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Bi K, Li J, Yang J, Qiu S, Zhang K, Wang H, Hu K, Chen L, Xu Y, Meng Q. The function of β-catenin and GSK-3β in Procambarus clarkii Wnt signaling pathway during Spiroplasma eriocheiris infection. Int J Biol Macromol 2025; 313:144269. [PMID: 40381786 DOI: 10.1016/j.ijbiomac.2025.144269] [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: 04/30/2025] [Revised: 05/13/2025] [Accepted: 05/14/2025] [Indexed: 05/20/2025]
Abstract
Wnt signaling pathway plays an important role in both the regulation of host innate immunity and the nervous system. In this study, two key genes in the Wnt signaling pathway, β-catenin and GSK-3β, were first characterized from Procambarus clarkii, and significantly upregulated in hemocytes during Spiroplasma eriocheiris infection. At the cellular level, overexpression of Pcβ-catenin in Drosophila S2 cells significantly increased the cell viability and reactive oxygen species (ROS) production, decreased the cell necrosis and intracellular S. eriocheiris replication, while PcGSK-3β overexpression exerted an opposite effect. The Co-IP results revealed that PcGSK-3β could interact with Pcβ-catenin. Further, co-transfection of PcGSK-3β and Pcβ-catenin into S2 cells markedly reduced the cell survival and ROS level upon S. eriocheiris infection. At the individual level, knockdown of Pcβ-catenin significantly induced the apoptosis of hemocytes and increased the mortality of the crayfish following S. eriocheiris infection. Conversely, PcGSK-3β deficiency significantly elevated the ROS level in hemocytes thereby enhancing the resistance of P. clarkii to S. eriocheiris infection. In conclusion, this study has proved the regulation mechanism of Wnt signaling pathway in response to S. eriocheiris infection, which may contribute to our understanding of innate immunity in invertebrates.
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Affiliation(s)
- Keran Bi
- Animal Husbandry and Veterinary College, Jiangsu Vocational College of Agriculture and Forestry, Jurong, Jiangsu 212400, China
| | - Jiajia Li
- Key Laboratory of Genetic Breeding and cultivation for Freshwater Crustacean, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing 210017, China
| | - Jianlong Yang
- Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Marine Science and Engineering, Nanjing Normal University, 2 Xuelin Road, Nanjing, 210023, China
| | - Suyue Qiu
- Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Marine Science and Engineering, Nanjing Normal University, 2 Xuelin Road, Nanjing, 210023, China
| | - Kun Zhang
- Animal Husbandry and Veterinary College, Jiangsu Vocational College of Agriculture and Forestry, Jurong, Jiangsu 212400, China
| | - Haibo Wang
- Animal Husbandry and Veterinary College, Jiangsu Vocational College of Agriculture and Forestry, Jurong, Jiangsu 212400, China
| | - Kai Hu
- Animal Husbandry and Veterinary College, Jiangsu Vocational College of Agriculture and Forestry, Jurong, Jiangsu 212400, China
| | - Luyao Chen
- Animal Husbandry and Veterinary College, Jiangsu Vocational College of Agriculture and Forestry, Jurong, Jiangsu 212400, China
| | - Yu Xu
- Key Laboratory of Genetic Breeding and cultivation for Freshwater Crustacean, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing 210017, China.
| | - Qingguo Meng
- Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Marine Science and Engineering, Nanjing Normal University, 2 Xuelin Road, Nanjing, 210023, China.
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黄 菊, 殷 丽, 牛 民, 耿 志, 左 芦, 李 静, 胡 建. [Nodakenin ameliorates TNBS-induced experimental colitis in mice by inhibiting pyroptosis of intestinal epithelial cells]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2025; 45:261-268. [PMID: 40031970 PMCID: PMC11875862 DOI: 10.12122/j.issn.1673-4254.2025.02.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Indexed: 03/05/2025]
Abstract
OBJECTIVES To investigate the therapeutic mechanism of nodakenin for Crohn's disease (CD)-like colitis in mice. METHODS Using a colonic organoid model with lipopolysaccharide (LPS)- and ATP-induced pyroptosis, we investigated the effects of nodakenin on pyroptosis, intestinal barrier function and inflammatory response by detecting key pyroptosis-regulating factors and assessing changes in permeability and pro-inflammatory factors. In a mouse model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced CD-like colitis, the therapeutic effect of nodakenin was evaluated by measuring changes in body weight, DAI score, colonic histopathologies, inflammation score, intestinal barrier function and intestinal epithelial cell pyroptosis. The mechanism of nodakenin protection against pyroptosis of intestinal epithelial cells was explored using network pharmacology analysis and in vivo and in vitro experiments. RESULTS In LPS- and ATP-induced colonic organoids, treatment with nodakenin significantly inhibited the expressions of NLRP3, GSDMD-N, cleaved caspase-1 and caspase-11, improved intestinal FITC-dextran (FD4, 4000) permeability, and decreased the levels of IL-1β and IL-18. In the mouse model of TNBS-induced colitis, nodakenin treatment significantly alleviated weight loss, reduced DAI score, inflammatory cell infiltration and inflammation score, and decreased serum FD4 and I-FABP levels and bacteria translocation to the mesenteric lymph nodes, spleen and liver. The mice with nodakenin treatment had also lowered expressions of NLRP3, GSDMD-N, cleaved caspase-1 and caspase-11 in the intestinal mucosa. Network pharmacology analysis suggested that the inhibitory effect of nodakenin on colitis was associated with the PI3K/Akt pathway. In both the colonic organoid model and mouse models of colitis, nodakenin effectively inhibited the activation of the PI3K/Akt pathway, and the application of IGF-1, a PI3K/Akt pathway activator, strongly attenuated the protective effect of nodakenin against intestinal epithelial cell pyroptosis and intestinal barrier dysfunction. CONCLUSIONS Nodakenin protects intestinal barrier function and alleviates CD-like colitis in mice at least partly by inhibiting PI3K/Akt signaling to reduce intestinal epithelial cell pyroptosis.
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Schöpe PC, Torke S, Kobelt D, Kortüm B, Treese C, Dumbani M, Güllü N, Walther W, Stein U. MACC1 revisited - an in-depth review of a master of metastasis. Biomark Res 2024; 12:146. [PMID: 39580452 PMCID: PMC11585957 DOI: 10.1186/s40364-024-00689-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 11/12/2024] [Indexed: 11/25/2024] Open
Abstract
Cancer metastasis remains the most lethal characteristic of tumors mediating the majority of cancer-related deaths. Identifying key molecules responsible for metastasis, understanding their biological functions and therapeutically targeting these molecules is therefore of tremendous value. Metastasis Associated in Colon Cancer 1 (MACC1), a gene first described in 2009, is such a key driver of metastatic processes, initiating cellular proliferation, migration, invasion, and metastasis in vitro and in vivo. Since its discovery, the value of MACC1 as a prognostic biomarker has been confirmed in over 20 cancer entities. Additionally, several therapeutic strategies targeting MACC1 and its pro-metastatic functions have been developed. In this review, we will provide a comprehensive overview on MACC1, from its clinical relevance, towards its structure and role in signaling cascades as well as molecular networks. We will highlight specific biological consequences of MACC1 expression, such as an increase in stem cell properties, its immune-modulatory effects and induced therapy resistance. Lastly, we will explore various strategies interfering with MACC1 expression and/or its functions. Conclusively, this review underlines the importance of understanding the role of individual molecules in mediating metastasis.
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Affiliation(s)
- Paul Curtis Schöpe
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
| | - Sebastian Torke
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
| | - Dennis Kobelt
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
| | - Benedikt Kortüm
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
| | - Christoph Treese
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
| | - Malti Dumbani
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
| | - Nazli Güllü
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
| | - Wolfgang Walther
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
| | - Ulrike Stein
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
- German Cancer Consortium (DKTK), Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany.
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El-Mayet F, Jones C. Stress Can Induce Bovine Alpha-Herpesvirus 1 (BoHV-1) Reactivation from Latency. Viruses 2024; 16:1675. [PMID: 39599791 PMCID: PMC11599084 DOI: 10.3390/v16111675] [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: 08/23/2024] [Revised: 10/16/2024] [Accepted: 10/24/2024] [Indexed: 11/29/2024] Open
Abstract
Bovine alpha-herpesvirus 1 (BoHV-1) is a significant problem for the cattle industry, in part because the virus establishes latency, and stressful stimuli increase the incidence of reactivation from latency. Sensory neurons in trigeminal ganglia and unknown cells in pharyngeal tonsils are importantsites for latency. Reactivation from latency can lead to reproductive problems in pregnant cows, virus transmission to young calves, suppression of immune responses, and bacterial pneumonia. BoHV-1 is also a significant cofactor in bovine respiratory disease (BRD). Stress, as mimicked by the synthetic corticosteroid dexamethasone, reproducibly initiates reactivation from latency. Stress-mediated activation of the glucocorticoid receptor (GR) stimulates viral replication and transactivation of viral promoters that drive the expression of infected cell protein 0 (bICP0) and bICP4. Notably, GR and Krüppel-like factor 15 (KLF15) form a feed-forward transcription loop that cooperatively transactivates immediate early transcription unit 1 (IEtu1 promoter). Two pioneer transcription factors, GR and KLF4, cooperatively transactivate the bICP0 early promoter. Pioneer transcription factors bind silent viral heterochromatin, remodel chromatin, and activate gene expression. Thus, wepredict that these novel transcription factors mediate early stages of BoHV-1 reactivation from latency.
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Affiliation(s)
- Fouad El-Mayet
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA;
- Department of Virology, Faculty of Veterinary Medicine, Benha University, Benha 74078, Egypt
| | - Clinton Jones
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA;
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Wu C, Yang J, Ye C, Wu H, Shu W, Li R, Wang S, Lu Y, Chen H, Zhang Z, Yao Q. Berberine attenuates 5-fluorouracil-induced intestinal mucosal injury by modulating the gut microbiota without compromising its anti-tumor efficacy. Heliyon 2024; 10:e34528. [PMID: 39114045 PMCID: PMC11305238 DOI: 10.1016/j.heliyon.2024.e34528] [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: 04/04/2024] [Revised: 07/10/2024] [Accepted: 07/10/2024] [Indexed: 08/10/2024] Open
Abstract
Background 5-Fluorouracil (5-Fu), a prominent chemotherapeutic agent for colorectal cancer (CRC) treatment, is often associated with gastrointestinal toxicities, particularly diarrhea. Our previous study demonstrated that berberine (BBR) ameliorates 5-Fu-induced intestinal mucosal injury by modulating the gut microbiota in rats. Nevertheless, the precise molecular mechanism underlying BBR's protective effect on intestinal mucosa remains elusive, and its impact on the anti-tumor efficacy of 5-Fu warrants further investigation. Methods The effect of BBR on 5-Fu-induced intestinal mucosal injury was investigated using a tumor-bearing murine model, employing H&E staining, 16 S rDNA sequencing, transcriptome sequencing, Western blot analysis, cell experiments and constructing a pseudo-germ-free tumor xenograft model. Result Our findings demonstrate that BBR alleviates intestinal mucosal damage, reduces the levels of inflammatory factors (IL-6, TNF-α, and IL-1β), and inhibits epithelial cell apoptosis in 5-Fu-treated mice without compromising 5-Fu's anti-tumor efficacy. Moreover, 16 S rDNA sequencing indicated that BBR significantly increases the abundance of Akkermansia and decreases the abundance of pathogenic bacteria Escherichia/Shigella at the genus level. Mechanistically, transcriptome sequencing and Western blot analysis confirmed that BBR upregulates PI3K/AKT/mTOR expression in the intestinal mucosa. However, this effect was not observed in tumor tissues. Notably, BBR did not demonstrate a direct protective effect on 5-Fu-treated CCD841 and SW480 cells. Additionally, BBR had no effect on the PI3K/AKT/mTOR pathway in the intestinal tissue of the 5-Fu-treated mouse model with a depleted gut microbiota. Conclusion This study indicates that BBR alleviates 5-Fu-induced intestinal mucosal injury by modulating the gut microbiota and regulating the PI3K/AKT/mTOR signaling pathway without compromising the anti-tumor efficacy of 5-Fu.
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Affiliation(s)
- Changhong Wu
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jie Yang
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Chenxiao Ye
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hui Wu
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Wenxi Shu
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Rongrong Li
- The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310012, China
| | - Sihan Wang
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yi Lu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Department of Clinical Nutrition, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Haitao Chen
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Integrated Traditional Chinese and Western Medicine Oncology Laboratory, Key Laboratory of Traditional Chinese Medicine of Zhejiang Province, Hangzhou, Zhejiang, 310022, China
| | - Zewei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, 310022, China
| | - Qinghua Yao
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Xinhua Hospital of Zhejiang Province, Hangzhou, Zhejiang, 310005, China
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Li Q, Zheng S, Niu K, Qiao Y, Liu Y, Zhang Y, Li B, Zheng C, Yu B. Paeoniflorin improves ulcerative colitis via regulation of PI3K‑AKT based on network pharmacology analysis. Exp Ther Med 2024; 27:125. [PMID: 38414786 PMCID: PMC10895587 DOI: 10.3892/etm.2024.12414] [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: 08/29/2022] [Accepted: 11/24/2023] [Indexed: 02/29/2024] Open
Abstract
Paeoniflorin (PF) is the primary component derived from Paeonia lactiflora and white peony root and has been used widely for the treatment of ulcerative colitis (UC) in China. UC primarily manifests as a chronic inflammatory response in the intestine. In the present study, a network pharmacology approach was used to explore the specific effects and underlying mechanisms of action of PF in the treatment of UC. A research strategy based on network pharmacology, combining target prediction, network construction, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and molecular docking simulation was used to predict the targets of PF. A total of 288 potential targets of PF and 599 UC-related targets were identified. A total of 60 therapeutic targets of PF against UC were identified. Of these, 20 core targets were obtained by protein-protein interaction network construction. GO and KEGG pathway analyses showed that PF alleviated UC through EGFR tyrosine kinase inhibitor resistance, the IL-17 signaling pathway, and the PI3K/AKT signaling pathway. Molecular docking simulation showed that AKT1 and EGFR had good binding energy with PF. Animal-based experiments revealed that the administration of PF ameliorated the colonic pathological damage in a dextran sulfate sodium-induced mouse model, resulting in lower levels of proinflammatory cytokines including IL-1β, IL-6, and TNF-α, and higher levels of IL-10 and TGF-β. PF decreased the mRNA and protein expression levels of AKT1, EGFR, mTOR, and PI3K. These findings suggested that PF plays a therapeutic protective role in the treatment of UC by regulating the PI3K/AKT signaling pathway.
