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1
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Guan X, Wu Q, Sun B. MicroRNA-regulated flounder CLDN4 functions in anti-bacterial immunity. FISH & SHELLFISH IMMUNOLOGY 2025; 161:110270. [PMID: 40074190 DOI: 10.1016/j.fsi.2025.110270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 02/18/2025] [Accepted: 03/08/2025] [Indexed: 03/14/2025]
Abstract
CLDN4 belongs to a multi-transmembrane protein family of claudins, which mainly functions in cell-cell adhesion and migration. MicroRNAs (miRNAs) are important post-transcriptional regulating factors that participate in broad biological process including immunity. Through high-throughput RNA sequencing strategy, a flounder miRNA, miR-29-x, was identified to be responsible to both bacteria and virus. In this study, we explored the regulatory mechanism and function of miR-29-x and its target gene of flounder CLDN4 (named PoCLDN4). We proved that miR-29-x could interact with the 3'UTR of PoCLDN4 and negatively regulate its expression. PoCLDN4 located on cell membrane, while the depletion of extracellular loop E2 abolished the membrane localization of this protein. E3 could bind different bacteria, and mutation of the amino acids of 13E and 18E enhanced this capacity, while mutation of 10L abolish this capacity. Further study revealed the bacteria killing effect of E3 and verified 10L as a key factor. These results identified the interaction between miR-29-x and PoCLDN4, and unraveled the function as well as the molecular basis of flounder CLDN4 in anti-bacterial immunity.
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Affiliation(s)
- Xiaolu Guan
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
| | - Qian Wu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, 266237, China
| | - Boguang Sun
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, 266237, China.
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2
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Meena K, Babu R, Pancholi B, Garabadu D. Exploring therapeutic potential of claudin in Flavivirus infection: A review on current advances and future perspectives. Int J Biol Macromol 2025; 309:142936. [PMID: 40203926 DOI: 10.1016/j.ijbiomac.2025.142936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/25/2025] [Accepted: 04/06/2025] [Indexed: 04/11/2025]
Abstract
Flavivirus such as Dengue, Zika, West Nile, Japanese encephalitis, and yellow fever virus, composed of single-stranded positive-sense RNA, predominantly contaminated through arthropods. Flavivirus infection characterises from asymptomatic signs to severe hemorrhagic fever and encephalitis. The host's immune system detects these viruses and provides a defence mechanism to sustain their life and growth. However, flaviviruses through different mechanisms compromise the host's immune defence. The current pharmacotherapeutic strategies against Flavivirus infection target different stages of the Flavivirus life cycle and its proteins. On the contrary, the host's immune defence mechanism is equally important to restrict their growth. It has been suggested that flaviviruses compromise claudins to sustain their life and growth inside the mammalian cells. This review primarily focuses on the effect of Flavivirus on claudins (CLDNs), transmembrane proteins that form tight junctions in mammalian cells. CLDNs are crucial in viral entry and pathogenesis by regulating paracellular permeability, particularly in tissues and the blood-brain barrier. Recent studies indicate that the Dengue and Zika viruses can potentially be treated by targeting specific CLDNs-specifically CLDN 1, CLDN 5, and CLDN 7 to inhibit viral entry and fusion. Additionally, it highlights the current challenges and future prospects in developing claudin-based antiviral agents against Flavivirus infections.
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Affiliation(s)
- Kiran Meena
- Department of Pharmacology, Central University of Punjab, Bathinda 151401, India
| | - Raja Babu
- Department of Pharmacology, Central University of Punjab, Bathinda 151401, India
| | | | - Debapriya Garabadu
- Department of Pharmacology, Central University of Punjab, Bathinda 151401, India.
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3
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Song X, Zhu Y, Geng W, Jiao J, Liu H, Chen R, He Q, Wang L, Sun X, Qin W, Geng J, Chen Z. Spatial and single-cell transcriptomics reveal cellular heterogeneity and a novel cancer-promoting Treg cell subset in human clear-cell renal cell carcinoma. J Immunother Cancer 2025; 13:e010183. [PMID: 39755578 PMCID: PMC11748785 DOI: 10.1136/jitc-2024-010183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 12/06/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) is the most common histologic type of RCC. However, the spatial and functional heterogeneity of immunosuppressive cells and the mechanisms by which their interactions promote immunosuppression in the ccRCC have not been thoroughly investigated. METHODS To further investigate the cellular and regional heterogeneity of ccRCC, we analyzed single-cell and spatial transcriptome RNA sequencing data from four patients, which were obtained from samples from multiple regions, including the tumor core, tumor-normal interface, and distal normal tissue. On the basis, the findings were investigated in vitro using tissue and blood samples from 15 patients with ccRCC and validated in the broader samples on tissue microarrays. RESULTS In this study, we revealed previously unreported subsets of both stromal and immune cells, as well as mapped their spatial location at finer resolution. In addition, we validated the clusters of tumor cells after removing batch effects according to six characterized gene sets, including epithelial-mesenchymal transitionhigh clusters, metastatic clusters and proximal tubulehigh clusters. Importantly, we identified a special regulatory T (Treg) cell subpopulation that has the molecular characteristics of terminal effector Treg cells but expresses multiple cytokines, such as interleukin (IL)-1β and IL-18. This group of Treg cells has stronger immunosuppressive function and was associated with a worse prognosis in ccRCC cohorts. They were colocalized with MRC1 + FOLR2 + tumor-associated macrophages (TAMs) at the tumor-normal interface to form a positive feedback loop, maintaining a synergistic procarcinogenic effect. In addition, we traced the origin of IL-1β+ Treg cells and revealed that IL-18 can induce the expression of IL-1β in Treg cells via the ERK/NF-κB pathway. CONCLUSIONS We demonstrated a novel cancer-promoting Treg cell subset and its interactions with MRC1 + FOLR2 +TAMs, which provides new insight into Treg cell heterogeneity and potential therapeutic targets for ccRCC.
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Affiliation(s)
- Xiyu Song
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
- Xijing Innovation Research Institute, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yumeng Zhu
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wenwen Geng
- Department of Breast Surgery, Shandong University, Jinan, Shandong, China
| | - Jianhua Jiao
- Xijing Innovation Research Institute, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Urology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Hongjiao Liu
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Ruo Chen
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qian He
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lijuan Wang
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiuxuan Sun
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Weijun Qin
- Department of Urology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jiejie Geng
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
- Xijing Innovation Research Institute, Fourth Military Medical University, Xi'an, Shaanxi, China
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Xian, Shaanxi, China
| | - Zhinan Chen
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Xian, Shaanxi, China
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Villagomez FR, Lang J, Nunez-Avellaneda D, Behbakht K, Dimmick HL, Webb PG, Nephew KP, Neville M, Woodruff ER, Bitler BG. Claudin-4 Stabilizes the Genome via Nuclear and Cell-Cycle Remodeling to Support Ovarian Cancer Cell Survival. CANCER RESEARCH COMMUNICATIONS 2025; 5:39-53. [PMID: 39625235 PMCID: PMC11705808 DOI: 10.1158/2767-9764.crc-24-0558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 01/11/2025]
Abstract
SIGNIFICANCE High-grade serous ovarian carcinoma is marked by chromosomal instability, which can serve to promote disease progression and allow cancer to evade therapeutic insults. The report highlights the role of claudin-4 in regulating genomic instability and proposes a novel therapeutic approach to exploit claudin-4-mediated regulation.
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Affiliation(s)
- Fabian R. Villagomez
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Julie Lang
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Daniel Nunez-Avellaneda
- Deputy Directorate of Technological Development, Linkage, and Innovation, National Council of Humanities, Sciences, and Technologies, Mexico City, Mexico
| | - Kian Behbakht
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Hannah L. Dimmick
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Patricia G. Webb
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Kenneth P. Nephew
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana
- Department of Anatomy, Cell Biology and Physiology, Indiana University, Indianapolis, Indiana
| | - Margaret Neville
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Elizabeth R. Woodruff
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Benjamin G. Bitler
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
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Das A, Giri S, Dey P. Cell-cell junctional proteins in cancer. Adv Clin Chem 2024; 125:93-142. [PMID: 39988409 DOI: 10.1016/bs.acc.2024.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
A hallmark change during carcinogenesis is disruption or dysregulation of cell-cell junctions. It enables a transformed cell to adopt mesenchymal phenotype and acquire higher potential to migrate and invade. This ultimately leads to cancer metastasis. During this process, junctional proteins undergo remarkable changes in terms of their expressional pattern, localization, and activity. De-localized junctional proteins may adopt atypical roles which might act to either suppress tumorigenesis or facilitate cancer development, depending on several factors. In this chapter, the authors attempt to know the expression pattern of junctional proteins in different types of cancer, understand its significance, and gather knowledge about the mechanisms by which they regulate tumorigenesis and cancer development.
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Affiliation(s)
- Aparajita Das
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Sarbani Giri
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India.
| | - Pubali Dey
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
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Büyücek S, Schraps N, Menz A, Lutz F, Chirico V, Viehweger F, Dum D, Schlichter R, Hinsch A, Fraune C, Bernreuther C, Kluth M, Hube-Magg C, Möller K, Reiswich V, Luebke AM, Lebok P, Weidemann S, Sauter G, Lennartz M, Jacobsen F, Clauditz TS, Marx AH, Simon R, Steurer S, Burandt E, Gorbokon N, Minner S, Krech T, Freytag M. Prevalence and clinical significance of Claudin-3 expression in cancer: a tissue microarray study on 14,966 tumor samples. Biomark Res 2024; 12:154. [PMID: 39658782 PMCID: PMC11633013 DOI: 10.1186/s40364-024-00702-w] [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: 10/15/2024] [Accepted: 11/30/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Claudin-3 (CLDN3) participates in the formation of the tight-junctions (TJs) that regulate intercellular permeability. Altered CLDN3 expression has been linked to tumor progression in multiple tumor types. Despite its widespread expression in normal epithelial cells, CLDN3 is considered an attractive drug target candidate, since it may be more accessible in cancer cells than in normal cells due to their less orchestrated cell growth. METHODS To comprehensively determine the prevalence of CLDN3 expression in cancer, a tissue microarray containing 14,966 samples from 133 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. RESULTS CLDN3 immunostaining was observed in 8,479 (68.9%) of 12,314 analyzable tumors, including 11.6% with weak, 6.2% with moderate, and 51.1% with strong positivity. CLDN3 staining was found in 96 of 133 tumor categories, 80 of which contained at least one strongly positive case. CLDN3 positivity was most seen in neuroendocrine neoplasms (92-100%) and in adenocarcinomas (67-100%), tumors of the female genital tract, including various subtypes of ovarian and endometrial carcinoma (up to 100%), as well as different subtypes of breast cancer (95.3-100%). CLDN3 positivity was less common in squamous cell carcinomas (0-43.2%) and mainly absent in melanoma, mesenchymal, and hematolymphatic neoplasms. In clear cell renal cell carcinoma (ccRCC), low CLDN3 was strongly linked to poor ISUP (p < 0.0001), Fuhrman (p < 0.0001), and Thoenes (p < 0.0001) grades, advanced pT category (p < 0.0001), high UICC stage (p = 0.0006) and distant metastasis (p = 0.0011), as well as shortened overall (p = 0.0118) and recurrence-free (p < 0.0001) survival. In papillary RCC (pRCC), low CLDN3 was associated with poor grade (p < 0.05), high pT (p = 0.0273) and distant metastasis (p = 0.0357). In urothelial carcinoma high CLDN3 was linked to high grade (p < 0.0001) and nodal metastasis (p = 0.0111). The level of CLDN3 staining was unrelated to parameters of tumor aggressiveness in pancreatic, gastric, and breast cancer. CONCLUSION In conclusion, our data demonstrate significant levels of CLDN3 expression in many different tumor entities and identify reduced CLDN3 expression as a potential prognostic marker in RCC.
