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Breideband L, Wächtershäuser KN, Sarkar R, Puspathasan M, Stelzer EH, Pampaloni F. Gravitational forces and matrix stiffness modulate the invasiveness of breast cancer cells in bioprinted spheroids. Mater Today Bio 2025; 31:101640. [PMID: 40124331 PMCID: PMC11930500 DOI: 10.1016/j.mtbio.2025.101640] [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: 10/13/2024] [Revised: 01/29/2025] [Accepted: 03/03/2025] [Indexed: 03/25/2025] Open
Abstract
The progression of breast cancer is influenced by the stiffness of the extracellular matrix (ECM), which becomes stiffer as cancer advances due to increased collagen IV and laminin secretion by cancer-associated fibroblasts. Intriguingly, breast cancer cells cultivated in two-dimensions exhibit a less aggressive behavior when exposed to weightlessness, or microgravity conditions. This study aims to elucidate the interplay between matrix stiffness and microgravity on breast cancer progression. For this purpose, three-dimensional spheroids of breast cancer cell lines (MCF-7 and MDA-MB-231) were formed. These spheroids were subsequently bioprinted in hydrogels of varying stiffness, obtained by the mixing of gelatin methacrylate and poly(ethylene) glycol diacrylate mixed at different ratios. The constructs were printed with a custom stereolithography (SLA) bioprinter converted from a low-cost, commercially available 3D printer. These bioprinted structures, encapsulating breast cancer spheroids, were then placed in a clinostat (microgravity simulation device) for a duration of seven days. Comparative analyses were conducted between objects cultured under microgravity and standard earth gravity conditions. Protein expression was characterized through fluorescent microscopy, while gene expression of MCF-7 constructs was analyzed via RNA sequencing. Remarkably, the influence of a stiffer ECM on the protein and gene expression levels of breast cancer cells could be modulated and sometimes even reversed in microgravity conditions. The study's findings hold implications for refining therapeutic strategies for advanced breast cancer stages - an array of genes involved in reversing aggressive or even metastatic behavior might lead to the discovery of new compounds that could be used in a clinical setting.
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Affiliation(s)
- Louise Breideband
- Biological Sciences (IZN), Buchman Institute for Molecular Life Sciences (BMLS), Goethe-Universität Frankfurt am Main, DE-Frankfurt am Main, Germany
| | - Kaja Nicole Wächtershäuser
- Biological Sciences (IZN), Buchman Institute for Molecular Life Sciences (BMLS), Goethe-Universität Frankfurt am Main, DE-Frankfurt am Main, Germany
| | - Ryan Sarkar
- Biological Sciences (IZN), Buchman Institute for Molecular Life Sciences (BMLS), Goethe-Universität Frankfurt am Main, DE-Frankfurt am Main, Germany
| | - Melosha Puspathasan
- Biological Sciences (IZN), Buchman Institute for Molecular Life Sciences (BMLS), Goethe-Universität Frankfurt am Main, DE-Frankfurt am Main, Germany
| | - Ernst H.K. Stelzer
- Biological Sciences (IZN), Buchman Institute for Molecular Life Sciences (BMLS), Goethe-Universität Frankfurt am Main, DE-Frankfurt am Main, Germany
| | - Francesco Pampaloni
- Biological Sciences (IZN), Buchman Institute for Molecular Life Sciences (BMLS), Goethe-Universität Frankfurt am Main, DE-Frankfurt am Main, Germany
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Hashemi MH, Moaiery H, Nikkhoo B, Zamani F, Mahmoodian S, Soheili M, Soleimani F, Bahramirad Z, KhademErfan M, Ghaderi B, Keyhani ME, Nasseri S. Molecular Dynamics of Breast Cancer Subtypes: The Role of FAM83H-AS1 Long Non-coding RNA in Breast Cancer Metastasis. Breast Cancer Res Treat 2025; 210:645-659. [PMID: 39891867 DOI: 10.1007/s10549-024-07603-4] [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: 08/23/2024] [Accepted: 12/26/2024] [Indexed: 02/03/2025]
Abstract
PURPOSE Breast cancer is the leading cause of cancer-related deaths in women. Long non-coding RNAs (lncRNAs) play an important role in gene regulation and are emerging as major players in cancer biology, This study investigates the expression of FAM83H-AS1 in breast cancer and its association with tumor grade, hormone receptors, pathological diagnosis, and molecular markers related to epithelial-mesenchymal transition (EMT). METHODS The expression of the long non-coding RNA FAM83H-AS1 in 80 breast cancer patients was assessed using quantitative real-time PCR (qRT-PCR). Clinical significance was evaluated through histopathological and immunohistochemical analyses. The associations of FAM83H-AS1 expression with tumor grade, hormone receptor status, and epithelial-mesenchymal transition (EMT) markers were analyzed. RESULTS A positive correlation was observed between tumor grade and the expression of FAM83H-AS1, N-cadherin, E-cadherin, and vimentin, whereas FGF-18, TGF-β, and β-catenin were downregulated. Estrogen receptor positivity was associated with CLDN1 and Snail-1 expression, while HER2 positivity was linked to vimentin expression. Snail-1 expression correlated positively with Ki-67 levels. All genes except MMP2 were significantly associated with lymph node metastasis. Comparative analysis revealed significant differences in FGF-18, TGF-β, N-cadherin, β-catenin, and MMP2 expression among luminal A, luminal B, and triple-negative breast cancer (TNBC) subtypes. FAM83H-AS1 was upregulated in TNBC compared to luminal A and inflammatory breast cancer (IBC), although the difference was not statistically significant. TNBC Exhibited upregulation of TGF-β, N-cadherin, and β-catenin, suggesting their role in the aggressive nature of this subtype. In contrast, MMP2 was downregulated in TNBC compared to IBC, potentially indicating a suppressive role in tumor invasion in TNBC. Vimentin was upregulated in IBC compared to luminal A, indicating its involvement in IBC's aggressive behavior. MMP2 and MMP9 were significantly upregulated in IBC compared to luminal A. CONCLUSION FAM83H-AS1 shows potential as a prognostic biomarker and therapeutic target, especially in TNBC and IBC, with implications for personalized breast cancer treatment strategies. Its expression correlates with tumor grade, hormone receptor status, and EMT markers, suggesting a role in cancer progression and metastasis.
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Affiliation(s)
- Mohammad Hossein Hashemi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, 6617957146, Iran
| | - Hassan Moaiery
- Department of Surgery, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Department of Pathology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Bahram Nikkhoo
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, 6617957146, Iran
- Lung Diseases and Allergy Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Fatemeh Zamani
- Lung Diseases and Allergy Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Soma Mahmoodian
- Department of Epidemiology and Biostatistics, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Marzieh Soheili
- College of Pharmacy, Western New England University, Springfield, MA, USA
| | - Farzad Soleimani
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, 6617957146, Iran
| | - Zhila Bahramirad
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, 6617957146, Iran
| | - MohammadBagher KhademErfan
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, 6617957146, Iran
| | - Bayazid Ghaderi
- Cancer & Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Erfan Keyhani
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, 6617957146, Iran
| | - Sherko Nasseri
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, 6617957146, Iran.
- Cancer & Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
- Department of Molecular Medicine and Medical Biotechnology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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Liu H, Ding S, Lyu W, Lu S, Liu X. Chito-oligosaccharide impairs the proliferation, invasion and migration of pancreatic cancer cells. Discov Oncol 2025; 16:298. [PMID: 40069446 PMCID: PMC11896950 DOI: 10.1007/s12672-025-02015-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 02/24/2025] [Indexed: 03/15/2025] Open
Abstract
BACKGROUND Chito-oligosaccharide (COS) is a low molecular weight polymer obtained by degrading chitosan through special enzymatic technology, with good water solubility and high biological activity. It is also the only positively charged cationic basic amino oligosaccharide in nature. Studies have confirmed that COS has antitumour effect, but research on its effect on pancreatic cancer (PC) remains limited and unclear. This study aimed to explore the effects of COS on PC cells (PANC-1 and MIAPaCa-2). METHOD We used different concentrations of COS to treat PC cells and conducted Cell Counting Kit-8, wound-healing, and transwell assays to evaluate the proliferation, invasion, and migration ability of PC cells, respectively. Western blot was conducted to assess the expression levels of epithelial-mesenchymal transition (EMT) related markers. RESULT The proliferation, invasion, and migration ability of PC cells (PANC-1 and MIAPaCa-2) gradually decreased in a manner dependent on COS concentration. COS at 10 mg/mL exerted the strongest inhibitory effect on the two PC cell lines. At 10 mg/mL, the proliferative activity was 60.61% ± 5.25% and 64.02% ± 4.96%, respectively; the invasive ability was (18.67 ± 4.416) and (31.33 ± 3.162), respectively; and the cell-migration ability was 26.83% ± 0.442% and 17.66% ± 0.647%, respectively. The expression levels of N-cadherin and vimentin were significantly downregulated in PANC-1 cells (0.198 ± 0.047 and 0.225 ± 0.038, respectively) and MIAPaCa-2 cells (0.214 ± 0.094 and 0.214 ± 0.094, respectively) at 10 mg/mL, respectively. Conversely, E-cadherin was upregulated (0.460 ± 0.037 and 0.491 ± 0.047, respectively). Compared with control group, the differences were statistically significant. CONCLUSION The upregulation of E-cadherin and the downregulation of vimentin and N-cadherin suggested that the specific mechanism of COS in PC may be related to EMT. This study provided a new direction for PC treatment.
