|
1
|
Xiong J, Huang J, Xu H, Wu Q, Zhao J, Chen Y, Fan G, Guan H, Xiao R, He Z, Wu S, Ouyang W, Wang S, Zhang L, Xia P, Zhang W, Wu M. CpG-Based Nanovaccines Enhance Ovarian Cancer Immune Response by Gbp2-Mediated Remodeling of Tumor-Associated Macrophages. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412881. [PMID: 39985265 PMCID: PMC12005807 DOI: 10.1002/advs.202412881] [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: 10/13/2024] [Revised: 01/13/2025] [Indexed: 02/24/2025]
Abstract
CpG oligodeoxynucleotides (CpG), as an immunoadjuvant, can facilitate the transformation of tumor-associated macrophages (TAMs)into tumoricidal M1 macrophages. However, the accumulation of free CpG in tumor tissues remains a substantial challenge. To address this, a nanovaccine (PLGA-CpG@ID8-M) is engineered by encapsulating CpG within PLGA using ID8 ovarian cancer cell membranes (ID8-M). This nanovaccine demonstrates remarkable efficacy in reprogramming TAMs in ovarian cancer and significantly extends survival in ID8-bearing mice. Notably, these findings indicate that the nanovaccine can also mitigate chemotherapy-induced immunosuppression by increasing the proportion of M1-like TAMs and reducing the expression of CD47 on tumor cells, thereby achieving a synergistic effect in tumor immunotherapy. Mechanistically, through transcriptome sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and mass spectrometry-based proteomics, it is elucidated that the nanovaccine enhances the expression of Gbp2 and promotes the recruitment of Pin1, which activates the NFκB signaling pathway, leading to the M1 polarization of TAMs. Furthermore, macrophages with elevated Gbp2 expression significantly inhibit tumor growth in both ID8 ovarian cancer and 4T1 breast cancer models. Conversely, targeting Gbp2 diminishes the antitumor efficacy of the nanovaccine in vivo. This study offers an innovative approach to immunotherapy and elucidates a novel mechanism (Gbp2-Pin1-NFκB pathway) for remodeling TAMs.
Collapse
Affiliation(s)
- Jiaqiang Xiong
- Department of Obstetrics and GynecologyZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Juyuan Huang
- Department of Obstetrics and GynecologyZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Hanxiao Xu
- Department of Gastrointestinal OncologyZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Qiuji Wu
- Department of Radiation and Medical OncologyHubei Key Laboratory of Tumor Biological BehaviorHubei Provincial Clinical Research Center for CancerZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Jiahui Zhao
- Department of Obstetrics and GynecologyZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Yurou Chen
- Department of Obstetrics and GynecologyZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Guanlan Fan
- Department of Obstetrics and GynecologyZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Haotong Guan
- Department of Obstetrics and GynecologyZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Rourou Xiao
- Department of Obstetrics and GynecologyZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Zhaojin He
- The Second Clinical College of Wuhan UniversityWuhan430071China
| | - Siqi Wu
- The Second Clinical College of Wuhan UniversityWuhan430071China
| | - Wenliang Ouyang
- The Second Clinical College of Wuhan UniversityWuhan430071China
| | - Shixuan Wang
- Department of Obstetrics and GynecologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430032China
| | - Lu Zhang
- Hubei Key Laboratory of Radiation Chemistry and Functional MaterialsSchool of Nuclear Technology and Chemistry & BiologyHubei University of Science and TechnologyXianning437100China
| | - Peng Xia
- Department of Hepatobiliary & Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Wei Zhang
- Department of Obstetrics and GynecologyZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Meng Wu
- Department of Obstetrics and GynecologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430032China
| |
Collapse
|
|
2
|
Kim HJ, Lee DS, Park JH, Hong HE, Choi HJ, Kim OH, Kim SJ. Exosome-based strategy against colon cancer using small interfering RNA-loaded vesicles targeting soluble a proliferation-inducing ligand. World J Stem Cells 2024; 16:956-973. [DOI: 10.4252/wjsc.v16.i11.956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 08/29/2024] [Accepted: 10/16/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND Recent advancements in nanomedicine have highlighted the potential of exosome (Ex)-based therapies, utilizing naturally derived nanoparticles, as a novel approach to targeted cancer treatment.
AIM To explore the targetability and anticancer effectiveness of small interfering peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 RNA (siPIN1)-loaded soluble a proliferation-inducing ligand (sAPRIL)-targeted Exs (designated as tEx[p]) in the treatment of colon cancer models.
METHODS tEx was generated by harvesting conditioned media from adipose-derived stem cells that had undergone transformation using pDisplay vectors encoding sAPRIL-binding peptide sequences. Subsequently, tEx[p] were created by incorporating PIN1 siRNA into the tEx using the Exofect kit. The therapeutic efficacy of these Exs was evaluated using both in vitro and in vivo models of colon cancer.
RESULTS The tEx[p] group exhibited superior anticancer effects in comparison to other groups, including tEx, Ex[p], and Ex, demonstrated by the smallest tumor size, the slowest tumor growth rate, and the lightest weight of the excised tumors observed in the tEx[p] group (P < 0.05). Moreover, analyses of the excised tumor tissues, using western blot analysis and immunohistochemical staining, revealed that tEx[p] treatment resulted in the highest increase in E-cadherin expression and the most significant reduction in the mesenchymal markers Vimentin and Snail (P < 0.05), suggesting a more effective inhibition of epithelial-mesenchymal transition tEx[p], likely due to the enhanced delivery of siPIN1.
CONCLUSION The use of bioengineered Exs targeting sAPRIL and containing siPIN1 demonstrated superior efficacy in inhibiting tumor growth and epithelial-mesenchymal transition, highlighting their potential as a therapeutic strategy for colon cancer.
Collapse
Affiliation(s)
- Hyung-Jin Kim
- Department of Surgery, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, South Korea
| | - Do Sang Lee
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- Catholic Central Laboratory of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Jung Hyun Park
- Department of Surgery, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, South Korea
- Catholic Central Laboratory of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Ha-Eun Hong
- Catholic Central Laboratory of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- Translational Research Team, Surginex Co., Ltd., Seoul 06591, South Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Ok-Hee Kim
- Catholic Central Laboratory of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- Translational Research Team, Surginex Co., Ltd., Seoul 06591, South Korea
| | - Say-June Kim
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- Catholic Central Laboratory of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| |
Collapse
|
|
3
|
Liu C, Dan L, Li Q, Bajinka O, Yuan X. The mechanisms of Pin1 as targets for cancer therapy. Front Immunol 2024; 15:1482088. [PMID: 39624096 PMCID: PMC11609185 DOI: 10.3389/fimmu.2024.1482088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 10/25/2024] [Indexed: 01/03/2025] Open
Abstract
Targeted therapy has considerable promise for the effective eradication of cancer at the primary tumor site prior to subsequent metastasis. Using this therapeutic approach, gaining an understanding of mechanistic cancer models is essential for facilitating the inhibition or suppression of tumor growth. Among different oncogenes and proteins, the protein interacting with never-in-mitosis kinase-1 (Pin1) is particularly important. The interaction between Pin1 and phosphorylated threonine-proline motifs results in significant alterations in protein structure and function. In this review, we provide a comprehensive summary of the processes involving Pin1 and its mechanisms in the context of cancer therapy. Pin1 enhances signaling pathways in a number of different human cancers and plays a pivotal role in the suppressive mechanisms relevant to cancer treatment. It is essential for the regulation of proline-directed phosphorylation and for modulating tumor suppressors. Inhibitors of Pin1, particularly naturally occurring substances, have been found to inhibit the carcinogenic activity of Pin1, and consequently this protein could represent an excellent candidate for novel cancer treatment strategies, offering a valuable therapeutic target in carcinogenesis and treatment resistance.