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Affiliation(s)
- Seyma Büyücek
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Nina Schraps
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anne Menz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Florian Lutz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Viktoria Chirico
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Florian Viehweger
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Ria Schlichter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Katharina Möller
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Viktor Reiswich
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Andreas M Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Andreas H Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany.
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Morton Freytag
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany
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Yang L, Wang X, Lin Q, Shen G, Chen H. CLDN11 deficiency upregulates FOXM1 to facilitate breast tumor progression through hedgehog signaling pathway. J Mol Histol 2024; 55:1259-1270. [PMID: 39438406 PMCID: PMC11567981 DOI: 10.1007/s10735-024-10267-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 09/09/2024] [Indexed: 10/25/2024]
Abstract
Claudins (CLDNs) play a crucial role in regulating the permeability of epithelial barriers and can impact tumor behavior through alterations in their expression. However, the precise mechanisms underlying the involvement of CLDNs in breast cancer progression remain unclear. This study aimed to investigate the role of CLDN11 in breast cancer progression. Utilizing the TCGA database and clinical specimens from breast cancer patients, we observed reduced expression of CLDN11 in tumor tissues, which correlated with poor prognosis in breast cancer patients. In vitro, silencing of CLDN11 enhanced the proliferative and migratory characteristics of breast cancer cell lines MCF-7 and MDA-MB-231. Mechanistically, CLDN11 deficiency promoted the upregulation of Forkhead Box M1 (FOXM1) by activating the hedgehog signaling pathway, thereby sustaining tumor progression in breast cancer. In vivo, blockade of hedgehog signaling suppressed the tumor progression induced by CLDN11 silencing. Our study highlights the significance of the CLDN11/FOXM1 axis in breast cancer progression, suggesting CLDN11 as a potential diagnostic indicator and therapeutic target for clinical therapy.
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Affiliation(s)
- Leyi Yang
- Department of Breast Surgery, Zhangzhou Hospital, Fujian Medical University, No 59 Shengli West Road, Xiangcheng district, Zhangzhou, Fujian province, 363000, China
| | - Xiaoping Wang
- Department of Breast Surgery, Zhangzhou Hospital, Fujian Medical University, No 59 Shengli West Road, Xiangcheng district, Zhangzhou, Fujian province, 363000, China
| | - Qinghai Lin
- Department of Breast Surgery, Zhangzhou Hospital, Fujian Medical University, No 59 Shengli West Road, Xiangcheng district, Zhangzhou, Fujian province, 363000, China.
| | - Guoyi Shen
- Department of Thoracic Surgery, Zhangzhou Hospital, Fujian Medical University, Zhangzhou, China
| | - Hong Chen
- Department of Ultrasound, Zhangzhou Hospital, Fujian Medical University, Zhangzhou, China
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Villagomez FR, Lang J, Nunez-Avellaneda D, Behbakht K, Dimmick HL, Webb P, Nephew KP, Neville M, Woodruff ER, Bitler BG. Claudin-4 remodeling of nucleus-cell cycle crosstalk maintains ovarian tumor genome stability and drives resistance to genomic instability-inducing agents. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.04.611120. [PMID: 39282307 PMCID: PMC11398366 DOI: 10.1101/2024.09.04.611120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/22/2024]
Abstract
During cancer development, the interplay between the nucleus and the cell cycle leads to a state of genomic instability, often accompanied by observable morphological aberrations. These aberrations can be controlled by tumor cells to evade cell death, either by preventing or eliminating genomic instability. In epithelial ovarian cancer (EOC), overexpression of the multifunctional protein claudin-4 is a key contributor to therapy resistance through mechanisms associated with genomic instability. However, the molecular mechanisms underlying claudin-4 overexpression in EOC remain poorly understood. Here, we altered claudin-4 expression and employed a unique claudin-4 targeting peptide (CMP) to manipulate the function of claudin-4. We found that claudin-4 facilitates genome maintenance by linking the nuclear envelope and cytoskeleton dynamics with cell cycle progression. Claudin-4 caused nuclei constriction by excluding lamin B1 and promoting perinuclear F-actin accumulation, associated with remodeling nuclear architecture, thus altering nuclear envelope dynamics. Consequently, cell cycle modifications due to claudin-4 overexpression resulted in fewer cells entering the S-phase and reduced genomic instability. Importantly, disrupting biological interactions of claudin-4 using CMP and forskolin altered oxidative stress cellular response and increased the efficacy of PARP inhibitor treatment. Our data indicate that claudin-4 protects tumor genome integrity by remodeling the crosstalk between the nuclei and the cell cycle, leading to resistance to genomic instability formation and the effects of genomic instability-inducing agents.
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Affiliation(s)
- Fabian R. Villagomez
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Julie Lang
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, USA
| | - Daniel Nunez-Avellaneda
- Deputy Directorate of Technological Development, Linkage, and Innovation, National Council of Humanities, Sciences, and Technologies, Mexico City, Mexico
| | - Kian Behbakht
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Hannah L. Dimmick
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Patricia Webb
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Kenneth P. Nephew
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana
- Department of Anatomy, Cell Biology & Physiology, Indiana University, Indianapolis, Indiana
| | - Margaret Neville
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Elizabeth R. Woodruff
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Benjamin G. Bitler
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
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9
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Wagner P, Gass P, Pöschke P, Eckstein M, Gloßner L, Hartmann A, Beckmann MW, Fasching PA, Ruebner M, Emons J, Erber R. Spatial expression of claudin 18.2 in matched primaries and metastases of tubo-ovarian carcinoma of all subtypes. Virchows Arch 2024; 485:63-74. [PMID: 38326579 PMCID: PMC11271439 DOI: 10.1007/s00428-024-03756-1] [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: 11/09/2023] [Revised: 01/10/2024] [Accepted: 01/27/2024] [Indexed: 02/09/2024]
Abstract
Physiologically, claudin 18 splice variant 2 (CLDN18.2) expression is restricted to the gastric epithelium, but its expression has been detected in solid cancers. Zolbetuximab, a chimeric IgG1 antibody targeting CLDN18.2, has demonstrated promising effects in patients suffering from CLDN18.2-positive, HER2-negative locally advanced gastric cancer and is currently being studied further. To date, little is known about CLDN18.2 expression in other histological subtypes of tubo-ovarian carcinoma (TOC) and their matching metastases.Using a cohort of all histological TOC subtypes, we investigated the immunohistochemical (IHC) CLDN18.2 expression in both TOCs (n = 536), their matching metastatic tissue (n = 385) and in 93 metastases without primary. Tissue microarrays comprised both the tumor center and periphery. IHC positivity was defined as biomarker expression of ≥ 75% in tumor cells with moderate-to-strong membranous staining.Overall CLDN18.2 positivity was 4.1% (21/515) in the TOC centers and 3.6% (18/498) in their peripheries. In primaries of mucinous tubo-ovarian carcinoma (MTOC), CLDN18.2 positivity rates were 45% (18/40) and 36.6% (15/41), respectively. Positivity rates for the corresponding metastases were 33% (4/12, center) and 27% (3/11, periphery). The expression was relatively homogenous throughout all tumor sites. With no expression in 99.5% of nonmucinous tumors, CLDN18.2 positivity was almost exclusively seen in the mucinous subtype.In tubo-ovarian carcinoma, CLDN18.2 expression was, with rare exceptions, restricted to the mucinous subtype. Among them, 33% of metastasized MTOCs presented with CLDN18.2 positivity. Hence, CLDN18.2 might display a promising target for personalized therapy in patients with advanced MTOC.
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Affiliation(s)
- Paul Wagner
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany.
| | - Paul Gass
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Patrik Pöschke
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Markus Eckstein
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Laura Gloßner
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Matthias Wilhelm Beckmann
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Peter Andreas Fasching
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Matthias Ruebner
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Julius Emons
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Ramona Erber
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
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10
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Villagomez FR, Lang J, Rosario FJ, Nunez-Avellaneda D, Webb P, Neville M, Woodruff ER, Bitler BG. Claudin-4 Modulates Autophagy via SLC1A5/LAT1 as a Mechanism to Regulate Micronuclei. CANCER RESEARCH COMMUNICATIONS 2024; 4:1625-1642. [PMID: 38867360 PMCID: PMC11218812 DOI: 10.1158/2767-9764.crc-24-0240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 05/21/2024] [Accepted: 06/07/2024] [Indexed: 06/14/2024]
Abstract
Genome instability is a hallmark of cancer crucial for tumor heterogeneity and is often a result of defects in cell division and DNA damage repair. Tumors tolerate genomic instability, but the accumulation of genetic aberrations is regulated to avoid catastrophic chromosomal alterations and cell death. In ovarian cancer tumors, claudin-4 is frequently upregulated and closely associated with genome instability and worse patient outcomes. However, its biological association with regulating genomic instability is poorly understood. Here, we used CRISPR interference and a claudin mimic peptide to modulate the claudin-4 expression and its function in vitro and in vivo. We found that claudin-4 promotes a tolerance mechanism for genomic instability through micronuclei generation in tumor cells. Disruption of claudin-4 increased autophagy and was associated with the engulfment of cytoplasm-localized DNA. Mechanistically, we observed that claudin-4 establishes a biological axis with the amino acid transporters SLC1A5 and LAT1, which regulate autophagy upstream of mTOR. Furthermore, the claudin-4/SLC1A5/LAT1 axis was linked to the transport of amino acids across the plasma membrane as one of the potential cellular processes that significantly decreased survival in ovarian cancer patients. Together, our results show that the upregulation of claudin-4 contributes to increasing the threshold of tolerance for genomic instability in ovarian tumor cells by limiting its accumulation through autophagy. SIGNIFICANCE Autophagy regulation via claudin-4/SLC1A5/LAT1 has the potential to be a targetable mechanism to interfere with genomic instability in ovarian tumor cells.
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Affiliation(s)
- Fabian R. Villagomez
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
| | - Julie Lang
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
| | - Fredrick J. Rosario
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
| | - Daniel Nunez-Avellaneda
- Deputy Directorate of Technological Development, Linkage, and Innovation, National Council of Humanities, Sciences, and Technologies, Mexico City, Mexico.
| | - Patricia Webb
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
| | - Margaret Neville
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
| | - Elizabeth R. Woodruff
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
| | - Benjamin G. Bitler
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
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11
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Bhavsar D, Raguraman R, Kim D, Ren X, Munshi A, Moore K, Sikavitsas V, Ramesh R. Exosomes in diagnostic and therapeutic applications of ovarian cancer. J Ovarian Res 2024; 17:113. [PMID: 38796525 PMCID: PMC11127348 DOI: 10.1186/s13048-024-01417-0] [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: 08/21/2023] [Accepted: 04/16/2024] [Indexed: 05/28/2024] Open
Abstract
Ovarian cancer accounts for more deaths than any other female reproductive tract cancer. The major reasons for the high mortality rates include delayed diagnoses and drug resistance. Hence, improved diagnostic and therapeutic options for ovarian cancer are a pressing need. Extracellular vesicles (EVs), that include exosomes provide hope in both diagnostic and therapeutic aspects. They are natural lipid nanovesicles secreted by all cell types and carry molecules that reflect the status of the parent cell. This facilitates their potential use as biomarkers for an early diagnosis. Additionally, EVs can be loaded with exogenous cargo, and have features such as high stability and favorable pharmacokinetic properties. This makes them ideal for tumor-targeted delivery of biological moieties. The International Society of Extracellular Vesicles (ISEV) based on the Minimal Information for Studies on Extracellular Vesicles (MISEV) recommends the usage of the term "small extracellular vesicles (sEVs)" that includes exosomes for particles that are 30-200 nm in size. However, majority of the studies reported in the literature and relevant to this review have used the term "exosomes". Therefore, this review will use the term "exosomes" interchangeably with sEVs for consistency with the literature and avoid confusion to the readers. This review, initially summarizes the different isolation and detection techniques developed to study ovarian cancer-derived exosomes and the potential use of these exosomes as biomarkers for the early diagnosis of this devastating disease. It addresses the role of exosome contents in the pathogenesis of ovarian cancer, discusses strategies to limit exosome-mediated ovarian cancer progression, and provides options to use exosomes for tumor-targeted therapy in ovarian cancer. Finally, it states future research directions and recommends essential research needed to successfully transition exosomes from the laboratory to the gynecologic-oncology clinic.