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Affiliation(s)
- Han Liu
- Department of Gastroenterology, General Hospital of Northern Theatre Command, 83 Wenhua Road, Shenyang, 110840, Liaoning, China
| | - Siyuan Ding
- Department of Gastroenterology, General Hospital of Northern Theatre Command, 83 Wenhua Road, Shenyang, 110840, Liaoning, China
| | - Weiyan Lyu
- Department of Gastroenterology, General Hospital of Northern Theatre Command, 83 Wenhua Road, Shenyang, 110840, Liaoning, China
| | - Shengyan Lu
- Department of Gastroenterology, General Hospital of Northern Theatre Command, 83 Wenhua Road, Shenyang, 110840, Liaoning, China
| | - Xu Liu
- Department of Gastroenterology, General Hospital of Northern Theatre Command, 83 Wenhua Road, Shenyang, 110840, Liaoning, China.
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Isaguliants M, Zhitkevich A, Petkov S, Gorodnicheva T, Mezale D, Fridrihsone I, Kuzmenko Y, Kostyushev D, Kostyusheva A, Gordeychuk I, Bayurova E. Enzymatic activity of HIV-1 protease defines migration of tumor cells in vitro and enhances their metastatic activity in vivo. Biochimie 2025; 228:32-43. [PMID: 39128490 DOI: 10.1016/j.biochi.2024.08.009] [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: 05/08/2024] [Revised: 07/09/2024] [Accepted: 08/08/2024] [Indexed: 08/13/2024]
Abstract
Overexpression of aspartic proteases, as cathepsin D, is an independent marker of poor prognosis in breast cancer, correlated with the incidence of clinical metastasis. We aimed to find if HIV-1 aspartic protease (PR) can play a similar role. Murine adenocarcinoma 4T1luc2 cells were transduced with lentivirus encoding inactivated drug-resistant PR, generating subclones PR20.1 and PR20.2. Subclones were assessed for production of reactive oxygen species (ROS), expression of epithelial-mesenchymal transition (EMT) factors, and in vitro migratory activity in the presence or absence of antioxidant N-acetyl cysteine and protease inhibitors. Tumorigenic activity was evaluated by implanting cells into BALB/c mice and following tumor growth by calipering and bioluminescence imaging in vivo, and metastases, by organ imaging ex vivo. Both subclones expressed PR mRNA, and PR20.2, also the protein detected by Western blotting. PR did not induce production of ROS, and had no direct effect on cell migration rate, however, treatment with inhibitors of drug-resistant PR suppressed the migratory activity of both subclones. Furthermore, expression of N-cadherin and Vimentin in PR20.2 cells and their migration were enhanced by antioxidant treatment. Sensitivity of in vitro migration to protease inhibitors and to antioxidant, known to restore PR activity, related the effects to the enzymatic activity of PR. In vivo, PR20.2 cells demonstrated higher tumorigenic and metastatic activity than PR20.1 or parental cells. Thus, HIV-1 protease expressed in breast cancer cells determines their migration in vitro and metastatic activity in vivo. This effect may aggravate clinical course of cancers in people living with HIV-1.
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Affiliation(s)
- M Isaguliants
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177, Stockholm, Sweden.
| | - A Zhitkevich
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, 108819, Moscow, Russia.
| | - S Petkov
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177, Stockholm, Sweden.
| | - T Gorodnicheva
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, 117997, Moscow, Russia.
| | - D Mezale
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177, Stockholm, Sweden.
| | - I Fridrihsone
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177, Stockholm, Sweden.
| | - Y Kuzmenko
- Engelhardt Institute of Molecular Biology, Academy of Sciences of the Russian Federation, 119991, Moscow, Russia.
| | - D Kostyushev
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, 119991, Moscow, Russia.
| | - A Kostyusheva
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, 119991, Moscow, Russia.
| | - I Gordeychuk
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177, Stockholm, Sweden; Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, 108819, Moscow, Russia.
| | - E Bayurova
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177, Stockholm, Sweden; Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, 108819, Moscow, Russia.
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Pallathadka H, Jabir M, Rasool KH, Hanumanthaiah M, Sharma N, Pramanik A, Rab SO, Jawad SF, Oghenemaro EF, Mustafa YF. siRNA-based therapy for overcoming drug resistance in human solid tumours; molecular and immunological approaches. Hum Immunol 2025; 86:111221. [PMID: 39700968 DOI: 10.1016/j.humimm.2024.111221] [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: 08/10/2024] [Revised: 11/25/2024] [Accepted: 12/09/2024] [Indexed: 12/21/2024]
Abstract
RNA interference (RNAi) is a primordial biological process that protects against external intrusion. SiRNA has the potential to selectively silence disease-related genes in a sequence-specific way, thus offering a promising therapeutic approach. The efficacy of siRNA-based therapies in cancer treatment has gained significant recognition due to multiple studies demonstrating its ability to effectively suppress cancer cells' growth and multiplication. Moreover, siRNA-based medicines have shown considerable promise in enhancing the sensitivity of cancer cells to chemotherapy and other treatment methods by suppressing genes that play a role in the development of drug resistance. Exploring and identifying functional genes linked to cancer cell characteristics and drug resistance is crucial for developing effective siRNAs for cancer treatment and advancing targeted and personalized therapeutics. Targeting and silencing genes in charge of resistance mechanisms, such as those involved in drug efflux, cell survival, or DNA repair, is possible with siRNA therapy in the context of drug resistance, especially cancer. Through inhibiting these genes, siRNA therapy can prevent resistance and restore the efficacy of traditional medications. This review addresses the potential of siRNAs in addressing drug resistance in human tumours, opening up new possibilities in cancer therapy. This review article offers a non-systematic summary of how different siRNA types contribute to cancer cells' treatment resistance. Using pertinent keywords, sources were chosen from reliable databases, including PubMed, Scopus, and Google Scholar. The review covered essential papers in this area and those that mainly addressed the function of siRNA in drug resistance. The articles examined in connection with the title of this review were primarily published from 2020 onward and are based on in vitro studies. Furthermore, this article examines the potential barriers and prospective perspectives of siRNA therapies.
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Affiliation(s)
| | - Majid Jabir
- Department of Applied Sciences, University of Technology, Iraq
| | | | - Malathi Hanumanthaiah
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Neha Sharma
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjeri - 140307, Mohali, Punjab, India
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University Dehradun, Uttarakhand, India
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Sabrean Farhan Jawad
- Department of Biochemistry, College of Science, Al-Mustaqbal University, 51001 Babil, Iraq.