Collapse
Affiliation(s)
- Chuanfeng Liu
- Department of Pulmonary and Critical Care Medicine, Lishui Hospital of Traditional Chinese Medicine, Lishui, China
| | - Lingying Dan
- Department of Endocrinology, Lishui Hospital of Traditional Chinese Medicine, Lishui, China
| | - Quan Li
- Department of Pulmonary and Critical Care Medicine, Lishui Hospital of Traditional Chinese Medicine, Lishui, China
| | - Ousman Bajinka
- School of Medicine and Allied Health Sciences, University of The Gambia, Banjul, Gambia
| | - Xingxing Yuan
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
| |
Collapse
|
|
4
|
Stewart R, Sharma S, Wu T, Okuda S, Xie G, Zhou XZ, Shilton B, Lu KP. The role of the master cancer regulator Pin1 in the development and treatment of cancer. Front Cell Dev Biol 2024; 12:1343938. [PMID: 38745861 PMCID: PMC11091292 DOI: 10.3389/fcell.2024.1343938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 03/28/2024] [Indexed: 05/16/2024] Open
Abstract
This review examines the complex role of Pin1 in the development and treatment of cancer. Pin1 is the only peptidyl-prolyl isomerase (PPIase) that can recognize and isomerize phosphorylated Ser/Thr-Pro peptide bonds. Pin1 catalyzes a structural change in phosphorylated Ser/Thr-Pro motifs that can modulate protein function and thereby impact cell cycle regulation and tumorigenesis. The molecular mechanisms by which Pin1 contributes to oncogenesis are reviewed, including Pin1 overexpression and its correlation with poor cancer prognosis, and the contribution of Pin1 to aggressive tumor phenotypes involved in therapeutic resistance is discussed, with an emphasis on cancer stem cells, the epithelial-to-mesenchymal transition (EMT), and immunosuppression. The therapeutic potential of Pin1 inhibition in cancer is discussed, along with the promise and the difficulties in identifying potent, drug-like, small-molecule Pin1 inhibitors. The available evidence supports the efficacy of targeting Pin1 as a novel cancer therapeutic by analyzing the role of Pin1 in a complex network of cancer-driving pathways and illustrating the potential of synergistic drug combinations with Pin1 inhibitors for treating aggressive and drug-resistant tumors.
Collapse
Affiliation(s)
- Robert Stewart
- Department of Biochemistry, Western University, London, ON, Canada
| | - Shaunik Sharma
- Department of Biochemistry, Western University, London, ON, Canada
| | - Timothy Wu
- Department of Biochemistry, Western University, London, ON, Canada
| | - Sho Okuda
- Department of Biochemistry, Western University, London, ON, Canada
| | - George Xie
- Department of Biochemistry, Western University, London, ON, Canada
| | - Xiao Zhen Zhou
- Department of Biochemistry, Western University, London, ON, Canada
- Robarts Research Institute, Western University, London, ON, Canada
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
- Lawson Health Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Brian Shilton
- Department of Biochemistry, Western University, London, ON, Canada
| | - Kun Ping Lu
- Department of Biochemistry, Western University, London, ON, Canada
- Robarts Research Institute, Western University, London, ON, Canada
- Lawson Health Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Department of Oncology, Western University, London, ON, Canada
| |
Collapse
|
|
5
|
Zhu X, Ji J, Han X. Osteopontin: an essential regulatory protein in idiopathic pulmonary fibrosis. J Mol Histol 2024; 55:1-13. [PMID: 37878112 DOI: 10.1007/s10735-023-10169-y] [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: 03/23/2023] [Accepted: 10/12/2023] [Indexed: 10/26/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic lung disease characterized by abnormal proliferation and activation of fibroblasts, excessive accumulation of extracellular matrix (ECM), inflammatory damage, and disrupted alveolar structure. Despite its increasing morbidity and mortality rates, effective clinical treatments for IPF remain elusive. Osteopontin (OPN), a multifunctional ECM protein found in various tissues, has been implicated in numerous biological processes such as bone remodeling, innate immunity, acute and chronic inflammation, and cancer. Recent studies have highlighted the pivotal role of OPN in the pathogenesis of IPF. This review aims to delve into the involvement of OPN in the inflammatory response, ECM deposition, and epithelial-mesenchymal transition (EMT) during IPF, and intends to lay a solid theoretical groundwork for the development of therapeutic strategies for IPF.
Collapse
Affiliation(s)
- Xiaoyu Zhu
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China
| | - Jie Ji
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China
| | - Xiaodong Han
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China.
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China.
| |
Collapse
|
|
6
|
Rodas F, Vidal-Vidal JA, Herrera D, Brown-Brown DA, Vera D, Veliz J, Püschel P, Erices JI, Sánchez Hinojosa V, Tapia JC, Silva-Pavez E, Quezada-Monrás C, Mendoza-Soto P, Salazar-Onfray F, Carrasco C, Niechi I. Targeting the Endothelin-1 pathway to reduce invasion and chemoresistance in gallbladder cancer cells. Cancer Cell Int 2023; 23:318. [PMID: 38072958 PMCID: PMC10710704 DOI: 10.1186/s12935-023-03145-9] [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: 08/04/2023] [Accepted: 11/14/2023] [Indexed: 01/03/2025] Open
Abstract
BACKGROUND Gallbladder cancer (GBC) is a prevalent and deadly biliary tract carcinoma, often diagnosed at advanced stages with limited treatment options. The 5-year survival rate varies widely from 4 to 60%, mainly due to differences in disease stage detection. With only a small fraction of patients having resectable tumors and a high incidence of metastasis, advanced GBC stages are characterized by significant chemoresistance. Identification of new therapeutic targets is crucial, and recent studies have shown that the Endothelin-1 (ET-1) signaling pathway, involving ETAR and/or ETBR receptors (ETRs), plays a crucial role in promoting tumor aggressiveness in various cancer models. Blocking one or both receptors has been reported to reduce invasiveness and chemoresistance in cancers like ovarian, prostate, and colon. Furthermore, transcriptomic studies have associated ET-1 levels with late stages of GBC; however, it remains unclear whether its signaling or its inhibition has implications for its aggressiveness. Although the role of ET-1 signaling in gallbladder physiology is minimally understood, its significance in other tumor models leads us to hypothesize its involvement in GBC malignancy. RESULTS In this study, we investigated the expression of ET-1 pathway proteins in three GBC cell lines and a primary GBC culture. Our findings demonstrated that both ETAR and ETBR receptors are expressed in GBC cells and tumor samples. Moreover, we successfully down-regulated ET-1 signaling using a non-selective ETR antagonist, Macitentan, which resulted in reduced migratory and invasive capacities of GBC cells. Additionally, Macitentan treatment chemosensitized the cells to Gemcitabine, a commonly used therapy for GBC. CONCLUSION For the first time, we reveal the role of the ET-1 pathway in GBC cells, providing insight into the potential therapeutic targeting of its receptors to mitigate invasion and chemoresistance in this cancer with limited treatment options. These findings pave the way for further exploration of Macitentan or other ETR antagonists as potential therapeutic strategies for GBC management. In summary, our study represents a groundbreaking contribution to the field by providing the first evidence of the ET 1 pathway's pivotal role in modulating the behavior and aggressiveness of GBC cells, shedding new light on potential therapeutic targets.