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Affiliation(s)
- Dhaval Bhavsar
- Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th Street, Oklahoma City, OK, 73104, USA
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
| | - Rajeswari Raguraman
- Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th Street, Oklahoma City, OK, 73104, USA
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
| | - Dongin Kim
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, 1110 N, Stonewall Ave, Oklahoma City, OK, 73104, USA
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
| | - Xiaoyu Ren
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, 1110 N, Stonewall Ave, Oklahoma City, OK, 73104, USA
| | - Anupama Munshi
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, 975 NE, 10th Street, Oklahoma City, OK, 73104, USA
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
| | - Kathleen Moore
- Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
| | - Vassilios Sikavitsas
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
- Department of Chemical, Biological and Materials Engineering, Oklahoma University, Norman, OK, 73019, USA
| | - Rajagopal Ramesh
- Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th Street, Oklahoma City, OK, 73104, USA.
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA.
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12
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Zhong YJ, Luo XM, Liu F, He ZQ, Yang SQ, Ma WJ, Wang JK, Dai YS, Zou RQ, Hu YF, Lv TR, Li FY, Hu HJ. Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma. J Transl Med 2024; 22:422. [PMID: 38702814 PMCID: PMC11071156 DOI: 10.1186/s12967-024-05238-z] [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: 01/09/2024] [Accepted: 04/26/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood. METHODS To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue. RESULTS Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs. CONCLUSIONS This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.
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Affiliation(s)
- Yan-Jie Zhong
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Xi-Mei Luo
- Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Fei Liu
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Zhi-Qiang He
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Si-Qi Yang
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Wen-Jie Ma
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Jun-Ke Wang
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Yu-Shi Dai
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Rui-Qi Zou
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Ya-Fei Hu
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Tian-Run Lv
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Fu-Yu Li
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China.
| | - Hai-Jie Hu
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China.
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13
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Hana C, Thaw Dar NN, Galo Venegas M, Vulfovich M. Claudins in Cancer: A Current and Future Therapeutic Target. Int J Mol Sci 2024; 25:4634. [PMID: 38731853 PMCID: PMC11083183 DOI: 10.3390/ijms25094634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/16/2024] [Accepted: 04/18/2024] [Indexed: 05/13/2024] Open
Abstract
Claudins are a family of 27 proteins that have an important role in the formation of tight junctions. They also have an important function in ion exchange, cell mobility, and the epithelial-to-mesenchymal transition, the latter being very important in cancer invasion and metastasis. Therapeutic targeting of claudins has been investigated to improve cancer outcomes. Recent evidence shows improved outcomes when combining monoclonal antibodies against claudin 18.2 with chemotherapy for patients with gastroesophageal junction cancer. Currently, chimeric antigen receptor T-cells targeting claudin 18 are under investigation. In this review, we will discuss the major functions of claudins, their distribution in the normal as well as cancerous tissues, and their effect in cancer metastasis, with a special focus on the therapeutic targeting of claudins to improve cancer outcomes.
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Affiliation(s)
- Caroline Hana
- Hematology/Oncology Department, Memorial Healthcare System, Pembroke Pines, FL 33028, USA; (N.N.T.D.); (M.G.V.)
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14
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Kubota Y, Shitara K. Zolbetuximab for Claudin18.2-positive gastric or gastroesophageal junction cancer. Ther Adv Med Oncol 2024; 16:17588359231217967. [PMID: 38188462 PMCID: PMC10768589 DOI: 10.1177/17588359231217967] [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: 09/09/2023] [Accepted: 11/15/2023] [Indexed: 01/09/2024] Open
Abstract
Claudins (CLDNs) are a family of major membrane proteins that form components of tight junctions. In normal tissues, CLDNs seal the intercellular space in the epithelial sheets to regulate tissue permeability, paracellular transport, and signal transduction. Claudin18.2 (CLDN18.2), a member of the CLDN family, is expressed specifically in gastric mucosal cells in normal tissue, and its expression is often retained in gastric cancer cells. CLDN18.2 is ectopically expressed in many cancers other than gastric cancer such as esophageal cancer, pancreatic cancer, biliary tract cancer, non-small-cell lung cancer, and ovarian cancer. Structurally, CLDN18.2 is localized on the apical side of the cell membrane and has extracellular loops capable of binding monoclonal antibodies. Upon malignant transformation, CLDN18.2 is exposed to the cell surface of the whole membrane, which enables the binding of monoclonal antibodies. Based on these characteristics, CLDN18.2 was considered to be optimal for target therapy, and zolbetuximab was developed which is a first-in-class chimeric immunoglobulin G1 monoclonal antibody highly specific for CLDN18.2. It binds to CLDN18.2 on the tumor cell surface and stimulates cellular and soluble immune effectors that activate antibody-dependent cytotoxicity and complement-dependent cytotoxicity. Recently, zolbetuximab combined with chemotherapy demonstrated a survival benefit in patients with CLDN18.2-positive and HER-2-negative gastric or gastroesophageal junction cancers in the global phase III SPOTLIGHT and GLOW trials. From these clinically meaningful results, CLDN18.2-targeting therapy including zolbetuximab has attracted a lot of attention. In this review, we summarize the clinical implications of CLDN18.2-positive gastric or GEJ cancer, and CLDN18.2-targeting therapy, mainly for zolbetuximab.
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Affiliation(s)
- Yohei Kubota
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
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15
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Chacón C, Mounieres C, Ampuero S, Urzúa U. Transcriptomic Analysis of the Aged Nulliparous Mouse Ovary Suggests a Stress State That Promotes Pro-Inflammatory Lipid Signaling and Epithelial Cell Enrichment. Int J Mol Sci 2023; 25:513. [PMID: 38203684 PMCID: PMC10779227 DOI: 10.3390/ijms25010513] [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: 11/02/2023] [Revised: 12/23/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Ovarian cancer (OC) incidence and mortality peaks at post-menopause while OC risk is either reduced by parity or increased by nulliparity during fertile life. The long-term effect of nulliparity on ovarian gene expression is largely unknown. In this study, we describe a bioinformatic/data-mining analysis of 112 coding genes upregulated in the aged nulliparous (NP) mouse ovary compared to the aged multiparous one as reference. Canonical gene ontology and pathway analyses indicated a pro-oxidant, xenobiotic-like state accompanied by increased metabolism of inflammatory lipid mediators. Up-regulation of typical epithelial cell markers in the aged NP ovary was consistent with synchronized overexpression of Cldn3, Ezr, Krt7, Krt8 and Krt18 during the pre-neoplastic phase of mOSE cell cultures in a former transcriptome study. In addition, 61/112 genes were upregulated in knockout mice for Fshr and for three other tumor suppressor genes (Pten, Cdh1 and Smad3) known to regulate follicular homeostasis in the mammalian ovary. We conclude that the aged NP ovary displays a multifaceted stress state resulting from oxidative imbalance and pro-inflammatory lipid signaling. The enriched epithelial cell content might be linked to follicle depletion and is consistent with abundant clefts and cysts observed in aged human and mouse ovaries. It also suggests a mesenchymal-to-epithelial transition in the mOSE of the aged NP ovary. Our analysis suggests that in the long term, nulliparity worsens a variety of deleterious effects of aging and senescence thereby increasing susceptibility to cancer initiation in the ovary.
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Affiliation(s)
- Carlos Chacón
- Laboratorio de Genómica Aplicada, Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (C.C.); (C.M.)
| | - Constanza Mounieres
- Laboratorio de Genómica Aplicada, Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (C.C.); (C.M.)
| | - Sandra Ampuero
- Programa de Virología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
| | - Ulises Urzúa
- Laboratorio de Genómica Aplicada, Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (C.C.); (C.M.)
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16
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Li Y, Cheng C, Wang H, Zhou L, Yang J, Zhang Y, Li H, Zhou D. Distribution, toxicity, and impacts of nano-biochar in mice following dietary exposure: Insights into environmental risks and mammalian effects. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 338:122652. [PMID: 37783417 DOI: 10.1016/j.envpol.2023.122652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/04/2023]
Abstract
Nano-biochar is a novel material with emerging applications in various fields, including agriculture and environmental remediation. The potential risks of nano-biochar (N-BC) in the food chain necessitate further investigation. We studied the distribution and toxicity of N-BC in mice through dietary exposure. Using Balb/c mice, we assessed N-BC accumulation in organs and its impact on vital organs. Isotope analysis showed significant accumulation of 13C-N-BC in the liver (53.1%-55.9%), kidneys (4.0%-5.9%), and blood (9.2%-13.6%), with lesser amounts in the intestines (0.8%-1.2%) and stool (28.0%-28.1%). N-BC induced liver damage, evident by increased oxidative stress markers and histopathological changes. It disrupted tight junction proteins in the intestine, potentially allowing systemic entry. N-BC also influenced gut microbiota composition and metabolites. Our study provides insights into N-BC's distribution, toxicity, and environmental risks, urging further research on its implications for mammalian health and the ecosystem.
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Affiliation(s)
- Yuliang Li
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China
| | - Cheng Cheng
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China; School of Applied Meteorology, Nanjing University of Information Science & Technology, Nanjing, 210044, PR China
| | - Hongyu Wang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China
| | - Lei Zhou
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China
| | - Jinlei Yang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China
| | - Yaosheng Zhang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China
| | - Hongbo Li
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China.
| | - Dongmei Zhou
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China.
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17
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Tao D, Guan B, Li H, Zhou C. Expression patterns of claudins in cancer. Heliyon 2023; 9:e21338. [PMID: 37954388 PMCID: PMC10637965 DOI: 10.1016/j.heliyon.2023.e21338] [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: 12/19/2022] [Revised: 10/17/2023] [Accepted: 10/19/2023] [Indexed: 11/14/2023] Open
Abstract
Claudins are four-transmembrane proteins, which were found in tight junctions. They maintain cell barriers and regulate cell differentiation and proliferation. They are involved in maintaining cellular polarity and normal functions. Different claudins show different expression patterns. The expression level and localization of claudins are altered in various cancers. They promote or inhibit proliferation, invasion, and migration of cancer cells through multiple signaling pathways. Therefore, claudins may serve as diagnostic markers, novel therapeutic targets, and prognostic risk factors. The important roles of claudins in cancer aroused our great interest. In the present review, we provide a summary of insights into expression patterns of claudins in cancer, which is more comprehensive and provides new ideas for further research.
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Affiliation(s)
- Daoyu Tao
- Department of Pathology, The Second Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Bingxin Guan
- Department of Pathology, The Second Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Hui Li
- Department of Pathology, The Second Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Chengjun Zhou
- Department of Pathology, The Second Hospital of Shandong University, Jinan, 250012, Shandong, China
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18
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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.
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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.
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19
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Pan C, Xu A, Ma X, Yao Y, Zhao Y, Wang C, Chen C. Research progress of Claudin-low breast cancer. Front Oncol 2023; 13:1226118. [PMID: 37904877 PMCID: PMC10613467 DOI: 10.3389/fonc.2023.1226118] [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: 05/20/2023] [Accepted: 09/26/2023] [Indexed: 11/01/2023] Open
Abstract
Claudin-low breast cancer (CLBC) is a subgroup of breast cancer discovered at the molecular level in 2007. Claudin is one of the primary proteins that make up tight junctions, and it plays crucial roles in anti-inflammatory and antitumor responses as well as the maintenance of water and electrolyte balance. Decreased expression of claudin results in the disruption of tight junction structures and the activation of downstream signaling pathways, which can lead to tumor formation. The origin of Claudin-low breast cancer is still in dispute. Claudin-low breast cancer is characterized by low expression of Claudin3, 4, 7, E-cadherin, and HER2 and high expression of Vimentin, Snai 1/2, Twist 1/2, Zeb 1/2, and ALDH1, as well as stem cell characteristics. The clinical onset of claudin-low breast cancer is at menopause age, and its histological grade is higher. This subtype of breast cancer is more likely to spread to lymph nodes than other subtypes. Claudin-low breast cancer is frequently accompanied by increased invasiveness and a poor prognosis. According to a clinical retrospective analysis, claudin-low breast cancer can achieve low pathological complete remission. At present, although several therapeutic targets of claudin-low breast cancer have been identified, the effective treatment remains in basic research stages, and no animal studies or clinical trials have been designed. The origin, molecular biological characteristics, pathological characteristics, treatment, and prognosis of CLBC are extensively discussed in this article. This will contribute to a comprehensive understanding of CLBC and serve as the foundation for the individualization of breast cancer treatment.
