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Jin X, Zhang Y, Wang Y, Cao H, Song Q, Huang J, Chen W, Tang H, Zeng Y. TULP3 Regulates Proliferation and Differentiation of 3T3-L1 Preadipocytes Through the Hedgehog Signaling Pathway. BIOLOGY 2025; 14:369. [PMID: 40282234 PMCID: PMC12024758 DOI: 10.3390/biology14040369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 03/17/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025]
Abstract
The TULP family was first identified in progressively obese mice, and TULP3, as a member of its family, has been much studied in tumor cells, but studies on its role in adipocytes have not yet been reported. This study found that the expression of TULP3 showed an increasing trend in the differentiation of 3T3-L1 cells, and overexpression of TULP3 enhanced the proliferation and differentiation capacity of the cells, while inhibition caused the opposite result. TULP3 is a negative regulator of the Hedgehog signaling pathway, which can control lipid metabolism in adipose tissues, but whether TULP3 can play a role in adipose tissues through the Hedgehog signaling pathway is not yet known. It was experimentally found that TULP3 could promote adipogenic differentiation of precursor adipocytes by inhibiting the activity of the Hedgehog signaling pathway. Our results elucidate the role of TULP3 in the generation of precursor adipocytes and provide useful information for a deeper understanding of the molecular mechanisms of adipocytogenesis, which will contribute to the improvement of the treatment of adipose tissue dysfunction or uncontrolled adipogenesis-related diseases.
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Affiliation(s)
- Xinlin Jin
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science and Technology, Shandong Agricultural University, Tai’an 271018, China; (X.J.); (Y.Z.); (H.C.); (Q.S.); (J.H.); (W.C.); (H.T.)
| | - Yu Zhang
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science and Technology, Shandong Agricultural University, Tai’an 271018, China; (X.J.); (Y.Z.); (H.C.); (Q.S.); (J.H.); (W.C.); (H.T.)
| | - Yunzhou Wang
- Department of Veterinary Medicine, Shandong Vocational Animal Science and Veterinary College, Weifang 261061, China;
| | - Hongzhen Cao
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science and Technology, Shandong Agricultural University, Tai’an 271018, China; (X.J.); (Y.Z.); (H.C.); (Q.S.); (J.H.); (W.C.); (H.T.)
| | - Qi Song
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science and Technology, Shandong Agricultural University, Tai’an 271018, China; (X.J.); (Y.Z.); (H.C.); (Q.S.); (J.H.); (W.C.); (H.T.)
| | - Jingsen Huang
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science and Technology, Shandong Agricultural University, Tai’an 271018, China; (X.J.); (Y.Z.); (H.C.); (Q.S.); (J.H.); (W.C.); (H.T.)
| | - Wei Chen
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science and Technology, Shandong Agricultural University, Tai’an 271018, China; (X.J.); (Y.Z.); (H.C.); (Q.S.); (J.H.); (W.C.); (H.T.)
| | - Hui Tang
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science and Technology, Shandong Agricultural University, Tai’an 271018, China; (X.J.); (Y.Z.); (H.C.); (Q.S.); (J.H.); (W.C.); (H.T.)
| | - Yongqing Zeng
- Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, College of Animal Science and Technology, Shandong Agricultural University, Tai’an 271018, China; (X.J.); (Y.Z.); (H.C.); (Q.S.); (J.H.); (W.C.); (H.T.)
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Mao S, Song R, Jin S, Pang S, Jovanovic A, Zimmerman A, Li P, Wu X, Wendland MF, Lin K, Chen WC, Choksi SP, Chen G, Holtzman MJ, Reiter JF, Wan Y, Xuan Z, Xiang YK, Xu CS, Upadhyayula S, Hess HF, He L. Multicilia dynamically transduce Sonic Hedgehog signaling to regulate choroid plexus functions. Cell Rep 2025; 44:115383. [PMID: 40057957 DOI: 10.1016/j.celrep.2025.115383] [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: 06/11/2024] [Revised: 11/17/2024] [Accepted: 02/11/2025] [Indexed: 03/29/2025] Open
Abstract
The choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by a multiciliated epithelial monolayer that regulates CSF production. We demonstrate that defective choroid plexus ciliogenesis or intraflagellar transport yields neonatal hydrocephalus, at least in part due to increased water channel Aqp1 and ion transporter Atp1a2 expression. We demonstrate choroid plexus multicilia as sensory cilia, transducing both canonical and non-canonical Sonic Hedgehog (Shh) signaling. Interestingly, it is the non-canonical Shh signaling that represses Aqp1 and Atp1a2 expression by the Smoothened (Smo)/Gαi/cyclic AMP (cAMP) pathway. Choroid plexus multicilia exhibit unique ciliary ultrastructure, carrying features of both primary and motile cilia. Unlike most cilia that elongate during maturation, choroid plexus ciliary length decreases during development, causing a decline of Shh signaling intensity in the developing choroid plexus, a derepression of Aqp1 and Atp1a2, and, ultimately, increased CSF production. Hence, the developmental dynamics of choroid plexus multicilia dampens the Shh signaling intensity to promote CSF production.