Collapse
Affiliation(s)
- Francisco Rodas
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Jetzabel A Vidal-Vidal
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Daniela Herrera
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - David A Brown-Brown
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Diego Vera
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Joaquín Veliz
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Pilar Püschel
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - José I Erices
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Verónica Sánchez Hinojosa
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Julio C Tapia
- Laboratorio de transformación celular, Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453, Santiago, Chile
| | - Eduardo Silva-Pavez
- Facultad de Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián, Bellavista, Santiago, Chile
| | - Claudia Quezada-Monrás
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
- Millennium Institute on Immunology and Immunotherapy, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Pablo Mendoza-Soto
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Flavio Salazar-Onfray
- Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, 8380453, Santiago, Chile
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, 8380453, Santiago, Chile
| | - Cristian Carrasco
- Subdepartamento de Anatomía Patológica, Hospital Base de Valdivia, 5090000, Valdivia, Chile
| | - Ignacio Niechi
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile.
- Millennium Institute on Immunology and Immunotherapy, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile.
| |
Collapse
|
|
7
|
Qin J, Cui Z, Zhou J, Zhang B, Lu R, Ding Y, Hu H, Cai J. IGF2BP3 drives gallbladder cancer progression by m6A-modified CLDN4 and inducing macrophage immunosuppressive polarization. Transl Oncol 2023; 37:101764. [PMID: 37643553 PMCID: PMC10472310 DOI: 10.1016/j.tranon.2023.101764] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/31/2023] [Accepted: 08/15/2023] [Indexed: 08/31/2023] Open
Abstract
INTRODUCTION N6-methyladenosine (m6A) is an emerging epigenetic modification, which plays a crucial role in the development of cancer. Nevertheless, the underlying mechanism of m6A-associated proteins and m6A modification in gallbladder cancer remains largely unknown. MATERIALS AND METHODS The Gene Expression Omnibus database and tissue microarray were used to identify the key m6A-related gene in gallbladder cancer. The function and mechanism of IGF2BP3 were further investigated by knockdown and overexpression techniques in vitro and in vivo. RESULTS We found that IGF2BP3 was elevated and correlated with poor prognosis in gallbladder cancer, which can be used as an independent prognostic factor for gallbladder cancer. IGF2BP3 accelerated the proliferation, invasion and migration of gallbladder cancer cells in vitro and in vivo. Mechanistically, IGF2BP3 interacted with and augmented the stability of CLDN4 mRNA by m6A modification. Enhancement of CLDN4 reversed the inhibitory effect of IGF2BP3 deficiency on gallbladder cancer. Furthermore, we demonstrated that IGF2BP3 promotes the activation of NF-κB signaling pathway by up-regulation of CLDN4. Overexpression of IGF2BP3 in gallbladder cancer cells obviously promoted the polarization of immunosuppressive phenotype in macrophages. Besides, Gallbladder cancer cells-derived IGF2BP3 up-regulated the levels of STAT3 in M2 macrophages, and promoted M2 polarization. CONCLUSIONS We manifested IGF2BP3 promotes the aggressive phenotype of gallbladder cancer by stabilizing CLDN4 mRNA in an m6A-dependent manner and induces macrophage immunosuppressive polarization, which might offer a new theoretical basis for against gallbladder cancer.
Collapse
Affiliation(s)
- Jian Qin
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Zheng Cui
- Department of Ultrasonic Medicine, Shanghai East Hospital, Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200120, China
| | - Jingyi Zhou
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Bosen Zhang
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200120, China
| | - Ruiqi Lu
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200120, China
| | - Youcheng Ding
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200120, China
| | - Hai Hu
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200120, China
| | - Jingli Cai
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200120, China.
| |
Collapse
|
|
8
|
Jena SK, Das S, Chakraborty S, Ain R. Molecular determinants of epithelial mesenchymal transition in mouse placenta and trophoblast stem cell. Sci Rep 2023; 13:10978. [PMID: 37414855 PMCID: PMC10325982 DOI: 10.1038/s41598-023-37977-2] [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: 03/22/2023] [Accepted: 06/30/2023] [Indexed: 07/08/2023] Open
Abstract
Trophectoderm cells of the blastocyst are the precursor of the placenta that is comprised of trophoblast, endothelial and smooth muscle cells. Since trophoectoderm cells are epithelial in nature, epithelial mesenchymal transition (EMT) of trophoblast stem (TS) cells might play pivotal role in placental morphogenesis. However, the molecular regulation of EMT during placental development and trophoblast differentiation still remained elusive. In this report, we sought to identify the molecular signature that regulates EMT during placental development and TS cell differentiation in mice. On E7.5 onwards the TS cells, located in the ectoplacental cone (EPC), rapidly divide and differentiate leading to formation of placenta proper. Using a real time PCR based array of functional EMT transcriptome with RNA from mouse implantation sites (IS) on E7.5 and E9.5, it was observed that there was an overall reduction of EMT gene expression in the IS as gestation progressed from E7.5 to E9.5 albeit the levels of EMT gene expression were substantial on both days. Further validation of array results using real time PCR and western blot analysis showed significant decrease in EMT-associated genes that included (a) transcription factors (Snai2, Zeb1, Stat3 and Foxc2), (b) extracellular matrix and cell adhesion related genes (Bmp1, Itga5, Vcan and Col3A1), (c) migration and motility- associated genes (Vim, Msn and FN1) and (d) differentiation and development related genes (Wnt5b, Jag1 and Cleaved Notch-1) on E9.5. To understand whether EMT is an ongoing process during placentation, the EMT-associated signatures genes, prevalent on E 7.5 and 9.5, were analysed on E12.5, E14.5 and E17.5 of mouse placenta. Interestingly, expression of these EMT-signature proteins were significantly higher at E12.5 though substantial expressions was observed in placenta with progression of gestation from mid- to late. To evaluate whether TS cells have the potential to undergo EMT ex vivo, TS cells were subjected to EMT induction, which was confirmed using morphological analysis and marker gene expression. Induction of EMT in TS cells showed similar gene expression profile of placental EMT. These results have broad biological implications, as inadequate mesenchymal transition leading to improper trophoblast-vasculogenic mimicry leads to placental pathophysiology and pregnancy failure.