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Affiliation(s)
- Qifang Li
- Department of Traditional Chinese Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong 272069, P.R. China
| | - Shuyue Zheng
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Kai Niu
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Yi Qiao
- School of Public Health, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Yuan Liu
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Ying Zhang
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Bingbing Li
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Canlei Zheng
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Bin Yu
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong 272067, P.R. China
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Hu X, Gan L, Tang Z, Lin R, Liang Z, Li F, Zhu C, Han X, Zheng R, Shen J, Yu J, Luo N, Peng W, Tan J, Li X, Fan J, Wen Q, Wang X, Li J, Zheng X, Liu Q, Guo J, Shi G, Mao H, Chen W, Yin S, Zhou Y. A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42-mediated GSK-3β/β-catenin Signaling. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2307850. [PMID: 38240457 PMCID: PMC10987128 DOI: 10.1002/advs.202307850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/08/2024] [Indexed: 04/04/2024]
Abstract
Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay-guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti-renal fibrotic lead. DA shows significant anti-kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down-regulates its downstream phospho-protein kinase Cζ(p-PKCζ)/phospho-glycogen synthase kinase-3β (p-GSK-3β), thereby promoting β-catenin Ser33/37/Thr41 phosphorylation and ubiquitin-dependent proteolysis to block classical pro-fibrotic β-catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.
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Affiliation(s)
- Xinrong Hu
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Lu Gan
- School of Pharmaceutical SciencesSun Yat‐sen UniversityGuangzhou510006China
| | - Ziwen Tang
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Ruoni Lin
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Zhou Liang
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Feng Li
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Changjian Zhu
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Xu Han
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Ruilin Zheng
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Jiani Shen
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Jing Yu
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Ning Luo
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Wenxing Peng
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Jiaqing Tan
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Xiaoyan Li
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Jinjin Fan
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Qiong Wen
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Xin Wang
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Jianbo Li
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Xunhua Zheng
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Qinghua Liu
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Jianping Guo
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhou510080China
| | - Guo‐Ping Shi
- Department of MedicineBrigham and Women's Hospital and Harvard Medical SchoolBostonMA02115USA
| | - Haiping Mao
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Wei Chen
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
| | - Sheng Yin
- School of Pharmaceutical SciencesSun Yat‐sen UniversityGuangzhou510006China
| | - Yi Zhou
- Department of NephrologyThe First Affiliated HospitalSun Yat‐sen UniversityNHC Key Laboratory of Clinical NephrologyGuangdong Provincial Key Laboratory of NephrologySun Yat‐Sen UniversityGuangzhou510080China
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Liu C, Shen A, Song J, Cheng L, Zhang M, Wang Y, Liu X. LncRNA-CCAT5-mediated crosstalk between Wnt/β-Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity. Cancer Commun (Lond) 2024; 44:76-100. [PMID: 38010289 PMCID: PMC10794011 DOI: 10.1002/cac2.12507] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 10/31/2023] [Accepted: 11/14/2023] [Indexed: 11/29/2023] Open
Abstract
BACKGROUND Although the constitutively activated Wnt/β-catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non-coding RNAs (lncRNAs) in GC intraperitoneal dissemination (IPD) remains elusive. Here, we investigated the function and therapeutic potential of Wnt-transactivated lncRNA, colon cancer-associated transcript 5 (CCAT5), in GC metastasis. METHODS LncRNA-sequencing assay was performed to document abundance changes of lncRNAs induced by Wnt family member 3A (Wnt3a) and degradation-resistant β-catenin (S33Y mutated) in ascites-derived GC cells with low Wnt activity. Luciferase reporter, Chromatin immunoprecipitation (ChIP)-re-ChIP assays were performed to determine how CCAT5 was transcribed. The clinical significance of CCAT5 was examined in 2 cohorts of GC patients. The biological function of CCAT5 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA-sequencing, mass spectrometry, and CRISPR/Cas9-knocknout system. The therapeutic potential of CCAT5 was examined through RNAi-based cell xenograft model and patient-derived xenograft (PDX) model of IPD. RESULTS We identified a novel Wnt-regulated lncRNA, CCAT5, which was transactivated by the β-catenin/transcription factor 3 (TCF3) complex. CCAT5 was significantly upregulated in GC and predicted poor prognosis. Functional studies confirmed the promotive role of CCAT5 in GC growth and metastasis. Mechanistically, CCAT5 bound to the C-end domain of signal transducer and activator of transcription 3 (STAT3) and blocks Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1)-mediated STAT3Y705 dephosphorylation, leading to STAT3 nuclear entry and transactivation, thus accelerating GC progression. Furthermore, we demonstrated that both Wnt3a and β-catenin acted as activator of STAT3 signaling pathway, and the interplay between CCAT5 and STAT3 was functionally essential for Wnt-drived STAT3 signaling and tumor evolution. Finally, we revealed in vivo si-CCAT5 selectively attenuated growth and metastasis of Wnthigh GC, but not Wntlow GC. The combination of si-CCAT5 and oxaliplatin displayed obvious synergistic therapeutic effects on Wnthigh PDX mice. CONCLUSIONS We identified a novel Wnt-transactivated lncRNA, CCAT5. Our study revealed a mechanism of STAT3 signaling regulation via canonical Wnt signaling and the functional significance of CCAT5 as critical mediator. We provided conceptual advance that lncRNAs serve as therapeutic targets reversing GC progression.
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Affiliation(s)
- Chenchen Liu
- Department of Gastric SurgeryFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiP. R. China
| | - Aiwen Shen
- Department of NephrologyShanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghaiP. R. China
| | - Junquan Song
- Department of Gastric SurgeryFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiP. R. China
| | - Lei Cheng
- Department of PulmonaryShanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiP. R. China
| | - Meng Zhang
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiP. R. China
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiP. R. China
| | - Yanong Wang
- Department of Gastric SurgeryFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiP. R. China
| | - Xiaowen Liu
- Department of Gastric SurgeryFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiP. R. China
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9
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Jones C. Intimate Relationship Between Stress and Human Alpha‑Herpes Virus 1 (HSV‑1) Reactivation from Latency. CURRENT CLINICAL MICROBIOLOGY REPORTS 2023; 10:236-245. [PMID: 38173564 PMCID: PMC10764003 DOI: 10.1007/s40588-023-00202-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2023] [Indexed: 01/05/2024]
Abstract
Purpose of Review Numerous studies concluded stress (acute, episodic acute, or chronic) increases the incidence of human alpha-herpes virus 1 (HSV-1) reactivation from latency in neurons. This review will summarize how stress stimulates viral gene expression, replication, and reactivation from latency. Recent Findings Stress (capital S) stress-mediated activation of the glucocorticoid receptor (GR) accelerates reactivation from latency, whereas a corticosteroid-specific antagonist impairs viral replication and reactivation from latency. GR and specific stress-induced cellular transcription factors also stimulate viral promoters that drive expression of key viral transcriptional regulators: infected cell protein 0 (ICP0), ICP4, ICP27 and viral tegument protein (VP16). Hence, GR is predicted to initially stimulate viral gene expression. GR-mediated immune-inhibitory functions are also predicted to enhance viral replication and viral spread. Summary Identifying cellular factors and viral regulatory proteins that trigger reactivation from latency in neurons may provide new therapeutic strategies designed to reduce the incidence of reactivation from latency.
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Affiliation(s)
- Clinton Jones
- College of Veterinary Medicine, Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, OK 74078, USA
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10
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Nozawa H, Taira T, Sonoda H, Sasaki K, Murono K, Emoto S, Yokoyama Y, Nagai Y, Abe S, Ishihara S. Enhancement of radiation therapy by indoleamine 2,3 dioxygenase 1 inhibition through multimodal mechanisms. BMC Cancer 2023; 23:62. [PMID: 36653774 PMCID: PMC9847047 DOI: 10.1186/s12885-023-10539-5] [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: 08/18/2022] [Accepted: 01/11/2023] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that converts tryptophan to kynurenine. IDO1 expression is found not only in tumor cells but also in immune cells and is associated with tumor proliferation and immune responses. IDO1 inhibitors and radiation may cooperatively suppress tumor proliferation through the alterations in the Wnt/β-catenin pathway, cell cycle, and immune response. We investigated the antitumor effects of combination therapy of an IDO1 inhibitor, 1-methyl tryptophan (1-MT), and radiation on colorectal cancer. METHODS In vitro experiments were conducted using human and murine colon cancer cell lines (HCT116, HT-29, and Colon26). Cell growth inhibition was assessed using a MTS assay and Clonogenic assay. Cells were cultured for 48 h with or without 500 µM 1-MT after exposure to radiation (4 Gy). Cell cycle effects and modulation of Wnt/β-catenin pathway were evaluated using western blot analysis, flow cytometry, RT-PCR. Subcutaneous Colon26 tumors in BALB/c mice were treated by oral 1-MT (6 mg/mL) for 2 weeks and/or local radiation (10 Gy/10 fr). Bromodeoxyuridine (BrdU) incorporation in tumor cells and expression of differentiation markers of immune cells were evaluated using immunohistochemistry. RESULTS 1-MT and a small interfering RNA against IDO1 suppressed proliferation of all cell lines, which was rescued by kynurenine. Clonogenic assay showed that administration of 1-MT improved radiosensitivity by suppressing the Wnt/β-catenin pathway activated by radiation and enhancing cell cycle arrest induced by radiation. Combination therapy showed a further reduction in tumor burden compared with monotherapies or untreated control, inducing the highest numbers of intratumoral CD3 + and CD8 + T cells and the lowest numbers of Foxp3 + and BrdU-positive tumor cells. CONCLUSIONS The combination of 1-MT and radiation suppressed colon cancer cells in vitro and in vivo via multiple mechanisms.
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Affiliation(s)
- Hiroaki Nozawa
- grid.26999.3d0000 0001 2151 536XDepartment of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655 Japan
| | - Tetsuro Taira
- grid.26999.3d0000 0001 2151 536XDepartment of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655 Japan
| | - Hirofumi Sonoda
- grid.26999.3d0000 0001 2151 536XDepartment of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655 Japan
| | - Kazuhito Sasaki
- grid.26999.3d0000 0001 2151 536XDepartment of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655 Japan
| | - Koji Murono
- grid.26999.3d0000 0001 2151 536XDepartment of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655 Japan
| | - Shigenobu Emoto
- grid.26999.3d0000 0001 2151 536XDepartment of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655 Japan
| | - Yuichiro Yokoyama
- grid.26999.3d0000 0001 2151 536XDepartment of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655 Japan
| | - Yuzo Nagai
- grid.26999.3d0000 0001 2151 536XDepartment of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655 Japan
| | - Shinya Abe
- grid.26999.3d0000 0001 2151 536XDepartment of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655 Japan
| | - Soichiro Ishihara
- grid.26999.3d0000 0001 2151 536XDepartment of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655 Japan
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11
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Zhang YG, Xia Y, Zhang J, Deb S, Garrett S, Sun J. Intestinal vitamin D receptor protects against extraintestinal breast cancer tumorigenesis. Gut Microbes 2023; 15:2202593. [PMID: 37074210 PMCID: PMC10120454 DOI: 10.1080/19490976.2023.2202593] [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: 05/12/2022] [Revised: 03/17/2023] [Accepted: 04/03/2023] [Indexed: 04/20/2023] Open
Abstract
The microbiota plays critical roles in regulating the function and health of the intestine and extraintestinal organs. A fundamental question is whether an intestinal-microbiome-breast axis exists during the development of breast cancer. If so, what are the roles of host factors? Vitamin D receptor (VDR) involves host factors and the human microbiome. Vdr gene variation shapes the human microbiome, and VDR deficiency leads to dysbiosis. We hypothesized that intestinal VDR protects hosts against tumorigenesis in the breast. We examined a 7,12-dimethylbenzanthracene (DMBA)-induced breast cancer model in intestinal epithelial VDR knockout (VDRΔIEC) mice with dysbiosis. We reported that VDRΔIEC mice with dysbiosis are more susceptible to breast cancer induced by DMBA. Intestinal and breast microbiota analysis showed that VDR deficiency leads to a bacterial profile shift from normal to susceptible to carcinogenesis. We found enhanced bacterial staining within breast tumors. At the molecular and cellular levels, we identified the mechanisms by which intestinal epithelial VDR deficiency led to increased gut permeability, disrupted tight junctions, microbial translocation, and enhanced inflammation, thus increasing tumor size and number in the breast. Furthermore, treatment with the beneficial bacterial metabolite butyrate or the probiotic Lactobacillus plantarum reduced breast tumors, enhanced tight junctions, inhibited inflammation, increased butyryl-CoA transferase, and decreased levels of breast Streptococcus bacteria in VDRΔIEC mice. The gut microbiome contributes to the pathogenesis of diseases not only in the intestine but also in the breast. Our study provides insights into the mechanism by which intestinal VDR dysfunction and gut dysbiosis lead to a high risk of extraintestinal tumorigenesis. Gut-tumor-microbiome interactions represent a new target in the prevention and treatment of breast cancer.