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Affiliation(s)
- Suifang Mao
- Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
| | - Rui Song
- Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
| | - Shibo Jin
- Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
| | - Song Pang
- Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
| | - Aleksandra Jovanovic
- Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
| | - Adam Zimmerman
- Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
| | - Peng Li
- Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
| | - Xinying Wu
- Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
| | - Michael F Wendland
- Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
| | - Kerry Lin
- Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
| | - Wei-Chi Chen
- Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
| | - Semil P Choksi
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Gang Chen
- Chongqing Key Laboratory of Cytomics, Chongqing 400038, China
| | - Michael J Holtzman
- Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Jeremy F Reiter
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
| | - Ying Wan
- Chongqing Key Laboratory of Cytomics, Chongqing 400038, China
| | - Zhenyu Xuan
- Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Yang K Xiang
- Department of Pharmacology, University of California at Davis, Davis, CA 95616, USA; VA Northern California Health Care System, Mather, CA 95655, USA
| | - C Shan Xu
- Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA
| | - Srigokul Upadhyayula
- Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
| | - Harald F Hess
- Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
| | - Lin He
- Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
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Hu Q, Qi X, Donnelly L, Li X. Inhibiting hedgehog signal by a patched-1 antibody. Cell Discov 2025; 11:29. [PMID: 40128518 PMCID: PMC11933295 DOI: 10.1038/s41421-025-00772-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Accepted: 01/10/2025] [Indexed: 03/26/2025] Open
Affiliation(s)
- Qinli Hu
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xiaofeng Qi
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Linda Donnelly
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xiaochun Li
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Mao S, Song R, Jin S, Pang S, Jovanovic A, Zimmerman A, Li P, Wu X, Wendland MF, Lin K, Chen WC, Choksi SP, Chen G, Holtzman MJ, Reiter JF, Wan Y, Xuan Z, Xiang YK, Xu CS, Upadhyayula S, Hess HF, He L. Multicilia dynamically transduce Shh signaling to regulate choroid plexus functions. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.21.633415. [PMID: 39896593 PMCID: PMC11785054 DOI: 10.1101/2025.01.21.633415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by a multiciliated epithelial monolayer that regulates CSF production. We demonstrate that defective choroid plexus ciliogenesis or Intraflagellar transport yields neonatal hydrocephalus, at least in part, due to increased water channel Aqp1 and ion transporter Atp1a2 expression. We demonstrate choroid plexus multicilia as sensory cilia, transducing both canonical and non-canonical Shh signaling. Interestingly, it is the non-canonical Shh signaling that represses Aqp1 and Atp1a2 expression by Smo/Gαi/cAMP pathway. Choroid plexus multicilia exhibit unique ciliary ultrastructure, carrying features of both primary and motile cilia. Unlike most cilia that elongate during maturation, choroid plexus ciliary length decreases during development, causing a decline of Shh signaling intensity in developing choroid plexus, a derepression of Aqp1 and Atp1a2, and ultimately, an increased CSF production. Hence, developmental dynamics of choroid plexus multicilia dampens the Shh signaling intensity to promote CSF production.
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Qi Z, Liu Q, Li H, Zhang Y, Yu Z, Luo W, Wang K, Zhang Y, Pan S, Wang C, Jiang H, Qiu Q, Wang W, Fan G, Li Y. Telomere-to-telomere genome assembly of Electrophorus electricus provides insights into the evolution of electric eels. Gigascience 2025; 14:giaf024. [PMID: 40167991 PMCID: PMC11959694 DOI: 10.1093/gigascience/giaf024] [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: 07/25/2024] [Revised: 11/05/2024] [Accepted: 02/18/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Electric eels evolved remarkable electric organs that enable them to instantaneously discharge hundreds of volts for predation, defense, and communication. However, the absence of a high-quality reference genome has extremely constrained the studies of electric eels in various aspects. RESULTS Using high-depth, multiplatform sequencing data, we successfully assembled the first telomere-to-telomere high-quality reference genome of Electrophorus electricus, which has a genome size of 833.43 Mb and comprises 26 chromosomes. Multiple evaluations, including N50 statistics (30.38 Mb), BUSCO scores (97.30%), and mapping ratio of short-insert sequencing data (99.91%), demonstrate the high contiguity and completeness of the electric eel genome assembly we obtained. Genome annotation predicted 396.63 Mb repetitive sequences and 20,992 protein-coding genes. Furthermore, evolutionary analyses indicate that Gymnotiformes, which the electric eel belongs to, has a closer relationship with Characiformes than Siluriformes and diverged from Characiformes 95.00 million years ago. Pairwise sequentially Markovian coalescent analysis found a sharply decreased trend of the population size of E. electricus over the past few hundred thousand years. Furthermore, many regulatory factors related to neurotransmitters and classical signaling pathways during embryonic development were significantly expanded, potentially contributing to the generation of high-voltage electricity. CONCLUSIONS This study not only provided the first high-quality telomere-to-telomere reference genome of E. electricus but also greatly enhanced our understanding of electric eels.