Collapse
Affiliation(s)
- Shipra Kanti Jena
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Calcutta, West Bengal, 700032, India
- Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, UP, 201002, India
| | - Shreya Das
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Calcutta, West Bengal, 700032, India
| | - Shreeta Chakraborty
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Calcutta, West Bengal, 700032, India
| | - Rupasri Ain
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Calcutta, West Bengal, 700032, India.
- Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, UP, 201002, India.
| |
Collapse
|
|
9
|
Chen H, Cai X, Du B, Cai J, Luo Z. MicroRNA-150-5p inhibits the proliferation and invasion of human larynx epidermiod cancer cells though regulating peptidyl-prolyl cis/trans isomerase. Braz J Otorhinolaryngol 2023; 89:383-392. [PMID: 37105032 PMCID: PMC10164829 DOI: 10.1016/j.bjorl.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/01/2023] [Accepted: 03/06/2023] [Indexed: 03/14/2023] Open
Abstract
OBJECTIVE This study aimed to investigate the molecular mechanism of miR-150-5p regulating the malignant biological behavior of Human Epidermoid cancer cell (HEp-2) by targeting peptidyl-prolyl cis/trans isomerase NIMA-Interacting-1 (PIN1). METHODS Firstly, qRT-PCR and Western blot were adopted to detect the expression levels of miR-150-5p and PIN1 in cancer tissue and paracancerous tissues of patients with LSCC, and those in human bronchial epithelial cells (16 HBE) and HEp-2. Next, the targeted relationship between miR-150-5p and PIN1 was assessed by bioinformatics website and dual-luciferase reporter assay, followed by their correlation analysis. Besides, after interfering with miR-150-5p or PIN1 expression in HEp-2 cells, CCK-8, cell colony formation assay, and transwell assay were utilized to detect the proliferation, viability, and invasion of cells, respectively. Subsequently, the protein levels of MMP-2, MMP-9, and EMT-related proteins in HEp-2 cells were checked by Western blot. RESULTS Expression of miR-150-5p was down-regulated in LSCC tissues and HEp-2 cells. Moreover, miR-150-5p suppressed proliferation and invasion of HEp-2 cells, affected protein expression related to MMP and EMT, thereby inhibiting development of cancer. The expression of PIN1 was significantly increased in cancer tissues and HEp-2 cells, and there was a targeted relationship and negative correlation between miR-150-5p and PIN1 in cancer tissue. However, overexpression of PIN1 could reverse the effect of miR-150-5p on the proliferation and invasion of HEp-2 cells. CONCLUSION In a nutshell, there is a targeted relationship between PIN1 and miR-150-5p. Besides, miR-150-5p can inhibit the proliferation and invasion of HEp-2 cells by regulating the expression of PIN1. LEVEL OF EVIDENCE: 3
Collapse
|
|
10
|
Sakamoto T, Kuboki S, Furukawa K, Takayashiki T, Takano S, Yoshizumi A, Ohtsuka M. TRIM27-USP7 complex promotes tumour progression via STAT3 activation in human hepatocellular carcinoma. Liver Int 2023; 43:194-207. [PMID: 35753056 DOI: 10.1111/liv.15346] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 05/31/2022] [Accepted: 06/23/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS TRIM27 is stabilized by binding to USP7 and mediates tumour progression in several cancers; however, the roles of TRIM27-USP7 complex on STAT3 activation in HCC are unknown. METHODS Regulations and functions of TRIM27 for activating STAT3 in HCC were assessed using 207 HCC samples or HCC cells. RESULTS TRIM27 expression was increased in some cases of HCC. High TRIM27 expression was an independent predictor for poor prognosis in HCC after surgery. It was correlated with the expression of EpCAM, vimentin, MMP-9, and activation of STAT3 in HCC. TRIM27 expression was correlated with USP7 expression, and HCC with high TRIM27 expression together with high USP7 expression showed enhanced STAT3 activation, resulting in poorer prognosis. p-JAK1 expression was correlated with STAT3 activation in HCC with high TRIM27 expression. In vitro, USP7 knockdown decreased TRIM27 expression, suggesting that USP7 was essential for TRIM27 stabilization. Knocking down of TRIM27 or USP7 suppressed STAT3 activation and overexpression of TRIM27 accelerated STAT3 activation; therefore, the formation of TRIM27-USP7 complex was needed for STAT3 activation, which led to aggressive tumour proliferation and invasion by enhancing EMT and CSC-like property. Binding of JAK1 to TRIM27-USP7 complex was confirmed in vitro. Deletion of TRIM27-USP7 complex by USP7 inhibitor significantly inhibited tumour cell invasion by suppressing STAT3 activation. CONCLUSIONS TRIM27 is stabilized by binding to USP7 and is related to aggressive tumour progression in HCC via STAT3 activation, resulting in poor prognosis after operation. Therefore, TRIM27-USP7 complex is a useful prognostic predictor and a promising therapeutic target for HCC.
Collapse
Affiliation(s)
- Toshiya Sakamoto
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Arihito Yoshizumi
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | | |
Collapse
|
|
11
|
Rojas A, Lindner C, Schneider I, Gonzàlez I, Morales MA. Receptor of advanced glycation end-products axis and gallbladder cancer: A forgotten connection that we should reconsider. World J Gastroenterol 2022; 28:5679-5690. [PMID: 36338887 PMCID: PMC9627425 DOI: 10.3748/wjg.v28.i39.5679] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/05/2022] [Accepted: 09/09/2022] [Indexed: 02/06/2023] Open
Abstract
Compelling evidence derived from clinical and experimental research has demonstrated the crucial contribution of chronic inflammation in the development of neoplasms, including gallbladder cancer. In this regard, data derived from clinical and experimental studies have demonstrated that the receptor of advanced glycation end-products (RAGE)/AGEs axis plays an important role in the onset of a crucial and long-lasting inflammatory milieu, thus supporting tumor growth and development. AGEs are formed in biological systems or foods, and food-derived AGEs, also known as dietary AGEs are known to contribute to the systemic pool of AGEs. Once they bind to RAGE, the activation of multiple and crucial signaling pathways are triggered, thus favoring the secretion of several proinflammatory cytokines also involved in the promotion of gallbladder cancer invasion and migration. In the present review, we aimed to highlight the relevance of the association between high dietary AGEs intakes and high risk for gallbladder cancer, and emerging data supporting that dietary intervention to reduce gallbladder cancer risk is a very attractive approach that deserves much more research efforts.
