolabeling revealed a marked increase in factors typically noted at more advanced stages of follicle maturation, with granulosa and theca/stroma cells also displaying molecular hallmarks of luteinization. These results suggest that superphysiologic AMH alone may contribute to ovulatory dysfunction by accelerating maturation and/or luteinization of antral-stage follicles.
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Affiliation(s)
- Limor Man
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Nicole Lustgarten Guahmich
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Eleni Kallinos
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Barbara Caiazza
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Monica Khan
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Zong-Ying Liu
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Ritaben Patel
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Carmen Torres
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
| | - David Pepin
- Department of Surgery, Harvard Medical School, Boston, MA 02215, USA
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02214, USA
| | - He S. Yang
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Richard Bodine
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Nikica Zaninovic
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
- Tri-Institutional Stem Cell Derivation Laboratory, Weill Cornell Medicine, New York, NY 10065, USA
| | - Glenn Schattman
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Zev Rosenwaks
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Daylon James
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY 10065, USA
- Tri-Institutional Stem Cell Derivation Laboratory, Weill Cornell Medicine, New York, NY 10065, USA
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA
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Advance of SOX Transcription Factors in Hepatocellular Carcinoma: From Role, Tumor Immune Relevance to Targeted Therapy. Cancers (Basel) 2022; 14:cancers14051165. [PMID: 35267473 PMCID: PMC8909699 DOI: 10.3390/cancers14051165] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/12/2022] [Accepted: 02/18/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the deadliest human health burdens worldwide. However, the molecular mechanism of HCC development is still not fully understood. Sex determining region Y-related high-mobility group box (SOX) transcription factors not only play pivotal roles in cell fate decisions during development but also participate in the initiation and progression of cancer. Given the significance of SOX factors in cancer and their ‘undruggable’ properties, we summarize the role and molecular mechanism of SOX family members in HCC and the regulatory effect of SOX factors in the tumor immune microenvironment (TIME) of various cancers. For the first time, we analyze the association between the levels of SOX factors and that of immune components in HCC, providing clues to the pivotal role of SOX factors in the TIME of HCC. We also discuss the opportunities and challenges of targeting SOX factors for cancer. Abstract Sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) factors belong to an evolutionarily conserved family of transcription factors that play essential roles in cell fate decisions involving numerous developmental processes. In recent years, the significance of SOX factors in the initiation and progression of cancers has been gradually revealed, and they act as potential therapeutic targets for cancer. However, the research involving SOX factors is still preliminary, given that their effects in some leading-edge fields such as tumor immune microenvironment (TIME) remain obscure. More importantly, as a class of ‘undruggable’ molecules, targeting SOX factors still face considerable challenges in achieving clinical translation. Here, we mainly focus on the roles and regulatory mechanisms of SOX family members in hepatocellular carcinoma (HCC), one of the fatal human health burdens worldwide. We then detail the role of SOX members in remodeling TIME and analyze the association between SOX members and immune components in HCC for the first time. In addition, we emphasize several alternative strategies involved in the translational advances of SOX members in cancer. Finally, we discuss the alternative strategies of targeting SOX family for cancer and propose the opportunities and challenges they face based on the current accumulated studies and our understanding.
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Pan S, Bao D, Li Y, Liu D, Quan S, Wang R. SOX4 induces drug resistance of colorectal cancer cells by downregulating CYLD through transcriptional activation of microRNA-17. J Biochem Mol Toxicol 2022; 36:e22910. [PMID: 34927777 DOI: 10.1002/jbt.22910] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 07/22/2021] [Accepted: 08/24/2021] [Indexed: 12/19/2022]
Abstract
Exposure to high doses of anticancer drugs can induce the emergence of a subpopulation of weakly proliferative and drug-tolerant cells. Drug tolerance can reduce the benefits obtained from canonical treatment and reduce the survival rate of patients. Regulation of SRY-related HMG box transcription factor 4 (SOX4) has been proved to affect drug sensitivity. The current study aimed to explore the role of SOX4 in drug resistance of colorectal cancer (CRC) cells as well as the related molecular mechanisms. Expression patterns of SOX4, microRNA-17 (miR-17), and CYLD in both CRC tissues and cells were determined with their relationship analyzed by bioinformatics analysis, dual-luciferase reporter gene assay, and ChIP. Loss- and gain-function assays were performed to ascertain the effect of SOX4, miR-17, and CYLD on biological cellular processes and drug resistance to 5-FU. SOX4 and miR-17 were found to be highly expressed while CYLD was poorly expressed in CRC tissues and cells. Silencing of SOX4 resulted in the suppression of cellular proliferation, invasion, migration as well as a reduction in CRC drug resistance. Mechanically, CYLD was specifically targeted by miR-17, while SOX4 upregulated the expression of miR-17. Functionally, SOX4 triggered drug resistance of CRC cells to 5-FU through the miR-17/CYLD axis. Taken together, the key findings of the present study provides evidence suggesting that SOX4 elevates miR-17 to decrease CYLD, thus inducing chemotherapy resistance of CRC cells.
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Affiliation(s)
- Shuang Pan
- Department of Physiology, Jinzhou Medical University, Jinzhou, P.R. China
| | - Dongyan Bao
- Department of Physiology, Jinzhou Medical University, Jinzhou, P.R. China
| | - Yao Li
- Department of Physiology, Jinzhou Medical University, Jinzhou, P.R. China
| | - Dahua Liu
- Jinzhou Medical University (Liaoning Province Key Laboratory of Human Phenome Research), Jinzhou, P.R. China
| | - Shuai Quan
- The First Clinical College, Jinzhou Medical University, Jinzhou, P.R. China
| | - Rong Wang
- Department of Respiratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, P.R. China
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Naik A, Dalpatraj N, Thakur N. Global Gene Expression Regulation Mediated by TGFβ Through H3K9me3 Mark. Cancer Inform 2022; 21:11769351221115135. [PMID: 35923287 PMCID: PMC9340917 DOI: 10.1177/11769351221115135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 07/02/2022] [Indexed: 11/30/2022] Open
Abstract
Background: Epigenetic alterations play an important part in carcinogenesis. Different biological responses, including cell proliferation, migration, apoptosis, invasion, and senescence, are affected by epigenetic alterations in cancer. In addition, growth factors, such as transforming growth factor beta (TGFβ) are important regulators of tumorigenesis. Our understanding of the interplay between the epigenetic bases of tumorigenesis and growth factor signaling in tumorigenesis is rudimentary. Some studies suggest a link between TGFβ signaling and the heterochromatinizing histone mark H3K9me3. There is evidence for signal-dependent interactions between R-Smads and histone methyltransferases. However, the effects of TGFβ signaling on genome wide H3K9me3 landscape remains unknown. Our research examines TGFβ -induced genome-wide H3K9me3 in prostate cancer. Method: Chromatin-Immunoprecipitation followed by sequencing was performed to analyze genome-wide association of H3K9me3 epigenetic mark. DAVID Functional annotation tool was utilized to understand the involvement of different Biological Processes and Molecular Function. MEME-ChIP tool was also used to analyze known and novel DNA-binding motifs. Results: H3K9me3 occupancy appears to increase at intronic regions after short-term (6 hours) TGFβ stimulation and at distal intergenic regions during long-term stimulation (24 hours). We also found evidence for a possible association of SLC transporters with H3K9me3 mark in presence of TGFβ during tumorigenesis. No direct correlation was found between the occupancy of H3K9me3 mark and the expression of various genes. The epigenetic mechanisms-mediated regulation of gene expression by TGFβ was concentrated at promoters rich in SRY and FOXJ3 binding sites. Conclusion: Our results point toward a positive association of oncogenic function of TGFβ and the H3K9me3 mark and provide a context to the role of H3K9me3 in TGFβ-induced cell migration and cell adhesion. Interestingly, these functions of TGFβ through H3K9me3 mark regulation seem to depend on transcriptional activation in contrast to the conventionally known repressive nature of H3K9me3.