| | - Enwa Felix Oghenemaro
- Department of Pharmaceutical Microbiology, Delta State University, Faculty of Pharmacy, PMB 1 Abraka, Delta State, Nigeria
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
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Xie B, Chen Q, Dai Z, Jiang C, Sun J, Guan A, Chen X. Prognostic significance of a 3-gene ferroptosis-related signature in lung cancer via LASSO analysis and cellular functions of UBE2Z. Comput Biol Chem 2024; 113:108192. [PMID: 39243550 DOI: 10.1016/j.compbiolchem.2024.108192] [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: 06/05/2024] [Revised: 08/07/2024] [Accepted: 08/28/2024] [Indexed: 09/09/2024]
Abstract
Ferroptosis is a newly identified form of non-apoptotic programmed cell death resulting from iron-dependent lipid peroxidation. It is controlled by integrated oxidation and antioxidant systems. Ferroptosis exerts a crucial effect on the carcinogenesis of several cancers, including pulmonary cancer. Herein, a ferroptosis-associated gene signature for lung cancer prognosis and diagnosis was identified using integrative bioinformatics analyses. From the FerrDB database, 256 ferroptotic regulators and markers were identified. Of these, 25 exhibited differential expression between lung cancer and non-cancerous samples, as evidenced by the GSE19804 and GSE7670 datasets from the GEO database. Utilizing LASSO Cox regression analysis on TCGA-LUAD data, a potent 3-gene risk signature comprising CAV1, RRM2, and EGFR was established. This signature adeptly differentiates various survival outcomes in lung cancer patients, including overall survival and disease-specific intervals. Based on the 3-gene risk signature, lung cancer patients were categorized into high-risk and low-risk groups. Comparative analysis revealed 69 differentially expressed genes between these groups, with UBE2Z significantly associated with overall survival in TCGA-LUAD. UBE2Z was found to be upregulated in LUAD tissues and cells compared to normal controls. Functionally, the knockdown of UBE2Z curtailed aggressive behaviors in LUAD cells, including viability, migration, and invasion. Moreover, this knockdown led to a decrease in the mesenchymal marker vimentin while elevating the epithelial marker E-cadherin within LUAD cell lines. In conclusion, the ferroptosis-associated 3-gene risk signature effectively differentiates prognosis and clinical features in patients with lung cancer. UBE2Z was identified through this model, and it is upregulated in LUAD samples. Its knockdown inhibits aggressive cellular behaviors, suggesting UBE2Z's potential as a therapeutic target for lung cancer treatment.
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Affiliation(s)
- Bin Xie
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Qiong Chen
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ziyu Dai
- Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Chen Jiang
- Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Jingyi Sun
- Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Anqi Guan
- Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xi Chen
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
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Vakili S, Behrooz AB, Whichelo R, Fernandes A, Emwas AH, Jaremko M, Markowski J, Los MJ, Ghavami S, Vitorino R. Progress in Precision Medicine for Head and Neck Cancer. Cancers (Basel) 2024; 16:3716. [PMID: 39518152 PMCID: PMC11544984 DOI: 10.3390/cancers16213716] [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: 09/25/2024] [Revised: 10/24/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
This paper presents a comprehensive comparative analysis of biomarkers for head and neck cancer (HNC), a prevalent but molecularly diverse malignancy. We detail the roles of key proteins and genes in tumourigenesis and progression, emphasizing their diagnostic, prognostic, and therapeutic relevance. Our bioinformatic validation reveals crucial genes such as AURKA, HMGA2, MMP1, PLAU, and SERPINE1, along with microRNAs (miRNA), linked to HNC progression. OncomiRs, including hsa-miR-21-5p, hsa-miR-31-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-196a-5p, and hsa-miR-200c-3p, drive tumourigenesis, while tumour-suppressive miRNAs like hsa-miR-375 and hsa-miR-145-5p inhibit it. Notably, hsa-miR-155-3p correlates with survival outcomes in addition to the genes RAI14, S1PR5, OSBPL10, and METTL6, highlighting its prognostic potential. Future directions should focus on leveraging precision medicine, novel therapeutics, and AI integration to advance personalized treatment strategies to optimize patient outcomes in HNC care.
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Affiliation(s)
- Sanaz Vakili
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0J9, Canada; (S.V.); (A.B.B.); (R.W.)
| | - Amir Barzegar Behrooz
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0J9, Canada; (S.V.); (A.B.B.); (R.W.)
| | - Rachel Whichelo
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0J9, Canada; (S.V.); (A.B.B.); (R.W.)
- Department of Medical Sciences, Institute of Biomedicine—iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Alexandra Fernandes
- Guelph College of Biological Science, University of Guelph, Guelph, ON N1G 2W1, Canada;
| | - Abdul-Hamid Emwas
- Core Lab of NMR, King Abdullah University of Science and Technology (KAUST), Thuwal, Makkah 23955-6900, Saudi Arabia;
| | - Mariusz Jaremko
- Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Makkah 23955-6900, Saudi Arabia;
| | - Jarosław Markowski
- Department of Laryngology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland;
| | - Marek J. Los
- Biotechnology Center, Silesian University of Technology, 44-100 Gliwice, Poland;
| | - Saeid Ghavami
- Academy of Silesia, Faculty of Medicine, Rolna 43, 40-555 Katowice, Poland
- Paul Albrechtsen Research Institute, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
| | - Rui Vitorino
- Guelph College of Biological Science, University of Guelph, Guelph, ON N1G 2W1, Canada;
- LAQV/REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, 4099-002 Porto, Portugal
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8
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He X, Ren E, Dong L, Yuan P, Zhu J, Liu D, Wang J. Contribution of PKS+ Escherichia coli to colon carcinogenesis through the inhibition of exosomal miR-885-5p. Heliyon 2024; 10:e37346. [PMID: 39315148 PMCID: PMC11417213 DOI: 10.1016/j.heliyon.2024.e37346] [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: 07/22/2023] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/25/2024] Open
Abstract
Objectives About 90 % of all colorectal cancer (CRC) fatalities are caused by the metastatic spread of primary tumors, which is closely correlated with patient survival and spreads by circulating tumor cells (CTCs). The epithelial-mesenchymal transition (EMT) that characterizes CTCs is associated with a poor prognosis. Organotropic metastasis is dictated by the transmission of miRNAs by cancer-derived exosomes. The purpose of this research is to examine PKS + E's function. Coli in CRC metastases and exosomal miR-885-5p suppression. Methods A cohort of 100 patients (50 CRC, 50 healthy) underwent colonoscopy screenings from February 2018 to August 2021. Exosomes were isolated using ultracentrifugation, and exosomal miRNA was analyzed using sequencing and qPCR. Results Among the patients, 40 tested positive for E. coli (12 CRC, 23 healthy). Serotyping revealed that 68.57 % harbored the PKS gene. Exosomal miR-885-5p levels were significantly altered in CRC patients with PKS + E. coli. Intriguingly, our findings indicate that exosomes derived from EMT-CRC cells did not affect miR-885-5p synthesis in HUVECs. Moreover, we observed that the levels of miR-885-5p in both exosomes and the total CRC-conditioned medium were comparable upon isolation of exosomes from CRC cells. What's more, an increased expression of miR-558-5p within the tumors, and the group that received exosome treatment, as well as the EMT-HCT116 group, exhibited a higher occurrence of distant metastasis. Conclusion PKS + E. By inhibiting exosomal miR-885-5p, coli is linked to CRC metastases, offering a possible target for therapeutic intervention.
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Affiliation(s)
- Xiaoming He
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Enbo Ren
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Lujia Dong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Pengfei Yuan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Jiaxin Zhu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Dechun Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Jianguang Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
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9
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Kotsifaki A, Maroulaki S, Karalexis E, Stathaki M, Armakolas A. Decoding the Role of Insulin-like Growth Factor 1 and Its Isoforms in Breast Cancer. Int J Mol Sci 2024; 25:9302. [PMID: 39273251 PMCID: PMC11394947 DOI: 10.3390/ijms25179302] [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: 07/30/2024] [Revised: 08/25/2024] [Accepted: 08/25/2024] [Indexed: 09/15/2024] Open
Abstract
Insulin-like Growth Factor-1 (IGF-1) is a crucial mitogenic factor with important functions in the mammary gland, mainly through its interaction with the IGF-1 receptor (IGF-1R). This interaction activates a complex signaling network that promotes cell proliferation, epithelial to mesenchymal transition (EMT) and inhibits apoptosis. Despite extensive research, the precise molecular pathways and intracellular mechanisms activated by IGF-1, in cancer, remain poorly understood. Recent evidence highlights the essential roles of IGF-1 and its isoforms in breast cancer (BC) development, progression, and metastasis. The peptides that define the IGF-1 isoforms-IGF-1Ea, IGF-1Eb, and IGF-1Ec-act as key points of convergence for various signaling pathways that influence the growth, metastasis and survival of BC cells. The aim of this review is to provide a detailed exami-nation of the role of the mature IGF-1 and its isoforms in BC biology and their potential use as possible therapeutical targets.