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Affiliation(s)
- Zan Qi
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Qun Liu
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
| | - Haorong Li
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Yaolei Zhang
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
| | - Ziwei Yu
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Wenkai Luo
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Kun Wang
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Yuxin Zhang
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Shoupeng Pan
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Chao Wang
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Hui Jiang
- College of Life Sciences, Hainan Normal University, Haikou 571158, China
| | - Qiang Qiu
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Wen Wang
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Guangyi Fan
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
| | - Yongxin Li
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
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Yang Q, Jiang P, Tang H, Wen J, Zhou L, Zhao Y, Wang L, Wang J, Yang Q. Shh regulates M2 microglial polarization and fibrotic scar formation after ischemic stroke. Neurochem Int 2024; 180:105862. [PMID: 39307461 DOI: 10.1016/j.neuint.2024.105862] [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: 06/18/2024] [Revised: 09/17/2024] [Accepted: 09/19/2024] [Indexed: 09/25/2024]
Abstract
BACKGROUND Fibrotic scar formation is a critical pathological change impacting tissue reconstruction and functional recovery after ischemic stroke. The regulatory mechanisms behind fibrotic scarring in the central nervous system (CNS) remain largely unknown. While macrophages are known to play a role in fibrotic scar formation in peripheral tissues, the involvement of microglia, the resident immune cells of the CNS, in CNS fibrosis requires further exploration. The Sonic Hedgehog (Shh) signaling pathway, pivotal in embryonic development and tissue regeneration, is also crucial in modulating fibrosis in peripheral tissues. However, the impact and regulatory mechanisms of Shh on fibrotic scar formation post-ischemic stroke have not been thoroughly investigated. METHODS This study explores whether Shh can regulate fibrotic scar formation post-ischemic stroke and its underlying mechanisms through in vivo and in vitro manipulation of Shh expression. RESULTS Our results showed that Shh expression was upregulated in the serum of acute ischemic stroke patients, as well as in the serum, CSF, and ischemic regions of MCAO/R mice. Moreover, the upregulation of Shh expression was positively correlated with fibrotic scar formation and M2 microglial polarization. Shh knockdown inhibited fibrotic scar formation and M2 microglial polarization while aggravating neurological deficits in MCAO/R mice. In vitro, adenoviral knockdown or Smoothened Agonist (SAG) activation of Shh expression in BV2 cells following OGD/R regulated their polarization and influenced the expression of TGFβ1 and PDGFA, subsequently affecting fibroblast activation. CONCLUSION These results suggest that Shh regulates M2 microglial polarization and fibrotic scar formation after cerebral ischemia.
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Affiliation(s)
- Qinghuan Yang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peiran Jiang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Tang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jun Wen
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Zhou
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yong Zhao
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ling Wang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiani Wang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qin Yang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Du Y, Sun H, Shi Z, Sui X, Liu B, Zheng Z, Liu Y, Xuan Z, Zhong M, Fu M, Bai Y, Zhang Q, Shao C. Targeting the hedgehog pathway in MET mutation cancers and its effects on cells associated with cancer development. Cell Commun Signal 2023; 21:313. [PMID: 37919751 PMCID: PMC10623711 DOI: 10.1186/s12964-023-01333-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 09/25/2023] [Indexed: 11/04/2023] Open
Abstract
The mutation of MET plays a crucial role in the initiation of cancer, while the Hedgehog (Hh) pathway also plays a significant role in cell differentiation and the maintenance of tumor stem cells. Conventional chemotherapy drugs are primarily designed to target the majority of cell populations within tumors rather than tumor stem cells. Consequently, after a brief period of remission, tumors often relapse. Moreover, the exclusive targeting of tumor stemness cell disregards the potential for other tumor cells to regain stemness and acquire drug resistance. As a result, current drugs that solely target the HGF/c-MET axis and the Hh pathway demonstrate only moderate efficacy in specific types of cancer. Mounting evidence indicates that these two pathways not only play important roles in cancer but also exert significant influence on the development of resistance to single-target therapies through the secretion of their own ligands. In this comprehensive review, we analyze and compare the potential impact of the Hh pathway on the tumor microenvironment (TME) in HGF/c-MET-driven tumor models, as well as the interplay between different cell types. Additionally, we further substantiate the potential and necessity of dual-pathway combination therapy as a critical target in MET addicted cancer treatment. Video Abstract.
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Affiliation(s)
- Yifan Du
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Huimin Sun
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Zhiyuan Shi
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Xiuyuan Sui
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Bin Liu
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Zeyuan Zheng
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Yankuo Liu
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Zuodong Xuan
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Min Zhong
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Meiling Fu
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Yang Bai
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Qian Zhang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China
| | - Chen Shao
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China.