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Affiliation(s)
- Ankit Naik
- Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Ahmedabad, Gujarat, India
| | - Nidhi Dalpatraj
- Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Ahmedabad, Gujarat, India
| | - Noopur Thakur
- Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Ahmedabad, Gujarat, India
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Djouadi F, Mouillet-Richard S. [Methylmalonic acid: A new link between ageing and tumour progression]. Med Sci (Paris) 2021; 37:1176-1177. [PMID: 34928224 DOI: 10.1051/medsci/2021174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
- Fatima Djouadi
- Centre de recherche des Cordeliers, Inserm U1138, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, 15 rue de l'École de Médecine, 75006 Paris, France
| | - Sophie Mouillet-Richard
- Centre de recherche des Cordeliers, Inserm U1138, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, 15 rue de l'École de Médecine, 75006 Paris, France
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Zhang M, Li H, Han Y, Wang M, Zhang J, Ma S. Clinicopathological significance of SOX4 and epithelial-mesenchymal transition markers in patients with laryngeal squamous cell carcinoma. Auris Nasus Larynx 2021; 48:1167-1175. [PMID: 34001394 DOI: 10.1016/j.anl.2021.04.013] [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: 02/24/2021] [Revised: 04/18/2021] [Accepted: 04/19/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVE Sex-determining region-Y-related high-mobility-group box 4 (SOX4) is associated with the metastasis and prognosis of many cancer types. However, studies on the role of SOX4 in laryngeal squamous cell carcinoma (LSCC) are few, and hence the mechanism is unclear. Epithelial-mesenchymal transition (EMT) allows neoplastic cells to gain the plasticity and motility required for tumor progression and metastasis. This study aimed to analyze the relationship between SOX4 and EMT, and their relationship with clinicopathological factors and related prognosis. METHODS Immunohistochemical staining was used to detect the positive expression of SOX4 protein, EMT-related transcription factor protein, and related marker protein in 127 LSCC tissue samples. At the same time, data on various parameters of clinical pathology and postoperative survival were collected. RESULTS The positive expression rate of SOX4 and Slug in LSCC was related to pathological differentiation, Lymph node metastasis (LNM), and pathological TNM of a tumor. The expression rates of ZEB1, E-cadherin, N-cadherin, and β-catenin in LSCC correlated with LNM and pTNM. The expression of SOX4, combined expression of SOX4 and ZEB1, and LNM were independent prognostic factors for the total survival time of patients with LSCC. CONCLUSIONS In summary, SOX4 was vital in the LSCC EMT process, which might be mediated by transcription factor ZEB1. SOX4 and ZEB1 might serve as potential biomarkers of metastasis and prognosis, as well as promising therapeutic targets of LSCC.
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Affiliation(s)
- Mingjie Zhang
- Department of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, Guangdong 510632, China; Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Hui Li
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Yuefeng Han
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Mengjun Wang
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Junjie Zhang
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Shiyin Ma
- Department of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, Guangdong 510632, China; Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, China.
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miR-335-laden B Cell-Derived Extracellular Vesicles Promote SOX4-Dependent Apoptosis in Human Multiple Myeloma Cells. J Pers Med 2021; 11:jpm11121240. [PMID: 34945712 PMCID: PMC8707697 DOI: 10.3390/jpm11121240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/12/2021] [Accepted: 11/18/2021] [Indexed: 12/03/2022] Open
Abstract
Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow. Despite novel therapies, MM still remains an incurable cancer and new strategies are needed. Increased expression of the transcription factor Sex-determining region Y-related high-mobility-group box transcription factor 4 (SOX4) has been correlated with tumor development and progression through a variety of distinct processes, including inhibition of apoptosis, increased cell invasion and metastasis, and induction and maintenance of cancer-initiating cells. The role of SOX4 in MM is largely unknown. Since SOX4 is a known target of miR-335, we used miR-335 to assess whether SOX4 modulation could promote apoptosis in MM cells. Using an MM cell model we show that miR-335 acts both on SOX4-related genes (AKT, PI3K) and hypoxia-inducible factor 1-alpha (Hif1-α). In addition, we show miR-335-laden extracellular vesicles induced in B cells (iEVs) are also effective in targeting SOX4, causing apoptosis. Collectively, we propose that miR-335-laden iEVs could be developed as a novel form of gene therapy in MM.
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Yi Y, Zhu H, Klausen C, Leung PCK. Transcription factor SOX4 facilitates BMP2-regulated gene expression during invasive trophoblast differentiation. FASEB J 2021; 35:e22028. [PMID: 34739154 DOI: 10.1096/fj.202100925rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 10/05/2021] [Accepted: 10/19/2021] [Indexed: 01/13/2023]
Abstract
The interplay between growth factors, signaling pathways and transcription factors during placental development is key to controlling trophoblast differentiation. Bone morphogenetic protein 2 (BMP2) has been implicated in trophoblast invasion and spiral artery remodeling during early placental development. However, the molecular mechanisms by which these are accomplished have not been fully elucidated, particularly for transcriptional regulation of key transcription factors. Here, we identified SOX4 as a direct target gene induced by BMP2 in first-trimester placental trophoblasts. Analysis of single-cell RNA-seq data from first-trimester placentas and decidua tissues revealed that SOX4 expression is mainly localized in extravillous trophoblast and decidual stromal cells. Moreover, gain- and loss-of-function approaches demonstrated that SOX4 exerts a pro-invasive role in human trophoblasts, and this effect contributes to BMP2-enhanced trophoblast invasion. Importantly, we found that SOX4 was required for BMP2-induced regulation of a subset of genes associated with cell migration and extracellular matrix organization. We also show that SOX4-dependent regulation of the BMP2 target SERPINE2 occurs via binding of SOX4 to regulatory elements such as enhancers, thereby promoting BMP2-induced trophoblast invasion. In conclusion, these findings uncover a novel mechanism involving SOX4 that shapes the BMP2-regulated transcriptional network during invasive trophoblast development.