Collapse
Affiliation(s)
- Armando Rojas
- Biomedical Research Laboratories, Catholic University of Maule, Talca 34600000, Maule, Chile
| | - Cristian Lindner
- Medicine Faculty, Catholic University of Maule, Talca 34600000, Maule, Chile
| | - Iván Schneider
- Medicine Faculty, Catholic University of Maule, Talca 34600000, Maule, Chile
| | - Ileana Gonzàlez
- Biomedical Research Laboratories, Catholic University of Maule, Talca 34600000, Maule, Chile
| | - Miguel Angel Morales
- Department of Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Santiago, Chile
| |
Collapse
|
|
12
|
Targeting prolyl isomerase Pin1 as a promising strategy to overcome resistance to cancer therapies. Pharmacol Res 2022; 184:106456. [PMID: 36116709 DOI: 10.1016/j.phrs.2022.106456] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 09/10/2022] [Accepted: 09/14/2022] [Indexed: 11/22/2022]
Abstract
The development of tumor therapeutic resistance is one of the important reasons for the failure of antitumor therapy. Starting with multiple targets and multiple signaling pathways is helpful in understanding the mechanism of tumor resistance. The overexpression of prolyl isomerase Pin1 is highly correlated with the malignancy of cancer, since Pin1 controls many oncogenes and tumor suppressors, as well as a variety of cancer-driving signaling pathways. Strikingly, numerous studies have shown that Pin1 is directly involved in therapeutic resistance. In this review, we mainly summarize the functions and mechanisms of Pin1 in therapeutic resistance of multifarious cancers, such as breast, liver, and pancreatic carcinomas. Furtherly, from the perspective of Pin1-driven cancer signaling pathways including Raf/MEK/ERK, PI3K/Akt, Wnt/β-catenin, NF-κB, as well as Pin1 inhibitors containing juglone, epigallocatechin-3-gallate (EGCG), all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), it is better to demonstrate the important potential role and mechanism of Pin1 in resistance and sensitization to cancer therapies. It will provide new therapeutic approaches for clinical reversal and prevention of tumor resistance by employing synergistic administration of Pin1 inhibitors and chemotherapeutics, implementing combination therapy of Pin1-related cancer signaling pathway inhibitors and Pin1 inhibitors, and exploiting novel Pin1-specific inhibitors.
Collapse
|
|
13
|
Bharti A, Kar AG, Singh D, Ansari MA, Tewari M, Narayan G, Singh S. Frequent promoter hypermethylation and down regulation of BNIP3: An early event during gallbladder cancer progression. Dig Liver Dis 2022; 54:1257-1263. [PMID: 35093273 DOI: 10.1016/j.dld.2022.01.121] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 12/18/2021] [Accepted: 01/05/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND Epigenetic alterations have been reported as one of the risk factors of gallbladder cancer. Promoter hypermethylation is associated with high incidence and poor prognosis of GBC. Bcl-2/adenovirus E1B 19 kDa interacting protein 3 is a pro-apoptotic protein member of Bcl-2 family. AIMS Present study was aimed to investigate expression profile and promoter methylation status of BNIP3 in GBC and its correlation with clinico-pathological parameters. METHODS The expression analysis and methylation status of BNIP3 was performed by semi-quantitative reverse transcription polymerase chain reaction and Methylation-specific polymerase chain reaction respectively in 84 GBC patients and 29 gallstone tissues (used as normal controls). RESULTS We demonstrate down regulation of BNIP3 in 56% of the GBC samples. BNIP3 promoter is also frequently hypermethylated (69%) in GBC samples. Interestingly, we found that 69% (40/58) of the BNIP3 promoter hypermethylated samples had also reduced expression of BNIP3. Our data demonstrate significant correlation of the mRNA expression and promoter hypermethylation with late stage and nodal metastasis. Hypermethylation of BNIP3 promoter is associated with low overall survival period. CONCLUSION Our results suggest that promoter hypermethylation is an early event and can be a frequent mechanism for downregulation of BNIP3 in GBC.
Collapse
Affiliation(s)
- Amisha Bharti
- Department of Zoology, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi, 221005, India
| | - Amrita Ghosh Kar
- Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Deepika Singh
- Deparment of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221005, India
| | - Mumtaz Ahmad Ansari
- Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Mallika Tewari
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Gopeshwar Narayan
- Deparment of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221005, India
| | - Sunita Singh
- Department of Zoology, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi, 221005, India.
| |
Collapse
|
|
14
|
Sadrkhanloo M, Entezari M, Orouei S, Ghollasi M, Fathi N, Rezaei S, Hejazi ES, Kakavand A, Saebfar H, Hashemi M, Goharrizi MASB, Salimimoghadam S, Rashidi M, Taheriazam A, Samarghandian S. STAT3-EMT axis in tumors: Modulation of cancer metastasis, stemness and therapy response. Pharmacol Res 2022; 182:106311. [PMID: 35716914 DOI: 10.1016/j.phrs.2022.106311] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/08/2022] [Accepted: 06/12/2022] [Indexed: 02/07/2023]
Abstract
Epithelial-to-mesenchymal transition (EMT) mechanism is responsible for metastasis of tumor cells and their spread to various organs and tissues of body, providing undesirable prognosis. In addition to migration, EMT increases stemness and mediates therapy resistance. Hence, pathways involved in EMT regulation should be highlighted. STAT3 is an oncogenic pathway that can elevate growth rate and migratory ability of cancer cells and induce drug resistance. The inhibition of STAT3 signaling impairs cancer progression and promotes chemotherapy-mediated cell death. Present review focuses on STAT3 and EMT interaction in modulating cancer migration. First of all, STAT3 is an upstream mediator of EMT and is able to induce EMT-mediated metastasis in brain tumors, thoracic cancers and gastrointestinal cancers. Therefore, STAT3 inhibition significantly suppresses cancer metastasis and improves prognosis of patients. EMT regulators such as ZEB1/2 proteins, TGF-β, Twist, Snail and Slug are affected by STAT3 signaling to stimulate cancer migration and invasion. Different molecular pathways such as miRNAs, lncRNAs and circRNAs modulate STAT3/EMT axis. Furthermore, we discuss how STAT3 and EMT interaction affects therapy response of cancer cells. Finally, we demonstrate targeting STAT3/EMT axis by anti-tumor agents and clinical application of this axis for improving patient prognosis.
Collapse
Affiliation(s)
- Mehrdokht Sadrkhanloo
- Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sima Orouei
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Marzieh Ghollasi
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Nikoo Fathi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shamin Rezaei
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elahe Sadat Hejazi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirabbas Kakavand
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hamidreza Saebfar
- European University Association, League of European Research Universities, University of Milan, Italy
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran.
| |
Collapse
|
|
15
|
Mirzaei S, Saghari S, Bassiri F, Raesi R, Zarrabi A, Hushmandi K, Sethi G, Tergaonkar V. NF-κB as a regulator of cancer metastasis and therapy response: A focus on epithelial-mesenchymal transition. J Cell Physiol 2022; 237:2770-2795. [PMID: 35561232 DOI: 10.1002/jcp.30759] [Citation(s) in RCA: 128] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/24/2022] [Accepted: 04/19/2022] [Indexed: 12/13/2022]
Abstract
Metastasis of tumor cells is a complex challenge and significantly diminishes the overall survival and prognosis of cancer patients. The epithelial-to-mesenchymal transition (EMT) is a well-known mechanism responsible for the invasiveness of tumor cells. A number of molecular pathways can regulate the EMT mechanism in cancer cells and nuclear factor-kappaB (NF-κB) is one of them. The nuclear translocation of NF-κB p65 can induce the transcription of several genes involved in EMT induction. The present review describes NF-κB and EMT interaction in cancer cells and their association in cancer progression. Due to the oncogenic role NF-κB signaling, its activation enhances metastasis of tumor cells via EMT induction. This has been confirmed in various cancers including brain, breast, lung and gastric cancers, among others. The ZEB1/2, transforming growth factor-β, and Slug as inducers of EMT undergo upregulation by NF-κB to promote metastasis of tumor cells. After EMT induction driven by NF-κB, a significant decrease occurs in E-cadherin levels, while N-cadherin and vimentin levels undergo an increase. The noncoding RNAs can potentially also function as upstream mediators and modulate NF-κB/EMT axis in cancers. Moreover, NF-κB/EMT axis is involved in mediating drug resistance in tumor cells. Thus, suppressing NF-κB/EMT axis can also promote the sensitivity of cancer cells to chemotherapeutic agents.