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Girich A, Sadriev K, Frolova L, Dolmatov I. Role of smoothened and sfrp genes in Eupentacta fraudatrix regeneration. Wound Repair Regen 2023; 31:464-474. [PMID: 37210604 DOI: 10.1111/wrr.13097] [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: 01/11/2023] [Revised: 03/14/2023] [Accepted: 03/30/2023] [Indexed: 05/22/2023]
Abstract
The secreted frizzled-related proteins (sfrp) and smoothened (smo) genes and their possible role in the regeneration of internal organs in the holothurian Eupentacta fraudatrix were studied. In this species, two sfrp genes were identified: sfrp1/2/5, sfrp3/4 and one smo gene. Their expression was analysed during regeneration of the aquapharyngeal bulb (AB) and intestine, and these genes were knock down by RNA interference. It has been shown that the expression of these genes is extremely important for the formation of AB. In all animals subjected to knockdown, at 7 days after evisceration, a full-sized AB rudiment was not formed. As a result of sfrp1/2/5 knockdown, the process of extracellular matrix remodelling in AB is interrupted, that leading to clusters of dense connective tissue formation, which slows down cell migration. When sfrp3/4 is knockdown, the connective tissue of AB anlage is completely disrupted and its symmetry is broken. The effect of smo knockdown was expressed in a significant impairment of AB regeneration, when connections between ambulacras were not formed after evisceration. However, despite severe disturbances in AB regeneration, a normal-sized gut anlage developed in all cases, which suggests that the regeneration of the digestive tube and AB occur independently of each other.
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Affiliation(s)
- Alexander Girich
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Vladivostok, Russia
| | - Konstantin Sadriev
- Institute of the World Ocean, Far Eastern Federal University (FEFU), Vladivostok, Russia
| | - Lidia Frolova
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Vladivostok, Russia
| | - Igor Dolmatov
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Vladivostok, Russia
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9
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Jiang J. Hedgehog signaling mechanism and role in cancer. Semin Cancer Biol 2022; 85:107-122. [PMID: 33836254 PMCID: PMC8492792 DOI: 10.1016/j.semcancer.2021.04.003] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/25/2021] [Accepted: 04/02/2021] [Indexed: 12/12/2022]
Abstract
Cell-cell communication through evolutionarily conserved signaling pathways governs embryonic development and adult tissue homeostasis. Deregulation of these signaling pathways has been implicated in a wide range of human diseases including cancer. One such pathway is the Hedgehog (Hh) pathway, which was originally discovered in Drosophila and later found to play a fundamental role in human development and diseases. Abnormal Hh pathway activation is a major driver of basal cell carcinomas (BCC) and medulloblastoma. Hh exerts it biological influence through a largely conserved signal transduction pathway from the activation of the GPCR family transmembrane protein Smoothened (Smo) to the conversion of latent Zn-finger transcription factors Gli/Ci proteins from their repressor (GliR/CiR) to activator (GliA/CiA) forms. Studies from model organisms and human patients have provided deep insight into the Hh signal transduction mechanisms, revealed roles of Hh signaling in a wide range of human cancers, and suggested multiple strategies for targeting this pathway in cancer treatment.
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Affiliation(s)
- Jin Jiang
- Department of Molecular Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA.
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10
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Morii A, Inazu T. HDAC8 is implicated in embryoid body formation via canonical Hedgehog signaling and regulates neuronal differentiation. Biochem Biophys Res Commun 2022; 629:78-85. [DOI: 10.1016/j.bbrc.2022.08.068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 08/20/2022] [Accepted: 08/23/2022] [Indexed: 11/28/2022]
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Reciprocal Regulation of Shh Trafficking and H2O2 Levels via a Noncanonical BOC-Rac1 Pathway. Antioxidants (Basel) 2022; 11:antiox11040718. [PMID: 35453403 PMCID: PMC9025708 DOI: 10.3390/antiox11040718] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/25/2022] [Accepted: 04/03/2022] [Indexed: 11/21/2022] Open
Abstract
Among molecules that bridge environment, cell metabolism, and cell signaling, hydrogen peroxide (H2O2) recently appeared as an emerging but central player. Its level depends on cell metabolism and environment and was recently shown to play key roles during embryogenesis, contrasting with its long-established role in disease progression. We decided to explore whether the secreted morphogen Sonic hedgehog (Shh), known to be essential in a variety of biological processes ranging from embryonic development to adult tissue homeostasis and cancers, was part of these interactions. Here, we report that H2O2 levels control key steps of Shh delivery in cell culture: increased levels reduce primary secretion, stimulate endocytosis and accelerate delivery to recipient cells; in addition, physiological in vivo modulation of H2O2 levels changes Shh distribution and tissue patterning. Moreover, a feedback loop exists in which Shh trafficking controls H2O2 synthesis via a non-canonical BOC-Rac1 pathway, leading to cytoneme growth. Our findings reveal that Shh directly impacts its own distribution, thus providing a molecular explanation for the robustness of morphogenesis to both environmental insults and individual variability.