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Affiliation(s)
- Yuyin Yi
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hua Zhu
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Christian Klausen
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Peter C K Leung
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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Roukens MG, Frederiks CL, Seinstra D, Braccioli L, Khalil AA, Pals C, De Neck S, Bornes L, Beerling E, Mokry M, de Bruin A, Westendorp B, van Rheenen J, Coffer PJ. Regulation of a progenitor gene program by SOX4 is essential for mammary tumor proliferation. Oncogene 2021; 40:6343-6353. [PMID: 34584219 PMCID: PMC8585668 DOI: 10.1038/s41388-021-02004-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 08/04/2021] [Accepted: 08/27/2021] [Indexed: 01/06/2023]
Abstract
In breast cancer the transcription factor SOX4 has been shown to be associated with poor survival, increased tumor size and metastasis formation. This has mostly been attributed to the ability of SOX4 to regulate Epithelial-to-Mesenchymal-Transition (EMT). However, SOX4 regulates target gene transcription in a context-dependent manner that is determined by the cellular and epigenetic state. In this study we have investigated the loss of SOX4 in mammary tumor development utilizing organoids derived from a PyMT genetic mouse model of breast cancer. Using CRISPR/Cas9 to abrogate SOX4 expression, we found that SOX4 is required for inhibiting differentiation by regulating a subset of genes that are highly activated in fetal mammary stem cells (fMaSC). In this way, SOX4 re-activates an oncogenic transcriptional program that is regulated in many progenitor cell-types during embryonic development. SOX4-knockout organoids are characterized by the presence of more differentiated cells that exhibit luminal or basal gene expression patterns, but lower expression of cell cycle genes. In agreement, primary tumor growth and metastatic outgrowth in the lungs are impaired in SOX4KO tumors. Finally, SOX4KO tumors show a severe loss in competitive capacity to grow out compared to SOX4-proficient cells in primary tumors. Our study identifies a novel role for SOX4 in maintaining mammary tumors in an undifferentiated and proliferative state. Therapeutic manipulation of SOX4 function could provide a novel strategy for cancer differentiation therapy, which would promote differentiation and inhibit cycling of tumor cells.
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Affiliation(s)
- M Guy Roukens
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands.
- Center for Molecular Medicine Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Cynthia L Frederiks
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
- Center for Molecular Medicine Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Danielle Seinstra
- Department of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Luca Braccioli
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
- Center for Molecular Medicine Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Antoine A Khalil
- Center for Molecular Medicine Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Cornelieke Pals
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
- Center for Molecular Medicine Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Simon De Neck
- Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Laura Bornes
- Department of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Evelyne Beerling
- Department of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Michal Mokry
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Alain de Bruin
- Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Bart Westendorp
- Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Jacco van Rheenen
- Department of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Paul J Coffer
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands.
- Center for Molecular Medicine Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands.
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Fu C, Xin J, Zhang W, Lai J, Huang Z. LINC00992 exerts oncogenic activities in prostate cancer via regulation of SOX4. Exp Cell Res 2021; 408:112855. [PMID: 34599930 DOI: 10.1016/j.yexcr.2021.112855] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/16/2021] [Accepted: 09/24/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The critical role of long non-coding RNAs (lncRNAs) has been implicated in prostate cancer (PCa). As one of them, LINC00992 (LNC992) has been revealed by bioinformatics prediction to be significantly overexpressed in PCa. However, the underlying mechanism of LNC992 in PCa has not been well investigated. METHODS First, gene expression microarrays of prostate adenocarcinoma (PRAD) were downloaded from the GEO database, and differentially expressed genes were analyzed. Subsequently, we assessed the LNC992 expression in PCa patients. PCa cells with overexpression or low expression of LNC992 were generated, followed by the examination of proliferation, invasion and migration in vitro and in vivo. The differentially expressed genes were analyzed by microarrays after altering LNC992 expression in PCa cells, and the downstream regulatory mechanisms of LNC992 were analyzed by bioinformatics analysis and validated by RIP and RNA pull-down assays. RESULTS LNC992 was highly expressed in the PRAD database and in cancer tissues from PCa patients, serving as a poor prognostic factor for PCa patients. Knockdown of LNC992 significantly inhibited PCa cell growth, metastasis, and angiogenesis in vitro and in vivo. Moreover, we found that knockdown of LNC992 significantly suppressed SOX4 expression in cells and that LNC992 could bind to EIF4A3 and promote the translation of SOX4. Inhibition of either EIF4A3 or SOX4 significantly suppressed the growth and metastasis of PCa cells. CONCLUSIONS LNC992 elevates SOX4 expression by binding to SOX4 mRNA and recruiting translation initiation factor EIF4A3, thereby promoting the growth and metastasis of PCa cells in vitro and in vivo.
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Affiliation(s)
- Changde Fu
- Department of Urology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, Fujian, PR China
| | - Jun Xin
- Department of Urology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, Fujian, PR China
| | - Wei Zhang
- Department of Urology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, Fujian, PR China
| | - Jinjin Lai
- Department of Urology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, Fujian, PR China
| | - Zhiyang Huang
- Department of Urology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, Fujian, PR China.
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Stevanovic M, Kovacevic-Grujicic N, Mojsin M, Milivojevic M, Drakulic D. SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation. World J Stem Cells 2021; 13:1417-1445. [PMID: 34786152 PMCID: PMC8567447 DOI: 10.4252/wjsc.v13.i10.1417] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/15/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.
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Affiliation(s)
- Milena Stevanovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
- Chair Biochemistry and Molecular Biology, Faculty of Biology, University of Belgrade, Belgrade 11158, Serbia
- Department of Chemical and Biological Sciences, Serbian Academy of Sciences and Arts, Belgrade 11000, Serbia.
| | - Natasa Kovacevic-Grujicic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Marija Mojsin
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Milena Milivojevic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Danijela Drakulic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
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Detailed characterization of the transcriptome of single B cells in mantle cell lymphoma suggesting a potential use for SOX4. Sci Rep 2021; 11:19092. [PMID: 34580376 PMCID: PMC8476518 DOI: 10.1038/s41598-021-98560-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 09/07/2021] [Indexed: 01/04/2023] Open
Abstract
Mantle cell lymphoma (MCL) is a malignancy arising from naive B lymphocytes with common bone marrow (BM) involvement. Although t(11;14) is a primary event in MCL development, the highly diverse molecular etiology and causal genomic events are still being explored. We investigated the transcriptome of CD19+ BM cells from eight MCL patients at single-cell level. The transcriptomes revealed marked heterogeneity across patients, while general homogeneity and clonal continuity was observed within the patients with no clear evidence of subclonal involvement. All patients were SOX11+CCND1+CD20+. Despite monotypic surface immunoglobulin (Ig) κ or λ protein expression in MCL, 10.9% of the SOX11 + malignant cells expressed both light chain transcripts. The early lymphocyte transcription factor SOX4 was expressed in a fraction of SOX11 + cells in two patients and co-expressed with the precursor lymphoblastic marker, FAT1, in a blastoid case, suggesting a potential prognostic role. Additionally, SOX4 was found to identify non-malignant SOX11– pro-/pre-B cell populations. Altogether, the observed expression of markers such as SOX4, CD27, IgA and IgG in the SOX11+ MCL cells, may suggest that the malignant cells are not fixed in the differentiation state of naïve mature B cells, but instead the patients carry B lymphocytes of different differentiation stages.