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Affiliation(s)
- Chenglong Pan
- Department of Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- Kunming Medical University, Kunming, Yunnan, China
| | - Anqi Xu
- Kunming Medical University, Kunming, Yunnan, China
- Department of Anesthesia, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Xiaoling Ma
- Department of Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- Kunming Medical University, Kunming, Yunnan, China
| | - Yanfei Yao
- Department of Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- Kunming Medical University, Kunming, Yunnan, China
| | - Youmei Zhao
- Department of Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- Kunming Medical University, Kunming, Yunnan, China
| | - Chunyan Wang
- Department of Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Ceshi Chen
- Academy of Biomedical Engineering, Kunming Medical University, Kunming, Yunnan, China
- The Third Affiliated Hospital, Kunming Medical University, Kunming, Yunnan, China
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20
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Sun Z, Yan T, Jiang H, Cai J, Zhu X, Chen Q. Claudin-3 facilitates the progression and mediates the tumorigenic effects of TGF-β in glioblastoma multiforme. Med Oncol 2023; 40:268. [PMID: 37578554 DOI: 10.1007/s12032-023-02136-0] [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: 05/03/2023] [Accepted: 07/18/2023] [Indexed: 08/15/2023]
Abstract
Glioblastoma multiforme (GBM) is a significantly malignant and lethal brain tumor with an average survival time of less than 12 months. Several researches had shown that Claudin-3 (CLDN3) is overexpressed in various cancers and might be important in their growth and spread. In this study, we used qRT-PCR, western blotting, immunohistochemistry, and immunofluorescence staining assays to investigate the expression levels of various proteins. To explore the proliferation abilities of GBM cells, we conducted the CCK-8 and EdU-DNA formation assays. Wound healing and transwell assays were used to investigate the capacities of invasion and migration of GBM cells. Additionally, we constructed an intracranial xenograft model of GBM to study the in vivo role of CLDN3. Our study devoted to investigate the function of CLDN3 in the pathogenesis and progression of GBM. Our study revealed that CLDN3 was upregulated in GBM and could stimulate tumor cell growth and epithelial-mesenchymal transition (EMT) in both laboratory and animal models. We also discovered that CLDN3 expression could be triggered by transforming growth factor-β (TGF-β) and reduced by specific inhibitors of the TGF-β signaling pathway, such as ITD-1. Further analysis revealed that increased CLDN3 levels enhanced TGF-β-induced growth and EMT in GBM cells, while reducing CLDN3 levels weakened these effects. Our study demonstrated the function of CLDN3 in facilitating GBM growth and metastasis and indicated its involvement in the tumorigenic effects of TGF-β. Developing specific inhibitors of CLDN3 might, therefore, represent a promising new approach for treating this devastating disease.
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Affiliation(s)
- Zhiqiang Sun
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Tengfeng Yan
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Institute of Neuroscience, Nanchang University, Nanchang, China
| | - Hongxiang Jiang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Jiayang Cai
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Xiwei Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Qianxue Chen
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
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21
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Takasawa A, Takasawa K, Murata M, Osanai M, Sawada N. Emerging roles of transmembrane-type tight junction proteins in cancers. Pathol Int 2023; 73:331-340. [PMID: 37449777 DOI: 10.1111/pin.13349] [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: 04/19/2023] [Accepted: 06/06/2023] [Indexed: 07/18/2023]
Abstract
Tight junctions (TJs) are the most apical components of the cell-cell adhesion machinery in epithelial and endothelial cells and they play essential roles in homeostasis. Recent studies have revealed that aberrant expression of tight junction proteins (TJPs) is frequently observed in various type of cancers. Here we review cancer-associated aberrant expression of TJPs with focus on transmembrane-type TJPs including claudins, junctional adhesion molecule-A (JAM-A), and occludin. Some transmembrane-type TJPs are upregulated at the early neoplastic stage and their expression persists during dedifferentiation. Aberrant expression of TJPs contributes to proliferation, invasion, and dysregulated signaling of cancer cells. In addition to an increase in their expression level, their localization is altered from a TJ-restricted pattern to distribution throughout the whole cell membrane, making them suitable as therapeutic targets. Extracellular domains of transmembrane-type TJPs can be approached by target drugs not only from the lumen side (apical side) but also from the extracellular matrix side (basal side), including blood vessels. Aberrantly expressed TJPs are potential useful diagnostic markers as well as therapeutic targets for cancers.
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Affiliation(s)
- Akira Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kumi Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masaki Murata
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Diagnostic Pathology, Tokeidai Memorial Hospital, Sapporo, Japan
| | - Makoto Osanai
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Norimasa Sawada
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
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22
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Zhu J, Jiang Q. Twist1‑mediated transcriptional activation of Claudin‑4 promotes cervical cancer cell migration and invasion. Oncol Lett 2023; 26:335. [PMID: 37427351 PMCID: PMC10326656 DOI: 10.3892/ol.2023.13921] [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: 02/18/2023] [Accepted: 05/25/2023] [Indexed: 07/11/2023] Open
Abstract
Claudin-4, a member of the claudin multigene family, participates in events associated with mesenchymal-like activity of cancerous cells. Claudin-4 expression is upregulated in cervical cancer tissue compared with that in adjoining non-neoplastic tissue. However, the mechanisms that regulate Claudin-4 expression in cervical cancer are poorly understood. Moreover, whether Claudin-4 contributes to the migration and invasion of cervical cancer cells remains unclear. By western blotting, reverse transcription-qPCR, bioinformatics analysis, dual-luciferase reporter assay, chromatin immunoprecipitation assay, wound healing assay and Transwell migration/invasion assay, the present study confirmed that Claudin-4 was a downstream target of Twist1, a helix-loop-helix transcriptional factor, the activity of which has a positive correlation with Claudin-4 expression. Mechanistically, Twist1 directly binds to Claudin-4 promoter, resulting in the transactivation of expression. The depletion of the Twist1-binding E-Box1 domain on Claudin-4 promoter via CRISPR-Cas9 knockout system downregulates Claudin-4 expression and suppresses the ability of cervical cancer cells to migrate and invade by elevating E-cadherin levels and lowering N-cadherin levels. Following activation by transforming growth factor-β, Twist1 induces Claudin-4 expression, thus enhancing migration and invasion of cervical cancer cells. In summary, the present data suggested that Claudin-4 was a direct downstream target of Twist1 and served a critical role in promoting Twist1-mediated cervical cancer cell migration and invasion.
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Affiliation(s)
- Jiaqi Zhu
- Department of Gynecology, Beilun People's Hospital, Beilun Branch of The First Affiliated Hospital, School of Medicine, Zhejiang University, Ningbo, Zhejiang 315826, P.R. China
| | - Qi Jiang
- Department of Obstetrics, Beilun People's Hospital, Beilun Branch of The First Affiliated Hospital, School of Medicine, Zhejiang University, Ningbo, Zhejiang 315826, P.R. China
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23
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Wu K, Liu M, Wang H, Rajput SA, Al Zoubi OM, Wang S, Qi D. Effect of zearalenone on aflatoxin B1-induced intestinal and ovarian toxicity in pregnant and lactating rats. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 258:114976. [PMID: 37148750 DOI: 10.1016/j.ecoenv.2023.114976] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 04/12/2023] [Accepted: 05/01/2023] [Indexed: 05/08/2023]
Abstract
Aflatoxin B1 (AFB1) and zearalenone (ZEN) cause serious damage to mammals, but few studies have investigated the impacts of these toxins on pregnant and lactating mammals. This study investigated the effects of ZEN on AFB1-induced intestinal and ovarian toxicity in pregnant and lactating rats. Based on the results, AFB1 reduces the digestion, absorption, and antioxidant capacity in the intestine, increases intestinal mucosal permeability, destroys intestinal mechanical barriers, and increases pathogenic bacteria' relative abundances. Simultaneously, ZEN can exacerbate the intestinal injury caused by AFB1. The intestines of the offspring were also damaged, but the damage was less severe than that observed for the dams. While AFB1 activates various signalling pathways in the ovary and affects genes related to endoplasmic reticulum stress, apoptosis, and inflammation, ZEN may exacerbate or antagonize the AFB1 toxicity on gene expression in the ovary through key node genes and abnormally expressed genes. Our study found that mycotoxins can not only directly damage the ovaries and affect gene expression in the ovaries but can also impact ovarian health by disrupting intestinal microbes. Mycotoxins are an important environmental pathogenic factor for intestinal and ovarian disease in pregnancy and lactation mammals.
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Affiliation(s)
- Kuntan Wu
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Minjie Liu
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Huanbin Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Shahid Ali Rajput
- Department of Animal Feed and Production, Faculty of Veterinary and Animal Sciences, Muhammad Nawaz Shareef University of Agriculture, Multan 60000, Pakistan
| | - Omar Mahmoud Al Zoubi
- Biology Department, Faculty of Science Yanbu, Taibah University, Yanbu El-Bahr 46423, Saudi Arabia
| | - Shuai Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; Shenzhen Institute of Nutrition and Health, Huazhong Agricultural University, Wuhan 430070, China; Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China.
| | - Desheng Qi
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
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24
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Fujiwara-Tani R, Mori S, Ogata R, Sasaki R, Ikemoto A, Kishi S, Kondoh M, Kuniyasu H. Claudin-4: A New Molecular Target for Epithelial Cancer Therapy. Int J Mol Sci 2023; 24:5494. [PMID: 36982569 PMCID: PMC10051602 DOI: 10.3390/ijms24065494] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/10/2023] [Accepted: 03/10/2023] [Indexed: 03/16/2023] Open
Abstract
Claudin-4 (CLDN4) is a key component of tight junctions (TJs) in epithelial cells. CLDN4 is overexpressed in many epithelial malignancies and correlates with cancer progression. Changes in CLDN4 expression have been associated with epigenetic factors (such as hypomethylation of promoter DNA), inflammation associated with infection and cytokines, and growth factor signaling. CLDN4 helps to maintain the tumor microenvironment by forming TJs and acts as a barrier to the entry of anticancer drugs into tumors. Decreased expression of CLDN4 is a potential marker of epithelial-mesenchymal transition (EMT), and decreased epithelial differentiation due to reduced CLDN4 activity is involved in EMT induction. Non-TJ CLDN4 also activates integrin beta 1 and YAP to promote proliferation, EMT, and stemness. These roles in cancer have led to investigations of molecular therapies targeting CLDN4 using anti-CLDN4 extracellular domain antibodies, gene knockdown, clostridium perfringens enterotoxin (CPE), and C-terminus domain of CPE (C-CPE), which have demonstrated the experimental efficacy of this approach. CLDN4 is strongly involved in promoting malignant phenotypes in many epithelial cancers and is regarded as a promising molecular therapeutic target.