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12
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Di Minin G, Holzner M, Grison A, Dumeau CE, Chan W, Monfort A, Jerome-Majewska LA, Roelink H, Wutz A. TMED2 binding restricts SMO to the ER and Golgi compartments. PLoS Biol 2022; 20:e3001596. [PMID: 35353806 PMCID: PMC9000059 DOI: 10.1371/journal.pbio.3001596] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 04/11/2022] [Accepted: 03/07/2022] [Indexed: 11/30/2022] Open
Abstract
Hedgehog (HH) signaling is important for embryonic pattering and stem cell differentiation. The G protein–coupled receptor (GPCR) Smoothened (SMO) is the key HH signal transducer modulating both transcription-dependent and transcription-independent responses. We show that SMO protects naive mouse embryonic stem cells (ESCs) from dissociation-induced cell death. We exploited this SMO dependency to perform a genetic screen in haploid ESCs where we identify the Golgi proteins TMED2 and TMED10 as factors for SMO regulation. Super-resolution microscopy shows that SMO is normally retained in the endoplasmic reticulum (ER) and Golgi compartments, and we demonstrate that TMED2 binds to SMO, preventing localization to the plasma membrane. Mutation of TMED2 allows SMO accumulation at the plasma membrane, recapitulating early events after HH stimulation. We demonstrate the physiologic relevance of this interaction in neural differentiation, where TMED2 functions to repress HH signal strength. Identification of TMED2 as a binder and upstream regulator of SMO opens the way for unraveling the events in the ER–Golgi leading to HH signaling activation. Hedgehog signals orchestrate tissue patterning by binding the receptor Patched and restricting the signal transducer Smoothened. A genetic screen reveals Tmed2 as a new interactor of Smoothened that is required for regulating Smoothened transport from the endoplasmic reticulum and Golgi to the plasma membrane and hence modulating the strength of Hedgehog signal transduction.
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Affiliation(s)
- Giulio Di Minin
- Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology ETH Hönggerberg, Zurich, Switzerland
- * E-mail: (GDM); (AW)
| | - Markus Holzner
- Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology ETH Hönggerberg, Zurich, Switzerland
| | - Alice Grison
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Charles E. Dumeau
- Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology ETH Hönggerberg, Zurich, Switzerland
| | - Wesley Chan
- Department Anatomy and Cell Biology, Human Genetics and McGill University, Montreal, Canada
- Department of Pediatrics, Human Genetics and McGill University, Montreal, Canada
| | - Asun Monfort
- Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology ETH Hönggerberg, Zurich, Switzerland
| | - Loydie A. Jerome-Majewska
- Department Anatomy and Cell Biology, Human Genetics and McGill University, Montreal, Canada
- Department of Pediatrics, Human Genetics and McGill University, Montreal, Canada
| | - Henk Roelink
- Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America
| | - Anton Wutz
- Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology ETH Hönggerberg, Zurich, Switzerland
- * E-mail: (GDM); (AW)
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13
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Trivedi P, Patel SK, Bellavia D, Messina E, Palermo R, Ceccarelli S, Marchese C, Anastasiadou E, Minter LM, Felli MP. When Viruses Cross Developmental Pathways. Front Cell Dev Biol 2021; 9:691644. [PMID: 34422814 PMCID: PMC8375270 DOI: 10.3389/fcell.2021.691644] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/20/2021] [Indexed: 12/24/2022] Open
Abstract
Aberrant regulation of developmental pathways plays a key role in tumorigenesis. Tumor cells differ from normal cells in their sustained proliferation, replicative immortality, resistance to cell death and growth inhibition, angiogenesis, and metastatic behavior. Often they acquire these features as a consequence of dysregulated Hedgehog, Notch, or WNT signaling pathways. Human tumor viruses affect the cancer cell hallmarks by encoding oncogenic proteins, and/or by modifying the microenvironment, as well as by conveying genomic instability to accelerate cancer development. In addition, viral immune evasion mechanisms may compromise developmental pathways to accelerate tumor growth. Viruses achieve this by influencing both coding and non-coding gene regulatory pathways. Elucidating how oncogenic viruses intersect with and modulate developmental pathways is crucial to understanding viral tumorigenesis. Many currently available antiviral therapies target viral lytic cycle replication but with low efficacy and severe side effects. A greater understanding of the cross-signaling between oncogenic viruses and developmental pathways will improve the efficacy of next-generation inhibitors and pave the way to more targeted antiviral therapies.
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Affiliation(s)
- Pankaj Trivedi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Diana Bellavia
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Elena Messina
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Rocco Palermo
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Simona Ceccarelli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Cinzia Marchese
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Eleni Anastasiadou
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Lisa M Minter
- Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA, United States
| | - Maria Pia Felli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
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14
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Trnski D, Sabol M, Tomić S, Štefanac I, Mrčela M, Musani V, Rinčić N, Kurtović M, Petrić T, Levanat S, Ozretić P. SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells. Sci Rep 2021; 11:14880. [PMID: 34290270 PMCID: PMC8295376 DOI: 10.1038/s41598-021-93971-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 06/28/2021] [Indexed: 02/08/2023] Open
Abstract
Prostate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. After initial effectiveness of androgen deprivation therapy, resistance quickly occurs. Therefore, we aimed to investigate the role of Hedgehog-GLI (HH-GLI) signaling in sustaining androgen-independent growth of prostate cancer cells. We found various modes of HH-GLI signaling activation in prostate cancer cells depending on androgen availability. When androgen was not deprived, we found evidence of non-canonical SMO signaling through the SRC kinase. After short-term androgen deprivation canonical HH-GLI signaling was activated, but we found little evidence of canonical HH-GLI signaling activity in androgen-independent prostate cancer cells. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification. Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence. Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Also, other non-canonical aspects of this signaling pathway should be investigated in more detail and considered when developing potential therapies.