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Rezayi Soufiani A, Dolatkhah R, Raeisi M, Chavoshi H, Mohammadi P, Mehdinavaz Aghdam A. Hypermethylation of MIR129-2 Regulates SOX4 Transcription and Associates with Metastasis in Patients with Colorectal Cancer. J Gastrointest Cancer 2021; 53:718-724. [PMID: 34499308 DOI: 10.1007/s12029-021-00708-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND MicroRNA-129-2 (miR-129-2), targeting SOX4, has been shown to be involved in the pathogenesis of different cancers. Here in this study, we examined the methylation levels of the promoter region of MIR19-2 gene as well as transcription of miR-129-2 and mRNA expression of SOX4 in the tumoral tissues from colorectal cancer (CRC) patients and compared those in the normal marginal tissues. METHODS Fifty CRC patients with Iranian Azari ethnicity were recruited. Genomic DNAs were extracted from the tumoral and normal tissues and the methylation level of the promoter regions of the MIR129-2 gene was determined using methylation-specific PCR (MSP) by evaluating 100 CG sites. The RNA content of the samples was isolated and the transcript levels of miR-129-2 and SOX4 were measured using quantitative real-time PCR. RESULTS Methylation level of the MIR192-2 promoter was significantly higher in the tumoral tissues compared to that in the normal marginal tissues (84% vs. 28%; P = 0.0041). The expression level of miR-192-2 was significantly downregulated (fold change = 0.34, P = 0.028) but SOX4 mRNA expression was upregulated (fold change = 2.7, P = 0.019) in the tumoral tissues compared to that in the normal marginal tissues. There was a significant correlation between the methylation level of the MIR192-2 promoter and the expression levels of miR-192-2 and SOX4 in the tumoral tissues. Associations were observed between the methylation of the MIR192-2 promoter and lymph node and liver metastasis. CONCLUSIONS It seems that MIR192-2 promoter hypermethylation might regulate the expression of SOX4 and therefore modulate metastasis in CRC.
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Affiliation(s)
- Alireza Rezayi Soufiani
- Tuberculosis and Lung Disease Research Center, Daneshgah St, Tabriz University of Medical Science, Tabriz, Iran
| | - Roya Dolatkhah
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mortaza Raeisi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Chavoshi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Payam Mohammadi
- Tuberculosis and Lung Disease Research Center, Daneshgah St, Tabriz University of Medical Science, Tabriz, Iran
| | - Abdolreza Mehdinavaz Aghdam
- Tuberculosis and Lung Disease Research Center, Daneshgah St, Tabriz University of Medical Science, Tabriz, Iran.
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Blanc V, Riordan JD, Soleymanjahi S, Nadeau JH, Nalbantoglu ILK, Xie Y, Molitor EA, Madison BB, Brunt EM, Mills JC, Rubin DC, Ng IO, Ha Y, Roberts LR, Davidson NO. Apobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis, and hepatocellular cancer. J Clin Invest 2021; 131:138699. [PMID: 33445170 DOI: 10.1172/jci138699] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 09/10/2020] [Indexed: 12/11/2022] Open
Abstract
The RNA-binding protein Apobec1 complementation factor (A1CF) regulates posttranscriptional ApoB mRNA editing, but the range of RNA targets and the long-term effect of altered A1CF expression on liver function are unknown. Here we studied hepatocyte-specific A1cf-transgenic (A1cf+/Tg), A1cf+/Tg Apobec1-/-, and A1cf-/- mice fed chow or high-fat/high-fructose diets using RNA-Seq, RNA CLIP-Seq, and tissue microarrays from human hepatocellular cancer (HCC). A1cf+/Tg mice exhibited increased hepatic proliferation and steatosis, with increased lipogenic gene expression (Mogat1, Mogat2, Cidea, Cd36) associated with shifts in polysomal RNA distribution. Aged A1cf+/Tg mice developed spontaneous fibrosis, dysplasia, and HCC, and this development was accelerated on a high-fat/high-fructose diet and was independent of Apobec1. RNA-Seq revealed increased expression of mRNAs involved in oxidative stress (Gstm3, Gpx3, Cbr3), inflammatory response (Il19, Cxcl14, Tnfα, Ly6c), extracellular matrix organization (Mmp2, Col1a1, Col4a1), and proliferation (Kif20a, Mcm2, Mcm4, Mcm6), and a subset of mRNAs (including Sox4, Sox9, Cdh1) were identified in RNA CLIP-Seq. Increased A1CF expression in human HCC correlated with advanced fibrosis and with reduced survival in a subset with nonalcoholic fatty liver disease. In conclusion, we show that hepatic A1CF overexpression selectively alters polysomal distribution and mRNA expression, promoting lipogenic, proliferative, and inflammatory pathways leading to HCC.
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Affiliation(s)
- Valerie Blanc
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Jesse D Riordan
- Pacific Northwest Research Institute, Seattle, Washington, USA
| | - Saeed Soleymanjahi
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Joseph H Nadeau
- Pacific Northwest Research Institute, Seattle, Washington, USA
| | - ILKe Nalbantoglu
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Yan Xie
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Elizabeth A Molitor
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Blair B Madison
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Elizabeth M Brunt
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Jason C Mills
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Deborah C Rubin
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Irene O Ng
- Department of Pathology and State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | - Yeonjung Ha
- Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Lewis R Roberts
- Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Nicholas O Davidson
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
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Seok J, Gil M, Dayem AA, Saha SK, Cho SG. Multi-Omics Analysis of SOX4, SOX11, and SOX12 Expression and the Associated Pathways in Human Cancers. J Pers Med 2021; 11:jpm11080823. [PMID: 34442467 PMCID: PMC8400412 DOI: 10.3390/jpm11080823] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/06/2021] [Accepted: 08/20/2021] [Indexed: 01/08/2023] Open
Abstract
The Sry-related HMG BOX (SOX) gene family encodes transcription factors containing highly conserved high-mobility group domains that bind to the minor groove in DNA. Although some SOX genes are known to be associated with tumorigenesis and cancer progression, their expression and prognostic value have not been systematically studied. We performed multi-omic analysis to investigate the expression of SOX genes in human cancers. Expression and phylogenetic tree analyses of the SOX gene family revealed that the expression of three closely related SOX members, SOX4, SOX11, and SOX12, was increased in multiple cancers. Expression, mutation, and alteration of the three SOX members were evaluated using the Oncomine and cBioPortal databases, and the correlation between these genes and clinical outcomes in various cancers was examined using the Kaplan–Meier, PrognoScan, and R2 database analyses. The genes commonly correlated with the three SOX members were categorized in key pathways related to the cell cycle, mitosis, immune system, and cancer progression in liver cancer and sarcoma. Additionally, functional protein partners with three SOX proteins and their probable signaling pathways were explored using the STRING database. This study suggests the prognostic value of the expression of three SOX genes and their associated pathways in various human cancers.