Collapse
Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Sam Saghari
- Department of Health Services Management, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Farzaneh Bassiri
- Department of Biology, Fars Science and Research Branch, Islamic Azad University, Fars, Iran.,Department of Biology, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Rasoul Raesi
- PhD in Health Services Management, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, Turkey
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology and Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Yong Loo Lin School of Medicine, NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore, Singapore
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology (IMCB), 61 Biopolis Drive, Proteos, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| |
Collapse
|
|
16
|
BAFF signaling drives interstitial transformation of mouse renal tubular epithelial cells in a Pin1-dependent manner. In Vitro Cell Dev Biol Anim 2021; 57:649-659. [PMID: 34128158 PMCID: PMC8316171 DOI: 10.1007/s11626-021-00598-y] [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: 01/25/2021] [Accepted: 05/26/2021] [Indexed: 11/23/2022]
Abstract
Aberrant expression of B cell–activating factor belonging to TNF superfamily (BAFF) and its receptors results in abnormal biological activities in hematopoietic and non-hematopoietic cells and is closely associated with the occurrence and development of various diseases. However, the biological significance and potential mechanisms underlying BAFF signaling in renal tubular epithelial cells (RTECs) remain unknown. This study aimed to investigate the biological role of BAFF signaling in RTECs. Mice primary RTECs were applied. The proliferation status and apoptotic rates were examined by MTS assay and flow cytometry, respectively. The expression of BAFF and its receptors was analyzed via flow cytometry and sodium ion transport function, and cytokeratin-18 expression was detected through immunofluorescence staining. In addition, Pin1 was knocked down via siRNA and its expression was assessed through reverse transcription PCR. Lastly, western blotting was performed to analyze E-cadherin, ɑ-SMA, and Pin1 expression. Results suggested that BAFF-R was significantly upregulated upon IFN-γ stimulation, and enhancement of BAFF signaling promoted cell survival and reduced their apoptotic rate, while simultaneously reducing the epithelial phenotype and promoting the interstitial transformation of cells. Furthermore, Pin1 was significantly increased, along with the upregulation of BAFF signaling in the RTECs, and participated in interstitial transformation induced by BAFF signaling. Collectively, the present results elucidate the potential mechanism of loss of normal function of RTECs under long-term high dose of BAFF stimulation provides a potential therapeutic target for renal interstitial fibrosis, and underlining mechanisms of shortening of long-term outcomes of kidney allografts via augmenting of BAFF signaling.
Collapse
|
|
17
|
Kawasaki K, Kuboki S, Furukawa K, Takayashiki T, Takano S, Ohtsuka M. LGR5 induces β-catenin activation and augments tumour progression by activating STAT3 in human intrahepatic cholangiocarcinoma. Liver Int 2021; 41:865-881. [PMID: 33249719 DOI: 10.1111/liv.14747] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 11/22/2020] [Accepted: 11/23/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS LGR5 enhances Wnt-β-catenin signalling; however, involvement of LGR5 or Wnt-β-catenin signalling in ICC progression has not been reported. METHODS Functions and regulations of LGR5-mediated β-catenin activation in ICC progression were evaluated using surgical specimens collected from 61 ICC patients or 2 ICC cell lines. RESULTS LGR5 expression was increased in some cases of ICC. It was positively correlated with β-catenin activation, OLFM4 expression and STAT3 activation, and negatively correlated with GRIM19 expression in ICC, thereby enhancing cancer stem cell (CSC)-like property and EMT. High LGR5 expression was an independent factor for poor prognosis in ICC after operation. In vitro, Wnt inhibition by IWP-2 suppressed β-catenin activation, OLFM4 expression and STAT3 activation. IWP-2 treatment decreased expression of EpCAM, CD133, vimentin and increased E-cadherin expression. The rate of mesenchymal cells was decreased and cell invasiveness was suppressed after IWP-2 treatment, suggesting that Wnt-β-catenin signalling enhanced CSC-like property and EMT by activating STAT3. In addition, LGR5 knockdown inhibited β-catenin activation, resulting in suppression of β-catenin-induced STAT3 activation through inhibition of OLFM4-GRIM19 cascade. As these results, LGR5 knockdown suppressed CSC-like property and EMT. Therefore, LGR5 was a key regulator for β-catenin activation, and β-catenin was unable to be activated without LGR5. CONCLUSIONS LGR5 is essential for β-catenin activation induced by Wnt signalling. Activated β-catenin further activates STAT3 and enhances CSC-like property and EMT, leading to aggressive tumour progression and poor prognosis in patients with ICC. Therefore, LGR5 is an excellent prognostic predictor and a promising therapeutic target for ICC.
Collapse
Affiliation(s)
- Keishi Kawasaki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| |
Collapse
|
|
18
|
Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy. Biomedicines 2021; 9:biomedicines9040359. [PMID: 33807199 PMCID: PMC8065645 DOI: 10.3390/biomedicines9040359] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 01/09/2023] Open
Abstract
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity.
Collapse
|
|
19
|
Yokota T, Nojima H, Kuboki S, Yoshitomi H, Furukawa K, Takayashiki T, Takano S, Ohtsuka M. Sphingosine-1-phosphate Receptor-1 Promotes Vascular Invasion and EMT in Hepatocellular Carcinoma. J Surg Res 2021; 259:200-210. [PMID: 33307511 DOI: 10.1016/j.jss.2020.11.044] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 10/14/2020] [Accepted: 11/01/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND It remains unknown whether epithelial-mesenchymal transition (EMT)-mediated vascular invasion and cancer stemness are associated with sphingosine-1-phosphate receptor-1 (S1PR1) expression in human hepatocellular carcinoma (HCC). The aim of this study was to investigate the correlation between S1PR1 expression and prognosis of patients with primary HCC and to define the potential of S1PR as a therapeutic target. MATERIALS AND METHODS We investigated 108 patients who underwent primary surgical resection for HCC treatment. Expression of S1PR1 and EMT markers was analyzed to predict prognosis of patients with HCC. Furthermore, three-dimensional organotypic culture, anoikis assay, and cell invasion were performed to validate the association of S1PR1 with EMT and cancer stemness. RESULTS Among patients with HCC, the high S1PR1 expression group had significantly shorter overall survival than the low expression group. Moreover, high S1PR1 expression was significantly associated with shorter recurrence-free survival, increased risk of portal and hepatic vein invasion, and intrahepatic metastasis. Multivariate analyses revealed that S1PR1 overexpression was an independent prognostic factor in patients with HCC. S1PR1 overexpression positively correlated with vimentin and MMP-9 expression and negatively correlated with E-cadherin. In addition, S1PR1 overexpression induced EMT and enhanced tumor invasion and cancer stemness. CONCLUSIONS S1PR1 overexpression, via EMT-induced vascular invasion and increased cancer stem cell properties, establishes a metastatic niche, enhances the capacity of hematogenous metastasis, and associates with poor outcomes in patients with HCC. Hence, S1PR1 may serve as a therapeutic target for patients with HCC with vascular invasion.