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Affiliation(s)
- Diana Trnski
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia.
| | - Maja Sabol
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia
| | - Sanja Tomić
- Laboratory for Protein Biochemistry and Molecular Modelling, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia.
| | - Ivan Štefanac
- Primary Health Care Center Osijek, Park kralja Petra Krešimira IV 6, 31000, Osijek, Croatia
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Josipa Huttlera 4, 31000, Osijek, Croatia
| | - Milanka Mrčela
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Josipa Huttlera 4, 31000, Osijek, Croatia
- Department of Pathology, Clinical Hospital Centre Osijek, Josipa Huttlera 4, 31000, Osijek, Croatia
| | - Vesna Musani
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia
| | - Nikolina Rinčić
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia
| | - Matea Kurtović
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia
| | - Tina Petrić
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia
| | - Sonja Levanat
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia
| | - Petar Ozretić
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia
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15
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Mellis D, Staines KA, Peluso S, Georgiou IC, Dora N, Kubiak M, van’t Hof R, Grillo M, Farquharson C, Kinsella E, Thornburn A, Ralston SH, Salter DM, Riobo-Del Galdo NA, Hill RE, Ditzel M. Ubiquitin-protein ligase Ubr5 cooperates with hedgehog signalling to promote skeletal tissue homeostasis. PLoS Genet 2021; 17:e1009275. [PMID: 33819267 PMCID: PMC8057592 DOI: 10.1371/journal.pgen.1009275] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 04/20/2021] [Accepted: 03/20/2021] [Indexed: 12/11/2022] Open
Abstract
Mammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway in Drosophila. To investigate a possible role of UBR5 in regulation of the musculoskeletal system through modulation of mammalian HH signaling, we created a mouse model for specific loss of Ubr5 function in limb bud mesenchyme. Our findings revealed a role for UBR5 in maintaining cartilage homeostasis and suppressing metaplasia. Ubr5 loss of function resulted in progressive and dramatic articular cartilage degradation, enlarged, abnormally shaped sesamoid bones and extensive heterotopic tissue metaplasia linked to calcification of tendons and ossification of synovium. Genetic suppression of smoothened (Smo), a key mediator of HH signalling, dramatically enhanced the Ubr5 mutant phenotype. Analysis of HH signalling in both mouse and cell model systems revealed that loss of Ubr5 stimulated canonical HH-signalling while also increasing PKA activity. In addition, human osteoarthritic samples revealed similar correlations between UBR5 expression, canonical HH signalling and PKA activity markers. Our studies identified a crucial function for the Ubr5 gene in the maintenance of skeletal tissue homeostasis and an unexpected mode of regulation of the HH signalling pathway.
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Affiliation(s)
- David Mellis
- Edinburgh CRUK Cancer Research Centre, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Katherine A. Staines
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom
| | - Silvia Peluso
- MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Ioanna Ch. Georgiou
- Leeds Institute of Medical Research and School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom
| | - Natalie Dora
- MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Malgorzata Kubiak
- Edinburgh CRUK Cancer Research Centre, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Rob van’t Hof
- Centre for Genomic and Experimental Medicine, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Michela Grillo
- Edinburgh CRUK Cancer Research Centre, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Colin Farquharson
- Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, United Kingdom
| | - Elaine Kinsella
- Edinburgh CRUK Cancer Research Centre, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Anna Thornburn
- MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Stuart H. Ralston
- Centre for Genomic and Experimental Medicine, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Donald M. Salter
- Centre for Genomic and Experimental Medicine, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Natalia A. Riobo-Del Galdo
- Leeds Institute of Medical Research and School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom
| | - Robert E. Hill
- MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Mark Ditzel
- Edinburgh CRUK Cancer Research Centre, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
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16
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Zhou D, He L. Sauchinone inhibits hypoxia-induced invasion and epithelial-mesenchymal transition in osteosarcoma cells via inactivation of the sonic hedgehog pathway. J Recept Signal Transduct Res 2021; 42:173-179. [PMID: 33563062 DOI: 10.1080/10799893.2021.1881556] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hypoxia is a typical feature of solid tumors and is closely associated with tumor progression. Sauchinone, a biologically diastereomeric lignan, is isolated from the root of Saururus chinensis and has been widely used for the treatment of various diseases. Recently, sauchinone has been reported to play an anti-cancer role in cancer development under normoxia or hypoxia. However, the specific effects of sauchinone on osteosarcoma (OS) remain unclear. The aim of the present study was to investigate the role of sauchinone in OS progression under hypoxic conditions. The human OS cell lines U2OS and MG-63 were exposed to hypoxia followed by treatment with sauchinone. Cell viability was assessed by the CCK-8 assay. Cell migration and invasion were detected by transwell assays. The expression levels of VEGF, HIF-1α, E-cadherin and N-cadherin were examined by the western blot analysis. Our study showed that OS cell migration and invasion were significantly enhanced by hypoxia. Besides, hypoxic conditions resulted in a remarkable change in the expression of EMT markers. All these effects induced by hypoxia were abrogated by sauchinone treatment. Moreover, sauchinone inhibited hypoxia-induced activation of the sonic hedgehog (Shh) pathway. Additionally, the Shh agonist reversed the inhibitory effect of sauchinone on hypoxia-induced invasion and EMT of OS cells. In conclusion, these findings demonstrated that sauchinone inhibits hypoxia-induced invasion and EMT in OS cells via inactivation of the Shh pathway. We provided a novel insight for understanding the mechanisms underlying the anti-cancer effect of sauchinone and suggested sauchinone as a promising agent for OS treatment.