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Affiliation(s)
| | | | | | | | - Ssang-Goo Cho
- Correspondence: ; Tel.: +82-2-450-4207 or +82-2-444-4207
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40
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Liu L, Dong T, Sheng J. Propofol Suppresses Gastric Cancer Progression by Regulating circPDSS1/miR-1324/SOX4 Axis. Cancer Manag Res 2021; 13:6031-6043. [PMID: 34377022 PMCID: PMC8349207 DOI: 10.2147/cmar.s312989] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 07/16/2021] [Indexed: 12/12/2022] Open
Abstract
Background Propofol is a common intravenous anesthetic that exerts an antitumor role in human cancers. Circular RNAs (circRNAs) play crucial roles in the progression of various cancers. However, the relationship between propofol and circRNA decaprenyl diphosphate synthase subunit 1 (circPDSS1) in gastric cancer (GC) remains unclear. Methods Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8), colony formation, and 5-ethynyl-2ʹ-deoxyuridine (EdU) assays. Cell migration and invasion were assessed by transwell assay. Cell apoptosis was determined by flow cytometry. All protein levels were detected by Western blot assay. The expression levels of circPDSS1, microRNA-1324 (miR-1324), and SRY-box transcription factor 4 (SOX4) mRNA were determined by quantitative real-time PCR (qRT-PCR). The interaction between miR-1324 and circPDSS1 or SOX4 was confirmed by dual-luciferase reporter and RNA pull-down assays. The mice xenograft model was established to investigate the role of propofol and circPDSS1 in vivo. Results Propofol inhibited cell proliferation, migration and invasion and induced apoptosis in GC cells, which could be reversed by upregulating circPDSS1. MiR-1324 was a target of circPDSS1, and circPDSS1 promoted cell proliferation, migration and invasion and reduced apoptosis in propofol-treated cells by sponging miR-1324. Moreover, SOX4 was a direct target of miR-1324, and miR-1324 exerted anticancer role by targeting SOX4 in propofol-treated cells. CircPDSS1 acted as a sponge of miR-1324 to regulate SOX4 expression. Additionally, circPDSS1 overexpression weakened the anticancer role of propofol in vivo. Conclusion Propofol exerted anticancer role in GC through regulating circPDSS1/miR-1324/SOX4 axis, indicating that propofol might be an effective therapeutic medicine for GC treatment.
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Affiliation(s)
- Leyi Liu
- Department of Anesthesiology, Wuhu Hospital of Traditional Chinese Medicine, Wuhu, 241000, People's Republic of China
| | - Ting Dong
- Yijishan Hospital, First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, People's Republic of China
| | - Jun Sheng
- Department of Oncology, Wuhu Hospital of Traditional Chinese Medicine, Wuhu, 241000, People's Republic of China
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41
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Wilk AJ, Lee MJ, Wei B, Parks B, Pi R, Martínez-Colón GJ, Ranganath T, Zhao NQ, Taylor S, Becker W, Stanford COVID-19 Biobank, Jimenez-Morales D, Blomkalns AL, O’Hara R, Ashley EA, Nadeau KC, Yang S, Holmes S, Rabinovitch M, Rogers AJ, Greenleaf WJ, Blish CA. Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19. J Exp Med 2021; 218:e20210582. [PMID: 34128959 PMCID: PMC8210586 DOI: 10.1084/jem.20210582] [Citation(s) in RCA: 136] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/13/2021] [Accepted: 05/13/2021] [Indexed: 12/20/2022] Open
Abstract
Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-κB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.
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Affiliation(s)
- Aaron J. Wilk
- Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA
- Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Madeline J. Lee
- Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Bei Wei
- Department of Genetics, Stanford University School of Medicine, Stanford, CA
| | - Benjamin Parks
- Department of Genetics, Stanford University School of Medicine, Stanford, CA
- Graduate Program in Computer Science, Stanford University School of Medicine, Stanford, CA
| | - Ruoxi Pi
- Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | | | - Thanmayi Ranganath
- Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Nancy Q. Zhao
- Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Shalina Taylor
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA
- Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA
| | - Winston Becker
- Department of Genetics, Stanford University School of Medicine, Stanford, CA
| | | | | | - Andra L. Blomkalns
- Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA
| | - Ruth O’Hara
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA
| | - Euan A. Ashley
- Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Kari C. Nadeau
- Department of Medicine, Stanford University School of Medicine, Stanford, CA
- Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA
| | - Samuel Yang
- Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA
| | - Susan Holmes
- Department of Statistics, Stanford University, Stanford, CA
| | - Marlene Rabinovitch
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA
- Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA
| | - Angela J. Rogers
- Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - William J. Greenleaf
- Department of Genetics, Stanford University School of Medicine, Stanford, CA
- Department of Applied Physics, Stanford University, Stanford, CA
| | - Catherine A. Blish
- Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA
- Chan Zuckerberg Biohub, San Francisco, CA
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42
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Morande PE, Yan XJ, Sepulveda J, Seija N, Marquez ME, Sotelo N, Abreu C, Crispo M, Fernández-Graña G, Rego N, Bois T, Methot SP, Palacios F, Remedi V, Rai KR, Buschiazzo A, Di Noia JM, Navarrete MA, Chiorazzi N, Oppezzo P. AID overexpression leads to aggressive murine CLL and nonimmunoglobulin mutations that mirror human neoplasms. Blood 2021; 138:246-258. [PMID: 34292322 DOI: 10.1182/blood.2020008654] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 02/12/2021] [Indexed: 11/20/2022] Open
Abstract
Most cancers become more dangerous by the outgrowth of malignant subclones with additional DNA mutations that favor proliferation or survival. Using chronic lymphocytic leukemia (CLL), a disease that exemplifies this process and is a model for neoplasms in general, we created transgenic mice overexpressing the enzyme activation-induced deaminase (AID), which has a normal function of inducing DNA mutations in B lymphocytes. AID not only allows normal B lymphocytes to develop more effective immunoglobulin-mediated immunity, but is also able to mutate nonimmunoglobulin genes, predisposing to cancer. In CLL, AID expression correlates with poor prognosis, suggesting a role for this enzyme in disease progression. Nevertheless, direct experimental evidence identifying the specific genes that are mutated by AID and indicating that those genes are associated with disease progression is not available. To address this point, we overexpressed Aicda in a murine model of CLL (Eμ-TCL1). Analyses of TCL1/AID mice demonstrate a role for AID in disease kinetics, CLL cell proliferation, and the development of cancer-related target mutations with canonical AID signatures in nonimmunoglobulin genes. Notably, our mouse models can accumulate mutations in the same genes that are mutated in human cancers. Moreover, some of these mutations occur at homologous positions, leading to identical or chemically similar amino acid substitutions as in human CLL and lymphoma. Together, these findings support a direct link between aberrant AID activity and CLL driver mutations that are then selected for their oncogenic effects, whereby AID promotes aggressiveness in CLL and other B-cell neoplasms.