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Affiliation(s)
- Amalia Kotsifaki
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Sousanna Maroulaki
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Efthymios Karalexis
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Martha Stathaki
- Surgical Clinic, "Elena Venizelou" General Hospital, 11521 Athens, Greece
| | - Athanasios Armakolas
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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10
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Wei X, Xiong H, Zhou Y, Chen X, Yang W. Tracking epithelial-mesenchymal transition in breast cancer cells based on a multiplex electrochemical immunosensor. Biosens Bioelectron 2024; 258:116372. [PMID: 38735081 DOI: 10.1016/j.bios.2024.116372] [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: 01/31/2024] [Revised: 04/15/2024] [Accepted: 04/29/2024] [Indexed: 05/14/2024]
Abstract
Epithelial-mesenchymal transition (EMT) promotes tumor cell infiltration and metastasis. Tracking the progression of EMT could potentially indicate early cancer metastasis. A key characteristic of EMT is the dynamic alteration in the molecular levels of E-cadherin and N-cadherin. Traditional assays have limited sensitivity and multiplexing capabilities, relying heavily on cell lysis. Here, we developed a multiplex electrochemical biosensor to concurrently track the upregulation of N-cadherin expression and reduction of E-cadherin in breast cancer cells undergoing EMT. Small-sized gold nanoparticles (Au NPs) tagged with redox probes (thionin or amino ferrocene) and bound to two types of antibodies were used as distinguishable signal tags. These tags specifically recognized E-cadherin and N-cadherin proteins on the tumor cell surface without cross-reactivity. The diphenylalanine dipeptide (FF)/chitosan (CS)/Au NPs (FF-CS@Au) composites with high surface area and good biocompatibility were used as the sensing platforms for efficiently fixing cells and recording the dynamic changes in electrochemical signals of surface proteins. The electrochemical immunosensor allowed for simultaneous monitoring of E- and N-cadherins on breast cancer cell surfaces in a single run, enabling tracking of the EMT dynamic process for up to 60 h. Furthermore, the electrochemical detection results are consistent with Western blot analysis, confirming the reliability of the methodology. This present work provides an effective, rapid, and low-cost approach for tracking the EMT process, as well as valuable insights into early tumor metastasis.
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Affiliation(s)
- Xue Wei
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China
| | - Hanzhi Xiong
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China
| | - Yunfan Zhou
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China
| | - Xu Chen
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China.
| | - Wensheng Yang
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China
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11
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Runa F, Ortiz-Soto G, de Barros NR, Kelber JA. Targeting SMAD-Dependent Signaling: Considerations in Epithelial and Mesenchymal Solid Tumors. Pharmaceuticals (Basel) 2024; 17:326. [PMID: 38543112 PMCID: PMC10975212 DOI: 10.3390/ph17030326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/19/2024] [Accepted: 02/23/2024] [Indexed: 04/01/2024] Open
Abstract
SMADs are the canonical intracellular effector proteins of the TGF-β (transforming growth factor-β). SMADs translocate from plasma membrane receptors to the nucleus regulated by many SMAD-interacting proteins through phosphorylation and other post-translational modifications that govern their nucleocytoplasmic shuttling and subsequent transcriptional activity. The signaling pathway of TGF-β/SMAD exhibits both tumor-suppressing and tumor-promoting phenotypes in epithelial-derived solid tumors. Collectively, the pleiotropic nature of TGF-β/SMAD signaling presents significant challenges for the development of effective cancer therapies. Here, we review preclinical studies that evaluate the efficacy of inhibitors targeting major SMAD-regulating and/or -interacting proteins, particularly enzymes that may play important roles in epithelial or mesenchymal compartments within solid tumors.
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Affiliation(s)
- Farhana Runa
- Department of Biology, California State University Northridge, Northridge, CA 91330, USA
| | | | | | - Jonathan A Kelber
- Department of Biology, California State University Northridge, Northridge, CA 91330, USA
- Department of Biology, Baylor University, Waco, TX 76706, USA
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12
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Chen X, Xu Y, Zhou Z, Zhao P, Zhou Z, Wang F, Zhong F, Du H. CircUSP10 promotes liver cancer progression by regulating miR-211-5p/TCF12/EMT signaling pathway. Heliyon 2023; 9:e20649. [PMID: 37829805 PMCID: PMC10565698 DOI: 10.1016/j.heliyon.2023.e20649] [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: 05/15/2023] [Revised: 09/22/2023] [Accepted: 10/03/2023] [Indexed: 10/14/2023] Open
Abstract
There is no precise diagnosis or prognosis for liver cancer (LC) using a single biomarker. Circular RNAs (circRNAs) contribute to the pathogenesis of different cancers, but their role in LC is not entirely understood. In this study, circUSP10, an aberrantly expressed circRNA in LC, was screened using the Gene Expression Omnibus database, and its tissue-specific expression was verified using qRT-PCR. In vitro, functional assays and nude mouse tumorigenesis models were used to investigate circUSP10 role in LC. RNA immunoprecipitation and dual-luciferase reporter assays were performed to study the mechanistic relationship between circUSP10, miR-211-5p, and transcription factor 12 (TCF12). We found that circUSP10 expression was upregulated in LC tissues and cells. CircUSP10 expression was linked to tumor size and tumor node metastasis stage and negatively correlated with LC prognosis. In vitro assays confirmed circUSP10-mediated proliferation, migration, and invasion of LC cells and their association with the epithelial-mesenchymal transition (EMT) pathway. Mechanistically, circUSP10 adsorbed miR-211-5p, which regulated TCF12 and promoted tumorigenesis via the EMT signaling pathway. Therefore, our results suggest that circUSP10 may promote LC progression by modulating the miR-211-5p/TCF12/EMT signaling cascade and may serve as a potential biomarker for LC diagnosis and prognosis.
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Affiliation(s)
- Xiang Chen
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
- Department of Laboratory Medicine, Nantong First People's Hospital and The Second Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Yao Xu
- Department of Laboratory Medicine, Nantong First People's Hospital and The Second Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Zhengyang Zhou
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Ping Zhao
- Department of Laboratory Medicine, Nantong First People's Hospital and The Second Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Zhou Zhou
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Feng Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Fengyun Zhong
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Hong Du
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
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13
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O'Connell I, Dongre A. Immune Checkpoint Blockade Therapy for Breast Cancer: Lessons from Epithelial-Mesenchymal Transition. Mol Diagn Ther 2023; 27:433-444. [PMID: 37193859 PMCID: PMC10299941 DOI: 10.1007/s40291-023-00652-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2023] [Indexed: 05/18/2023]
Abstract
Immune checkpoint blockade therapies have generated efficacious responses in certain tumor types; however, the responses of breast carcinomas have been largely limited. Moreover, the identity of various parameters that can predict responses to immunotherapies, and at the same time, serve as putative biomarkers that can be therapeutically targeted to enhance the effectiveness of immunotherapies for breast cancers, remains to be comprehensively delineated. Activation of epithelial-mesenchymal plasticity in cancer cells, including those of the breast, increases their tumor-initiating potential and promotes their aggressiveness and resistance to multiple treatment regimens. Moreover, the residence of cancer cells in alternating epithelial or mesenchymal plastic phenotypic states can also influence their immuno-modulatory properties and susceptibilities to immune checkpoint blockade therapies. In this current opinion, we discuss the lessons that can be learnt from epithelial-mesenchymal transition to potentiate the efficacy of immunotherapy for breast cancers. We also discuss strategies to sensitize more-mesenchymal cancer cells to anti-tumor immunity and immune checkpoint blockade therapies, with the hope that these can serve as new translational avenues for the treatment of human breast tumors.
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Affiliation(s)
- Isabel O'Connell
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, T7-012A VRT, 930 Campus Road, Ithaca, NY, 14853, USA
| | - Anushka Dongre
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, T7-012A VRT, 930 Campus Road, Ithaca, NY, 14853, USA.
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14
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Meng X, Morita M, Kuba S, Hayashi H, Otsubo R, Matsumoto M, Yamanouchi K, Kobayashi K, Soyama A, Hidaka M, Kanetaka K, Nagayasu T, Eguchi S. Association of quantitative analysis of intratumoral reduced E-cadherin expression with lymph node metastasis and prognosis in patients with breast cancer. Sci Rep 2023; 13:10434. [PMID: 37369698 PMCID: PMC10300190 DOI: 10.1038/s41598-023-37012-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Loss of E-cadherin expression is a poor prognostic factor in patients with breast cancer. Breast cancer cells co-cultured with adipocytes reportedly promote E-cadherin attenuation and tumor progression. The current study aimed to investigate the association of reduced E-cadherin expression with adipose tissue invasion (ATI) and prognosis in breast cancer. Surgical specimens were collected from 188 women with invasive ductal carcinoma of the breast who had undergone surgery without neoadjuvant treatment. We compared E-cadherin expression in ATI and invasive front (IF) using immunohistochemistry with ImageJ. Reduced E-cadherin expression was detected not only in the ATI area but also in the IF, and the degree of reduced E-cadherin expression was positively correlated with both areas. In patients with lymph node metastasis compared to those without, E-cadherin expression was reduced and this reduction was associated with poor recurrence-free survival. We concluded that E-cadherin expression is reduced not only at the ATI area but also at the IF of the tumor. Reduced E-cadherin expression is a clear prognostic factor for breast cancer. Hence, future research is warranted for establishing an objective and quantitative E-cadherin staining assay that will allow clinical use of E-cadherin as a prognostic factor.