Collapse
Affiliation(s)
- Tetsuo Yokota
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroyuki Nojima
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Surgery, Teikyo Chiba Medical Center, Chiba, Japan.
| | - Satoshi Kuboki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hideyuki Yoshitomi
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| |
Collapse
|
|
20
|
Zhang J, Hu Z, Wen C, Liao Q, He B, Peng J, Tang X, Chen Z, Xie Y. MicroRNA-182 promotes epithelial-mesenchymal transition by targeting FOXN3 in gallbladder cancer. Oncol Lett 2021; 21:200. [PMID: 33574939 PMCID: PMC7816289 DOI: 10.3892/ol.2021.12461] [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: 07/20/2020] [Accepted: 12/29/2020] [Indexed: 01/11/2023] Open
Abstract
Increasing evidence has suggested an association between the expression profiles of microRNAs (miRs) and gallbladder cancer (GBC). Recently, miR-182 has been demonstrated to exert tumor-promoting effects. However, the biological activity and molecular mechanisms of miR-182 in GBC remain unclear. The results of the present study demonstrated that miR-182 expression was significantly upregulated in GBC tissues and cell lines (GBC-SD and SGC-996). In addition, miR-182-knockdown attenuated epithelial-mesenchymal transition (EMT) in GBC cells, as indicated by decreased cell migratory and invasive abilities, decreased vimentin expression, and increased E-cadherin expression. The activities of β-catenin and its downstream factors, Cyclin D1 and c-Myc, were also demonstrated to decrease following miR-182-knockdown. Forkhead box N3 (FOXN3) was identified as the direct target of miR-182. Overexpression of FOXN3 ameliorated EMT and the β-catenin pathway. Taken together, the results of the present study suggested that miR-182 promotes EMT in GBC cells by targeting FOXN3, which suppresses the Wnt/β-catenin pathway.
Collapse
Affiliation(s)
- Jianhong Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Zeming Hu
- Department of General Surgery, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang 311202, P.R. China
| | - Chao Wen
- School of Nursing, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Qicheng Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Baoqing He
- Department of General Surgery, The People's Hospital of Ningdu County, Ganzhou, Jiangxi 342800, P.R. China
| | - Jing Peng
- Department of General Surgery, The People's Hospital of Shangyou County, Ganzhou, Jiangxi 341200, P.R. China
| | - Xin Tang
- Department of General Surgery, The Third Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Zhixi Chen
- College of Pharmacy, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Yuankang Xie
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| |
Collapse
|
|
21
|
Sun Q, Fan G, Zhuo Q, Dai W, Ye Z, Ji S, Xu W, Liu W, Hu Q, Zhang Z, Liu M, Yu X, Xu X, Qin Y. Pin1 promotes pancreatic cancer progression and metastasis by activation of NF-κB-IL-18 feedback loop. Cell Prolif 2020; 53:e12816. [PMID: 32347623 PMCID: PMC7260075 DOI: 10.1111/cpr.12816] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 02/16/2020] [Accepted: 02/29/2020] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES Accumulated evidence suggests that Pin1 contributes to oncogenesis of diverse cancers. However, the underlying mechanism of oncogenic function of Pin1 in PDAC requires further exploration. MATERIALS AND METHODS IHC was performed using PDAC tissues. Western blot, PCR, immunofluorescence and transwell were performed using cell lines. GSEA were applied for possible downstream pathways. ChIP assay and dual luciferase were used for assessment of transcriptional activity. RESULTS Both Pin1 and IL-18 levels are increased in primary PDAC tissues and that their levels are positively correlated. High expression of IL-18 is a predictor of poor prognoses. Pin1 promoted pancreatic cancer cell proliferation and motility by increasing IL-18 expression, while Pin1 knockdown also inhibited the tumour-promoting effect of IL-18. Both Pin1 and IL-18 could enhance the NFκB activity in pancreatic cancer cells. When bound to the p65 protein, Pin1 promoted p65 phosphorylation and its nuclear translocation. In the nucleus, Pin1 and p65 simultaneously bound to the IL-18 promoter and enhanced IL-18 transcription. In addition, recruitment of p65 to the IL-18 promoter was decreased in Pin1-silenced cells. CONCLUSIONS Our study improves the understanding of Pin1 in tumour-promoting inflammation in PDAC, which is a hallmark of cancer; Pin1 interacted with p65 in PDAC and enhanced NF-κB signalling and downstream transcriptional activation of IL-18, with increased IL-18 continuously activating NF-κB signalling, which then forms a positive feedback loop.
Collapse
|
|
22
|
Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy. Cells 2020; 9:cells9040892. [PMID: 32268506 PMCID: PMC7226806 DOI: 10.3390/cells9040892] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 03/30/2020] [Accepted: 04/03/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.
Collapse
|
|
23
|
Pu W, Zheng Y, Peng Y. Prolyl Isomerase Pin1 in Human Cancer: Function, Mechanism, and Significance. Front Cell Dev Biol 2020; 8:168. [PMID: 32296699 PMCID: PMC7136398 DOI: 10.3389/fcell.2020.00168] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 02/29/2020] [Indexed: 02/05/2023] Open
Abstract
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is an evolutionally conserved and unique enzyme that specifically catalyzes the cis-trans isomerization of phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif and, subsequently, induces the conformational change of its substrates. Mounting evidence has demonstrated that Pin1 is widely overexpressed and/or overactivated in cancer, exerting a critical influence on tumor initiation and progression via regulation of the biological activity, protein degradation, or nucleus-cytoplasmic distribution of its substrates. Moreover, Pin1 participates in the cancer hallmarks through activating some oncogenes and growth enhancers, or inactivating some tumor suppressors and growth inhibitors, suggesting that Pin1 could be an attractive target for cancer therapy. In this review, we summarize the findings on the dysregulation, mechanisms, and biological functions of Pin1 in cancer cells, and also discuss the significance and potential applications of Pin1 dysregulation in human cancer.