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Affiliation(s)
- Yong-Guo Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Yinglin Xia
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Jilei Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Shreya Deb
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Shari Garrett
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Jun Sun
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL, USA
- UIC Cancer Center, University of Illinois Chicago, Chicago, IL, USA
- Jesse Brown VA Medical Center Chicago, Chicago, IL, USA
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12
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Wu J, Luo Y, Shen Y, Hu Y, Zhu F, Wu J, Liu Y. Integrated Metabonomics and Network Pharmacology to Reveal the Action Mechanism Effect of Shaoyao Decoction on Ulcerative Colitis. Drug Des Devel Ther 2022; 16:3739-3776. [PMID: 36324421 PMCID: PMC9620839 DOI: 10.2147/dddt.s375281] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022] Open
Abstract
Background Traditional Chinese medicine (TCM) has the advantage of multi-component and multi-target, which becomes a hot spot in the treatment of numerous diseases. Shaoyao decoction (SYD) is a TCM prescription, which is mainly used to treat damp-heat dysentery clinically, with small side effects and low cost. However, its mechanism remains elusive. The purpose of this study is to explore the mechanism of SYD in the treatment of mice with ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) through metabolomics and network pharmacology, and verify through molecular docking and immunohistochemistry, so as to provide a scientific basis for the role of SYD in the treatment of UC. Materials and Methods Firstly, DSS-induced UC models were established and then untargeted metabolomics analysis of feces, livers, serum and urine was performed to determine biomarkers and metabolic pathways closely related to the role of SYD. Besides, network pharmacology was applied to screen the active components and UC-related targets, which was verified by molecular docking. Finally, metabonomics and network pharmacology were combined to draw the metabolite-pathway-target network and verified by immunohistochemistry. Results Metabolomics results showed that a total of 61 differential metabolites were discovered in SYD-treated UC with 3 main metabolic pathways containing glycerophospholipid metabolism, sphingolipid metabolism and biosynthesis of unsaturated fatty acids, as well as 8 core targets involving STAT3, IL1B, IL6, IL2, AKT1, IL4, ICAM1 and CCND1. Molecular docking demonstrated that the first five targets had strong affinity with quercetin, wogonin, kaempferol and baicalein. Combined with metabolomics and network pharmacology, sphingolipid signaling pathway, PI3K/AKT-mTOR signaling pathway and S1P3 pathway were identified as the main pathways. Conclusion SYD can effectively ameliorate various symptoms and alleviate intestinal mucosal damage and metabolic disorder in DSS induced UC mice. Its effect is mainly related to sphingolipid metabolism, PI3K/AKT-mTOR signaling pathway and S1P3 pathway.
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Affiliation(s)
- Jin Wu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Yiting Luo
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Yan Shen
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, People’s Republic of China
| | - Yuyao Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, People’s Republic of China
| | - Fangyuan Zhu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Jiaqian Wu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Yingchao Liu
- Academic Affairs Office, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China,Correspondence: Yingchao Liu, Academic Affairs Office, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China, Email
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13
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Kortüm B, Radhakrishnan H, Zincke F, Sachse C, Burock S, Keilholz U, Dahlmann M, Walther W, Dittmar G, Kobelt D, Stein U. Combinatorial treatment with statins and niclosamide prevents CRC dissemination by unhinging the MACC1-β-catenin-S100A4 axis of metastasis. Oncogene 2022; 41:4446-4458. [PMID: 36008464 PMCID: PMC9507965 DOI: 10.1038/s41388-022-02407-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 06/30/2022] [Accepted: 07/01/2022] [Indexed: 11/29/2022]
Abstract
Colorectal cancer (CRC) is the second-most common malignant disease worldwide, and metastasis is the main culprit of CRC-related death. Metachronous metastases remain to be an unpredictable, unpreventable, and fatal complication, and tracing the molecular chain of events that lead to metastasis would provide mechanistically linked biomarkers for the maintenance of remission in CRC patients after curative treatment. We hypothesized, that Metastasis-associated in colorectal cancer-1 (MACC1) induces a secretory phenotype to enforce metastasis in a paracrine manner, and found, that the cell-free culture medium of MACC1-expressing CRC cells induces migration. Stable isotope labeling by amino acids in cell culture mass spectrometry (SILAC-MS) of the medium revealed, that S100A4 is significantly enriched in the MACC1-specific secretome. Remarkably, both biomarkers correlate in expression data of independent cohorts as well as within CRC tumor sections. Furthermore, combined elevated transcript levels of the metastasis genes MACC1 and S100A4 in primary tumors and in blood plasma robustly identifies CRC patients at high risk for poor metastasis-free (MFS) and overall survival (OS). Mechanistically, MACC1 strengthens the interaction of β-catenin with TCF4, thus inducing S100A4 synthesis transcriptionally, resulting in elevated secretion to enforce cell motility and metastasis. In cell motility assays, S100A4 was indispensable for MACC1-induced migration, as shown via knock-out and pharmacological inhibition of S100A4. The direct transcriptional and functional relationship of MACC1 and S100A4 was probed by combined targeting with repositioned drugs. In fact, the MACC1-β-catenin-S100A4 axis by statins (MACC1) and niclosamide (S100A4) synergized in inhibiting cancer cell motility in vitro and metastasis in vivo. The MACC1-β-catenin-S100A4 signaling axis is causal for CRC metastasis. Selectively repositioned drugs synergize in restricting MACC1/S100A4-driven metastasis with cross-entity potential.
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Affiliation(s)
- Benedikt Kortüm
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Harikrishnan Radhakrishnan
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Fabian Zincke
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany
| | | | - Susen Burock
- Charité University Hospital Berlin Centre 10 Charite Comprehensive Cancer Center, Berlin, Germany
| | - Ulrich Keilholz
- Charité University Hospital Berlin Centre 10 Charite Comprehensive Cancer Center, Berlin, Germany
| | - Mathias Dahlmann
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Wolfgang Walther
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Gunnar Dittmar
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Dennis Kobelt
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Ulrike Stein
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. .,German Cancer Consortium (DKTK), Heidelberg, Germany.
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14
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Ye Z, Li Y, She Y, Wu M, Hu Y, Qin K, Li L, Yu H, Zhao Q, Jin Z, Lu F, Ye Q. Renshen Baidu powder protects ulcerative colitis via inhibiting the PI3K/Akt/NF-κB signaling pathway. Front Pharmacol 2022; 13:880589. [PMID: 36034874 PMCID: PMC9399752 DOI: 10.3389/fphar.2022.880589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 07/11/2022] [Indexed: 12/20/2022] Open
Abstract
Ulcerative colitis is a chronic and relapsing inflammatory bowel disease without satisfactory therapy available recently. Renshen Baidu powder (RSBDP) is a classic Chinese medicinal formula used since Chinese Song dynasty and has been proven as an effective treatment of ulcerative colitis in clinics. However, the active ingredients and the molecular mechanism have not been fully disclosed. It is imperative to explore the active ingredients and the mechanism of RSBDP. In this study, the potential active components for ulcerative colitis treatment in RSBDP were determined and predicted in silicon, and its molecular mechanisms were also presented, in which the PI3K/Akt/NF-κB signaling pathway was recognized to be vital. Basically, the pharmacodynamics and mechanistic studies of RSBDP for ulcerative colitis were implemented on TNBS-induced experimental rats. The results showed that RSBDP could ameliorate the disease activity index and colon weight, as well as improve colonic shortening and colon histology. In addition, the tumor necrosis factor-α (TNF-α), diamine oxidase, intercellular adhesion molecule-1, and endotoxin in serum were also reduced. It is worth mentioning that the PI3K/Akt/NF-κB signaling pathway was inhibited after RSBDP administration via inhibiting the phosphorylation of proteins. In conclusion, RSBDP effectively ameliorates TNBS-induced colitis rats by inhibiting the PI3K/Akt/NF-κB signaling pathway.
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Affiliation(s)
- Zhen Ye
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuzheng Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yingqi She
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mingquan Wu
- Department of Pharmacy, Sichuan Orthopedic Hospital, Chengdu, China
| | - Yu Hu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kaihua Qin
- Health Preservation and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Linzhen Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Han Yu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qian Zhao
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhao Jin
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fating Lu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Fating Lu, ; Qiaobo Ye,
| | - Qiaobo Ye
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Fating Lu, ; Qiaobo Ye,
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15
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Nagao-Kitamoto H, Kitamoto S, Kamada N. Inflammatory bowel disease and carcinogenesis. Cancer Metastasis Rev 2022; 41:301-316. [PMID: 35416564 DOI: 10.1007/s10555-022-10028-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 03/27/2022] [Indexed: 11/24/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer mortality worldwide. Colitis-associated colorectal cancer (CAC) is a subtype of CRC associated with inflammatory bowel disease (IBD). It is well known that individuals with IBD have a 2-3 times higher risk of developing CRC than those who do not, rendering CAC a major cause of death in this group. Although the etiology and pathogenesis of CAC are incompletely understood, animal models of chronic inflammation and human cohort data indicate that changes in the intestinal environment, including host response dysregulation and gut microbiota perturbations, may contribute to the development of CAC. Genomic alterations are a hallmark of CAC, with patterns that are distinct from those in sporadic CRC. The discovery of the biological changes that underlie the development of CAC is ongoing; however, current data suggest that chronic inflammation in IBD increases the risk of developing CAC. Therefore, a deeper understanding of the precise mechanisms by which inflammation triggers genetic alterations and disrupts intestinal homeostasis may provide insight into novel therapeutic strategies for the prevention of CAC.
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Affiliation(s)
- Hiroko Nagao-Kitamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA.
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
| | - Sho Kitamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Nobuhiko Kamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA.
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
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16
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Cancer evolution: special focus on the immune aspect of cancer. Semin Cancer Biol 2022; 86:420-435. [PMID: 35589072 DOI: 10.1016/j.semcancer.2022.05.006] [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: 12/15/2021] [Revised: 04/18/2022] [Accepted: 05/12/2022] [Indexed: 11/20/2022]
Abstract
Cancer is an evolutionary disease. Intra-tumor heterogeneity (ITH), which describes the diversity within individual tumors, sets the foundation for evolution. The fitness of tumor cells is determined by their microenvironment, which exerts intense selection pressure that generally favors cells with survival and proliferation advantages. It has been revealed that host immunity dramatically influences the evolutionary trajectory of cancer. As technologies advance, a refined map of the immune system's involvement in cancer evolution has gradually come to our knowledge. Here we specifically view cancer through the lens of evolutionary immunological biology. We will cover the neoplastic evolution under immunosurveillance, including how the host immunity shapes the tumor evolutionary trajectory and how progressive tumors modulate the host immunity to survive. A comprehensive understanding of the interplay between cancer evolution and cancer immunity provides clues to combating cancer strategically.
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17
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β-Arrestin2 Is Critically Involved in the Differential Regulation of Phosphosignaling Pathways by Thyrotropin-Releasing Hormone and Taltirelin. Cells 2022; 11:cells11091473. [PMID: 35563779 PMCID: PMC9103620 DOI: 10.3390/cells11091473] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/22/2022] [Accepted: 04/25/2022] [Indexed: 12/17/2022] Open
Abstract
In recent years, thyrotropin-releasing hormone (TRH) and its analogs, including taltirelin (TAL), have demonstrated a range of effects on the central nervous system that represent potential therapeutic agents for the treatment of various neurological disorders, including neurodegenerative diseases. However, the molecular mechanisms of their actions remain poorly understood. In this study, we investigated phosphosignaling dynamics in pituitary GH1 cells affected by TRH and TAL and the putative role of β-arrestin2 in mediating these effects. Our results revealed widespread alterations in many phosphosignaling pathways involving signal transduction via small GTPases, MAP kinases, Ser/Thr- and Tyr-protein kinases, Wnt/β-catenin, and members of the Hippo pathway. The differential TRH- or TAL-induced phosphorylation of numerous proteins suggests that these ligands exhibit some degree of biased agonism at the TRH receptor. The different phosphorylation patterns induced by TRH or TAL in β-arrestin2-deficient cells suggest that the β-arrestin2 scaffold is a key factor determining phosphorylation events after TRH receptor activation. Our results suggest that compounds that modulate kinase and phosphatase activity can be considered as additional adjuvants to enhance the potential therapeutic value of TRH or TAL.
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18
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Vaghari-Tabari M, Targhazeh N, Moein S, Qujeq D, Alemi F, Majidina M, Younesi S, Asemi Z, Yousefi B. From inflammatory bowel disease to colorectal cancer: what's the role of miRNAs? Cancer Cell Int 2022; 22:146. [PMID: 35410210 PMCID: PMC8996392 DOI: 10.1186/s12935-022-02557-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 03/21/2022] [Indexed: 12/27/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease with relapse and remission periods. Ulcerative colitis and Crohn's disease are two major forms of the disease. IBD imposes a lot of sufferings on the patient and has many consequences; however, the most important is the increased risk of colorectal cancer, especially in patients with Ulcerative colitis. This risk is increased with increasing the duration of disease, thus preventing the progression of IBD to cancer is very important. Therefore, it is necessary to know the details of events contributed to the progression of IBD to cancer. In recent years, the importance of miRNAs as small molecules with 20-22 nucleotides has been recognized in pathophysiology of many diseases, in which IBD and colorectal cancer have not been excluded. As a result, the effectiveness of these small molecules as therapeutic target is hopefully confirmed. This paper has reviewed the related studies and findings about the role of miRNAs in the course of events that promote the progression of IBD to colorectal carcinoma, as well as a review about the effectiveness of some of these miRNAs as therapeutic targets.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Forough Alemi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidina
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Simin Younesi
- Schoole of Health and Biomedical Sciences, RMIT University, Melborne, VIC, Australia
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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19
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Li T, Liu W, Hui W, Shi T, Liu H, Feng Y, Gao F. Integrated Analysis of Ulcerative Colitis Revealed an Association between PHLPP2 and Immune Infiltration. DISEASE MARKERS 2022; 2022:4983471. [PMID: 35308140 PMCID: PMC8931176 DOI: 10.1155/2022/4983471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/08/2022] [Accepted: 02/17/2022] [Indexed: 02/07/2023]
Abstract
Ulcerative colitis (UC) is a progressive intestine inflammatory disease that is prone to recur. Herein, we utilize microarray technology and bioinformatics to reveal the underlying pathogenesis of UC and provide novel markers. Colonic biopsies were taken from eight UC patients and eight healthy controls. Three differentially expressed miRNAs (DEMIs) and 264 differentially expressed genes (DEGs) were screened using mRNA and miRNA microarray. Most DEGs were significantly associated with immune response and were markedly enriched in the IL-17 signaling pathway. Among the target genes of DEMIs, PHLPP2 overlapped with DEGs and the downregulation of PHLPP2 group was mainly involved in the epithelial-mesenchymal transition. PHLPP2 was downregulated in UC patients, which was validated in 5 GEO datasets and qRT-PCR. The ROC curve demonstrated that PHLPP2 has a perfect ability to distinguish UC patients from healthy controls. Moreover, PHLPP2 was low expression in patients with active UC. CIBERSORT algorithm indicated that the abundance of gamma delta T cells (P = 0.04), M0 macrophages (P = 0.01), and activated mast cells (P < 0.01) was significantly greater than that of the control group. The Spearman correlation analysis showed that PHLPP2 was positively correlated with the proportion of activated NK cells (rho = 0.62, P = 0.013) and Tregs (rho = 0.55, P = 0.03), but negatively correlated with those of activated mast cells (rho = -0.8, P < 0.01) and macrophages (rho = -0.73, P < 0.01). These results indicate that PHLPP2 is associated with immune cells in the pathogenesis of UC, as well as provide new prospects and future directions of investigation.