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Affiliation(s)
- Xiangyue Meng
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Michi Morita
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Sayaka Kuba
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan.
| | - Hiroko Hayashi
- Department of Pathology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Ryota Otsubo
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Megumi Matsumoto
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Kosho Yamanouchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Kazuma Kobayashi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Kengo Kanetaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Takeshi Nagayasu
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
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15
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Multi-Parameter Analysis of Disseminated Tumor Cells (DTCs) in Early Breast Cancer Patients with Hormone-Receptor-Positive Tumors. Cancers (Basel) 2023; 15:cancers15030568. [PMID: 36765527 PMCID: PMC9913363 DOI: 10.3390/cancers15030568] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/13/2023] [Accepted: 01/13/2023] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Patients with hormone-receptor-positive (HR+) breast cancer are at increased risk for late recurrence. One reason might be disseminated tumor cells (DTCs), which split off in the early stages of the disease and metastasize into the bone marrow (BM). METHODS We developed a novel multi-parameter immunofluorescence staining protocol using releasable and bleachable antibody-fluorochrome-conjugates. This sequential procedure enabled us to analyze six distinct phenotypical and therapy-related markers on the same DTC. We characterized BM aspirates from 29 patients with a HR+ tumor and a known positive DTC status-based on the standardized detection of epithelial cells in BM. RESULTS Using the immunofluorescence staining, a total of 153 DTCs were detected. Luminal A patients revealed a higher DTC count compared with luminal B. The majority of the detected DTCs were CK-positive (128/153). However, in 16 of 17 luminal A patients we found HER2-positive DTCs. We detected CK-negative DTCs (25/153) in 12 of 29 patients. Of those cells, 76% were Ki67-positive and 68% were HER2-positive. Moreover, we detected DTC clusters consisting of mixed characteristics in 6 of 29 patients. CONCLUSIONS Using sequential multi-parameter imaging made it possible to identify distinct DTC profiles not solely based on epithelial features. Our findings indicate that characterization rather than quantification of DTCs might be relevant for treatment decisions.
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16
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Vitaliti A, Roccatani I, Iorio E, Perta N, Gismondi A, Chirico M, Pisanu ME, Di Marino D, Canini A, De Luca A, Rossi L. AKT-driven epithelial-mesenchymal transition is affected by copper bioavailability in HER2 negative breast cancer cells via a LOXL2-independent mechanism. Cell Oncol (Dordr) 2023; 46:93-115. [PMID: 36454513 PMCID: PMC9947069 DOI: 10.1007/s13402-022-00738-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND The main mechanism underlying cancer dissemination is the epithelial to mesenchymal transition (EMT). This process is orchestrated by cytokines like TGFβ, involving "non-canonical" AKT- or STAT3-driven pathways. Recently, the alteration of copper homeostasis seems involved in the onset and progression of cancer. METHODS We expose different breast cancer cell lines, including two triple negative (TNBC) ones, an HER2 enriched and one cell line representative of the Luminal A molecular subtype, to short- or long-term copper-chelation by triethylenetetramine (TRIEN). We analyse changes in the expression of EMT markers (E-cadherin, fibronectin, vimentin and αSMA), in the levels and activity of extracellular matrix components (LOXL2, fibronectin and MMP2/9) and of copper homeostasis markers by Western blot analyses, immunofluorescence, enzyme activity assays and RT-qPCR. Boyden Chamber and wound healing assays revealed the impact of copper chelation on cell migration. Additionally, we explored whether perturbation of copper homeostasis affects EMT prompted by TGFβ. Metabolomic and lipidomic analyses were applied to search the effects of copper chelation on the metabolism of breast cancer cells. Finally, bioinformatics analysis of data on breast cancer patients obtained from different databases was employed to correlate changes in kinases and copper markers with patients' survival. RESULTS Remarkably, only HER2 negative breast cancer cells differently responded to short- or long-term exposure to TRIEN, initially becoming more aggressive but, upon prolonged exposure, retrieving epithelial features, reducing their invasiveness. This phenomenon may be related to the different impact of the short and prolonged activation of the AKT kinase and to the repression of STAT3 signalling. Bioinformatics analyses confirmed the positive correlation of breast cancer patients' survival with AKT activation and up-regulation of CCS. Eventually, metabolomics studies demonstrate a prevalence of glycolysis over mitochondrial energetic metabolism and of lipidome changes in TNBC cells upon TRIEN treatment. CONCLUSIONS We provide evidence of a pivotal role of copper in AKT-driven EMT activation, acting independently of HER2 in TNBC cells and via a profound change in their metabolism. Our results support the use of copper-chelators as an adjuvant therapeutic strategy for TNBC.
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Affiliation(s)
- Alessandra Vitaliti
- Department of Biology, University of Rome “Tor Vergata”, Via Della Ricerca Scientifica 1, 00133 Rome, Italy ,PhD program in Cellular and Molecular Biology, Department of Biology, University of Rome “Tor Vergata”, Via della Ricerca Scientifica 1, 00133 Rome, Italy
| | - Ilenia Roccatani
- Department of Biology, University of Rome “Tor Vergata”, Via Della Ricerca Scientifica 1, 00133 Rome, Italy
| | - Egidio Iorio
- Core Facilities High Resolution NMR Unit, Istituto Superiore Di Sanità, 00161 Rome, Italy
| | - Nunzio Perta
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy
| | - Angelo Gismondi
- Department of Biology, University of Rome “Tor Vergata”, Via Della Ricerca Scientifica 1, 00133 Rome, Italy
| | - Mattea Chirico
- Core Facilities High Resolution NMR Unit, Istituto Superiore Di Sanità, 00161 Rome, Italy
| | - Maria Elena Pisanu
- Core Facilities High Resolution NMR Unit, Istituto Superiore Di Sanità, 00161 Rome, Italy
| | - Daniele Di Marino
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy
| | - Antonella Canini
- Department of Biology, University of Rome “Tor Vergata”, Via Della Ricerca Scientifica 1, 00133 Rome, Italy
| | - Anastasia De Luca
- Department of Biology, University of Rome "Tor Vergata", Via Della Ricerca Scientifica 1, 00133, Rome, Italy.
| | - Luisa Rossi
- Department of Biology, University of Rome "Tor Vergata", Via Della Ricerca Scientifica 1, 00133, Rome, Italy.
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17
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Niu ZS, Wang WH, Niu XJ. Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma. World J Gastroenterol 2022; 28:6433-6477. [PMID: 36569275 PMCID: PMC9782839 DOI: 10.3748/wjg.v28.i46.6433] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Department of Internal Medicine, Qingdao Shibei District People's Hospital, Qingdao 266033, Shandong Province, China
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18
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Bottner J, Ribbat-Idel J, Klapper L, Jagomast T, Lemster AL, Perner S, Idel C, Kirfel J. Elevated LSD1 and SNAIL Expression Indicate Poor Prognosis in Hypopharynx Carcinoma. Int J Mol Sci 2022; 23:ijms23095075. [PMID: 35563463 PMCID: PMC9100259 DOI: 10.3390/ijms23095075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 04/29/2022] [Accepted: 04/29/2022] [Indexed: 12/23/2022] Open
Abstract
Head and neck squamous cell carcinomas (HNSCC) are among the most common cancers worldwide and are associated with a poor prognosis for patients. Among HNSCC, those originating in the hypopharynx have the worst prognosis. The histone demethylase LSD1 has been shown to promote cancer initiation, progression, and relapse through various mechanisms and is upregulated in many cancer tissues. LSD1 physically interacts with SNAIL and is required for SNAIL mediated transcriptional repression. Previous studies of the prognostic value of LSD1 in HNSCC have been limited in their analysis of sub-sites, and a correlation between LSD1 and SNAIL has not been shown in HNSCC patient samples. Here we used a large, representative, and clinically well-characterized cohort of 339 HNSCC patients to investigate the co-expression of LSD1 and SNAIL and their prognostic value in all HNSCC using immunohistochemical staining. Elevated LSD1 expression correlated with advanced tumor stage and poor progression-free survival (PFS) in HNSCC originating in the hypopharynx. Overexpression of the transcription factor SNAIL independently correlated with worse overall survival (OS) and PFS in HNSCC in general and prominently in tumors of the hypopharynx. Furthermore, increased LSD1 expression significantly correlated with elevated SNAIL expression in patient samples. Therefore, the presented data implicates LSD1 and SNAIL as independent prognostic biomarkers.