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Affiliation(s)
- Rina Fujiwara-Tani
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
| | - Shiori Mori
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
| | - Ruiko Ogata
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
| | - Rika Sasaki
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
| | - Ayaka Ikemoto
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
| | - Shingo Kishi
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
| | - Masuo Kondoh
- Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, 6-1 Yamadaoka, Suita 565-0871, Japan;
| | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
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25
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Gogola-Mruk J, Krawczyk K, Marynowicz W, Rokita M, Nimpsz S, Ptak A. Bisphenols S and F drive ovarian granulosa cell tumor invasion via a metabolic switch. Toxicol Lett 2023; 375:39-47. [PMID: 36584861 DOI: 10.1016/j.toxlet.2022.12.011] [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: 10/17/2022] [Revised: 12/06/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022]
Abstract
Alterations in the metabolism of cancer cells are crucial for tumor growth and progression. However, the mechanism whereby environmental pollutants such as bisphenols F (BPF) and S (BPS) affect glucose metabolism through the glycolytic pathway, and therefore influence tumor progression, are unclear. Both bisphenols are endocrine-disrupting molecules that are used in plastics. As a consequence of their widespread use, these compounds have been detected in various human body fluids. Thus, hormone-sensitive cancers, such as ovarian cancers, are exposed to these compounds. In the present study, we aimed to determine the effects of the concentrations of BPS and BPF found in body fluids on the cell viability, glucose uptake, glycolysis, oxygen consumption, and invasion by the adult ovarian granulosa cell tumor (AGCT) cell line. We found that BPS and BPF increased the glucose uptake, hexokinase activity, proliferation, and invasion of the cells at environmentally relevant concentrations. Furthermore, we identified an inhibition of glycolysis in parallel with an increase in oxygen consumption, suggesting a BPS/BPF-induced switch from aerobic glycolysis to mitochondrial respiration. In summary, these findings demonstrate a new mechanism through which BPS and BPF promote ovarian granulosa cell tumor progression by increasing energy production through mitochondrial respiration. Thus, both bisphenols induced a metabolic switch that appears to be a stimulus for AGCT progression.
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Affiliation(s)
- Justyna Gogola-Mruk
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387 Krakow, Poland
| | - Kinga Krawczyk
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387 Krakow, Poland
| | - Weronika Marynowicz
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387 Krakow, Poland
| | - Magdalena Rokita
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387 Krakow, Poland
| | - Samantha Nimpsz
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387 Krakow, Poland
| | - Anna Ptak
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387 Krakow, Poland.
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26
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Differential Expression of Claudin 1 and 4 in Basal Cell Carcinoma of the Skin. Dermatol Res Pract 2023; 2023:9936551. [PMID: 36714681 PMCID: PMC9883106 DOI: 10.1155/2023/9936551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/28/2022] [Accepted: 01/04/2023] [Indexed: 01/21/2023] Open
Abstract
Basal cell carcinoma (BCC) is the most common human malignancy. The biological behavior of this entity is remarkably indolent. Claudin plays an important role in tight junctions, regulating paracellular passage of variable substance including growth factors and maintaining the polarity of epithelia. Up- or downregulated claudin expression has been reported in many cancers. Nevertheless, claudin expression in BCC of the skin remains unclear. We therefore examined the status of claudin 1 and 4 expressions in BCC and adjacent normal skin by immunohistochemistry (IHC). Our IHC results demonstrated high claudin 1 expression and low claudin 4 expression in 33 of 34 lower-grade BCCs. In lower-grade BCC, claudin 1 was increased and claudin 4 was decreased compared with the normal skin. Claudin 1 was inclined to be highly expressed in the membrane and cytoplasm of tumour cells in the periphery of tumour nest. Conversely, almost all lower-grade BCCs (33/34) and one of two higher-grade BCC lacked or showed focal positivity for claudin 4. These results imply that the expression pattern is characteristics of lower-risk BCC. Interestingly, one of the two higher-grade BCCs demonstrated the converse expression patterns of claudins, with decreased claudin 1 and increased claudin 4. The combination of immunohistochemical claudin 1 and 4 expression may offer a useful ancillary tool for the pathological diagnosis of BCC. Furthermore, membranous and intracellular claudins may present future therapeutic targets for uncontrollable BCC.
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27
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Brunner N, Stein L, Amasheh S. Cellular Distribution Pattern of tjp1 (ZO-1) in Xenopus laevis Oocytes Heterologously Expressing Claudins. J Membr Biol 2023; 256:51-61. [PMID: 35737002 PMCID: PMC9884258 DOI: 10.1007/s00232-022-00251-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 06/02/2022] [Indexed: 02/07/2023]
Abstract
Epithelial barriers constitute a fundamental requirement in every organism, as they allow the separation of different environments and set boundaries against noxious and other adverse effectors. In many inflammatory and degenerative diseases, epithelial barrier function is impaired because of a disturbance of the paracellular seal. Recently, the Xenopus laevis oocyte has been established as a heterologous expression model for the analysis of transmembrane tight junction protein interactions and is currently considered to be a suitable screening model for barrier effectors. A prerequisite for this application is a physiological anchoring of claudins to the cytoskeleton via the major scaffolding protein tjp1 (tight junction protein 1, ZO-1). We have analyzed the oocyte model with regard to the interaction of heterologously expressed claudins and tjp1. Our experiments have revealed endogenous tjp1 expression in protein and mRNA analyses of unfertilized Xenopus laevis oocytes expressing human claudin 1 (CLDN1) to claudin 5 (CLDN5). The amphibian cell model can therefore be used for the analysis of claudin interactions.
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Affiliation(s)
- Nora Brunner
- Institute of Veterinary Physiology, Freie Universität Berlin, Oertzenweg 19b, 14163 Berlin, Germany
| | - Laura Stein
- Institute of Veterinary Physiology, Freie Universität Berlin, Oertzenweg 19b, 14163 Berlin, Germany
| | - Salah Amasheh
- Institute of Veterinary Physiology, Freie Universität Berlin, Oertzenweg 19b, 14163 Berlin, Germany
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28
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KLAAB ZEINAB, HASSAN AZIZA, ALBAQAMI JAWAHER, A. ALMALKI FAIZAH. The effect of natural products combination on MCF-7 cells exceeds tamoxifen therapeutic dose effects in vitro. BIOCELL 2023. [DOI: 10.32604/biocell.2023.026556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/10/2023]
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29
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Wang DW, Zhang WH, Danil G, Yang K, Hu JK. The role and mechanism of claudins in cancer. Front Oncol 2022; 12:1051497. [PMID: 36620607 PMCID: PMC9818346 DOI: 10.3389/fonc.2022.1051497] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/28/2022] [Indexed: 12/24/2022] Open
Abstract
Claudins are a tetraspan membrane protein multigene family that plays a structural and functional role in constructing tight junctions. Claudins perform crucial roles in maintaining cell polarity in epithelial and endothelial cell sheets and controlling paracellular permeability. In the last two decades, increasing evidence indicates that claudin proteins play a major role in controlling paracellular permeability and signaling inside cells. Several types of claudins are dysregulated in various cancers. Depending on where the tumor originated, claudin overexpression or underexpression has been shown to regulate cell proliferation, cell growth, metabolism, metastasis and cell stemness. Epithelial-to-mesenchymal transition is one of the most important functions of claudin proteins in disease progression. However, the exact molecular mechanisms and signaling pathways that explain why claudin proteins are so important to tumorigenesis and progression have not been determined. In addition, claudins are currently being investigated as possible diagnostic and treatment targets. Here, we discuss how claudin-related signaling pathways affect tumorigenesis, tumor progression, and treatment sensitivity.
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Affiliation(s)
- De-Wen Wang
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Han Zhang
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Galiullin Danil
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China,Central Research Laboratory, Bashkir State Medical University, Ufa, Russia
| | - Kun Yang
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jian-Kun Hu
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Jian-Kun Hu,
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30
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Yu Z, Ouyang L. Identification of prognosis-related hub genes of ovarian cancer through bioinformatics analyses and experimental verification. Medicine (Baltimore) 2022; 101:e30374. [PMID: 36086731 PMCID: PMC10980417 DOI: 10.1097/md.0000000000030374] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 07/21/2022] [Indexed: 11/25/2022] Open
Abstract
Ovarian cancer (OC) is a lethal and highly prevalent disease in women worldwide. The disease is often diagnosed in late stages, which leads to its rapid progression and low survival rate. This study aims to identify new prognostic genes for OC. Based on 2 datasets from the National Center for Biotechnology Information Gene Expression Omnibus public database, we constructed 2 Weighted Gene Co-expression Network Analysis networks. Then, we selected and intersected 2 key modules to screen key genes. Enrichment analyses were performed, and a protein-protein interaction network was constructed. The cytoHubba plugin of Cytoscape and survival analysis were used to screen hub genes related to prognosis. The expression of hub genes was analyzed by GEPIA and verified by quantitative Real-Time PCR. Gene alteration frequency analysis, gene set variation analysis, immune infiltration analysis, drug sensitivity analysis, tumor mutation burden, and neoantigen analyses were conducted to determine the prognostic value and molecular mechanisms of the hub genes. In total, 214 key genes were selected from 2 Weighted Gene Co-expression Network Analysis networks, and 3 hub genes, namely ALDH1A2, CLDN4, and GPR37, were identified as prognostic candidates through cytoHubba and survival analysis. Three hub genes were significantly associated with overall survival of OC patients. GEPIA and quantitative Real-Time PCR indicated that ALDH1A2 expression was significantly downregulated, while expression of CLDN4 and GPR37 was upregulated in OC samples compared with normal samples. CIBERSORT showed that 3 hub genes were closely associated with the infiltrating immune cells. GDSC showed that hub genes expression influenced IC50 values of chemotherapeutic drugs. OC patients with high expression of ALDH1A2 and CLDN4 had lower TMB and low ALDH1A2 expression could produce a larger number of neoantigens. In conclusion, the 3 hub genes (ALDH1A2, CLDN4 and GPR37) identified through bioinformatics analyses in the present study may serve as OC prognosis biomarkers. The study findings offer valuable insights into OC progression and mechanisms.
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Affiliation(s)
- Zhong Yu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ling Ouyang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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Hao S, Yang C, Song P, Shi H, Zou Y, Chen M, Wu X, Yin Y, Yu Z, Zhu W, Li M. CLDN4 promotes growth of acute myeloid leukemia cells via regulating AKT and ERK1/2 signaling. Biochem Biophys Res Commun 2022; 619:137-143. [PMID: 35760010 DOI: 10.1016/j.bbrc.2022.06.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/09/2022] [Accepted: 06/09/2022] [Indexed: 11/30/2022]
Abstract
Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults. The tight junction protein CLDN4 is closely related to the development of various epithelial cell carcinomas. However, whether CLDN4 contributes to AML development remains unclear. For the first time, we found that expression of CLDN4 is aberrantly up-regulated in AML cells. Knockdown of CLDN4 expression resulted in a dramatic decreased cell growth, elevated apoptosis of AML cells. Further, we revealed that knockdown of CLDN4 inhibits mRNA expression of PIK3R3 and MAP2K2, thus suppresses activation of AKT and ERK1/2. More importantly, activating AKT branch by SC79 partially compromised CLDN4 knockdown induced cell viability inhibition. In addition, we found that higher expression of CLDN4 is connected to worse survival and is an independent indicator of shorter disease free survival (DFS) in AML patients. Together, our results indicate that CLDN4 contributes to AML pathogenesis, and suggests that targeting CLDN4 is a promising option for AML treatment.
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Affiliation(s)
- Shiyu Hao
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China.
| | - Chunyan Yang
- The School of Dental Medicine, Binzhou Medical University, Yantai, 264003, China.
| | - Peng Song
- Institute of Integrated Medicine, Binzhou Medical University, Yantai, 264003, China.
| | - Hewen Shi
- Institute of Integrated Medicine, Binzhou Medical University, Yantai, 264003, China.
| | - Ying Zou
- Institute of Integrated Medicine, Binzhou Medical University, Yantai, 264003, China.
| | - Meiyang Chen
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China.
| | - Xingli Wu
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China.
| | - Yancun Yin
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China.
| | - Zhenhai Yu
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China.
| | - Weiwei Zhu
- Clinical Trial Agency, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, 264000, China.
| | - Minjing Li
- Institute of Integrated Medicine, Binzhou Medical University, Yantai, 264003, China.