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Affiliation(s)
- Ting Li
- Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Weidong Liu
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Wenjia Hui
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Tian Shi
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Huan Liu
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Yan Feng
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Feng Gao
- Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
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20
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Ma L, Yu J, Zhang H, Zhao B, Zhang J, Yang D, Luo F, Wang B, Jin B, Liu J. Effects of Immune Cells on Intestinal Stem Cells: Prospects for Therapeutic Targets. Stem Cell Rev Rep 2022; 18:2296-2314. [DOI: 10.1007/s12015-022-10347-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2022] [Indexed: 11/29/2022]
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21
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Luo Y, Lan C, Xie K, Li H, Devillard E, He J, Liu L, Cai J, Tian G, Wu A, Ren Z, Chen D, Yu B, Huang Z, Zheng P, Mao X, Yu J, Luo J, Yan H, Wang Q, Wang H, Tang J. Active or Autoclaved Akkermansia muciniphila Relieves TNF-α-Induced Inflammation in Intestinal Epithelial Cells Through Distinct Pathways. Front Immunol 2022; 12:788638. [PMID: 34975882 PMCID: PMC8716699 DOI: 10.3389/fimmu.2021.788638] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 11/30/2021] [Indexed: 12/28/2022] Open
Abstract
Intestinal inflammation is a major threat to the health and growth of young animals such as piglets. As a next-generation probiotics, limited studies have shown that Akkermansia muciniphila could alleviate inflammation of intestinal epithelial cells (IECs). In this study, a TNF-α-induced inflammatory model of IPEC-J2 cells, the intestinal porcine enterocytes, was built to evaluate the effects of active or inactive A. muciniphila on the inflammation of IECs. The viability of IPEC-J2 cells was the highest when treated with active (108 copies/mL) or inactive (109 copies/mL) A. muciniphila for 7.5 h (P < 0.01). Treated with 20 ng/mL of TNF-α and followed by a treatment of A. muciniphila, the mRNA level of proinflammatory cytokines (IL-8, IL-1β, IL-6 and TNF-α) was remarkably reduced (P < 0.05) along with the increased mRNA level of tight junction proteins (ZO-1 and Occludin, P < 0.05). Flow cytometry analysis showed that active or inactive A. muciniphila significantly suppressed the rate of the early and total apoptotic of the inflammatory IPEC-J2 cells (P < 0.05). According to results of transcriptome sequencing, active and inactive A. muciniphila may decline cell apoptosis by down-regulating the expression of key genes in calcium signaling pathway, or up-regulating the expression of key genes in cell cycle signaling pathway. And the bacterium may alleviate the inflammation of IECs by down-regulating the expression of PI3K upstream receptor genes. Our results indicate that A. muciniphila may be a promising NGP targeting intestinal inflammation.
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Affiliation(s)
- Yuheng Luo
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Cong Lan
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Kunhong Xie
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Hua Li
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Estelle Devillard
- Center of Research for Nutrition and Health, Adisseo France SAS, Commentry, France
| | - Jun He
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Li Liu
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Jingyi Cai
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Gang Tian
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Aimin Wu
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Zhihua Ren
- College of Veterinary Medicine, Sichuan Province Key Laboratory of Animal Disease and Human Health, Key Laboratory of Environmental Hazard and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Daiwen Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Bing Yu
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Zhiqing Huang
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Ping Zheng
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Xiangbing Mao
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Jie Yu
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Junqiu Luo
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Hui Yan
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Quyuan Wang
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Huifen Wang
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Jiayong Tang
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition and Feed of Ministry of Agriculture of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
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22
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Spitzer N, Patterson KCK, Kipps DW. Akt and MAPK/ERK signaling regulate neurite extension in adult neural progenitor cells but do not directly mediate disruption of cytoskeletal structure and neurite dynamics by low-level silver nanoparticles. Toxicol In Vitro 2021; 74:105151. [PMID: 33753175 DOI: 10.1016/j.tiv.2021.105151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/23/2021] [Accepted: 03/18/2021] [Indexed: 11/23/2022]
Abstract
Silver nanoparticles (AgNPs) are an environmental contaminant of emerging concern. Ionic and colloidal silver has long been used for its antimicrobial properties, but with the development of engineered AgNPs, these are increasingly incorporated in the manufacture of nano-enhanced products. AgNPs are released into the environment from manufacturing plants and they can be shed from products during use and after disposal. This can lead to chronic low-level environmental exposure in animals. Unlike traditional forms of silver, the unique physical properties of AgNPs allow them to bypass biological barriers and enter tissues, like the brain, where they can bioaccumulate. Thus, it is important to understand if low-level AgNPs induce physiological changes in brain cells. Previously we found that 1.0 μg/mL AgNP exposure resulted in disruption of f-actin organization and neurite collapse in cultured differentiating adult neural stem cells, and that interaction with β-catenin signaling was involved. Here, we report that AgNP exposure may interact with pAkt signaling irreversibly or indirectly to disrupt cytoskeleton and inhibit neurite extension. Furthermore, the MAPK/ERK signaling pathway is not a target for AgNP-mediated dysregulation. Environmental exposure to low-level AgNPs therefore appears to target specific cellular mechanisms to alter brain cell physiology. Understanding these underlying mechanisms is important for decisions regulating the use and disposal of manufactured AgNPs.
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Affiliation(s)
- Nadja Spitzer
- Department of Biological Sciences, Marshall University, One John Marshall Dr., Huntington, WV, 25755, United States of America.
| | - Kay-Cee K Patterson
- Department of Biological Sciences, Marshall University, One John Marshall Dr., Huntington, WV, 25755, United States of America
| | - Daniel W Kipps
- Department of Biological Sciences, Marshall University, One John Marshall Dr., Huntington, WV, 25755, United States of America
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23
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Wu C, Bendriem RM, Freed WJ, Lee CT. Transcriptome analysis of human dorsal striatum implicates attenuated canonical WNT signaling in neuroinflammation and in age-related impairment of striatal neurogenesis and synaptic plasticity. Restor Neurol Neurosci 2021; 39:247-266. [PMID: 34275915 DOI: 10.3233/rnn-211161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Motor and cognitive decline as part of the normal aging process is linked to alterations in synaptic plasticity and reduction of adult neurogenesis in the dorsal striatum. Neuroinflammation, particularly in the form of microglial activation, is suggested to contribute to these age-associated changes. OBJECTIVE AND METHODS To explore the molecular basis of alterations in striatal function during aging we analyzed RNA-Seq data for 117 postmortem human dorsal caudate samples and 97 putamen samples acquired through GTEx. RESULTS Increased expression of neuroinflammatory transcripts including TREM2, MHC II molecules HLA-DMB, HLA-DQA2, HLA-DPA1, HLA-DPB1, HLA-DMA and HLA-DRA, complement genes C1QA, C1QB, CIQC and C3AR1, and MHCI molecules HLA-B and HLA-F was identified. We also identified down-regulation of transcripts involved in neurogenesis, synaptogenesis, and synaptic pruning, including DCX, CX3CL1, and CD200, and the canonical WNTs WNT7A, WNT7B, and WNT8A. The canonical WNT signaling pathway has previously been shown to mediate adult neurogenesis and synapse formation and growth. Recent findings also highlight the link between WNT/β-catenin signaling and inflammation pathways. CONCLUSIONS These findings suggest that age-dependent attenuation of canonical WNT signaling plays a pivotal role in regulating striatal plasticity during aging. Dysregulation of WNT/β-catenin signaling via astrocyte-microglial interactions is suggested to be a novel mechanism that drives the decline of striatal neurogenesis and altered synaptic connectivity and plasticity, leading to a subsequent decrease in motor and cognitive performance with age. These findings may aid in the development of therapies targeting WNT/β-catenin signaling to combat cognitive and motor impairments associated with aging.
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Affiliation(s)
- Chun Wu
- Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Raphael M Bendriem
- Brain and Mind Research Institute, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
| | - William J Freed
- Department of Biology, Lebanon Valley College, Annville, PA, USA
| | - Chun-Ting Lee
- Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA
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24
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Zhang T, Beeharry MK, Zheng Y, Wang Z, Li J, Zhu Z, Li C. Long Noncoding RNA SNHG12 Promotes Gastric Cancer Proliferation by Binding to HuR and Stabilizing YWHAZ Expression Through the AKT/GSK-3β Pathway. Front Oncol 2021; 11:645832. [PMID: 34195070 PMCID: PMC8236831 DOI: 10.3389/fonc.2021.645832] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 05/17/2021] [Indexed: 12/24/2022] Open
Abstract
Background Gastric cancer (GC) is a malignancy with high morbidity and mortality rates worldwide. SNHG12 is a long noncoding RNA (lncRNA) commonly involved many types of cancers in the contexts of tumorigenesis, migration and drug resistance. Nevertheless, its role in GC proliferation is poorly understood. Methods Bioinformatics and qRT-PCR assays were used to analyze the expression of SNHG12 in GC tissues and cells. In vitro and in vivo experiments were conducted to detect the role of SNHG12 in GC development. qRT-PCR, PCR, western blotting (WB), RNA binding protein immunoprecipitation (RIP), immunoprecipitation (IP), immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and in situ hybridization (ISH) were performed to investigate the underlying mechanisms by which SNHG12 promotes GC proliferation. Results SNHG12 was highly expressed in GC cells and tissues, and predicted poor survival. In vitro and in vivo assays showed that SNHG12 knockdown inhibited GC proliferation, while SNHG12 overexpression promoted GC proliferation. Further experiments confirmed that SNHG12 was mainly located in the cytoplasm and bound to HuR. Bioinformatics analysis predicted that YWHAZ was the common target of SNHG12 and HuR, and that the “SNHG12-HuR” complex enhanced the stability of YWHAZ mRNA. Furthermore, YWHAZ, which was highly expressed in GC, predicted poor survival and promoted GC proliferation by phosphorylating AKT. Rescue assays verified that SNHG12 promoted GC proliferation by activating the AKT/GSK-3β pathway. Conclusions SNHG12 binds to HuR and stabilizes YWHAZ. SNHG12 promotes GC proliferation via modulation of the YWHAZ/AKT/GSK-3β axis in vitro and in vivo. Thus, SNHG12 could become a novel therapeutic target for anti-tumor therapy.
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Affiliation(s)
- Tianqi Zhang
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Maneesh Kumarsing Beeharry
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanan Zheng
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenqiang Wang
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianfang Li
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenggang Zhu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Li
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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25
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Li Y, Wu B, An C, Jiang D, Gong L, Liu Y, Liu Y, Li J, Ouyang H, Zou X. Mass cytometry and transcriptomic profiling reveal body-wide pathology induced by Loxl1 deficiency. Cell Prolif 2021; 54:e13077. [PMID: 34105806 PMCID: PMC8249785 DOI: 10.1111/cpr.13077] [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: 12/19/2020] [Revised: 05/10/2021] [Accepted: 05/21/2021] [Indexed: 12/17/2022] Open
Abstract
Objective The loss of LOXL1 expression reportedly leads to the prolapse of pelvic organs or to exfoliation syndrome glaucoma. Increasing evidence suggests that LOXL1 deficiency is associated with the pathogenesis of several other diseases. However, the characterization of the systemic functions of LOXL1 is limited by the lack of relevant investigative technologies. Materials and Methods To determine the functions of LOXL1, a novel method for body‐wide organ transcriptome profiling, combined with single‐cell mass cytometry, was developed. A body‐wide organ transcriptomic (BOT) map was created by RNA‐Seq of tissues from 17 organs from both Loxl1 knockout (KO) and wild‐type mice. Results The BOT results indicated the systemic upregulation of genes encoding proteins associated with the immune response and proliferation processes in multiple tissues of KO mice, and histological and immune staining confirmed the hyperplasia and infiltration of local immune cells in the tissues of KO mice. Furthermore, mass cytometry analysis of peripheral blood samples revealed systemic immune changes in KO mice. These findings were well correlated with results obtained from cancer databases. Patients with tumours had higher Loxl1 mutation frequencies, and patients with Loxl1‐mutant tumours showed the upregulation of immune processes and cell proliferation and lower survival rates. Conclusion This study provides an effective strategy for the screening of gene functions in multiple organs and also illustrates the important biological roles of LOXL1 in the cells of multiple organs as well as in systemic immunity.
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Affiliation(s)
- Yu Li
- Clinical Research Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regeneration Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China
| | - Bingbing Wu
- Clinical Research Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regeneration Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China
| | - Chengrui An
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regeneration Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China
| | - Deming Jiang
- Clinical Research Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regeneration Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China
| | - Lin Gong
- Clinical Research Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regeneration Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China
| | - Yanshan Liu
- Clinical Research Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regeneration Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China
| | - Yixiao Liu
- Clinical Research Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regeneration Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China
| | - Jun Li
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regeneration Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China
| | - Hongwei Ouyang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regeneration Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China.,Zhejiang University-University of Edinburgh Institute, Hangzhou, China.,China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
| | - XiaoHui Zou
- Clinical Research Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regeneration Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China
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26
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Behrouj H, Seghatoleslam A, Mokarram P, Ghavami S. Effect of casein kinase 1α inhibition on autophagy flux and the AKT/phospho-β-catenin (S552) axis in HCT116, a RAS-mutated colorectal cancer cell line. Can J Physiol Pharmacol 2021; 99:284-293. [PMID: 33635146 DOI: 10.1139/cjpp-2020-0449] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The Wnt/β-catenin pathway, which interferes with cell proliferation, differentiation, and autophagy, is commonly dysregulated in colorectal cancer (CRC). Mutation of the RAS oncogene is the most prevalent genetic alteration in CRC and has been linked to activation of protein kinase B (AKT) signaling. Phosphorylation of β-catenin at Ser 552 by AKT contributes to β-catenin stability, transcriptional activity, and increase of cell proliferation. Casein kinase 1 alpha (CK1α) is an enzyme that simultaneously regulates Wnt/β-catenin and AKT. The link of the AKT and Wnt pathway to autophagy in RAS-mutated CRC cells has not well identified. Therefore, we investigated how pharmacological CK1α inhibition (D4476) is involved in regulation of autophagy, Wnt/β-catenin, and AKT pathways in RAS-mutated CRC cell lines. qRT-PCR and immunoblotting experiments revealed that phospho-AKT (S473) and phospho-β-catenin (S552) are constitutively increased in RAS-mutated CRC cell lines, in parallel with augmented CK1α expression. The results also showed that D4476 significantly reduced the AKT/phospho-β-catenin (S552) axis concomitantly with autophagy flux inhibition in RAS-mutated CRC cells. Furthermore, D4476 significantly induced apoptosis in RAS-mutated CRC cells. In conclusion, our results indicate that CK1α inhibition reduces autophagy flux and promotes apoptosis by interfering with the AKT/phospho-β-catenin (S552) axis in RAS-mutated CRC cells.