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MESH Headings
- Animals
- Cytidine Deaminase/genetics
- Disease Models, Animal
- Gene Expression Regulation, Leukemic
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Mutation
- Up-Regulation
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Affiliation(s)
- Pablo Elías Morande
- Research Laboratory on Chronic Lymphocytic Leukemia, Institut Pasteur de Montevideo, Montevideo, Uruguay
- Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina de Buenos Aires, Buenos Aires, Argentina
- Tumor-Stroma Interactions, Department of Oncology, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Xiao-Jie Yan
- The Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Julieta Sepulveda
- Laboratory of Molecular Medicine, Centro Asistencial Docente e Investigación de la Universidad de Magallanes (CADI-UMAG), School of Medicine, University of Magallanes, Punta Arenas, Chile
| | - Noé Seija
- Research Laboratory on Chronic Lymphocytic Leukemia, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - María Elena Marquez
- Research Laboratory on Chronic Lymphocytic Leukemia, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Natalia Sotelo
- Research Laboratory on Chronic Lymphocytic Leukemia, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Cecilia Abreu
- Research Laboratory on Chronic Lymphocytic Leukemia, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | | | | | - Natalia Rego
- Bioinformatics Unit, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Therence Bois
- Institut de Recherches Cliniques de Montreal, Montréal, QC, Canada
| | - Stephen P Methot
- Institut de Recherches Cliniques de Montreal, Montréal, QC, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Florencia Palacios
- The Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Victoria Remedi
- Hospital Maciel, Administración de los Servicios de Salud del Estado (ASSE), Ministerio de Salud, Montevideo, Uruguay
| | - Kanti R Rai
- The Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Alejandro Buschiazzo
- Laboratory of Molecular and Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, Uruguay; and
- Integrative Microbiology of Zoonotic Agents-International Joint Unit, Department of Microbiology, Institut Pasteur, Paris, France
| | - Javier M Di Noia
- Institut de Recherches Cliniques de Montreal, Montréal, QC, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Marcelo A Navarrete
- Laboratory of Molecular Medicine, Centro Asistencial Docente e Investigación de la Universidad de Magallanes (CADI-UMAG), School of Medicine, University of Magallanes, Punta Arenas, Chile
| | - Nicholas Chiorazzi
- The Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Pablo Oppezzo
- Research Laboratory on Chronic Lymphocytic Leukemia, Institut Pasteur de Montevideo, Montevideo, Uruguay
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UTX maintains the functional integrity of the murine hematopoietic system by globally regulating aging-associated genes. Blood 2021; 137:908-922. [PMID: 33174606 DOI: 10.1182/blood.2019001044] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 09/18/2020] [Indexed: 02/07/2023] Open
Abstract
Epigenetic regulation is essential for the maintenance of the hematopoietic system, and its deregulation is implicated in hematopoietic disorders. In this study, UTX, a demethylase for lysine 27 on histone H3 (H3K27) and a component of COMPASS-like and SWI/SNF complexes, played an essential role in the hematopoietic system by globally regulating aging-associated genes. Utx-deficient (UtxΔ/Δ) mice exhibited myeloid skewing with dysplasia, extramedullary hematopoiesis, impaired hematopoietic reconstituting ability, and increased susceptibility to leukemia, which are the hallmarks of hematopoietic aging. RNA-sequencing (RNA-seq) analysis revealed that Utx deficiency converted the gene expression profiles of young hematopoietic stem-progenitor cells (HSPCs) to those of aged HSPCs. Utx expression in hematopoietic stem cells declined with age, and UtxΔ/Δ HSPCs exhibited increased expression of an aging-associated marker, accumulation of reactive oxygen species, and impaired repair of DNA double-strand breaks. Pathway and chromatin immunoprecipitation analyses coupled with RNA-seq data indicated that UTX contributed to hematopoietic homeostasis mainly by maintaining the expression of genes downregulated with aging via demethylase-dependent and -independent epigenetic programming. Of note, comparison of pathway changes in UtxΔ/Δ HSPCs, aged muscle stem cells, aged fibroblasts, and aged induced neurons showed substantial overlap, strongly suggesting common aging mechanisms among different tissue stem cells.
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Parol-Kulczyk M, Gzil A, Maciejewska J, Bodnar M, Grzanka D. Clinicopathological significance of the EMT-related proteins and their interrelationships in prostate cancer. An immunohistochemical study. PLoS One 2021; 16:e0253112. [PMID: 34157052 PMCID: PMC8219170 DOI: 10.1371/journal.pone.0253112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 05/29/2021] [Indexed: 11/19/2022] Open
Abstract
The chronic inflammation influences a microenvironment, where as a result of losing control over tissue homeostatic mechanisms, the carcinogenesis process may be induced. Inflammatory response cells can secrete a number of factors that support both initiation and progression of cancer and also they may consequently induct an epithelial-mesenchymal transition (EMT), the process responsible for development of distant metastasis. Macrophage migration inhibitory factor (MIF) acts as a pro-inflammatory cytokine that is considered as a link between chronic inflammation and tumor development. MIF can function as a modulator of important cancer-related genes expression, as well as an activator of signaling pathways that promotes the development of prostate cancer. The study was performed on FFPE tissues resected from patients who underwent radical prostatectomy. To investigate the relationship of studied proteins with involvement in tumor progression and initiation of epithelial-to-mesenchymal transition (EMT) process, we selected clinicopathological parameters related to tumor progression. Immunohistochemical analyses of MIF, SOX-4, β-catenin and E-cadherin were performed on TMA slides. We found a statistically significant correlation of overall β-catenin expression with the both lymph node metastasis (p<0.001) and presence of angioinvasion (p = 0.012). Membrane β-catenin expression was associated with distant metastasis (p = 0.021). In turn, nuclear MIF was correlated with lymph node metastasis (p = 0.003). The positive protein-protein correlations have been shown between the total β-catenin protein expression level with level of nuclear SOX-4 protein expression (r = 0.27; p<0.05) as well as negative correlation of β-catenin expression with level of nuclear MIF protein expression (r = -0.23; p<0.05). Our results seem promising and strongly highlight the potential role of MIF in development of nodal metastases as well as may confirm an involvement of β-catenin in disease spread in case of prostate cancer.
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Affiliation(s)
- Martyna Parol-Kulczyk
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
| | - Arkadiusz Gzil
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
| | - Joanna Maciejewska
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
| | - Magdalena Bodnar
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
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González-González R, Ortiz-Sarabia G, Molina-Frechero N, Salas-Pacheco JM, Salas-Pacheco SM, Lavalle-Carrasco J, López-Verdín S, Tremillo-Maldonado O, Bologna-Molina R. Epithelial-Mesenchymal Transition Associated with Head and Neck Squamous Cell Carcinomas: A Review. Cancers (Basel) 2021; 13:3027. [PMID: 34204259 PMCID: PMC8234594 DOI: 10.3390/cancers13123027] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/09/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are aggressive, recurrent, and metastatic neoplasms with a high occurrence around the world and can lead to death when not treated appropriately. Several molecules and signaling pathways are involved in the malignant conversion process. Epithelial-mesenchymal transition (EMT) has been described in HNSCCs, a major type of aggressive carcinoma. EMT describes the development of epithelial cells into mesenchymal cells, which depends on several molecular interactions and signaling pathways that facilitate mesenchymal conversion. This is related to interactions with the microenvironment of the tumor, hypoxia, growth factors, matrix metalloproteinases, and the presence of viral infections. In this review, we focus on the main molecules related to EMT, their interactions with the tumor microenvironment, plasticity phenomena, epigenetic regulation, hypoxia, inflammation, their relationship with immune cells, and the inhibition of EMT in the context of HNSCCs.