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Feng S, Lou K, Zou X, Zou J, Zhang G. The Potential Role of Exosomal Proteins in Prostate Cancer. Front Oncol 2022; 12:873296. [PMID: 35747825 PMCID: PMC9209716 DOI: 10.3389/fonc.2022.873296] [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: 02/10/2022] [Accepted: 05/16/2022] [Indexed: 01/10/2023] Open
Abstract
Prostate cancer is the most prevalent malignant tumor in men across developed countries. Traditional diagnostic and therapeutic methods for this tumor have become increasingly difficult to adapt to today’s medical philosophy, thus compromising early detection, diagnosis, and treatment. Prospecting for new diagnostic markers and therapeutic targets has become a hot topic in today’s research. Notably, exosomes, small vesicles characterized by a phospholipid bilayer structure released by cells that is capable of delivering different types of cargo that target specific cells to regulate biological properties, have been extensively studied. Exosomes composition, coupled with their interactions with cells make them multifaceted regulators in cancer development. Numerous studies have described the role of prostate cancer-derived exosomal proteins in diagnosis and treatment of prostate cancer. However, so far, there is no relevant literature to systematically summarize its role in tumors, which brings obstacles to the later research of related proteins. In this review, we summarize exosomal proteins derived from prostate cancer from different sources and summarize their roles in tumor development and drug resistance.
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Affiliation(s)
- Shangzhi Feng
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated hospital of Gannan Medical University, Ganzhou, China
| | - Kecheng Lou
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated hospital of Gannan Medical University, Ganzhou, China
| | - Xiaofeng Zou
- Department of Urology, The First Affiliated hospital of Gannan Medical University, Ganzhou, China
- Institute of Urology, The First Affiliated Hospital of Ganna Medical University, Ganzhou, China
- Department of Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junrong Zou
- Department of Urology, The First Affiliated hospital of Gannan Medical University, Ganzhou, China
- Institute of Urology, The First Affiliated Hospital of Ganna Medical University, Ganzhou, China
- Department of Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, Ganzhou, Jiangxi, China
- *Correspondence: Junrong Zou, ; Guoxi Zhang,
| | - Guoxi Zhang
- Department of Urology, The First Affiliated hospital of Gannan Medical University, Ganzhou, China
- Institute of Urology, The First Affiliated Hospital of Ganna Medical University, Ganzhou, China
- Department of Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, Ganzhou, Jiangxi, China
- *Correspondence: Junrong Zou, ; Guoxi Zhang,
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Yang L, Chen X, Qian X, Zhang J, Wu M, Yu A. Comprehensive Analysis of the Transcriptome-Wide m6A Methylome in Endometrioid Ovarian Cancer. Front Oncol 2022; 12:844613. [PMID: 35280730 PMCID: PMC8904756 DOI: 10.3389/fonc.2022.844613] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/01/2022] [Indexed: 12/27/2022] Open
Abstract
Emerging studies have revealed that N6-methyladenosine modification is involved in the development of various cancers. However, the m6A modification pattern of endometrioid ovarian cancer (EOC) has not been demonstrated. In the present study, high-throughput sequencing combined with methylated RNA immunoprecipitation (MeRIP-seq) and RNA sequencing were used to obtain the transcriptome-wide m6A modifications of endometrioid ovarian cancer for the first time. The roles of methyltransferase-like 3 (METTL3) in EOC cell line COV362 were explored. In total, 39,237 m6A-modified peaks related to 17,082 genes were identified in the EOC group, and 52,848 m6A peaks representing 19,349 genes were detected in endometriosis group. Functional enrichment analysis revealed that m6A enriched genes were associated with tight junctions, cell adhesion molecules, platinum drug resistance, adherens junction, and more. METTL3 knockdown in the COV362 cells significantly decreased cell proliferation, promoted cell apoptosis, and induced cell cycle arrest at the G0/G1 phase. Our study presented the transcriptome-wide m6A modifications of endometrioid ovarian cancer for the first time and revealed various differentially expressed genes with methylated m6A modifications. This study may provide new directions for in-depth research of the underlying molecular mechanisms and signaling pathways of EOC development and progression.
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Affiliation(s)
- Li Yang
- Department of Gynecological Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Xin Chen
- Department of Gynecological Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Xiang Qian
- Department of Traditional Chinese Medicine, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Jiejie Zhang
- Department of Gynecological Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Meijuan Wu
- Department of Pathology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Aijun Yu
- Department of Gynecological Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
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Stalla FM, Astegiano M, Ribaldone DG, Saracco GM, Pellicano R. The small intestine: barrier, permeability and microbiota. Minerva Gastroenterol (Torino) 2022; 68:98-110. [PMID: 33267569 DOI: 10.23736/s2724-5985.20.02808-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
In recent years, there has been growing interest in the comprehension of the physiology of intestinal permeability and microbiota; and how these elements could influence the pathogenesis of diseases. The term intestinal permeability describes all the processes that allow the passage of molecules as water, electrolytes and nutrients through the intestinal barrier by the paracellular or the transcellular transport systems with several implications for self-tolerance and not-self immunity. An increased permeability might induce a more significant interaction of the immune system with unknown external antigens. This might favor the onset of several immune-related extra-intestinal diseases including coeliac disease, diabetes mellitus type 1, bronchial asthma and inflammatory bowel diseases. Furthermore, the intestinal permeability interacts every day with microbiota, the complex system of mutualistic inhabitants and commensal microorganisms living in the healthy gut. Microbiota is implicated in physiological functions by actively participating in digestion, absorption, synthesis of vitamins and protection from external aggressions. The critical site where these processes occur is the small intestine to which this updated review is dedicated. Understanding its anatomy, its barrier structure and permeability modulation and its microbiota composition is the essential skill to comprehend the complex pathogenesis of several - not only gastroenterological - diseases.
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Affiliation(s)
| | | | | | - Giorgio M Saracco
- Department of Medical Sciences, University of Turin, Turin, Italy
- Unit of Gastroenterology, Molinette Hospital, Turin, Italy
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Melatonin antagonizes ovarian aging via YTHDF2-MAPK-NF-κB pathway. Genes Dis 2022; 9:494-509. [PMID: 35224163 PMCID: PMC8843885 DOI: 10.1016/j.gendis.2020.08.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/29/2020] [Accepted: 08/16/2020] [Indexed: 11/22/2022] Open
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Feng J, Xu Y, Wei Z, Xia Y, Zhang H, Shen C, Wang P, Yan W, Fang D, Fang Y. Capsaicin inhibits migration and invasion via inhibiting epithelial-mesenchymal transition in esophageal squamous cell carcinoma by up-regulation of claudin-3 expression. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.104934] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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Claudins and Gastric Cancer: An Overview. Cancers (Basel) 2022; 14:cancers14020290. [PMID: 35053454 PMCID: PMC8773541 DOI: 10.3390/cancers14020290] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/02/2022] [Accepted: 01/03/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Gastric cancer (GC) is one of the most common cancers and the third leading cause of cancer deaths worldwide, with a high frequency of recurrence and metastasis, and a poor prognosis. This review presents novel biological and clinical significance of claudin (CLDN) expression in GC, especially CLDN18, and clinical trials centered around CLDN18.2. It also presents new findings for other CLDNs. Abstract Despite recent improvements in diagnostic ability and treatment strategies, advanced gastric cancer (GC) has a high frequency of recurrence and metastasis, with poor prognosis. To improve the treatment results of GC, the search for new treatment targets from proteins related to epithelial–mesenchymal transition (EMT) and cell–cell adhesion is currently being conducted. EMT plays an important role in cancer metastasis and is initiated by the loss of cell–cell adhesion, such as tight junctions (TJs), adherens junctions, desmosomes, and gap junctions. Among these, claudins (CLDNs) are highly expressed in some cancers, including GC. Abnormal expression of CLDN1, CLDN2, CLDN3, CLDN4, CLDN6, CLDN7, CLDN10, CLDN11, CLDN14, CLDN17, CLDN18, and CLDN23 have been reported. Among these, CLDN18 is of particular interest. In The Cancer Genome Atlas, GC was classified into four new molecular subtypes, and CLDN18–ARHGAP fusion was observed in the genomically stable type. An anti-CLDN18.2 antibody drug was recently developed as a therapeutic drug for GC, and the results of clinical trials are highly predictable. Thus, CLDNs are highly expressed in GC as TJs and are expected targets for new antibody drugs. Herein, we review the literature on CLDNs, focusing on CLDN18 in GC.
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Subhan A, Attia SA, P Torchilin V. Targeted siRNA nanotherapeutics against breast and ovarian metastatic cancer: a comprehensive review of the literature. Nanomedicine (Lond) 2021; 17:41-64. [PMID: 34930021 DOI: 10.2217/nnm-2021-0207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Metastasis is considered the major cause of unsuccessful cancer therapy. The metastatic development requires tumor cells to leave their initial site, circulate in the blood stream, acclimate to new cellular environments at a remote secondary site and endure there. There are several steps in metastasis, including invasion, intravasation, circulation, extravasation, premetastatic niche formation, micrometastasis and metastatic colonization. siRNA therapeutics are appreciated for their usefulness in treatment of cancer metastasis. However, siRNA therapy as a single therapy may not be a sufficient option for control of metastasis. By combining siRNA with targeting, functional agents or small-molecule drugs have shown potential effects that enhance therapeutic effectiveness. This review addresses multidrug resistance and metastasis in breast and ovarian cancers and highlights drug-delivery strategies using siRNA therapeutics.
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Affiliation(s)
- Abdus Subhan
- Department of Chemistry, ShahJalal University of Science & Technology, Sylhet 3114, Bangladesh
| | - Sara Aly Attia
- Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA
| | - Vladimir P Torchilin
- Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.,Department of Oncology, Radiotherapy & Plastic Surgery, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia
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SPTBN2 regulated by miR-424-5p promotes endometrial cancer progression via CLDN4/PI3K/AKT axis. Cell Death Dis 2021; 7:382. [PMID: 34887379 PMCID: PMC8660803 DOI: 10.1038/s41420-021-00776-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/16/2021] [Accepted: 11/29/2021] [Indexed: 12/24/2022]
Abstract
Endometrioid Endometrial Cancer (EEC) is the main subtype of endometrial cancer. In our study, we demonstrated that SPTBN2 was significantly overexpressed in EEC tissues. Upregulated SPTBN2 expression was positively associated with poor prognosis. In addition, we testified that SPTBN2 knockdown significantly inhibited the proliferation, migration, and invasion of EEC cells. Moreover, we found SPTBN2 could interact with CLDN4 to promote endometrial cancer metastasis via PI3K/AKT pathway. Then we further demonstrated that CLDN4 is upregulated in EEC and promotes EEC metastasis. CLDN4 overexpression could partially reversed the decrease in cell migration and invasion caused by SPTBN2 downregulation. In addition, we confirmed that SPTBN2 was a target of miR-424-5p, which plays a tumor suppressor in endometrial cancer. Rescue experiments showed that inhibition of SPTBN2 could partially reverse the effect of miR-424-5p in EEC. In conclusion, we demonstrated that by acting as a significant target of miR-424-5p, SPTBN2 could interact with CLDN4 to promote endometrial cancer metastasis via PI3K/AKT pathway in EEC. Our study revealed the prognostic and metastatic effects of SPTBN2 in EEC, suggesting that SPTBN2 could serve as a prognostic biomarker and a target for metastasis therapy.