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Affiliation(s)
- Hamid Behrouj
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Atefeh Seghatoleslam
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Pooneh Mokarram
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeid Ghavami
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.,Research Institute in Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada.,Faculty of Medicine, Katowice School of Technology, Katowice, Poland
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27
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He Y, Chen L, Chen K, Sun Y. Immunohistochemical analysis of HNF4A and β-catenin expression to predict low-grade dysplasia in the colitis-neoplastic sequence. Acta Biochim Biophys Sin (Shanghai) 2021; 53:94-101. [PMID: 33300557 DOI: 10.1093/abbs/gmaa147] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Indexed: 01/15/2023] Open
Abstract
Animal studies indicated that P1 promoter-driven hepatocyte nuclear factor 4 alpha (HFN4A) prevents carcinogenesis in colitis. But the function of total HNF4A protein has not been fully investigated, and it was assumed to be involved in the colitis-neoplastic sequence. The aim of this study was to determine the clinical value of total P1-/P2-driven HNF4A combined with β-catenin in the colitis-neoplastic sequence. A total of 69 samples, including 4 normal colon tissues, 16 sporadic colorectal cancer (CRC) tissues, 35 inflammatory bowel disease (IBD) tissues, and 14 IBD-associated low-grade dysplasia tissues, were collected to assess P1-/P2-driven HNF4A and β-catenin expressions by immunohistochemical assay. In addition, a colonic epithelial cell line Caco2 with stable P1-/P2-driven HNF4A knockdown was constructed. β-Catenin expression and skeleton structure were determined in the transfected cells by western blot analysis and immunofluorescence assay respectively. Increased expression of nuclear P1-/P2-driven HNF4A was observed in the colitis-associated colorectal neoplasm and sporadic CRC samples, compared with that in colitis samples. The parallel alterations between cytoplasmic β-catenin and nuclear P1-/P2-driven HNF4A were also verified. Silencing of P1-/P2-driven HNF4A expression in Caco2 cells decreased β-catenin expression and F-actin formation. Our results confirmed the elevated expressions of nuclear P1-/P2-driven HNF4A and cytoplasmic β-catenin in the colitis-neoplastic sequence, and both of them may be used as potential biomarkers to predict low-grade dysplasia.
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Affiliation(s)
- Yiping He
- Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Lezong Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Ke Chen
- Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yunwei Sun
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai 200025, China
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Weinberg SE, Sun LY, Yang AL, Liao J, Yang GY. Overview of Inositol and Inositol Phosphates on Chemoprevention of Colitis-Induced Carcinogenesis. Molecules 2020; 26:E31. [PMID: 33374769 PMCID: PMC7796135 DOI: 10.3390/molecules26010031] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 12/18/2020] [Accepted: 12/20/2020] [Indexed: 12/17/2022] Open
Abstract
Chronic inflammation is one of the most common and well-recognized risk factors for human cancer, including colon cancer. Inflammatory bowel disease (IBD) is defined as a longstanding idiopathic chronic active inflammatory process in the colon, including ulcerative colitis and Crohn's disease. Importantly, patients with IBD have a significantly increased risk for the development of colorectal carcinoma. Dietary inositol and its phosphates, as well as phospholipid derivatives, are well known to benefit human health in diverse pathologies including cancer prevention. Inositol phosphates including InsP3, InsP6, and other pyrophosphates, play important roles in cellular metabolic and signal transduction pathways involved in the control of cell proliferation, differentiation, RNA export, DNA repair, energy transduction, ATP regeneration, and numerous others. In the review, we highlight the biologic function and health effects of inositol and its phosphates including the nature and sources of these molecules, potential nutritional deficiencies, their biologic metabolism and function, and finally, their role in the prevention of colitis-induced carcinogenesis.
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Affiliation(s)
- Samuel E. Weinberg
- Department of Pathology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611, USA; (S.E.W.); (L.Y.S.); (J.L.)
| | - Le Yu Sun
- Department of Pathology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611, USA; (S.E.W.); (L.Y.S.); (J.L.)
| | - Allison L. Yang
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 1293 York Avenue, New York, NY 10065, USA;
| | - Jie Liao
- Department of Pathology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611, USA; (S.E.W.); (L.Y.S.); (J.L.)
| | - Guang Yu Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611, USA; (S.E.W.); (L.Y.S.); (J.L.)
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Wei G, Gao N, Chen J, Fan L, Zeng Z, Gao G, Li L, Fang G, Hu K, Pang X, Fan HY, Clevers H, Liu M, Zhang X, Li D. Erk and MAPK signaling is essential for intestinal development through Wnt pathway modulation. Development 2020; 147:dev.185678. [PMID: 32747435 DOI: 10.1242/dev.185678] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 07/23/2020] [Indexed: 12/28/2022]
Abstract
Homeostasis of intestinal stem cells (ISCs) is maintained by the orchestration of niche factors and intrinsic signaling networks. Here, we have found that deletion of Erk1 and Erk2 (Erk1/2) in intestinal epithelial cells at embryonic stages resulted in an unexpected increase in cell proliferation and migration, expansion of ISCs, and formation of polyp-like structures, leading to postnatal death. Deficiency of epithelial Erk1/2 results in defects in secretory cell differentiation as well as impaired mesenchymal cell proliferation and maturation. Deletion of Erk1/2 strongly activated Wnt signaling through both cell-autonomous and non-autonomous mechanisms. In epithelial cells, Erk1/2 depletion resulted in loss of feedback regulation, leading to Ras/Raf cascade activation that transactivated Akt activity to stimulate the mTor and Wnt/β-catenin pathways. Moreover, Erk1/2 deficiency reduced the levels of Indian hedgehog and the expression of downstream pathway components, including mesenchymal Bmp4 - a Wnt suppressor in intestines. Inhibition of mTor signaling by rapamycin partially rescued Erk1/2 depletion-induced intestinal defects and significantly prolonged the lifespan of mutant mice. These data demonstrate that Erk/Mapk signaling functions as a key modulator of Wnt signaling through coordination of epithelial-mesenchymal interactions during intestinal development.
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Affiliation(s)
- Gaigai Wei
- Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Na Gao
- Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jiwei Chen
- Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Lingling Fan
- Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Zhiyang Zeng
- Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Ganglong Gao
- Fengxian Hospital affiliated to Southern Medical University, Shanghai 201499, China
| | - Liang Li
- Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Guojiu Fang
- Fengxian Hospital affiliated to Southern Medical University, Shanghai 201499, China
| | - Kewen Hu
- Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Xiufeng Pang
- Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Heng-Yu Fan
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Hans Clevers
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Uppsalalaan 8, Utrecht 3584 CT, The Netherlands
| | - Mingyao Liu
- Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Xueli Zhang
- Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China .,Fengxian Hospital affiliated to Southern Medical University, Shanghai 201499, China
| | - Dali Li
- Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
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30
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Wang S, Han Y, Zhang J, Yang S, Fan Z, Song F, He L, Yue W, Li Y, Pei X. Me6TREN targets β-catenin signaling to stimulate intestinal stem cell regeneration after radiation. Theranostics 2020; 10:10171-10185. [PMID: 32929341 PMCID: PMC7481405 DOI: 10.7150/thno.46415] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 07/30/2020] [Indexed: 01/08/2023] Open
Abstract
Background: Acute gastrointestinal syndrome (AGS) is one of the most severe clinical manifestations after exposure to high doses of radiation, and is life-threatening in radiological emergency scenarios. However, an unmet challenge is lacking of an FDA-approved drug that can ameliorate the damage of radiation-exposed intestinal tissues and accelerate the regeneration of injured epithelia. In this study, we investigated whether the small molecule Me6TREN (Me6) can regulate intestinal stem cell (ISC) proliferation and promote crypt regeneration after irradiation. Methods: Lethally irradiated mice were administered with Me6 or PBS to study the survival rate, and sections of their small intestine were subjected to immunostaining to evaluate epithelial regeneration. An intestinal organoid culture system was employed to detect the role of Me6 in organoid growth and ISC proliferation. We further investigated the key signaling pathways associated with Me6 using microarray, western blotting, and RNA interference techniques. Results: We identified the small molecule Me6 as a potent intestinal radiation countermeasure. Systemic administration of Me6 significantly improved ISC and crypt cell regeneration and enhanced the survival of mice after high doses of radiation. Using an in vitro intestinal organoid culture system, we found that Me6 not only induced ISC proliferation but also increased the budding rate of intestinal organoids under unirradiated and irradiated conditions. Me6 remarkably activated the expression of ISC-associated and proliferation-promoting genes, such as Ascl2, Lgr5, Myc, and CyclinD1. Mechanistically, Me6 strongly stimulated the phosphorylation of β-catenin at the S552 site and increased the transcriptional activity of β-catenin, a key signaling pathway for ISC self-renewal and proliferation. This is further evidenced by the fact that knockdown of β-catenin abolished the effect of Me6 on intestinal organoid growth in vitro and crypt regeneration in irradiated mice. Conclusion: The small molecule Me6TREN induced ISC proliferation, enhanced intestinal organoid growth in vitro, and promoted intestinal tissue regeneration after radiation injury by activating β-catenin signaling.
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Perry JM, Tao F, Roy A, Lin T, He XC, Chen S, Lu X, Nemechek J, Ruan L, Yu X, Dukes D, Moran A, Pace J, Schroeder K, Zhao M, Venkatraman A, Qian P, Li Z, Hembree M, Paulson A, He Z, Xu D, Tran TH, Deshmukh P, Nguyen CT, Kasi RM, Ryan R, Broward M, Ding S, Guest E, August K, Gamis AS, Godwin A, Sittampalam GS, Weir SJ, Li L. Overcoming Wnt-β-catenin dependent anticancer therapy resistance in leukaemia stem cells. Nat Cell Biol 2020; 22:689-700. [PMID: 32313104 PMCID: PMC8010717 DOI: 10.1038/s41556-020-0507-y] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 03/12/2020] [Indexed: 02/07/2023]
Abstract
Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt-β-catenin and PI3K-Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt-β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.
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MESH Headings
- Animals
- Antibiotics, Antineoplastic/pharmacology
- Apoptosis
- Cell Proliferation
- Doxorubicin/pharmacology
- Drug Resistance, Neoplasm
- Female
- Humans
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Male
- Mice
- Mice, Knockout
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- PTEN Phosphohydrolase/physiology
- Phosphatidylinositol 3-Kinases/genetics
- Phosphatidylinositol 3-Kinases/metabolism
- Proto-Oncogene Proteins c-akt/genetics
- Proto-Oncogene Proteins c-akt/metabolism
- Tumor Cells, Cultured
- Wnt Proteins/physiology
- Xenograft Model Antitumor Assays
- beta Catenin/physiology
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Affiliation(s)
- John M Perry
- Stowers Institute for Medical Research, Kansas City, MO, USA
- Children's Mercy Kansas City, Kansas City, MO, USA
- University of Kansas Medical Center, Kansas City, KS, USA
- University of Missouri Kansas City School of Medicine, Kansas City, MO, USA
| | - Fang Tao
- Stowers Institute for Medical Research, Kansas City, MO, USA
- Children's Mercy Kansas City, Kansas City, MO, USA
| | - Anuradha Roy
- High Throughput Screening Laboratory, University of Kansas, Lawrence, KS, USA
| | - Tara Lin
- University of Kansas Medical Center, Kansas City, KS, USA
| | - Xi C He
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | - Shiyuan Chen
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | - Xiuling Lu
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA
| | | | - Linhao Ruan
- Stowers Institute for Medical Research, Kansas City, MO, USA
- Center for Cell Dynamics, Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Xiazhen Yu
- Stowers Institute for Medical Research, Kansas City, MO, USA
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Debra Dukes
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | - Andrea Moran
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | | | | | - Meng Zhao
- Stowers Institute for Medical Research, Kansas City, MO, USA
- Key Laboratory of Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China
| | | | - Pengxu Qian
- Stowers Institute for Medical Research, Kansas City, MO, USA
- Center of Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Zhenrui Li
- Stowers Institute for Medical Research, Kansas City, MO, USA
- St. Jude, Memphis, TN, USA
| | - Mark Hembree
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | - Ariel Paulson
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | - Zhiquan He
- Department of Electrical Engineering and Computer Science and C.S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Dong Xu
- Department of Electrical Engineering and Computer Science and C.S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Thanh-Huyen Tran
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA
- Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, US
| | - Prashant Deshmukh
- Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT, USA
| | - Chi Thanh Nguyen
- Department of Chemistry, University of Connecticut, Storrs, CT, USA
| | - Rajeswari M Kasi
- Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT, USA
- Department of Chemistry, University of Connecticut, Storrs, CT, USA
| | - Robin Ryan
- Children's Mercy Kansas City, Kansas City, MO, USA
| | | | - Sheng Ding
- School of Pharmaceutical Science, Tsinghua University, Beijing, China
| | - Erin Guest
- Children's Mercy Kansas City, Kansas City, MO, USA
| | - Keith August
- Children's Mercy Kansas City, Kansas City, MO, USA
| | - Alan S Gamis
- Children's Mercy Kansas City, Kansas City, MO, USA
| | - Andrew Godwin
- University of Kansas Medical Center, Kansas City, KS, USA
| | - G Sitta Sittampalam
- University of Kansas Medical Center, Kansas City, KS, USA
- Therapeutics for Rare and Neglected Diseases, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Scott J Weir
- Department of Cancer Biology, The Institute for Advancing Medical Innovation and University of Kansas Cancer Center, Kansas City, Kansas, USA
| | - Linheng Li
- Stowers Institute for Medical Research, Kansas City, MO, USA.