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Affiliation(s)
- Justus Bottner
- Institute of Pathology, University of Luebeck and University Hospital Schleswig-Holstein, Campus Luebeck, 23538 Luebeck, Germany; (J.B.); (J.R.-I.); (L.K.); (T.J.); (A.-L.L.); (S.P.)
| | - Julika Ribbat-Idel
- Institute of Pathology, University of Luebeck and University Hospital Schleswig-Holstein, Campus Luebeck, 23538 Luebeck, Germany; (J.B.); (J.R.-I.); (L.K.); (T.J.); (A.-L.L.); (S.P.)
| | - Luise Klapper
- Institute of Pathology, University of Luebeck and University Hospital Schleswig-Holstein, Campus Luebeck, 23538 Luebeck, Germany; (J.B.); (J.R.-I.); (L.K.); (T.J.); (A.-L.L.); (S.P.)
| | - Tobias Jagomast
- Institute of Pathology, University of Luebeck and University Hospital Schleswig-Holstein, Campus Luebeck, 23538 Luebeck, Germany; (J.B.); (J.R.-I.); (L.K.); (T.J.); (A.-L.L.); (S.P.)
| | - Anna-Lena Lemster
- Institute of Pathology, University of Luebeck and University Hospital Schleswig-Holstein, Campus Luebeck, 23538 Luebeck, Germany; (J.B.); (J.R.-I.); (L.K.); (T.J.); (A.-L.L.); (S.P.)
| | - Sven Perner
- Institute of Pathology, University of Luebeck and University Hospital Schleswig-Holstein, Campus Luebeck, 23538 Luebeck, Germany; (J.B.); (J.R.-I.); (L.K.); (T.J.); (A.-L.L.); (S.P.)
- Institute of Pathology, Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany
| | - Christian Idel
- Department of Otorhinolaryngology, University of Luebeck and University Hospital Schleswig-Holstein, Campus Luebeck, 23538 Luebeck, Germany;
| | - Jutta Kirfel
- Institute of Pathology, University of Luebeck and University Hospital Schleswig-Holstein, Campus Luebeck, 23538 Luebeck, Germany; (J.B.); (J.R.-I.); (L.K.); (T.J.); (A.-L.L.); (S.P.)
- Correspondence:
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19
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Lima de Oliveira J, Moré Milan T, Longo Bighetti‐Trevisan R, Fernandes RR, Leopoldino AM, Almeida LO. Epithelial‐mesenchymal transition and cancer stem cells: a route to acquired cisplatin resistance through epigenetics in HNSCC. Oral Dis 2022. [DOI: 10.1111/odi.14209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/02/2022] [Accepted: 04/06/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Julia Lima de Oliveira
- Department of Basic and Oral Biology School of Dentistry of Ribeirão Preto University of São Paulo Ribeirão Preto SP Brazil
| | - Thaís Moré Milan
- Department of Basic and Oral Biology School of Dentistry of Ribeirão Preto University of São Paulo Ribeirão Preto SP Brazil
| | - Rayana Longo Bighetti‐Trevisan
- Department of Basic and Oral Biology School of Dentistry of Ribeirão Preto University of São Paulo Ribeirão Preto SP Brazil
| | - Roger Rodrigo Fernandes
- Department of Basic and Oral Biology School of Dentistry of Ribeirão Preto University of São Paulo Ribeirão Preto SP Brazil
| | - Andréia Machado Leopoldino
- Department of Clinical Analyses, Toxicology and Food Sciences School of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo Ribeirão Preto SP Brazil
| | - Luciana Oliveira Almeida
- Department of Basic and Oral Biology School of Dentistry of Ribeirão Preto University of São Paulo Ribeirão Preto SP Brazil
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20
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Liao H, Ding M, Zhou N, Yang Y, Chen L. B7‑H3 promotes the epithelial‑mesenchymal transition of NSCLC by targeting SIRT1 through the PI3K/AKT pathway. Mol Med Rep 2022; 25:79. [PMID: 35029291 PMCID: PMC8778653 DOI: 10.3892/mmr.2022.12595] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/13/2021] [Indexed: 12/24/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a key step in cancer metastasis. B7-H3, a co-signaling molecule associated with poor prognosis of non-small cell lung cancer (NSCLC), promotes the metastasis of NSCLC by activating the EMT process. However, its underlying mechanism remains poorly understood. In the present study, it was shown that CRISPR/Cas9-mediated B7-H3 deletion downregulated the expression of the class III histone deacetylase, sirtuin-1 (SIRT1), in NSCLC A549 cells. Accordingly, SIRT1 silencing resulted in markedly decreased migration and invasion of A549 cells. Both B7-H3 gene-edited and SIRT1-silenced cells were typically characterized by an increased expression of the epithelial marker E-cadherin, and downregulation of the mesenchymal markers N-cadherin and vimentin, as compared with mock-edited and scrambled negative small interfering RNA control, respectively. It was further demonstrated that B7-H3 ablation significantly downregulated phosphorylated AKT/protein kinase B expression, and SIRT1 expression was substantially suppressed by the PI3K-specific inhibitor, LY294002. Taken together, the findings of the present study revealed that B7-H3-induced signaling upregulates SIRT1 expression via the PI3K/AKT pathway to promote EMT activation that is associated with metastasis in NSCLC.
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Affiliation(s)
- Haixiu Liao
- Department of Laboratory Medicine, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Meng Ding
- Department of Laboratory Medicine, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Nannan Zhou
- Department of Laboratory Medicine, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Ying Yang
- Department of Laboratory Medicine, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Liwen Chen
- Department of Laboratory Medicine, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
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21
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Erwin F, Ceauşu AR, Gaje NP, Suciu SC, Cosoroabă RM, Porumb A, Popovici RA, Raica M, Raica M. The molecular profile of breast cancer: primary tumor versus corresponding lymph node metastases. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2022; 63:421-429. [PMID: 36374147 PMCID: PMC9801673 DOI: 10.47162/rjme.63.2.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Breast cancer (BrCa) is the most frequent malignancy in female, and lymph node metastases (LNM) is an important prognostic and therapeutic parameter. The molecular classification is nowadays largely applied to characterize the primary tumors, but few studies focused on the comparison between the molecular profiles of the primary with corresponding LNM. In the current work, we investigated the expression of conventional markers used by molecular classification in both primary tumors and axillary LNM. A series of 156 patients with BrCa was investigated, and from these 80 cases showed LNM. After routine pathological investigation, including the histopathological form and grade, we performed additional step sections from the primary and lymph nodes for immunohistochemistry. All procedures for hormone receptors, human epidermal growth factor receptor 2 (HER2), Ki67, cytokeratin 5 (CK5), epidermal growth factor receptor (EGFR), p53, E-cadherin, and B-cell leukemia∕lymphoma-2 (Bcl-2) were performed using the standard automated procedures. We found significant differences between the primary tumors and corresponding LNM in luminal A, luminal B, and basal-like carcinoma. No phenotypical interconversions were noticed in HER2 and unclassified BrCa. Our data demonstrate that in almost 20% of the cases the molecular profile of the primary does not overlap with aspects found in the lymph nodes. Our results strongly suggest performing the molecular classification in both primary tumors and in LNM. Current data suggest that the application of this diagnostic procedure will significantly influence the therapeutic strategy.