Collapse
Affiliation(s)
- Wenchen Pu
- Laboratory of Molecular Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Yuanyuan Zheng
- Laboratory of Molecular Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Yong Peng
- Laboratory of Molecular Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University Collaborative Innovation Center of Biotherapy, Chengdu, China
| |
Collapse
|
|
24
|
Hu X, Chen LF. Pinning Down the Transcription: A Role for Peptidyl-Prolyl cis-trans Isomerase Pin1 in Gene Expression. Front Cell Dev Biol 2020; 8:179. [PMID: 32266261 PMCID: PMC7100383 DOI: 10.3389/fcell.2020.00179] [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: 12/15/2019] [Accepted: 03/04/2020] [Indexed: 12/14/2022] Open
Abstract
Pin1 is a peptidyl-prolyl cis-trans isomerase that specifically binds to a phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) motif and catalyzes the cis-trans isomerization of proline imidic peptide bond, resulting in conformational change of its substrates. Pin1 regulates many biological processes and is also involved in the development of human diseases, like cancer and neurological diseases. Many Pin1 substrates are transcription factors and transcription regulators, including RNA polymerase II (RNAPII) and factors associated with transcription initiation, elongation, termination and post-transcription mRNA decay. By changing the stability, subcellular localization, protein-protein or protein-DNA/RNA interactions of these transcription related proteins, Pin1 modulates the transcription of many genes related to cell proliferation, differentiation, apoptosis and immune response. Here, we will discuss how Pin regulates the properties of these transcription relevant factors for effective gene expression and how Pin1-mediated transcription contributes to the diverse pathophysiological functions of Pin1.
Collapse
Affiliation(s)
- Xiangming Hu
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Lin-Feng Chen
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, United States.,Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| |
Collapse
|
|
25
|
The Antitumor Efficacy of β-Elemene by Changing Tumor Inflammatory Environment and Tumor Microenvironment. BIOMED RESEARCH INTERNATIONAL 2020; 2020:6892961. [PMID: 32149121 PMCID: PMC7054771 DOI: 10.1155/2020/6892961] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 01/21/2020] [Indexed: 02/06/2023]
Abstract
Inflammatory mediators and inflammatory cells in the inflammatory microenvironment promote the transformation of normal cells to cancer cells in the early stage of cancer, promote the growth and development of cancer cells, and induce tumor immune escape. The monomeric active ingredient β-elemene is extracted from the traditional Chinese medicine Curcuma wenyujin and has been proven to have good anti-inflammatory and antitumor activities in clinical applications for more than 20 years in China. Recent studies have found that this traditional Chinese medicine plays a vital role in macrophage infiltration and M2 polarization, as well as in regulating immune disorders, and it even regulates the transcription factors NF-κB and STAT3 to alter inflammation, tumorigenesis, and development. In addition, β-elemene regulates not only different inflammatory factors (such as TNF-α, IFN, TGF-β, and IL-6/10) but also oxidative stress in vivo and in vitro. The excellent anti-inflammatory and antitumor effects of β-elemene and its ability to alter the inflammatory microenvironment of tumors have been gradually elaborated. Although the study of monomeric active ingredients in traditional Chinese medicines is insufficient in terms of quality and quantity, the pharmacological effects of more active ingredients of traditional Chinese medicines will be revealed after β-elemene.
Collapse
|
|
26
|
Feng YL, Chen DQ, Vaziri ND, Guo Y, Zhao YY. Small molecule inhibitors of epithelial-mesenchymal transition for the treatment of cancer and fibrosis. Med Res Rev 2020; 40:54-78. [PMID: 31131921 DOI: 10.1002/med.21596] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 03/20/2019] [Accepted: 04/26/2019] [Indexed: 02/07/2023]
Abstract
Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial-mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc-finger E-box-binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor-β1, RAC-α serine/threonine-protein kinase, Wnt, nuclear factor-kappa B, peroxisome proliferator-activated receptor, Notch, and RAS), RNA-binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.
Collapse
Affiliation(s)
- Ya-Long Feng
- School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Dan-Qian Chen
- School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Nosratola D Vaziri
- Department of Medicine, University of California Irvine, Irvine, California
| | - Yan Guo
- School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China
- Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico
| | - Ying-Yong Zhao
- School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China
| |
Collapse
|
|
27
|
Ashizawa Y, Kuboki S, Nojima H, Yoshitomi H, Furukawa K, Takayashiki T, Takano S, Miyazaki M, Ohtsuka M. OLFM4 Enhances STAT3 Activation and Promotes Tumor Progression by Inhibiting GRIM19 Expression in Human Hepatocellular Carcinoma. Hepatol Commun 2019; 3:954-970. [PMID: 31304451 PMCID: PMC6601327 DOI: 10.1002/hep4.1361] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 04/03/2019] [Indexed: 12/11/2022] Open
Abstract
Olfactomedin 4 (OLFM4) induces signal transducer and activator of transcription 3 (STAT3) activation by inhibiting gene associated with retinoid-interferon-induced mortality 19 (GRIM19), a strong STAT3 suppressor gene; however, the mechanisms of OLFM4 for regulating GRIM19-STAT3 cascade in hepatocellular carcinoma (HCC) remain unclear. The functions and regulations of OLFM4, GRIM19, and STAT3 activation in HCC progression were evaluated using surgical specimens collected from 111 HCC patients or 2 HCC cell lines in vitro. Moreover, the cancer stem cell-like property of OLFM4 mediated by leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), known as an intestinal stem cell marker, was investigated. OLFM4 was increased in HCC compared with adjacent liver tissue. The multivariate analysis revealed that high OLFM4 expression was an independent factor for poor prognosis. OLFM4 expression was negatively correlated with GRIM19 expression and positively correlated with STAT3 activation in HCC, thereby increasing cell cycle progression. OLFM4 knockdown in HCC cells increased GRIM19 expression and inhibited STAT3 activation; however, after double knockdown of GRIM19 and OLFM4, STAT3 activation decreased by OLFM4 knockdown was increased again. OLFM4 knockdown increased cell apoptosis, inhibited cell proliferation, and suppressed cancer stem cell-like property in HCC cells. The incidence of hematogenous recurrence was higher in HCC patients with high OLFM4 expression, suggesting that anoikis resistance of HCC was enhanced by OLFM4. In clinical cases, LGR5 expression and CD133 expression was correlated with OLFM4 expression in HCC, leading to poor patient prognosis. In vitro, LGR5 enhanced cancer stem cell-like property by up-regulating OLFM4 through the Wnt signaling pathway. Conclusion: OLFM4 is induced by the LGR5-Wnt signaling pathway and is strongly associated with aggressive tumor progression and poor prognosis in HCC by regulating STAT3-induced tumor cell proliferation and cancer stem cell-like property. Therefore, OLFM4 is a novel prognostic predictor and a potential therapeutic target for patients with HCC.
Collapse
Affiliation(s)
- Yosuke Ashizawa
- Department of General Surgery, Graduate School of MedicineChiba UniversityChibaJapan
| | - Satoshi Kuboki
- Department of General Surgery, Graduate School of MedicineChiba UniversityChibaJapan
| | - Hiroyuki Nojima
- Department of General Surgery, Graduate School of MedicineChiba UniversityChibaJapan
| | - Hideyuki Yoshitomi
- Department of General Surgery, Graduate School of MedicineChiba UniversityChibaJapan
| | - Katsunori Furukawa
- Department of General Surgery, Graduate School of MedicineChiba UniversityChibaJapan
| | - Tsukasa Takayashiki
- Department of General Surgery, Graduate School of MedicineChiba UniversityChibaJapan
| | - Shigetsugu Takano
- Department of General Surgery, Graduate School of MedicineChiba UniversityChibaJapan
| | - Masaru Miyazaki
- Department of General Surgery, Graduate School of MedicineChiba UniversityChibaJapan
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of MedicineChiba UniversityChibaJapan
| |
Collapse
|