- Department of Pathology and Laboratory Medicine and Division of Medical Oncology, Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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32
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Farr L, Ghosh S, Jiang N, Watanabe K, Parlak M, Bucala R, Moonah S. CD74 Signaling Links Inflammation to Intestinal Epithelial Cell Regeneration and Promotes Mucosal Healing. Cell Mol Gastroenterol Hepatol 2020; 10:101-112. [PMID: 32004754 PMCID: PMC7215244 DOI: 10.1016/j.jcmgh.2020.01.009] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 12/31/2019] [Accepted: 01/20/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The inflammatory response to intestinal damage promotes healing through mechanisms that are incompletely understood. Gene expression of cluster of differentiation 74 (CD74), the receptor for cytokine macrophage migration inhibitory factor, is increased in patients with inflammatory bowel disease (IBD), however, the role of CD74 signaling in intestinal inflammation remains poorly understood. The aim of this study was to determine the functional role of CD74 signaling in intestinal inflammation. METHODS We studied the characteristics of CD74 protein expression in human IBD and experimental colitis. The functional role of CD74 signaling in the intestine was investigated using cellular models; wild-type, CD74-/-, and bone marrow chimera mice; neutralizing anti-CD74 antibodies; flow cytometry; immunohistochemistry; immunofluorescence; immunoblotting; and clustered regularly interspaced short palindromic repeats and associated protein 9 technology. RESULTS In IBD patients and experimental colitis, CD74-receptor protein expression was increased in inflamed intestinal tissue, prominently in the crypt epithelial cells. By using distinct but complementary chemical and non-chemically induced mouse models of colitis with genetic and antibody neutralization approaches, we found that CD74 signaling was necessary for gut repair. Mechanistically, we found that the macrophage migration inhibitory factor cytokine, which also is increased in colitis, stimulated the CD74 receptor, enhancing intestinal epithelial cell proliferation through activation of the protein kinase B and the extracellular signal-regulated kinase pathways. Our data also suggest that CD74 signaling in immune cells was not essential for mucosal healing. CONCLUSIONS CD74 signaling is strongly activated during intestinal inflammation and protects the host by promoting epithelial cell regeneration, healing, and maintaining mucosal barrier integrity. Enhancing the CD74 pathway may represent a unique therapeutic strategy for promoting healing in IBD.
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Affiliation(s)
- Laura Farr
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Swagata Ghosh
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Nona Jiang
- Department of Medicine, Yale University, New Haven, Connecticut
| | - Koji Watanabe
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Mahmut Parlak
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Richard Bucala
- Department of Medicine, Yale University, New Haven, Connecticut
| | - Shannon Moonah
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia,Correspondence Address correspondence to: Shannon Moonah, MD, ScM, Department of Medicine, University of Virginia, PO Box 801340, Charlottesville, Virginia 22908-1340. fax: (434) 243-1230.
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Shankar G. M, Alex VV, Nisthul A. A, Bava SV, Sundaram S, Retnakumari AP, Chittalakkottu S, Anto RJ. Pre-clinical evidences for the efficacy of tryptanthrin as a potent suppressor of skin cancer. Cell Prolif 2020; 53:e12710. [PMID: 31663659 PMCID: PMC6985671 DOI: 10.1111/cpr.12710] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 08/22/2019] [Accepted: 09/11/2019] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE Clinical trials have demonstrated the efficacy of indigo naturalis, a traditional Chinese medicine ingredient, against psoriasis, a skin disease characterized by keratinocyte hyperproliferation and inflammation. The present study investigates the efficacy of tryptanthrin, a bioactive compound in indigo naturalis, against non-melanoma skin cancer (NMSC) and the signalling events involved. METHODS Efficacy of tryptanthrin against NMSC was assessed using DMBA/PMA-induced skin carcinogenesis model in Swiss albino mice. Immunostaining for PCNA and ki-67 was used to mark proliferating cells in tissues. Haematoxylin and eosin staining and toluidine staining were employed to assess inflammation, and TUNEL assay was used to detect apoptosis in tissues. The signalling events were evaluated using Western blot, imunohistochemistry and immunofluorescence staining. MTT assay and clonogenic assay were performed to assess the viability and proliferation of cancer cells, in vitro. RESULTS In mice, topical application of tryptanthrin suppressed skin carcinogenesis. It attenuated inflammation, impeded the proliferation of hair follicle (HF) cells and suppressed the activation of β-catenin, a major driver of HF cell proliferation. Additionally tryptanthrin suppressed the activation of ERK1/2 and p38, both of which promote β-catenin activation and lowered the expression of c-Myc and cyclin-D1. Tryptanthrin suppressed the proliferation of the human NMSC cell line, A431 and abrogated EGF-induced activation of β-catenin and subsequent cytoskeletal rearrangement. CONCLUSION The study demonstrates with molecular evidence that tryptanthrin is an effective suppressor of NMSC.
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Affiliation(s)
- Mohan Shankar G.
- Division of Cancer ResearchRajiv Gandhi Centre for BiotechnologyThiruvananthapuramKeralaIndia
- Research ScholarManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Vijai V. Alex
- Division of Cancer ResearchRajiv Gandhi Centre for BiotechnologyThiruvananthapuramKeralaIndia
| | - Amrutha Nisthul A.
- Department of Biotechnology and MicrobiologyKannur UniversityKannurKeralaIndia
| | - Smitha V. Bava
- Department of BiotechnologyUniversity of CalicutCalicutKeralaIndia
| | - Sankar Sundaram
- Department of PathologyGovernment Medical CollegeKottayamKeralaIndia
| | - Archana P. Retnakumari
- Division of Cancer ResearchRajiv Gandhi Centre for BiotechnologyThiruvananthapuramKeralaIndia
| | | | - Ruby John Anto
- Division of Cancer ResearchRajiv Gandhi Centre for BiotechnologyThiruvananthapuramKeralaIndia
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34
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Silva AL, Faria M, Matos P. Inflammatory Microenvironment Modulation of Alternative Splicing in Cancer: A Way to Adapt. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1219:243-258. [PMID: 32130703 DOI: 10.1007/978-3-030-34025-4_13] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The relationship between inflammation and cancer has been long recognized by the medical and scientific community. In the last decades, it has returned to the forefront of clinical oncology since a wealth of knowledge has been gathered about the cells, cytokines and physiological processes that are central to both inflammation and cancer. It is now robustly established that chronic inflammation can induce certain cancers but also that solid tumors, in turn, can initiate and perpetuate local inflammatory processes that foster tumor growth and dissemination. Inflammation is the hallmark of the innate immune response to tissue damage or infection, but also mediates the activation, expansion and recruitment to the tissues of cells and antibodies of the adaptive immune system. The functional integration of both components of the immune response is crucial to identify and subdue tumor development, progression and dissemination. When this tight control goes awry, altered cells can avoid the immune surveillance and even subvert the innate immunity to promote their full oncogenic transformation. In this chapter, we make a general overview of the most recent data linking the inflammatory process to cancer. We start with the overall inflammatory cues and processes that influence the relationship between tumor and the microenvironment that surrounds it and follow the ever-increasing complexity of processes that end up producing subtle changes in the splicing of certain genes to ascertain survival advantage to cancer cells.
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Affiliation(s)
- Ana Luísa Silva
- Serviço de Endocrinologia, Diabetes e Metabolismo do CHLN-Hospital Santa Maria, Lisbon, Portugal
- ISAMB-Instituto de Saúde Ambiental, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Márcia Faria
- Serviço de Endocrinologia, Diabetes e Metabolismo do CHLN-Hospital Santa Maria, Lisbon, Portugal
- Faculdade de Ciências, BioISI-Biosystems and Integrative Sciences Institute, Universidade de Lisboa, Lisbon, Portugal
| | - Paulo Matos
- Faculdade de Ciências, BioISI-Biosystems and Integrative Sciences Institute, Universidade de Lisboa, Lisbon, Portugal
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon, Portugal
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Callejas BE, Mendoza-Rodríguez MG, Villamar-Cruz O, Reyes-Martínez S, Sánchez-Barrera CA, Rodríguez-Sosa M, Delgado-Buenrostro NL, Martínez-Saucedo D, Chirino YI, León-Cabrera SA, Pérez-Plasencia C, Vaca-Paniagua F, Arias-Romero LE, Terrazas LI. Helminth-derived molecules inhibit colitis-associated colon cancer development through NF-κB and STAT3 regulation. Int J Cancer 2019; 145:3126-3139. [PMID: 31407335 DOI: 10.1002/ijc.32626] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 07/30/2019] [Indexed: 12/28/2022]
Abstract
Inflammation is currently considered a hallmark of cancer and plays a decisive role in different stages of tumorigenesis, including initiation, promotion, progression, metastasis and resistance to antitumor therapies. Colorectal cancer is a disease widely associated with local chronic inflammation. Additionally, extrinsic factors such as infection may beneficially or detrimentally alter cancer progression. Several reports have noted the ability of various parasitic infections to modulate cancer development, favoring tumor progression in many cases and inhibiting tumorigenesis in others. The aim of our study was to determine the effects of excreted/secreted products of the helminth Taenia crassiceps (TcES) as a treatment in a murine model of colitis-associated colon cancer (CAC). Here, we found that after inducing CAC, treatment with TcES was able to reduce inflammatory cytokines such as IL-1β, TNF-α, IL-33 and IL-17 and significantly attenuate colon tumorigenesis. This effect was associated with the inhibition of signal transducer and activator of transcription 3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation. Furthermore, we determined that TcES interfered with LPS-induced NF-κB p65 activation in human colonic epithelial cell lines in a Raf-1 proto-oncogene-dependent manner. Moreover, in three-dimensional cultures, TcES promoted reorganization of the actin cytoskeleton, altering cell morphology and forming colonospheres, features associated with a low grade of aggressiveness. Our study demonstrates a remarkable effect of helminth-derived molecules on suppressing ongoing colorectal cancer by downregulating proinflammatory and protumorigenic signaling pathways.
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Affiliation(s)
- Blanca E Callejas
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Mónica G Mendoza-Rodríguez
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Olga Villamar-Cruz
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Sandy Reyes-Martínez
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Cuauhtémoc Angel Sánchez-Barrera
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Miriam Rodríguez-Sosa
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Norma L Delgado-Buenrostro
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Diana Martínez-Saucedo
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Yolanda I Chirino
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Sonia A León-Cabrera
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Carlos Pérez-Plasencia
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico.,Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México, Mexico
| | - Felipe Vaca-Paniagua
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico.,Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México, Mexico.,Laboratorio Nacional en Salud, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Luis E Arias-Romero
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Luis I Terrazas
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico.,Laboratorio Nacional en Salud, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
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Costa R, Peruzzo R, Bachmann M, Montà GD, Vicario M, Santinon G, Mattarei A, Moro E, Quintana-Cabrera R, Scorrano L, Zeviani M, Vallese F, Zoratti M, Paradisi C, Argenton F, Brini M, Calì T, Dupont S, Szabò I, Leanza L. Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction. Cell Rep 2019; 28:1949-1960.e6. [PMID: 31433973 DOI: 10.1016/j.celrep.2019.07.050] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 03/01/2019] [Accepted: 07/16/2019] [Indexed: 02/02/2023] Open
Abstract
Wnt signaling affects fundamental development pathways and, if aberrantly activated, promotes the development of cancers. Wnt signaling is modulated by different factors, but whether the mitochondrial energetic state affects Wnt signaling is unknown. Here, we show that sublethal concentrations of different compounds that decrease mitochondrial ATP production specifically downregulate Wnt/β-catenin signaling in vitro in colon cancer cells and in vivo in zebrafish reporter lines. Accordingly, fibroblasts from a GRACILE syndrome patient and a generated zebrafish model lead to reduced Wnt signaling. We identify a mitochondria-Wnt signaling axis whereby a decrease in mitochondrial ATP reduces calcium uptake into the endoplasmic reticulum (ER), leading to endoplasmic reticulum stress and to impaired Wnt signaling. In turn, the recovery of the ATP level or the inhibition of endoplasmic reticulum stress restores Wnt activity. These findings reveal a mechanism that links mitochondrial energetic metabolism to the control of the Wnt pathway that may be beneficial against several pathologies.
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Affiliation(s)
- Roberto Costa
- Department of Biology, University of Padova, Padova, Italy
| | | | | | | | - Mattia Vicario
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Giulia Santinon
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Andrea Mattarei
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Enrico Moro
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Rubén Quintana-Cabrera
- Department of Biology, University of Padova, Padova, Italy; Venetian Institute of Molecular Medicine, Padova, Padova, Italy
| | - Luca Scorrano
- Department of Biology, University of Padova, Padova, Italy; Venetian Institute of Molecular Medicine, Padova, Padova, Italy
| | - Massimo Zeviani
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
| | - Francesca Vallese
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Mario Zoratti
- Department of Biomedical Sciences, University of Padova, Padova, Italy; CNR Institute of Neuroscience, Padova, Italy
| | - Cristina Paradisi
- Department of Chemical Sciences, University of Padova, Padova, Italy
| | | | - Marisa Brini
- Department of Biology, University of Padova, Padova, Italy
| | - Tito Calì
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Sirio Dupont
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Ildikò Szabò
- Department of Biology, University of Padova, Padova, Italy; CNR Institute of Neuroscience, Padova, Italy.
| | - Luigi Leanza
- Department of Biology, University of Padova, Padova, Italy.
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Chang LC, Sun HL, Tsai CH, Kuo CW, Liu KL, Lii CK, Huang CS, Li CC. 1,25(OH) 2 D 3 attenuates indoxyl sulfate-induced epithelial-to-mesenchymal cell transition via inactivation of PI3K/Akt/β-catenin signaling in renal tubular epithelial cells. Nutrition 2019; 69:110554. [PMID: 31536856 DOI: 10.1016/j.nut.2019.110554] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/30/2019] [Accepted: 07/11/2019] [Indexed: 12/31/2022]
Abstract
OBJECTIVES Indoxyl sulfate (IS), a uremic toxin, has been shown to promote the epithelial-to-mesenchymal transition (EMT) of human proximal tubular cells and to accelerate the progression of chronic kidney disease (CKD). Despite the well-known protective role of 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3] in EMT, the effect of 1,25(OH)2 D3 on IS-induced EMT in human proximal tubular epithelial cells and the underlying mechanism remain unclear. The aim of this study was to determine whether IS (0-1 mM) dose-dependently inhibited the protein expression of E-cadherin and increased the protein expression of alpha-smooth muscle actin, N-cadherin, and fibronectin. METHODS This study investigated the molecular mechanism by which 1,25(OH)2 D3 attenuates IS-induced EMT. HK-2 human renal tubular epithelial cells was used as the study model, and the MTT assay, Western Blotting, siRNA knockdown technique were used to explore the effects of 1,25(OH)2 D3 on EMT in the presence of IS. RESULTS Pretreatment with 1,25(OH)2 D3 inhibited the IS-induced EMT-associated protein expression in HK-2 cells. IS induced the phosphorylation of Akt (S473) and β-catenin (S552) and subsequently increased the nuclear accumulation of β-catenin. Pretreatment with 1,25(OH)2 D3 and LY294002 (phosphoinositide 3-kinase [PIK3] inhibitor) significantly inhibited the IS-induced phosphorylation of Akt and β-catenin, nuclear β-catenin accumulation, and EMT-associated protein expression. CONCLUSIONS Results from the present study revealed that the anti-EMT effect of 1,25(OH)2 D3 is likely through inhibition of the PI3K/Akt/β-catenin pathway, which leads to down-regulation of IS-driven EMT-associated protein expression in HK-2 human renal tubular epithelial cells.