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Affiliation(s)
- Rogelio González-González
- Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango 34000, Mexico; (R.G.-G.); (G.O.-S.); (O.T.-M.)
| | - Gamaliel Ortiz-Sarabia
- Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango 34000, Mexico; (R.G.-G.); (G.O.-S.); (O.T.-M.)
| | - Nelly Molina-Frechero
- Xochimilco Unit, Department of Health Care, Universidad Autónoma Metropolitana (UAM) Xochimilco, Mexico City 04960, Mexico; (N.M.-F.); (J.L.-C.)
| | - José Manuel Salas-Pacheco
- Scientific Research Institute, Universidad Juárez del Estado de Durango, Avenida Universidad S/N, Durango 34000, Mexico; (J.M.S.-P.); (S.M.S.-P.)
| | - Sergio Manuel Salas-Pacheco
- Scientific Research Institute, Universidad Juárez del Estado de Durango, Avenida Universidad S/N, Durango 34000, Mexico; (J.M.S.-P.); (S.M.S.-P.)
| | - Jesús Lavalle-Carrasco
- Xochimilco Unit, Department of Health Care, Universidad Autónoma Metropolitana (UAM) Xochimilco, Mexico City 04960, Mexico; (N.M.-F.); (J.L.-C.)
| | - Sandra López-Verdín
- Health Science Center, Dentistry Research Institute, Universidad de Guadalajara, Guadalajara 4430, Mexico;
| | - Omar Tremillo-Maldonado
- Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango 34000, Mexico; (R.G.-G.); (G.O.-S.); (O.T.-M.)
| | - Ronell Bologna-Molina
- Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango 34000, Mexico; (R.G.-G.); (G.O.-S.); (O.T.-M.)
- Molecular Pathology Area, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
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Huang JL, Wang XK, Liao XW, Han CY, Yu TD, Huang KT, Yang CK, Liu XG, Yu L, Zhu GZ, Su H, Qin W, Han QF, Liu ZQ, Zhou X, Liu JQ, Ye XP, Peng T. SOX4 as biomarker in hepatitis B virus-associated hepatocellular carcinoma. J Cancer 2021; 12:3486-3500. [PMID: 33995626 PMCID: PMC8120190 DOI: 10.7150/jca.46579] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 03/28/2021] [Indexed: 01/12/2023] Open
Abstract
Background: Hepatitis B virus infection is associated with liver disease, including cancers. In this study, we assessed the power of sex-determining region Y (SRY)-related high-mobility group (HMG)-box 4(SOX4) gene to predict the clinical course of hepatocellular carcinoma (HCC). Methods: To evaluate the differential expression of SOX4 and its diagnostic and prognostic potential in HCC, we analyzed the GSE14520 dataset. Stratified analysis and joint-effect analysis were done using SOX4 and clinical factor. We then designed a nomogram for predicting the clinical course of HCC. Differential SOX4 expression and its correlation with tumor stage as well as its diagnostic and prognostic value were analyzed on the oncomine and GEPIA websites. Gene set enrichment analysis was explored as well as candidate gene ontology and metabolic pathways modulated by in SOX4 HCC. Results: Our analysis revealed that the level of SOX4 was significantly upregulated in tumor issue (P <0.001). This observation was validated through oncomine dataset and MERAV analysis (all P <0.05). Diagnostic receiver operating characteristic (ROC) analysis of SOX4 suggested it has diagnostic potential in HCC (GSE14520 dataset: P <0.001, area under curve (AUC) = 0.782; Oncomine: (Wurmbach dataset) P = 0.002, AUC = 0.831 and (Mas dataset) P <0.001, AUC = 0.947). In addition, SOX4 exhibited high correlation with overall survival of HBV-associated HCC (adjusted P = 0.004, hazard ratio (HR) (95% confidence interval (CI)) = 2.055 (1.261-3.349) and recurrence-free survival (adjusted P = 0.008, HR (95% CI) = 1.721 (1.151-2.574). These observations which were verified by GEPIA analysis for overall survival (P = 0.007) and recurrence-free survival (P= 0.096). Gene enrichment analysis revealed that affected processes included lymphocyte differentiation, pancreatic endocrine pathways, and insulin signaling pathway. SOX4 prognostic value was evaluated using nomogram analysis for HCC 1, 3, and 5-year, survival. Conclusion: Differential SOX4 expression presents an avenue of diagnosing and predicting clinical course of HCC. In HCC, SOX4 may affect TP53 metabolic processes, lymphocyte differentiation and the insulin signaling pathway.
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Affiliation(s)
- Jian-Lv Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xiang-Kun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Chuang-Ye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Ting-Dong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Ke-Tuan Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Cheng-Kun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xiao-Guang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.,Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong Province, China
| | - Long Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan Province, China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Quan-Fa Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Zheng-Qian Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Jun-Qi Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xin-Ping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
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Mehta GA, Angus SP, Khella CA, Tong K, Khanna P, Dixon SAH, Verzi MP, Johnson GL, Gatza ML. SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2. NPJ Breast Cancer 2021; 7:40. [PMID: 33837205 PMCID: PMC8035213 DOI: 10.1038/s41523-021-00248-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 03/15/2021] [Indexed: 12/11/2022] Open
Abstract
Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulator of PI3K signaling in TNBC. Genomic and proteomic analyses coupled with mechanistic studies identified TGFBR2 as a direct transcriptional target of SOX4 and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further report that SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors, form a previously unreported complex that is required to maintain an open chromatin conformation at the TGFBR2 regulatory regions in order to mediate TGFBR2 expression and PI3K signaling. Collectively, our findings delineate the mechanism by which SOX4 and SMARCA4 cooperatively regulate PI3K/Akt signaling and suggest that this complex may play an essential role in TNBC genesis and/or progression.
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Affiliation(s)
- Gaurav A Mehta
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Steven P Angus
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Christen A Khella
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Kevin Tong
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Pooja Khanna
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Shelley A H Dixon
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Michael P Verzi
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Gary L Johnson
- Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Michael L Gatza
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
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48
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Zhang M, Li H, Han Y, Wang M, Zhang J, Ma S. Clinicopathological significance of SOX4 and epithelial-mesenchymal transition markers in patients with laryngeal squamous cell carcinoma. Medicine (Baltimore) 2021; 100:e25028. [PMID: 33761659 PMCID: PMC9282127 DOI: 10.1097/md.0000000000025028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 02/07/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND AND AIM Sex-determining region-Y-related high-mobility-group box 4 (SOX4) is associated with the metastasis and prognosis of many cancer types. However, studies on the role of SOX4 in laryngeal squamous cell carcinoma (LSCC) are few, and hence the mechanism is unclear. Epithelial-mesenchymal transition (EMT) allows neoplastic cells to gain the plasticity and motility required for tumor progression and metastasis. This study aimed to analyze the relationship between SOX4 and EMT, and their relationship with clinicopathological factors and related prognosis. METHODS Immunohistochemical staining was used to detect the positive expression of SOX4 protein, EMT-related transcription factor protein, and related marker protein in 127 LSCC tissue samples. At the same time, data on various parameters of clinical pathology and postoperative survival were collected. RESULTS The positive expression rate of SOX4 and Slug in LSCC was related to pathological differentiation, lymphatic invasion, and pathological tumor node metastasis (TNM) of a tumor. The expression rates of ZEB1, Twist, E-cadherin, N-cadherin, and β-catenin in LSCC correlated with lymphatic invasion and pathological tumor node metastasis. The expression of SOX4, combined expression of SOX4 and ZEB1, and lymphatic invasion were independent prognostic factors for the total survival time of patients with LSCC. CONCLUSIONS In summary, SOX4 was vital in the LSCC EMT process, which might be mediated by transcription factor ZEB1. SOX4 and ZEB1 might serve as potential biomarkers of metastasis and prognosis, as well as promising therapeutic targets of LSCC.