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Affiliation(s)
- Floroni Erwin
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center Timişoara, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania
| | - Amalia Raluca Ceauşu
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center Timişoara, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania
| | - Nela Puşa Gaje
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center Timişoara, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania
| | - Silviu Cristian Suciu
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center Timişoara, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania
| | - Raluca Mioara Cosoroabă
- Discipline of Management, Legislation and Communication in Dental Medicine, Faculty of Dental Medicine, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania
| | - Anca Porumb
- Department of Dental Medicine, Faculty of Medicine and Pharmacy, University of Oradea, Romania
| | - Ramona Amina Popovici
- Discipline of Management, Legislation and Communication in Dental Medicine, Faculty of Dental Medicine, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania
| | - Marius Raica
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center Timişoara, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania
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22
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Zhang Z, Wuethrich A, Wang J, Korbie D, Lin LL, Trau M. Dynamic Monitoring of EMT in CTCs as an Indicator of Cancer Metastasis. Anal Chem 2021; 93:16787-16795. [PMID: 34889595 DOI: 10.1021/acs.analchem.1c03167] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Epithelial to mesenchymal transition (EMT) results in the genesis of circulating tumor cells (CTCs) from tumor sites and promotes the metastatic capability of CTCs in circulation. In this study, we develop a multiplex surface-enhanced Raman scattering nanotechnology for comprehensive characterization of EMT-associated phenotypes in CTCs, to monitor cancer metastasis. We observe the downregulation of the CTC marker (EpCAM) and the epithelial marker (E-cadherin), as well as the upregulation of a mesenchymal marker (N-cadherin) and a stem cell marker (ABCB5) during the transforming growth factor-β-induced EMT process in breast cancer cell line models. Additionally, we also find changes in the heterogeneity levels of these selected markers in cells. With this method, we successfully detect the presence of disease in samples from breast cancer patients and characterize EMT-associated phenotypes in their CTCs. Overall, this approach and findings provide a new means for monitoring the EMT process in cancer, insights into the detailed mechanistic progress of the diseases, and have potential for detecting the early occurrence of cancer metastasis.
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Affiliation(s)
- Zhen Zhang
- Centre for Personalized Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia
| | - Alain Wuethrich
- Centre for Personalized Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia
| | - Jing Wang
- Centre for Personalized Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia
| | - Darren Korbie
- Centre for Personalized Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia
| | - Lynlee L Lin
- Centre for Personalized Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia.,Dermatology Research Centre, University of Queensland Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia
| | - Matt Trau
- Centre for Personalized Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia.,School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia
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23
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Unveiling the tumour-regulatory roles of miR-1275 in cancer. Pathol Res Pract 2021; 230:153745. [PMID: 34953353 DOI: 10.1016/j.prp.2021.153745] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 12/10/2021] [Accepted: 12/16/2021] [Indexed: 12/13/2022]
Abstract
The rapid development of small RNA and molecular biology research in the past 20 years has enabled scientists to discover many new miRNAs that are proven to play essential roles in regulating the development of different cancer types. Among these miRNAs, miR-1275 is one of the well-studied miRNAs that has been described to act as a tumour-promoting or tumour-suppressing miRNA in various cancer types. Even though miR-1275 has been widely reported in different original research articles on its roles in modulating the progression of different cancer types, however, there is scarce an in-depth review that could constructively summarize the findings from different studies on the regulatory roles of miR-1275 in different cancer types. To fill up this literature gap, therefore, this review was aimed to provide an overview and summary of the roles of miR-1275 in modulating the development of different cancers and to unravel the mechanism of how miR-1275 regulates cancer progression. Based on the findings summarized from various sources, it was found that miR-1275 plays a vital role in regulating various cellular signaling pathways like the PI3K/AKT, ERK/JNK, MAPK, and Wnt signaling pathways, and the dysregulation of this miRNA has been shown to contribute to the development of multiple cancer types such as cancers of the liver, breast, lung, gastrointestinal tract and genitourinary tract. Therefore, miR-1275 has great potential to be employed as a biomarker to diagnose cancer and to predict the prognosis of cancer patients. In addition, by inhibiting the expression of its unique downstream targets that are involved in regulating the mentioned cellular pathways, this miRNA could also be utilized as a novel therapeutic agent to halt cancer development.
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24
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The Role of ATRA, Natural Ligand of Retinoic Acid Receptors, on EMT-Related Proteins in Breast Cancer: Minireview. Int J Mol Sci 2021; 22:ijms222413345. [PMID: 34948142 PMCID: PMC8705994 DOI: 10.3390/ijms222413345] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 12/17/2022] Open
Abstract
The knowledge of the structure, function, and abundance of specific proteins related to the EMT process is essential for developing effective diagnostic approaches to cancer with the perspective of diagnosis and therapy of malignancies. The success of all-trans retinoic acid (ATRA) differentiation therapy in acute promyelocytic leukemia has stimulated studies in the treatment of other tumors with ATRA. This review will discuss the impact of ATRA use, emphasizing epithelial-mesenchymal transition (EMT) proteins in breast cancer, of which metastasis and recurrence are major causes of death.
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25
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D’Andrea MR, Cereda V, Coppola L, Giordano G, Remo A, De Santis E. Propensity for Early Metastatic Spread in Breast Cancer: Role of Tumor Vascularization Features and Tumor Immune Infiltrate. Cancers (Basel) 2021; 13:cancers13235917. [PMID: 34885027 PMCID: PMC8657227 DOI: 10.3390/cancers13235917] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 11/17/2021] [Accepted: 11/22/2021] [Indexed: 02/05/2023] Open
Abstract
Breast cancer is a complex and highly heterogeneous disease consisting of various subtypes. It is classified into human epidermal growth receptor 2 (HER-2)-enriched, luminal A, luminal B and basal-like/triple negative (TNBC) breast cancer, based on histological and molecular features. At present, clinical decision-making in breast cancer is focused only on the assessment of tumor cells; nevertheless, it has been recognized that the tumor microenvironment (TME) plays a critical biologic role in breast cancer. This is constituted by a large group of immune and non-immune cells, but also by non-cellular components, such as several cytokines. TME is deeply involved in angiogenesis, immune-evasion strategies, and propensity for early metastatic spread, impacting on prognosis and prediction of response to specific treatments. In this review, we focused our attention on the early morphological changes of tumor microenvironment (tumor vasculature features, presence of immune and non-immune cells infiltrating the stroma, levels of cytokines) during breast cancer development. At the same time, we correlate these characteristics with early metastatic propensity (defined as synchronous metastasis or early recurrence) with particular attention to breast cancer subtypes.
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Affiliation(s)
- Mario Rosario D’Andrea
- Clinical Oncology Unit, San Paolo Hospital, Largo Donatori del Sangue 1, Civitavecchia, 00053 Rome, Italy;
| | - Vittore Cereda
- Clinical Oncology Unit, San Paolo Hospital, Largo Donatori del Sangue 1, Civitavecchia, 00053 Rome, Italy;
- Correspondence: ; Tel.: +39-07-6659-1230
| | - Luigi Coppola
- Unit of Anatomy, Pathological Histology and Diagnostic Cytology, Department of Diagnostic and Pharma-Ceutical Services, Sandro Pertini Hospital, 00157 Rome, Italy;
| | - Guido Giordano
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy;
| | - Andrea Remo
- Pathology Unit, Mater Salutis Hospital, ULSS9, Legnago, 37045 Verona, Italy;
| | - Elena De Santis
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00185 Rome, Italy;
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26
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Gaur G, Sawant JY, Chavan AS, Khatri VA, Liu YH, Zhang M, Sapi E. Effect of Invasion of Borrelia burgdorferi in Normal and Neoplastic Mammary Epithelial Cells. Antibiotics (Basel) 2021; 10:antibiotics10111295. [PMID: 34827233 PMCID: PMC8614906 DOI: 10.3390/antibiotics10111295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/13/2021] [Accepted: 10/22/2021] [Indexed: 12/23/2022] Open
Abstract
Borrelia burgdorferi, the causative agent of Lyme Disease, is known to be able to disseminate and colonize various organs and tissues of its hosts, which is very crucial for its pathogenicity and survival. Recent studies have shown the presence of B. burgdorferi DNA in various breast cancer tissues, in some with poor prognosis, which raises the question about whether B. burgdorferi can interact with mammary epithelial cells and could have any effect on their physiology, including tumorigenic processes. As the model in this study, we have used MCF 10A normal and MDA-MB-231 tumorigenic mammary epithelial cells and infected both cell lines with B. burgdorferi. Our immunofluorescence and confocal microscopy results showed that B. burgdorferi is capable of invading normal epithelial and breast carcinoma cell lines within 24 h; however, the infection rate for the breast carcinoma cell lines was significantly higher. While the infection of epithelial cells with B. burgdorferi did not cause any changes in cell proliferation rates, it showed a significant effect on the invasion and migratory capacity of the breast cancer cells, but not on the normal epithelial cells, as determined by Matrigel invasion and wound healing assays. We have also found that the levels of expression of several epithelial-mesenchymal transition (EMT) markers (fibronectin, vimentin, and Twist1/2) changed, with a significant increase in tissue remodeling marker (MMP-9) in MDA-MB-231 cells demonstrated by quantitative Western blot analyses. This observation further confirmed that B. burgdorferi infection can affect the in vitro migratory and invasive properties of MDA-MB-231 tumorigenic mammary epithelial cells. In summary, our results suggest that B. burgdorferi can invade breast cancer tumor cells and it can increase their tumorigenic phenotype, which urges the need for further studies on whether B. burgdorferi could have any role in breast cancer development.