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Affiliation(s)
- Dan Zhou
- Emergency Department, People's Hospital of Dazu, Chongqing, China
| | - Ling He
- The First Department of Orthopedics, People's Hospital of Dazu, Chongqing, China
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17
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Kokkorakis N, Gaitanou M. Minibrain-related kinase/dual-specificity tyrosine-regulated kinase 1B implication in stem/cancer stem cells biology. World J Stem Cells 2020; 12:1553-1575. [PMID: 33505600 PMCID: PMC7789127 DOI: 10.4252/wjsc.v12.i12.1553] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/29/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023] Open
Abstract
Dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B), also known as minibrain-related kinase (MIRK) is one of the best functionally studied members of the DYRK kinase family. DYRKs comprise a family of protein kinases that are emerging modulators of signal transduction pathways, cell proliferation and differentiation, survival, and cell motility. DYRKs were found to participate in several signaling pathways critical for development and cell homeostasis. In this review, we focus on the DYRK1B protein kinase from a functional point of view concerning the signaling pathways through which DYRK1B exerts its cell type-dependent function in a positive or negative manner, in development and human diseases. In particular, we focus on the physiological role of DYRK1B in behavior of stem cells in myogenesis, adipogenesis, spermatogenesis and neurogenesis, as well as in its pathological implication in cancer and metabolic syndrome. Thus, understanding of the molecular mechanisms that regulate signaling pathways is of high importance. Recent studies have identified a close regulatory connection between DYRK1B and the hedgehog (HH) signaling pathway. Here, we aim to bring together what is known about the functional integration and cross-talk between DYRK1B and several signaling pathways, such as HH, RAS and PI3K/mTOR/AKT, as well as how this might affect cellular and molecular processes in development, physiology, and pathology. Thus, this review summarizes the major known functions of DYRK1B kinase, as well as the mechanisms by which DYRK1B exerts its functions in development and human diseases focusing on the homeostasis of stem and cancer stem cells.
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Affiliation(s)
- Nikolaos Kokkorakis
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens 11521, Greece
| | - Maria Gaitanou
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens 11521, Greece.
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18
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Qi X, Friedberg L, De Bose-Boyd R, Long T, Li X. Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling. Nat Chem Biol 2020; 16:1368-1375. [PMID: 32929279 PMCID: PMC7669734 DOI: 10.1038/s41589-020-0646-2] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 07/16/2020] [Accepted: 07/23/2020] [Indexed: 12/11/2022]
Abstract
Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. Sterols can bind to its extracellular cysteine-rich domain (CRD) and to several sites in the seven transmembrane helices (7-TMs) of SMO. However, the mechanism by which sterols regulate SMO via multiple sites is unknown. Here we determined the structures of SMO-Gi complexes bound to the synthetic SMO agonist (SAG) and to 24(S),25-epoxycholesterol (24(S),25-EC). A novel sterol-binding site in the extracellular extension of TM6 was revealed to connect other sites in 7-TMs and CRD, forming an intramolecular sterol channel from the middle side of 7-TMs to CRD. Additional structures of two gain-of-function variants, SMOD384R and SMOG111C/I496C, showed that blocking the channel at its midpoints allows sterols to occupy the binding sites in 7-TMs, thereby activating SMO. These data indicate that sterol transport through the core of SMO is a major regulator of SMO-mediated signaling.