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Affiliation(s)
- Mingjie Zhang
- Department Of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, Guangdong
- Department Of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Hui Li
- Department Of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, Guangdong
- Department Of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Yuefeng Han
- Department Of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, Guangdong
- Department Of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Mengjun Wang
- Department Of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, Guangdong
- Department Of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Junjie Zhang
- Department Of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, Guangdong
- Department Of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Shiyin Ma
- Department Of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, Guangdong
- Department Of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
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49
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Zhang J, Chai S, Ruan X. SOX4 Serves an Oncogenic Role in the Tumourigenesis of Human Breast Adenocarcinoma by Promoting Cell Proliferation, Migration and Inhibiting Apoptosis. Recent Pat Anticancer Drug Discov 2021; 15:49-58. [PMID: 32048979 DOI: 10.2174/1574892815666200212112119] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 01/24/2020] [Accepted: 02/06/2020] [Indexed: 01/02/2023]
Abstract
BACKGROUND Breast cancer is among the most common malignant cancers worldwide, and breast adenocarcinoma in glandular tissue cells has excessive metastasis and invasion capability. However, little is known on the molecular process by which this disease develops and progresses. OBJECTIVE In this study, we explored the effects of sex-determining region Y-box 4 (SOX4) protein on proliferation, migration, apoptosis and tumourigenesis of breast adenocarcinoma and its possible mechanisms. METHODS The SOX4 overexpression or knockdown Michigan Cancer Foundation-7 (MCF-7) cell lines were established. Among the SOX4 overexpression or MCF-7 knockdown cell lines, proliferation, migration ability and apoptosis rate were detected. The expression levels of apoptosis-related proteins (Bax and Cleaved caspase-3) were analysed using Western blot. The effect of SOX4 on tumourigenesis was analysed using the clone formation assay in vitro and tumour xenograft experiment in nude mice. RESULTS Compared with the overexpression of control cells, proliferation and migration ability of SOX4 overexpression cells significantly increased, the apoptosis rate significantly decreased in addition to the expression levels of Bax and Cleaved caspase-3 (P < 0.05). Compared with the knockdown of control cells, proliferation and migration ability of SOX4 knockdown cells significantly decreased, and the apoptosis rate and expression levels of Bax and Cleaved caspase-3 significantly increased (P < 0.05). Clone formation and tumour growth abilities of SOX4 overexpression cells were significantly higher than those of the control cells (P < 0.05), whereas SOX4 knockdown cells had the opposite effect. CONCLUSION SOX4 plays an oncogenic role in breast adenocarcinoma tumourigenesis by promoting cell proliferation, migration and inhibiting apoptosis. It can be used as a potential molecular target for breast cancer gene therapy.
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Affiliation(s)
- Junhe Zhang
- Department of Biochemistry and Molecular Biology, Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Shujie Chai
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Xinyu Ruan
- Xinxiang Medical University, Xinxiang 453003, Henan, China
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50
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Bagati A, Kumar S, Jiang P, Pyrdol J, Zou AE, Godicelj A, Mathewson ND, Cartwright ANR, Cejas P, Brown M, Giobbie-Hurder A, Dillon D, Agudo J, Mittendorf EA, Liu XS, Wucherpfennig KW. Integrin αvβ6-TGFβ-SOX4 Pathway Drives Immune Evasion in Triple-Negative Breast Cancer. Cancer Cell 2021; 39:54-67.e9. [PMID: 33385331 PMCID: PMC7855651 DOI: 10.1016/j.ccell.2020.12.001] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 09/18/2020] [Accepted: 12/01/2020] [Indexed: 02/07/2023]
Abstract
Cancer immunotherapy shows limited efficacy against many solid tumors that originate from epithelial tissues, including triple-negative breast cancer (TNBC). We identify the SOX4 transcription factor as an important resistance mechanism to T cell-mediated cytotoxicity for TNBC cells. Mechanistic studies demonstrate that inactivation of SOX4 in tumor cells increases the expression of genes in a number of innate and adaptive immune pathways important for protective tumor immunity. Expression of SOX4 is regulated by the integrin αvβ6 receptor on the surface of tumor cells, which activates TGFβ from a latent precursor. An integrin αvβ6/8-blocking monoclonal antibody (mAb) inhibits SOX4 expression and sensitizes TNBC cells to cytotoxic T cells. This integrin mAb induces a substantial survival benefit in highly metastatic murine TNBC models poorly responsive to PD-1 blockade. Targeting of the integrin αvβ6-TGFβ-SOX4 pathway therefore provides therapeutic opportunities for TNBC and other highly aggressive human cancers of epithelial origin.
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MESH Headings
- Animals
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/pharmacology
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/metabolism
- Antineoplastic Agents, Immunological/therapeutic use
- Cell Line, Tumor
- Drug Resistance, Neoplasm
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Integrins/antagonists & inhibitors
- Integrins/genetics
- Integrins/metabolism
- Mice
- Neoplasm Transplantation
- SOXC Transcription Factors/genetics
- SOXC Transcription Factors/metabolism
- Sequence Analysis, RNA
- Signal Transduction/drug effects
- T-Lymphocytes, Cytotoxic/drug effects
- T-Lymphocytes, Cytotoxic/metabolism
- Transforming Growth Factor beta/genetics
- Triple Negative Breast Neoplasms/drug therapy
- Triple Negative Breast Neoplasms/genetics
- Triple Negative Breast Neoplasms/immunology
- Tumor Escape/drug effects
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Archis Bagati
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02215, USA
| | - Sushil Kumar
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA
| | - Peng Jiang
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Jason Pyrdol
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA
| | - Angela E Zou
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA
| | - Anze Godicelj
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA
| | - Nathan D Mathewson
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA
| | - Adam N R Cartwright
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA
| | - Paloma Cejas
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Myles Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Anita Giobbie-Hurder
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Deborah Dillon
- Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Judith Agudo
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA
| | - Elizabeth A Mittendorf
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA 02215, USA; Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - X Shirley Liu
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Kai W Wucherpfennig
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA; Department of Neurology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02215, USA.
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