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Affiliation(s)
- Li-Chien Chang
- Department of Internal Medicine, Taichung Armed Forces General Hospital, Taichung, Taiwan; Department of Medicine, National Defense Medical Center, Taipei, Taiwan; Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan
| | - Hai-Lun Sun
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chia-Han Tsai
- Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan
| | - Chia-Wen Kuo
- Department of Internal Medicine, Taichung Armed Forces General Hospital, Taichung, Taiwan; Department of Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Kai-Li Liu
- Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan; Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chong-Kuei Lii
- Department of Nutrition, China Medical University, Taichung, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
| | - Chin-Shiu Huang
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
| | - Chien-Chun Li
- Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan; Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan.
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38
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Sun C, Wang L, Yang XX, Jiang YH, Guo XL. The aberrant expression or disruption of desmocollin2 in human diseases. Int J Biol Macromol 2019; 131:378-386. [DOI: 10.1016/j.ijbiomac.2019.03.041] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 03/05/2019] [Accepted: 03/05/2019] [Indexed: 12/21/2022]
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39
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Zhong ME, Chen Y, Zhang G, Xu L, Ge W, Wu B. LncRNA H19 regulates PI3K-Akt signal pathway by functioning as a ceRNA and predicts poor prognosis in colorectal cancer: integrative analysis of dysregulated ncRNA-associated ceRNA network. Cancer Cell Int 2019; 19:148. [PMID: 31164794 PMCID: PMC6543669 DOI: 10.1186/s12935-019-0866-2] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 05/27/2019] [Indexed: 01/15/2023] Open
Abstract
Background It is becoming increasingly clear that cancers can rarely be ascribed to just one or a few genomic variations. Genes generally do not function alone, but in groups that function as “networks”. This study aimed to develop a competing endogenous RNA (ceRNA) network to elucidate the role of long non-coding RNA H19 in colorectal cancer. Methods Large-scale RNA-seq data was obtained from The Cancer Genome Atlas database. Differentially expressed RNAs were identified by bioinformatics analysis, and a competing endogenous RNA network was constructed. Functional enrichment analysis and correlation analysis between competing endogenous RNAs and clinical features were performed to reveal their roles in the tumorigenesis of colorectal cancer. To verify the conclusions derived from bioinformatics analysis, we investigated the effect of lncRNA H19 knockdown in human colorectal cancer cell lines HT-29 and HCT116. Results The present study successfully identify various cancer-specific lncRNAs and pseudogenes in CRC. The lncRNA/pseudogene–miRNA–mRNA ceRNA network was constructed using 10 lncRNAs, 5 pseudogenes, 122 mRNAs and 39 miRNAs. In the ceRNA network of CRC, H19 up-regulates various cancer-related mRNA by competitively sponging various miRNA, and participates in PI3K–Akt signaling pathway in this manner. Cox regression and correlation analysis showed that H19 and some other competing endogenous RNAs in the network are associated with poor prognosis and clinical parameters such as tumor grade and metastasis. Knockdown of H19 reduces the protein level of MET, ZEB1, and COL1A1 in vitro. Conclusions H19 regulates PI3K–Akt signal pathway through a competing endogenous RNA network and predicts poor prognosis in colorectal cancer. The pseudogene RPLP0P2 may be an important oncogene like H19 and needs to be studied further. Electronic supplementary material The online version of this article (10.1186/s12935-019-0866-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Min-Er Zhong
- 1Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Road, Wangfujing, Dongcheng District, Beijing, 100730 China
| | - Yanyu Chen
- 2National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, 5 Dong Dan San Tiao, Dongcheng District, Beijing, 100005 China
| | - Guannan Zhang
- 1Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Road, Wangfujing, Dongcheng District, Beijing, 100730 China
| | - Lai Xu
- 1Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Road, Wangfujing, Dongcheng District, Beijing, 100730 China
| | - Wei Ge
- 2National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, 5 Dong Dan San Tiao, Dongcheng District, Beijing, 100005 China
| | - Bin Wu
- 1Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Road, Wangfujing, Dongcheng District, Beijing, 100730 China
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40
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Richardson AI, Yin CC, Cui W, Li N, Medeiros LJ, Li L, Zhang D. p53 and β-Catenin Expression Predict Poorer Prognosis in Patients With Anaplastic Large-Cell Lymphoma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2019; 19:e385-e392. [PMID: 31078446 DOI: 10.1016/j.clml.2019.03.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 03/30/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND The Wnt/β-catenin signaling pathway is a major target of p53. β-Catenin/p53 coexpression predicts poorer survival in carcinoma patients. Conversely, CD99 inhibits tumor metastasis through the Wnt/β-catenin pathway. We therefore assessed p53, β-catenin, and CD99 by immunohistochemistry. PATIENTS AND METHODS We studied 45 patients with systemic anaplastic large-cell lymphoma (ALCL), including 20 anaplastic lymphoma kinase (ALK)-positive and 25 ALK-negative ALCL. β-Catenin expression was analyzed using phospho-β-catenin-S552 antibody because its nuclear localization indicates Wnt signaling. RESULTS In this cohort, p53 expression was associated with ALK-negative ALCL. Furthermore, p53 or β-catenin expression alone or β-catenin/p53 double expression showed poorer overall survival and disease-free survival in patients with ALCL overall and in patients with ALK-negative ALCL. CD99 expression was more frequent in ALK-positive ALCL but had no prognostic significance. CONCLUSION This is the first study to evaluate phospho-β-catenin-S552 expression in ALCL. The results of this study, although limited by small patient size, suggest that β-catenin and p53 may play a role in pathogenesis and may be helpful in risk stratification of ALCL patients.
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Affiliation(s)
- Aida Ibricevic Richardson
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS
| | - C Cameron Yin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Wei Cui
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS
| | - Nianyi Li
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - L Jeffrey Medeiros
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Linheng Li
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS; Stowers Institute for Medical Research, Kansas City, MO
| | - Da Zhang
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS.
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Radhakrishnan H, Walther W, Zincke F, Kobelt D, Imbastari F, Erdem M, Kortüm B, Dahlmann M, Stein U. MACC1-the first decade of a key metastasis molecule from gene discovery to clinical translation. Cancer Metastasis Rev 2019; 37:805-820. [PMID: 30607625 DOI: 10.1007/s10555-018-9771-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Deciphering the paths to metastasis and identifying key molecules driving this process is one important issue for understanding and treatment of cancer. Such a key driver molecule is Metastasis Associated in Colon Cancer 1 (MACC1). A decade long research on this evolutionarily conserved molecule with features of a transcription factor as well as an adapter protein for versatile protein-protein interactions has shown that it has manifold properties driving tumors to their metastatic stage. MACC1 transcriptionally regulates genes involved in epithelial-mesenchymal transition (EMT), including those which are able to directly induce metastasis like c-MET, impacts tumor cell migration and invasion, and induces metastasis in solid cancers. MACC1 has proven as a valuable biomarker for prognosis of metastasis formation linked to patient survival and gives promise to also act as a predictive marker for individualized therapies in a broad variety of cancers. This review discusses the many features of MACC1 in the context of the hallmarks of cancer and the potential of this molecule as biomarker and novel therapeutic target for restriction and prevention of metastasis.
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Affiliation(s)
- Harikrishnan Radhakrishnan
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125, Berlin, Germany
| | - Wolfgang Walther
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125, Berlin, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany
| | - Fabian Zincke
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125, Berlin, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany
| | - Dennis Kobelt
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125, Berlin, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany
| | - Francesca Imbastari
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125, Berlin, Germany
| | - Müge Erdem
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125, Berlin, Germany
| | - Benedikt Kortüm
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125, Berlin, Germany
| | - Mathias Dahlmann
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125, Berlin, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany
| | - Ulrike Stein
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125, Berlin, Germany. .,German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany.
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Reisdorf WC, Xie Q, Zeng X, Xie W, Rajpal N, Hoang B, Burgert ME, Kumar V, Hurle MR, Rajpal DK, O’Donnell S, MacDonald TT, Vossenkämper A, Wang L, Reilly M, Votta BJ, Sanchez Y, Agarwal P. Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease. PLoS One 2019; 14:e0215033. [PMID: 31002701 PMCID: PMC6474586 DOI: 10.1371/journal.pone.0215033] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 03/25/2019] [Indexed: 12/14/2022] Open
Abstract
Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature. To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Follow-up immunohistochemistry analysis verified the presence of EPHX2 protein in infiltrated immune cells from Crohn's patient tissue biopsies. We further demonstrated that GSK2256294, a clinical EPHX2i, reduced the production of IL2, IL12p70, IL10 and TNFα in both ulcerative colitis and Crohn's disease patient-derived explant cultures. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1β in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD.
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Affiliation(s)
- William C. Reisdorf
- Computational Biology, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
- * E-mail:
| | - Qing Xie
- Computational Biology, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Xin Zeng
- Target & Pathway Validation, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Wensheng Xie
- Target & Pathway Validation, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Neetu Rajpal
- Computational Biology, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Bao Hoang
- Exploratory Biomarkers, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Mark E. Burgert
- Research Statistics, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Vinod Kumar
- Computational Biology, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Mark R. Hurle
- Computational Biology, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Deepak K. Rajpal
- Computational Biology, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Sarah O’Donnell
- Centre for Digestive Diseases, Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
| | | | - Anna Vossenkämper
- Centre for Immunobiology, Blizard Institute, QMUL, London, United Kingdom
| | - Lin Wang
- Pattern Recognition Receptor DPU, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Mike Reilly
- Pattern Recognition Receptor DPU, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Bart J. Votta
- Pattern Recognition Receptor DPU, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Yolanda Sanchez
- Stress and Repair DPU, Respiratory Therapy Area, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Pankaj Agarwal
- Computational Biology, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
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Gowrikumar S, Ahmad R, Uppada SB, Washington MK, Shi C, Singh AB, Dhawan P. Upregulated claudin-1 expression promotes colitis-associated cancer by promoting β-catenin phosphorylation and activation in Notch/p-AKT-dependent manner. Oncogene 2019; 38:5321-5337. [PMID: 30971761 PMCID: PMC6597297 DOI: 10.1038/s41388-019-0795-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 12/21/2018] [Accepted: 01/31/2019] [Indexed: 12/18/2022]
Abstract
In IBD patients, integration between a hyper-activated immune system and epithelial cell plasticity underlies colon cancer development. However, molecular regulation of such a circuity remains undefined. Claudin-1(Cld-1), a tight-junction integral protein deregulation alters colonic epithelial cell (CEC) differentiation, and promotes colitis severity while impairing colitis-associated injury/repair. Tumorigenesis is a product of an unregulated wound healing process and therefore we postulated that upregulated Cld-1 levels render IBD patients susceptible to the colitis-associated cancer (CAC). Villin Cld-1 mice is used to carryout overexpressed studies in mice. The role of deregulated Cld-1 expression in CAC and underlying mechanism using a well-constructed study scheme and mouse models of DSS colitis/recovery and CAC. Using an inclusive investigative scheme, we here report that upregulated Cld-1 expression promotes susceptibility to the CAC and its malignancy. Increased mucosal inflammation, defective epithelial homeostasis accompanied the increased CAC in Villin-Cld1-Tg mice. We further found significantly increased levels of pro-tumorigenic M2 macrophages and β-CateninSer552 (β-CatSer552) expression in the CAC in Cld-1Tg versus WT mice. Mechanistic studies identified the role of PI3K/Akt signaling in Cld-1 dependent activation of the β-CatSer552, which, in turn, was dependent on pro-inflammatory signals. Our studies identify a critical role of Cld-1 in promoting susceptibility to CAC. Importantly, these effects of deregulated Cld-1 were not associated with altered tight junction integrity, but on its non-canonical role in regulating Notch/PI3K/Wnt/ β-CatSer552 signaling. Overall, outcome from our current studies identifies Cld-1 as potential prognostic biomarker for IBD severity and CAC, and a novel therapeutic target.
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Affiliation(s)
- Saiprasad Gowrikumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Rizwan Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | | | - Mary K Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Chanjuan Shi
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Amar B Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.,Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. .,VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA. .,Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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Bishnupuri KS, Alvarado DM, Khouri AN, Shabsovich M, Chen B, Dieckgraefe BK, Ciorba MA. IDO1 and Kynurenine Pathway Metabolites Activate PI3K-Akt Signaling in the Neoplastic Colon Epithelium to Promote Cancer Cell Proliferation and Inhibit Apoptosis. Cancer Res 2019; 79:1138-1150. [PMID: 30679179 DOI: 10.1158/0008-5472.can-18-0668] [Citation(s) in RCA: 148] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 11/27/2018] [Accepted: 01/16/2019] [Indexed: 12/12/2022]
Abstract
The tryptophan-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) is frequently overexpressed in epithelial-derived malignancies, where it plays a recognized role in promoting tumor immune tolerance. We previously demonstrated that the IDO1-kynurenine pathway (KP) also directly supports colorectal cancer growth by promoting activation of β-catenin and driving neoplastic growth in mice lacking intact adaptive immunity. In this study, we sought to delineate the specific role of epithelial IDO1 in colon tumorigenesis and define how IDO1 and KP metabolites interact with pivotal neoplastic signaling pathways of the colon epithelium. We generated a novel intestinal epithelial-specific IDO1 knockout mouse and utilized established colorectal cancer cell lines containing β-catenin-stabilizing mutations, human colorectal cancer samples, and human-derived epithelial organoids (colonoids and tumoroids). Mice with intestinal epithelial-specific knockout of IDO1 developed fewer and smaller tumors than wild-type littermates in a model of inflammation-driven colon tumorigenesis. Moreover, their tumors exhibited reduced nuclear β-catenin and neoplastic proliferation but increased apoptosis. Mechanistically, KP metabolites (except kynurenic acid) rapidly activated PI3K-Akt signaling in the neoplastic epithelium to promote nuclear translocation of β-catenin, cellular proliferation, and resistance to apoptosis. Together, these data define a novel cell-autonomous function and mechanism by which IDO1 activity promotes colorectal cancer progression. These findings may have implications for the rational design of new clinical trials that exploit a synergy of IDO1 inhibitors with conventional cancer therapies for which Akt activation provides resistance such as radiation.Significance: This study identifies a new mechanistic link between IDO1 activity and PI3K/AKT signaling, both of which are important pathways involved in cancer growth and resistance to cancer therapy.