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Cao D, Li J, Wang X, Wang J, Liu R, Lu J, Liu Q, Luo Y. The effect of AAV-mediated downregulation of Claudin-3 on the development of mouse retinal vasculature. Exp Eye Res 2021; 213:108836. [PMID: 34774487 DOI: 10.1016/j.exer.2021.108836] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 10/31/2021] [Accepted: 11/08/2021] [Indexed: 12/24/2022]
Abstract
Retinal vascular development is a very tightly regulated and organized process of vessel formation and regression to generate the mature vasculature system. Claudin-3 has been found to be required for the normal development of the neural retina and its vessels in zebrafish in our recent study. In this study, we investigated whether Claudin-3 played a role in the development of mouse retinal vasculature. Immunofluorescent staining was performed to detect the expression and localization of Claudin-3 in the mouse retina. Intravitreal injection of a recombinant adeno-associated virus (AAV) expressing a short hairpin RNA targeting Claudin-3 mRNA was performed to down-regulate Claudin-3 expression in retina in neonatal (Postnatal Day 3, P3) C57BL/6J mice. Retinal vessels were examined by isolectin B4 immunofluorescent staining on the whole-mount retinas and frozen retinal sections at P10. The apoptotic retinal ganglion cells (RGCs) were measured by TdT-mediated dUTP nick-end labelling (TUNEL) staining. Vascular endothelial growth factor A (VEGF-A) expression was detected by immunofluorescent staining. The protein levels of Claudin-3, VEGF-A and B cell lymphoma 2 (Bcl-2) were evaluated by Western blot at P7, P10 and P14. We found that Claudin-3 mainly expressed in the RGCs and progressively increased during the retinal development. The AAV-mediated downregulation of Claudin-3 at P3 impeded the development of retinal deep vascularization of P10 mouse, but without effect on the development of the retinal superficial plexus. Claudin-3 knockdown increased RGC apoptosis and reduced the expression of VEGF-A and Bcl-2 in the retinas. These results suggested that the downregulation of Claudin-3 induced RGC apoptosis and impeded the mouse retinal vascular development by downregulating the levels of VEGF-A and Bcl-2.
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Affiliation(s)
- Di Cao
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China
| | - Jing Li
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China
| | - Xiao Wang
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China
| | - Jing Wang
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China
| | - Ruyuan Liu
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China
| | - Jing Lu
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China
| | - Qiuhui Liu
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China
| | - Yan Luo
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China.
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Rao X, Jiang J, Liang Z, Zhang J, Zhuang Z, Qiu H, Luo H, Weng N, Wu X. Down-Regulated CLDN10 Predicts Favorable Prognosis and Correlates With Immune Infiltration in Gastric Cancer. Front Genet 2021; 12:747581. [PMID: 34721537 PMCID: PMC8548647 DOI: 10.3389/fgene.2021.747581] [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: 07/26/2021] [Accepted: 09/28/2021] [Indexed: 12/24/2022] Open
Abstract
Background: CLDN10, an important component of the tight junctions of epithelial cells, plays a crucial role in a variety of tumors. The effect of CLDN10 expression in gastric cancer, however, has yet to be elucidated. Methods: Differential expression of CLDN10 at the mRNA and protein levels was evaluated using Oncomine, ULCAN, HPA and TIMER2.0 databases. Real-time polymerase chain reaction (RT-PCR) was utilized to further verify the expression of CLDN10 in vitro. Correlations between CLDN10 expression and clinical outcomes of gastric cancer were explored by Kaplan-Meier Plotter. Gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) were performed via LinkedOmics and GeneMANIA. The correlations between CLDN10 expression and immune cell infiltration and somatic copy number alternations (SCNA) in gastric cancer were explored by TIMER2.0 and GEPIA2.0. Results: CLDN10 expression was lower in gastric cancer compared to adjacent normal tissues, and associated with better prognosis. CLDN10 also showed significant differences at different T stages, Lauren classification, treatments and HER2 status. PPI and GSEA analysis showed that CLDN10 might be involved in signal transmission, transmembrane transport and metabolism. In some major immune cells, low expression of CLDN10 was associated with increased levels of immune cell infiltration. In addition, it was found that different SCNA status in CLDN10 might affect the level of immune cell infiltration. Furthermore, the expression of CLDN10 was significantly associated with the expression of several immune cell markers, especially B cell markers, follicular helper T cell (Tfh) markers and T cell exhaustion markers. Conclusion: Down-regulated CLDN10 was associated with better overall survival (OS) in gastric cancer. And CLDN10 may serve as a potential prognostic biomarker and correlate to immune infiltration levels in gastric cancer.
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Affiliation(s)
- XiongHui Rao
- Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - JianLong Jiang
- Department of Gastrointestinal Surgery, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - ZhiHao Liang
- Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - JianBao Zhang
- Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - ZheHong Zhuang
- Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - HuaiYu Qiu
- Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Huixing Luo
- Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Nuoqing Weng
- Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Xiaobin Wu
- Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
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Bekusova V, Droessler L, Amasheh S, Markov AG. Effects of 1,2-Dimethylhydrazine on Barrier Properties of Rat Large Intestine and IPEC-J2 Cells. Int J Mol Sci 2021; 22:10278. [PMID: 34638619 PMCID: PMC8508681 DOI: 10.3390/ijms221910278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 11/26/2022] Open
Abstract
Colon cancer is accompanied by a decrease of epithelial barrier properties, which are determined by tight junction (TJ) proteins between adjacent epithelial cells. The aim of the current study was to analyze the expression of TJ proteins in a rat model of 1,2-dimethylhydrazine (DMH)-induced colorectal cancer, as well as the barrier properties and TJ protein expression of IPEC-J2 cell monolayers after incubation with DMH. Transepithelial electrical resistance and paracellular permeability for sodium fluorescein of IPEC-J2 were examined by an epithelial volt/ohm meter and spectrophotometry. The expression and localization of TJ proteins were analyzed by immunoblotting and immunohistochemistry. In the colonic tumors of rats with DMH-induced carcinogenesis, the expression of claudin-3 and -4 was significantly increased compared to controls. The transepithelial electrical resistance of IPEC-J2 cells increased, while paracellular permeability for sodium fluorescein decreased, accompanied by an increased expression of claudin-4. The increase of claudin-4 in rat colon after chronic DMH exposure was consistent with the acute effect of DMH on IPEC-J2 cells, which may indicate an essential role of this protein in colorectal cancer development.
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Affiliation(s)
- Viktoria Bekusova
- Department of General Physiology, Faculty of Biology, Saint Petersburg State University, Universitetskaya nab., 7–9, 199034 Saint Petersburg, Russia;
| | - Linda Droessler
- Institute of Veterinary Physiology, Department of Veterinary Medicine, Freie Universität Berlin, 14163 Berlin, Germany; (L.D.); (S.A.)
| | - Salah Amasheh
- Institute of Veterinary Physiology, Department of Veterinary Medicine, Freie Universität Berlin, 14163 Berlin, Germany; (L.D.); (S.A.)
| | - Alexander G. Markov
- Department of General Physiology, Faculty of Biology, Saint Petersburg State University, Universitetskaya nab., 7–9, 199034 Saint Petersburg, Russia;
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The Role and Clinical Interest of Extracellular Vesicles in Pregnancy and Ovarian Cancer. Biomedicines 2021; 9:biomedicines9091257. [PMID: 34572444 PMCID: PMC8464910 DOI: 10.3390/biomedicines9091257] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/14/2021] [Accepted: 09/14/2021] [Indexed: 12/21/2022] Open
Abstract
Ovarian cancer and pregnancy are two states in which the host immune system is exposed to novel antigens. Indeed, both the tumor and placenta must invade tissues, remodel vasculature to establish a robust blood supply, and evade detection by the immune system. Interestingly, tumor and placenta tissue use similar mechanisms to induce these necessary changes. One mediator is emerging as a key player in invasion, vascular remodeling, and immune evasion: extracellular vesicles (EVs). Many studies have identified EVs as a key mediator of cell-to-cell communication. Specifically, the cargo carried by EVs, which includes proteins, nucleic acids, and lipids, can interact with cells to induce changes in the target cell ranging from gene expression to migration and metabolism. EVs can promote cell division and tissue invasion, immunosuppression, and angiogenesis which are essential for both cancer and pregnancy. In this review, we examine the role of EVs in ovarian cancer metastasis, chemoresistance, and immune modulation. We then focus on the role of EVs in pregnancy with special attention on the vascular remodeling and regulation of the maternal immune system. Lastly, we discuss the clinical utility of EVs as markers and therapeutics for ovarian cancer and pre-eclampsia.
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Imada EL, Sanchez DF, Dinalankara W, Vidotto T, Ebot EM, Tyekucheva S, Franco GR, Mucci LA, Loda M, Schaeffer EM, Lotan T, Marchionni L. Transcriptional landscape of PTEN loss in primary prostate cancer. BMC Cancer 2021; 21:856. [PMID: 34311724 PMCID: PMC8314517 DOI: 10.1186/s12885-021-08593-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/06/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND PTEN is the most frequently lost tumor suppressor in primary prostate cancer (PCa) and its loss is associated with aggressive disease. However, the transcriptional changes associated with PTEN loss in PCa have not been described in detail. In this study, we highlight the transcriptional changes associated with PTEN loss in PCa. METHODS Using a meta-analysis approach, we leveraged two large PCa cohorts with experimentally validated PTEN and ERG status by Immunohistochemistry (IHC), to derive a transcriptomic signature of PTEN loss, while also accounting for potential confounders due to ERG rearrangements. This signature was expanded to lncRNAs using the TCGA quantifications from the FC-R2 expression atlas. RESULTS The signatures indicate a strong activation of both innate and adaptive immune systems upon PTEN loss, as well as an expected activation of cell-cycle genes. Moreover, we made use of our recently developed FC-R2 expression atlas to expand this signature to include many non-coding RNAs recently annotated by the FANTOM consortium. Highlighting potential novel lncRNAs associated with PTEN loss and PCa progression. CONCLUSION We created a PCa specific signature of the transcriptional landscape of PTEN loss that comprises both the coding and an extensive non-coding counterpart, highlighting potential new players in PCa progression. We also show that contrary to what is observed in other cancers, PTEN loss in PCa leads to increased activation of the immune system. These findings can help the development of new biomarkers and help guide therapy choices.
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Affiliation(s)
- Eddie Luidy Imada
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
| | | | - Wikum Dinalankara
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thiago Vidotto
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ericka M Ebot
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Svitlana Tyekucheva
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Gloria Regina Franco
- Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Lorelei Ann Mucci
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Massimo Loda
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | | | - Tamara Lotan
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Luigi Marchionni
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Tabariès S, Annis MG, Lazaris A, Petrillo SK, Huxham J, Abdellatif A, Palmieri V, Chabot J, Johnson RM, Van Laere S, Verhoef C, Hachem Y, Yumeen S, Meti N, Omeroglu A, Altinel G, Gao ZH, Yu ASL, Grünhagen DJ, Vermeulen P, Metrakos P, Siegel PM. Claudin-2 promotes colorectal cancer liver metastasis and is a biomarker of the replacement type growth pattern. Commun Biol 2021; 4:657. [PMID: 34079064 PMCID: PMC8172859 DOI: 10.1038/s42003-021-02189-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 04/29/2021] [Indexed: 02/07/2023] Open
Abstract
Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that Claudin-2 is functionally required for colorectal cancer liver metastasis and that Claudin-2 expression in primary colorectal cancers is associated with poor overall and liver metastasis-free survival. We have examined the role of Claudin-2, and other claudin family members, as potential prognostic biomarkers of the desmoplastic and replacement histopathological growth pattern associated with colorectal cancer liver metastases. Immunohistochemical analysis revealed higher Claudin-2 levels in replacement type metastases when compared to those with desmoplastic features. In contrast, Claudin-8 was highly expressed in desmoplastic colorectal cancer liver metastases. Similar observations were made following immunohistochemical staining of patient-derived xenografts (PDXs) that we have established, which faithfully retain the histopathology of desmoplastic or replacement type colorectal cancer liver metastases. We provide evidence that Claudin-2 status in patient-derived extracellular vesicles may serve as a relevant prognostic biomarker to predict whether colorectal cancer patients have developed replacement type liver metastases. Such a biomarker will be a valuable tool in designing optimal treatment strategies to better manage patients with colorectal cancer liver metastases. Tabariès et al. describe that claudin 2 is a promoter of colorectal cancer liver metastasis. Furthermore, high Claudin-2 expression is associated with shorter time to liver-specific recurrence and is a biomarker of replacement type CRC liver metastases.