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Affiliation(s)
- Xiaofeng Qi
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Lucas Friedberg
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ryan De Bose-Boyd
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tao Long
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xiaochun Li
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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19
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The Role of Smoothened in Cancer. Int J Mol Sci 2020; 21:ijms21186863. [PMID: 32962123 PMCID: PMC7555769 DOI: 10.3390/ijms21186863] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/13/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023] Open
Abstract
Smoothened (SMO) belongs to the Hedgehog (HH) signaling pathway, which regulates cell growth, migration, invasion and stem cells in cancer. The HH signaling pathway includes both canonical and noncanonical pathways. The canonical HH pathway functions through major HH molecules such as HH ligands, PTCH, SMO and GLI, whereas the noncanonical HH pathway involves the activation of SMO or GLI through other pathways. The role of SMO has been discussed in different types of cancer, including breast, liver, pancreatic and colon cancers. SMO expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity. A better understanding of the role of SMO in cancer could contribute to the development of novel therapeutic approaches.
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20
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Qi X, Li X. Mechanistic Insights into the Generation and Transduction of Hedgehog Signaling. Trends Biochem Sci 2020; 45:397-410. [PMID: 32311334 PMCID: PMC7174405 DOI: 10.1016/j.tibs.2020.01.006] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 01/19/2020] [Accepted: 01/23/2020] [Indexed: 12/23/2022]
Abstract
Cell differentiation and proliferation require Hedgehog (HH) signaling and aberrant HH signaling causes birth defects or cancers. In this signaling pathway, the N-terminally palmitoylated and C-terminally cholesterylated HH ligand is secreted into the extracellular space with help of the Dispatched-1 (DISP1) and Scube2 proteins. The Patched-1 (PTCH1) protein releases its inhibition of the oncoprotein Smoothened (SMO) after binding the HH ligand, triggering downstream signaling events. In this review, we discuss the recent structural and biochemical studies on four major components of the HH pathway: the HH ligand, DISP1, PTCH1, and SMO. This research provides mechanistic insights into how HH signaling is generated and transduced from the cell surface into the intercellular space and will aid in facilitating the treatment of HH-related diseases.
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Affiliation(s)
- Xiaofeng Qi
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | - Xiaochun Li
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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21
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Cavodeassi F, Creuzet S, Etchevers HC. The hedgehog pathway and ocular developmental anomalies. Hum Genet 2018; 138:917-936. [PMID: 30073412 PMCID: PMC6710239 DOI: 10.1007/s00439-018-1918-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 07/24/2018] [Indexed: 12/18/2022]
Abstract
Mutations in effectors of the hedgehog signaling pathway are responsible for a wide variety of ocular developmental anomalies. These range from massive malformations of the brain and ocular primordia, not always compatible with postnatal life, to subtle but damaging functional effects on specific eye components. This review will concentrate on the effects and effectors of the major vertebrate hedgehog ligand for eye and brain formation, Sonic hedgehog (SHH), in tissues that constitute the eye directly and also in those tissues that exert indirect influence on eye formation. After a brief overview of human eye development, the many roles of the SHH signaling pathway during both early and later morphogenetic processes in the brain and then eye and periocular primordia will be evoked. Some of the unique molecular biology of this pathway in vertebrates, particularly ciliary signal transduction, will also be broached within this developmental cellular context.
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Affiliation(s)
- Florencia Cavodeassi
- Institute for Medical and Biomedical Education, St. George´s University of London, Cranmer Terrace, London, SW17 0RE, UK
| | - Sophie Creuzet
- Institut des Neurosciences Paris-Saclay (Neuro-PSI), UMR 9197, CNRS, Université Paris-Sud, 1 Avenue de la Terrasse, 91198, Gif-sur-Yvette Cedex, France
| | - Heather C Etchevers
- Aix-Marseille Univ, Marseille Medical Genetics (MMG), INSERM, Faculté de Médecine, 27 boulevard Jean Moulin, 13005, Marseille, France.
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22
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Singh R, Lauth M. Emerging Roles of DYRK Kinases in Embryogenesis and Hedgehog Pathway Control. J Dev Biol 2017; 5:E13. [PMID: 29615569 PMCID: PMC5831797 DOI: 10.3390/jdb5040013] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 11/17/2017] [Accepted: 11/18/2017] [Indexed: 12/19/2022] Open
Abstract
Hedgehog (Hh)/GLI signaling is an important instructive cue in various processes during embryonic development, such as tissue patterning, stem cell maintenance, and cell differentiation. It also plays crucial roles in the development of many pediatric and adult malignancies. Understanding the molecular mechanisms of pathway regulation is therefore of high interest. Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) comprise a group of protein kinases which are emerging modulators of signal transduction, cell proliferation, survival, and cell differentiation. Work from the last years has identified a close regulatory connection between DYRKs and the Hh signaling system. In this manuscript, we outline the mechanistic influence of DYRK kinases on Hh signaling with a focus on the mammalian situation. We furthermore aim to bring together what is known about the functional consequences of a DYRK-Hh cross-talk and how this might affect cellular processes in development, physiology, and pathology.
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Affiliation(s)
- Rajeev Singh
- Philipps University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor and Immune Biology (ZTI), Hans-Meerwein-Str. 3, 35043 Marburg, Germany.
| | - Matthias Lauth
- Philipps University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor and Immune Biology (ZTI), Hans-Meerwein-Str. 3, 35043 Marburg, Germany.
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