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Affiliation(s)
- Kumar S Bishnupuri
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri.
| | - David M Alvarado
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri
| | - Alexander N Khouri
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri
| | - Mark Shabsovich
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri
| | - Baosheng Chen
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri
| | - Brian K Dieckgraefe
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri
| | - Matthew A Ciorba
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri.
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Niu W, Wu Z, Wang J, Zhang H, Jia W, Yang M, Luo Y, Zhang X. Tumor Necrosis Factor Ligand-Related Molecule 1A Regulates the Occurrence of Colitis-Associated Colorectal Cancer. Dig Dis Sci 2018; 63:2341-2350. [PMID: 29796912 DOI: 10.1007/s10620-018-5126-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 05/16/2018] [Indexed: 01/08/2023]
Abstract
BACKGROUND Tumor necrosis factor ligand-related molecule 1 A (TLlA) is closely related to the occurrence and development of inflammatory bowel disease. AIMS We aimed to explore whether TLlA was involved in the occurrence of colitis-associated colorectal cancer (CAC). METHODS Firstly, azoxymethane (AOM) and dextran sulfate sodium (DSS) were used to construct the CAC mice model in wild-type (WT) and TL1A transgenic (Tg) mice with TL1A high expression. The histopathological analysis was used for the evaluation of inflammation level, and the immunohistochemistry staining analysis was used to test the expression and location of proliferating cell nuclear antigen (PCNA) and β-catenin. Secondly, the HCT116 and HT29 cell lines were used for knockdown of TL1A gene for further assay including cell viability, cell clone, cell apoptosis and matrigel invasion. Western blot were used for quantitative protein expression of β-catenin and downstream oncogenes including c-myc and Cyclin D1 after knockdown of TL1A gene. RESULTS The evaluation of inflammation level showed that the disease activity index score and tumor formation rate were significantly higher in AOM + DSS/Tg group than that in AOM + DSS/WT group. The expression of PCNA, β-catenin, c-myc, and Cyclin D1 in AOM + DSS/Tg group was significantly higher than that in AOM + DSS/WT group. The cell experiment showed that TL1A knockdown inhibited the cell proliferation, invasion, and migration. Moreover, the expression of c-myc and Cyclin D1 was significantly decreased after TL1A knockdown. CONCLUSIONS TL1A can induce tumor cell proliferation and promote the occurrence of CAC by activating Wnt/β-catenin pathway.
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Affiliation(s)
- Weiwei Niu
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, West Heping Road, Shijiazhuang City, Hebei Province, People's Republic of China
| | - Zhe Wu
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, West Heping Road, Shijiazhuang City, Hebei Province, People's Republic of China
| | - Jing Wang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, West Heping Road, Shijiazhuang City, Hebei Province, People's Republic of China
| | - Hong Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, West Heping Road, Shijiazhuang City, Hebei Province, People's Republic of China
| | - Wenxiu Jia
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, West Heping Road, Shijiazhuang City, Hebei Province, People's Republic of China
| | - Mingyue Yang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, West Heping Road, Shijiazhuang City, Hebei Province, People's Republic of China
| | - Yuxin Luo
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, West Heping Road, Shijiazhuang City, Hebei Province, People's Republic of China
| | - Xiaolan Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, West Heping Road, Shijiazhuang City, Hebei Province, People's Republic of China.
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Yang VW, Liu Y, Kim J, Shroyer KR, Bialkowska AB. Increased Genetic Instability and Accelerated Progression of Colitis-Associated Colorectal Cancer through Intestinal Epithelium-specific Deletion of Klf4. Mol Cancer Res 2018; 17:165-176. [PMID: 30108164 DOI: 10.1158/1541-7786.mcr-18-0399] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 07/05/2018] [Accepted: 08/08/2018] [Indexed: 12/15/2022]
Abstract
Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, regulates homeostasis of the intestinal epithelium. Previously, it was reported that KLF4 functions as a tumor suppressor in colorectal cancer. Here, evidence demonstrates that KLF4 mitigates the development and progression of colitis-associated colorectal cancer (CAC) in a murine model. Mice with intestinal epithelium-specific deletion of Klf4 (Klf4ΔIS ) and control mice (Klf4fl/fl ) were used to explore the role of KLF4 in the development of azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced CAC. Upon AOM and DSS treatment, KLF4 expression was progressively lost in colonic tissues of Klf4fl/fl mice during tumor development. Klf4ΔIS mice treated with AOM/DSS developed significantly more adenomatous polyps and carcinomas in situ in comparison with treated Klf4fl/fl mice. Adenomatous polyps, but not normal-appearing mucosa, from colonic tissues of treated Klf4ΔIS mice contained a significantly increased number of mitotic cells with more than 2 centrosomes relative to treated control mice. KLF4 and p53 colocalize to the centrosomes in mouse embryonic fibroblasts (MEF). Absence of KLF4 in Klf4-/- MEFs inhibits and its overexpression restores p53 localization to the centrosomes in Klf4-/- MEFs. IMPLICATIONS: Taken together, these results indicate that KLF4 plays a protective role against progression of CAC by guarding against genetic instability.
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Affiliation(s)
- Vincent W Yang
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York. .,Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, New York
| | - Yang Liu
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York
| | - Julie Kim
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York
| | - Kenneth R Shroyer
- Department of Pathology, Stony Brook University School of Medicine, Stony Brook, New York
| | - Agnieszka B Bialkowska
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York.
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Hu N, Zhang H. CYP24A1 depletion facilitates the antitumor effect of vitamin D3 on thyroid cancer cells. Exp Ther Med 2018; 16:2821-2830. [PMID: 30233662 PMCID: PMC6143870 DOI: 10.3892/etm.2018.6536] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 03/14/2018] [Indexed: 02/06/2023] Open
Abstract
It has been demonstrated that 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1) is a key enzyme that neutralizes vitamin D activity, which may have an anti-tumor effect. Therefore, the aim of the current study was to explore the effect of the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25-D3) on thyroid cancer cells following the downregulation of CYP24A1. A Cell Counting Kit-8 assay identified that CYP24A1 knockdown enhanced the anti-proliferative effects of 1,25-D3 on thyroid cancer cells. Furthermore, the results of the scratch wound and Transwell assays indicated that CYP24A1 knockdown enhanced the inhibitory effect of 1,25-D3 on cell migration. The results from reverse transcription-quantitative polymerase chain reaction and western blot analysis indicated that treatment with 1,25-D3 and CYP24A1 knockdown synergistically enhanced the expression of the epithelial-related gene E-cadherin and decreased the expression of the mesenchymal-related genes N-cadherin and vimentin. Following CYP24A1 knockdown and treatment with 1,25-D3, the expression of matrix metalloproteinase 2 and metalloproteinase inhibitor 1 were significantly decreased and increased, respectively, compared with the group that underwent treatment with 25-D3 alone. Furthermore, protein kinase B (Akt) and β-catenin activity was significantly decreased by this synergetic effect compared with the group that underwent treatment with 1,25-D3 alone. The results of the current study suggest that CYP24A1 knockdown contributes to the anti-tumor effect of 1,25-D3 and that this effect may be due to deactivation of the Akt and β-catenin signaling pathways. Therefore, CYP24A1 knockdown and 1,25-D3 treatment may be used synergistically as a novel therapeutic strategy to treat patients with thyroid cancer.
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Affiliation(s)
- Ning Hu
- The Second Sector of Department of Thyroid Breast Surgery, Southern Branch of Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
| | - Hao Zhang
- The First Sector of Department of Thyroid Breast Surgery, Northern Branch of Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
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Palanissami G, Paul SFD. RAGE and Its Ligands: Molecular Interplay Between Glycation, Inflammation, and Hallmarks of Cancer—a Review. Discov Oncol 2018; 9:295-325. [DOI: 10.1007/s12672-018-0342-9] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 06/25/2018] [Indexed: 12/15/2022] Open
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Workman A, Zhu L, Keel BN, Smith TPL, Jones C. The Wnt Signaling Pathway Is Differentially Expressed during the Bovine Herpesvirus 1 Latency-Reactivation Cycle: Evidence That Two Protein Kinases Associated with Neuronal Survival, Akt3 and BMPR2, Are Expressed at Higher Levels during Latency. J Virol 2018; 92:e01937-17. [PMID: 29321317 PMCID: PMC5972910 DOI: 10.1128/jvi.01937-17] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 01/04/2018] [Indexed: 12/20/2022] Open
Abstract
Sensory neurons in trigeminal ganglia (TG) of calves latently infected with bovine herpesvirus 1 (BoHV-1) abundantly express latency-related (LR) gene products, including a protein (ORF2) and two micro-RNAs. Recent studies in mouse neuroblastoma cells (Neuro-2A) demonstrated ORF2 interacts with β-catenin and a β-catenin coactivator, high-mobility group AT-hook 1 (HMGA1) protein, which correlates with increased β-catenin-dependent transcription and cell survival. β-Catenin and HMGA1 are readily detected in a subset of latently infected TG neurons but not TG neurons from uninfected calves or reactivation from latency. Consequently, we hypothesized that the Wnt/β-catenin signaling pathway is differentially expressed during the latency and reactivation cycle and an active Wnt pathway promotes latency. RNA-sequencing studies revealed that 102 genes associated with the Wnt/β-catenin signaling pathway were differentially expressed in TG during the latency-reactivation cycle in calves. Wnt agonists were generally expressed at higher levels during latency, but these levels decreased during dexamethasone-induced reactivation. The Wnt agonist bone morphogenetic protein receptor 2 (BMPR2) was intriguing because it encodes a serine/threonine receptor kinase that promotes neuronal differentiation and inhibits cell death. Another differentially expressed gene encodes a protein kinase (Akt3), which is significant because Akt activity enhances cell survival and is linked to herpes simplex virus 1 latency and neuronal survival. Additional studies demonstrated ORF2 increased Akt3 steady-state protein levels and interacted with Akt3 in transfected Neuro-2A cells, which correlated with Akt3 activation. Conversely, expression of Wnt antagonists increased during reactivation from latency. Collectively, these studies suggest Wnt signaling cooperates with LR gene products, in particular ORF2, to promote latency.IMPORTANCE Lifelong BoHV-1 latency primarily occurs in sensory neurons. The synthetic corticosteroid dexamethasone consistently induces reactivation from latency in calves. RNA sequencing studies revealed 102 genes associated with the Wnt/β-catenin signaling pathway are differentially regulated during the latency-reactivation cycle. Two protein kinases associated with the Wnt pathway, Akt3 and BMPR2, were expressed at higher levels during latency but were repressed during reactivation. Furthermore, five genes encoding soluble Wnt antagonists and β-catenin-dependent transcription inhibitors were induced during reactivation from latency. These findings are important because Wnt, BMPR2, and Akt3 promote neurogenesis and cell survival, processes crucial for lifelong viral latency. In transfected neuroblastoma cells, a viral protein expressed during latency (ORF2) interacts with and enhances Akt3 protein kinase activity. These findings provide insight into how cellular factors associated with the Wnt signaling pathway cooperate with LR gene products to regulate the BoHV-1 latency-reactivation cycle.
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Affiliation(s)
- Aspen Workman
- United States Department of Agriculture, Agricultural Research Service, U.S. Meat Animal Research Center, Clay Center, Nebraska, USA
| | - Liqian Zhu
- Oklahoma State University Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA
- College of Veterinary Medicine and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, China
| | - Brittney N Keel
- United States Department of Agriculture, Agricultural Research Service, U.S. Meat Animal Research Center, Clay Center, Nebraska, USA
| | - Timothy P L Smith
- United States Department of Agriculture, Agricultural Research Service, U.S. Meat Animal Research Center, Clay Center, Nebraska, USA
| | - Clinton Jones
- Oklahoma State University Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA
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Sastre-Perona A, Riesco-Eizaguirre G, Zaballos MA, Santisteban P. β-catenin signaling is required for RAS-driven thyroid cancer through PI3K activation. Oncotarget 2018; 7:49435-49449. [PMID: 27384483 PMCID: PMC5226519 DOI: 10.18632/oncotarget.10356] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 06/16/2016] [Indexed: 11/26/2022] Open
Abstract
Mutations in ß-catenin are traditionally described as late events in thyroid cancer progression. However, the functional implications of ß-catenin dysregulation in the context of tumor initiating events remain unclear. The aim of this work was to investigate whether the two main oncogenic drivers in thyroid cancer, RAS and BRAF, could activate the Wnt/ß-catenin pathway. Expression of HRASV12 but not BRAFV600E in thyroid cells induced ß-catenin nuclear localization, increased ß-catenin-dependent transcriptional activity and inhibited GSK3ß. In a panel of human thyroid cancer cell lines representative of the main genetic events in thyroid cancer, ß-catenin activation was highly dependent on PI3K/AKT activity through its phosphorylation at S552, but not on MAPK. Silencing of ß-catenin expression in cell lines led to a dramatic reduction in proliferation due to an induction of senescence, which was concordant with a reduction in tumor size in nude mice. Moreover, ß-catenin silencing suppressed the expression of EMT-related genes and reduced the invasive capacity of the tumor cells. In conclusion, this work demonstrates that RAS-driven tumors induce PI3K/AKT-dependent ß-catenin activation.
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Affiliation(s)
- Ana Sastre-Perona
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Garcilaso Riesco-Eizaguirre
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain.,Servicio de Endocrinología, Hospital Universitario de Móstoles, Madrid, Spain
| | - Miguel A Zaballos
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Pilar Santisteban
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain
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