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Affiliation(s)
- Sébastien Tabariès
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada. .,Departments of Medicine, McGill University, Montréal, QC, Canada.
| | - Matthew G Annis
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada.,Departments of Medicine, McGill University, Montréal, QC, Canada
| | - Anthoula Lazaris
- Department of Surgery, McGill University Health Center, Montréal, QC, Canada
| | | | - Jennifer Huxham
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada.,Departments of Medicine, McGill University, Montréal, QC, Canada
| | - Amri Abdellatif
- Department of Surgery, McGill University Health Center, Montréal, QC, Canada
| | - Vincent Palmieri
- Department of Surgery, McGill University Health Center, Montréal, QC, Canada
| | - Jaclyn Chabot
- Department of Surgery, McGill University Health Center, Montréal, QC, Canada
| | - Radia M Johnson
- Department of Bioinformatics & Computational Biology, Genentech Inc., South San Francisco, CA, USA
| | - Steven Van Laere
- University of Antwerp, Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO), Edegem, Antwerp, Belgium.,Translational Cancer Research Unit, Oncologisch Centrum GZA, Wilrijk, Antwerp, Belgium
| | - Cornelis Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Yasmina Hachem
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada
| | - Sara Yumeen
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada
| | - Nicholas Meti
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada
| | - Atilla Omeroglu
- Department of Pathology, McGill University Health Center, Montréal, QC, Canada
| | - Gulbeyaz Altinel
- Department of Pathology, McGill University Health Center, Montréal, QC, Canada
| | - Zu-Hua Gao
- Department of Pathology, McGill University Health Center, Montréal, QC, Canada
| | - Alan S L Yu
- Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Dirk J Grünhagen
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Peter Vermeulen
- University of Antwerp, Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO), Edegem, Antwerp, Belgium.,Translational Cancer Research Unit, Oncologisch Centrum GZA, Wilrijk, Antwerp, Belgium
| | - Peter Metrakos
- Department of Surgery, McGill University Health Center, Montréal, QC, Canada
| | - Peter M Siegel
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada. .,Departments of Medicine, McGill University, Montréal, QC, Canada.
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Tavsan Z, Ayar Kayalı H. EpCAM-claudin-tetraspanin-modulated ovarian cancer progression and drug resistance. Cell Adh Migr 2021; 14:57-68. [PMID: 32091301 PMCID: PMC7757826 DOI: 10.1080/19336918.2020.1732761] [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] [Indexed: 12/15/2022] Open
Abstract
Alterations of cell adhesion are involved in cancer progression, but the mechanisms underlying the progression and cell adhesion have remained poorly understood. Focusing on the complex between EpCAM, claudins and tetraspanins, we described a sequence of events by which of the molecules associate each other in ovarian cancer. The interactions between molecules were evaluated by immunoprecipitations and then immunoblotting. To identify the effects of complex formation on the ovarian cancer progression, the different types of ovarian cancer cell lines were compared. In this study, we report the identification of the EpCAM-claudin-4 or -7-CD82 complex in the ovarian cancer progression and metastasis in vitro. Additionally, we demonstrated palmitoylation and intra- or extra-cellular regions are critically required for the complex formation. These results represent the first direct evidence for the link between the dynamism of cell adhesion molecules and ovarian cancer progression.
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Affiliation(s)
- Zehra Tavsan
- Chemistry Department, The Graduate School of Natural and Applied Science, Dokuz Eylül University, İzmir, Turkey.,Izmir Biomedicine and Genome Center, Izmir, Turkey
| | - Hülya Ayar Kayalı
- Izmir Biomedicine and Genome Center, Izmir, Turkey.,Chemistry Department, Science Faculty, Dokuz Eylül University, Izmir, Turkey.,International Biomedicine and Genome Institute, Dokuz Eylül University, Izmir, Turkey
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Kolchakova D, Moten D, Batsalova T, Dzhambazov B. Tight Junction Protein Claudin-12 Is Involved in Cell Migration during Metastasis. Biomolecules 2021; 11:biom11050636. [PMID: 33922921 PMCID: PMC8145645 DOI: 10.3390/biom11050636] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/12/2022] Open
Abstract
Claudins are important components of the tight junctions determining barrier properties, cell polarity, and paracellular permeability. Although many functions of claudins in cancer cells have not been elucidated, recent studies have shown that claudins play an important role in cell migration and metastasis. Loss of epithelial/endothelial integrity, disruption of tight junctions, and increased paracellular leakage are often observed during metastasis. The aim of our study was to investigate the involvement of claudin-12 in the process of cell migration as well as to evaluate the possibility of using this protein as a specific target for the regulation of tumorigenesis. We have performed immunocytochemistry assays to detect the expression of claudin-12 in different epithelial/endothelial human cell lines, and selected three (A549, LS180, and HeLa) for further experiments. Using transwell chamber migration assays, we found that anti-claudin-12 antibodies inhibited both the migration and proliferation of claudin-12 expressing cells (A549 and LS180), inducing apoptosis, as well as the migration capacity of Jurkat cells through the monolayers formed from A549 or LS180 cells. In addition, co-cultures of Jurkat cells on monolayers from A549 or LS180 cells, in the presence of synthetic claudin-12 peptides representing the extracellular domains of the claudin-12 protein, also reduced the number of migrated Jurkat cells. Two of the tested peptides (p5 and p6) almost completely blocked the migration of Jurkat cells. All migrated Jurkat cells expressed LFA-1 and CD62L, but not CD44. Thus, claudin-12 is a suitable biomarker for tumor progression and metastasis and an attractive target for antitumor therapy. Anti-claudin-12 antibodies and competitive inhibitory peptides could be useful in the therapeutic approach applied to cancer metastasis in tissues expressing claudin-12.
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Horev A, Shalom G, Weintraub AY, Freud T, Cohen AD. Atopic Dermatitis and Infertility: A Nationwide Retrospective Cohort Study. Dermatology 2021; 238:313-319. [PMID: 33882489 DOI: 10.1159/000515600] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 02/24/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Given that common pathophysiological factors play a role in atopic dermatitis (AD) and infertility, we assumed that the 2 conditions might demonstrate an epidemiological association. Large-scale epidemiological data on this topic are lacking. OBJECTIVES The aim of this work was to evaluate the potential association between AD and infertility in a broad community-based population. METHODS A nationwide retrospective cohort study was conducted, analyzing the association between AD and infertility. We compared AD patients diagnosed by a dermatologist between 2002 and 2018 and a matched control group. The study population was subdivided according to age into adults (age ≥18 years) and children (age <18 years), and was further subdivided according to AD severity, classified as either mild or moderate-to-severe according to AD-related drug use and healthcare services utilization. RESULTS The study included 127,150 patients with AD and 127,071 comparison enrollees. AD was associated with a higher prevalence of infertility than that of the control group (1.4 and 1.1%, respectively). The prevalence of infertility, per 1,000 patient-years, was increased in patients with AD compared to that of the control group (2.17 and 1.7, respectively). Multivariate analysis for infertility demonstrated that AD was a key risk factor for infertility in both males and females with mild AD and moderate-to-severe AD. CONCLUSION A significant association between AD and infertility was observed. This association suggests that infertility may be an additional manifestation of AD. Further studies are warranted to evaluate the impact of AD management in the setting of infertility and vice versa.
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Affiliation(s)
- Amir Horev
- Pediatric Dermatology Service, Soroka University Medical Center, Beer Sheva, Israel.,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Guy Shalom
- Clalit Health Services, Tel Aviv, Israel.,Siaal Research Center for Family Medicine and Primary Care, Division of Community Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Adi Y Weintraub
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.,Department of Obstetrics and Gynecology, Soroka University Medical Center, Beer Sheva, Israel
| | - Tamar Freud
- Siaal Research Center for Family Medicine and Primary Care, Division of Community Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Arnon D Cohen
- Siaal Research Center for Family Medicine and Primary Care, Division of Community Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.,Department of Quality Measurements and Research, Chief Physician's Office, Clalit Health Services, Tel Aviv, Israel
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49
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Sun Z, Li H, Li Y, Qiao J. Lactobacillus salivarius, a Potential Probiotic to Improve the Health of LPS-Challenged Piglet Intestine by Alleviating Inflammation as Well as Oxidative Stress in a Dose-Dependent Manner During Weaning Transition. Front Vet Sci 2020; 7:547425. [PMID: 33392276 PMCID: PMC7772421 DOI: 10.3389/fvets.2020.547425] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 11/23/2020] [Indexed: 12/23/2022] Open
Abstract
Intestinal health is a critical issue for piglets during their weaning transition period. Previous reports have emphasized the promise of distinct probiotics in improving the enteric health. Here in this research, a newly isolated Lactobacillus salivarius strain was pretreated to Lipopolysaccharide (LPS)-challenged piglets and its association with integrity of the intestinal barrier coupled with effective dosage were expected to be signified. In the present study, 72 piglets (Landrace × Yorkshiere × Duroc) were randomly allotted to four groups, each group with six replicates. The subjects in the control group were provided with basal diet while those in other tested groups with extra 0.05, 0.1, and 0.2% L. salivarius, respectively. Fourteen days later, LPS was intraperitoneally injected and sodium pentobarbital was then delivered to euthanize those LPS-challenged piglets. An increase of average daily gain and body weight along with an apparent decline of diarrhea rate were observed in L. salivarius-treated groups. Both 0.1 and 0.2% L. salivarius supplement in total diet had the capability to markedly elevate levels of CAT, GSH-Px, SOD, anti-inflammatory cytokine from the serum as well as tight junction proteins (Claudin-1, Occludin, and ZO-1) extracted from intestine in LPS-challenged piglets. These changes were accompanied by the obvious downregulation of D-lactic acid, DAO, MDA and pro-inflammatory mediators in the serum, including IL-1β, IL-6, IFN-γ, and TNF-α. Meanwhile, the expression levels of TLR2 and TLR4 in spleen and mesenteric lymph nodes were significantly lower whereas the oxidation-related gene, ho-1 was up-regulated with L. salivarius administration. Our findings suggested that relatively high dose L. salivarius (0.1–0.2%) could regulate the progression of inflammatory response and oxidative stress when individuals were exposed to LPS, thus probably offering valuable assistance in restoring barrier function and improving overall performance.
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Affiliation(s)
- Zeyang Sun
- Tianjin Key Laboratory of Conservation and Utilization of Animal Diversity, College of Life Sciences, Tianjin Normal University, Tianjin, China
| | - Haihua Li
- Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin, China
| | - Yupeng Li
- College of Life Sciences, Tianjin Institute of Animal Husbandry and Veterinary Medicine, Tianjin, China
| | - Jiayun Qiao
- Tianjin Key Laboratory of Conservation and Utilization of Animal Diversity, College of Life Sciences, Tianjin Normal University, Tianjin, China
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Role of tight junctions in the epithelial-to-mesenchymal transition of cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1863:183503. [PMID: 33189716 DOI: 10.1016/j.bbamem.2020.183503] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/15/2022]
Abstract
The epithelial-mesenchymal transition (EMT) is an essential step in cancer progression. Epithelial cells possess several types of cell-cell junctions, and tight junctions are known to play important roles in maintaining the epithelial program. EMT is characterized by a loss of epithelial markers, including E-cadherin and tight junction proteins. Somewhat surprisingly, the evidence is accumulating that upregulated expression of tight junction proteins plays an important role in the EMT of cancer cells. Tight junctions have distinct tissue-specific and cancer-specific regulatory mechanisms, enabling them to play different roles in EMT. Tight junctions and related signaling pathways are attractive targets for cancer treatments; signal transduction inhibitors and monoclonal antibodies for tight junction proteins may be used to suppress EMT, invasion, and metastasis. Here we review the role of bicellular and tricellular tight junction proteins during EMT. Further investigation of regulatory mechanisms of tight junctions during EMT in cancer cells will inform the development of biomarkers for predicting prognosis as well as novel therapies.
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