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Affiliation(s)
- Gauri Gaur
- Lyme Disease Research Group, Department of Biology and Environmental Science, University of New Haven, 300 Boston Post Road, GH 104A, West Haven, CT 06516, USA; (G.G.); (J.Y.S.); (A.S.C.); (V.A.K.); (Y.-H.L.); (M.Z.)
| | - Janhavi Y. Sawant
- Lyme Disease Research Group, Department of Biology and Environmental Science, University of New Haven, 300 Boston Post Road, GH 104A, West Haven, CT 06516, USA; (G.G.); (J.Y.S.); (A.S.C.); (V.A.K.); (Y.-H.L.); (M.Z.)
| | - Ankita S. Chavan
- Lyme Disease Research Group, Department of Biology and Environmental Science, University of New Haven, 300 Boston Post Road, GH 104A, West Haven, CT 06516, USA; (G.G.); (J.Y.S.); (A.S.C.); (V.A.K.); (Y.-H.L.); (M.Z.)
| | - Vishwa A. Khatri
- Lyme Disease Research Group, Department of Biology and Environmental Science, University of New Haven, 300 Boston Post Road, GH 104A, West Haven, CT 06516, USA; (G.G.); (J.Y.S.); (A.S.C.); (V.A.K.); (Y.-H.L.); (M.Z.)
| | - Yueh-Hsin Liu
- Lyme Disease Research Group, Department of Biology and Environmental Science, University of New Haven, 300 Boston Post Road, GH 104A, West Haven, CT 06516, USA; (G.G.); (J.Y.S.); (A.S.C.); (V.A.K.); (Y.-H.L.); (M.Z.)
| | - Min Zhang
- Lyme Disease Research Group, Department of Biology and Environmental Science, University of New Haven, 300 Boston Post Road, GH 104A, West Haven, CT 06516, USA; (G.G.); (J.Y.S.); (A.S.C.); (V.A.K.); (Y.-H.L.); (M.Z.)
- Department of Criminal Justice, Coppin State University, Baltimore, MD 21216, USA
| | - Eva Sapi
- Lyme Disease Research Group, Department of Biology and Environmental Science, University of New Haven, 300 Boston Post Road, GH 104A, West Haven, CT 06516, USA; (G.G.); (J.Y.S.); (A.S.C.); (V.A.K.); (Y.-H.L.); (M.Z.)
- Correspondence: ; Tel.: +1-203-479-4552
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27
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Wilk SS, Zabielska-Koczywąs KA. Molecular Mechanisms of Canine Osteosarcoma Metastasis. Int J Mol Sci 2021; 22:3639. [PMID: 33807419 PMCID: PMC8036641 DOI: 10.3390/ijms22073639] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/24/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023] Open
Abstract
Osteosarcoma (OSA) represents the most common bone tumor in dogs. The malignancy is highly aggressive, and most of the dogs die due to metastasis, especially to the lungs. The metastatic process is complex and consists of several main steps. Assessment of the molecular mechanisms of metastasis requires in vitro and especially in vivo studies for a full evaluation of the process. The molecular and biological resemblance of canine OSA to its human counterpart enables the utilization of dogs as a spontaneous model of this disease in humans. The aim of the present review article is to summarize the knowledge of genes and proteins, including p63, signal transducer and activator of transcription 3 (STAT3), Snail2, ezrin, phosphorylated ezrin-radixin-moesin (p-ERM), hepatocyte growth factor-scatter factor (HGF-SF), epidermal growth factor receptor (EGFR), miR-9, and miR-34a, that are proven, by in vitro and/or in vivo studies, to be potentially involved in the metastatic cascade of canine OSA. The determination of molecular targets of metastatic disease may enhance the development of new therapeutic strategies.
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Affiliation(s)
| | - Katarzyna A. Zabielska-Koczywąs
- Department of Small Animal Diseases and Clinic, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland;
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28
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CD73 facilitates EMT progression and promotes lung metastases in triple-negative breast cancer. Sci Rep 2021; 11:6035. [PMID: 33727591 PMCID: PMC7966763 DOI: 10.1038/s41598-021-85379-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 02/24/2021] [Indexed: 12/18/2022] Open
Abstract
CD73 is a cell surface ecto-5′-nucleotidase, which converts extracellular adenosine monophosphate to adenosine. High tumor CD73 expression is associated with poor outcome among triple-negative breast cancer (TNBC) patients. Here we investigated the mechanisms by which CD73 might contribute to TNBC progression. This was done by inhibiting CD73 with adenosine 5′-(α, β-methylene) diphosphate (APCP) in MDA-MB-231 or 4T1 TNBC cells or through shRNA-silencing (sh-CD73). Effects of such inhibition on cell behavior was then studied in normoxia and hypoxia in vitro and in an orthotopic mouse model in vivo. CD73 inhibition, through shRNA or APCP significantly decreased cellular viability and migration in normoxia. Inhibition of CD73 also resulted in suppression of hypoxia-induced increase in viability and prevented cell protrusion elongation in both normoxia and hypoxia in cancer cells. Sh-CD73 4T1 cells formed significantly smaller and less invasive 3D organoids in vitro, and significantly smaller orthotopic tumors and less lung metastases than control shRNA cells in vivo. CD73 suppression increased E-cadherin and decreased vimentin expression in vitro and in vivo, proposing maintenance of a more epithelial phenotype. In conclusion, our results suggest that CD73 may promote early steps of tumor progression, possibly through facilitating epithelial–mesenchymal transition.
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29
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Gupta I, Jabeen A, Vranic S, Al Moustafa AE, Al-Thawadi H. Oncoproteins of High-Risk HPV and EBV Cooperate to Enhance Cell Motility and Invasion of Human Breast Cancer Cells via Erk1/Erk2 and β-Catenin Signaling Pathways. Front Oncol 2021; 11:630408. [PMID: 33777781 PMCID: PMC7994530 DOI: 10.3389/fonc.2021.630408] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 02/08/2021] [Indexed: 12/13/2022] Open
Abstract
Breast cancer is a leading cause of death in women around the world. Most breast cancer-related deaths are a result of complications from the metastatic spread. Several recent studies reported that high-risk human papillomaviruses (HPVs) and Epstein-Barr virus (EBV) are co-presented in different types of human carcinomas including breast; however, the cooperative effects between high-risk HPVs and EBV oncoproteins in human breast cancer have not been investigated yet. Thus, we herein explored the cooperation outcome between E6/E7 and latent membrane protein 1 (LMP1) oncoproteins of high-risk HPV type 16 and EBV, respectively, in two human breast cancer cell lines, MCF7 and MDA-MB-231. Our data revealed that the cooperation of E6/E7 and LMP1 oncoproteins stimulates cell proliferation and deregulates cell cycle progression of human breast cancer and normal mammary cells; in parallel, we noted that E6/E7/LMP1 incite colony formation of both breast cancer cell lines but not normal cells. More significantly, our results point out that the co-expression of E6/E7 and LMP1 oncoproteins enhances cell motility and invasion of MCF7 and MDA-MB-231 cell lines; this is accompanied by deregulation of epithelial-mesenchymal transition biomarkers including E-cadherin, β-catenin, fascin, and vimentin. The molecular pathway analysis of HPV and EBV oncoproteins cooperation shows that it can enhance the phosphorylation of extracellular signal-regulated kinases (Erk1/Erk2) in addition to β-catenin, which could be behind the effect of this cooperation in our cell models. The study clearly suggests that high-risk HPV and EBV coinfection can play an important role in breast cancer progression via Erk1/Erk2 and β-catenin signaling pathways.
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Affiliation(s)
- Ishita Gupta
- College of Medicine, Qatar University Health, Qatar University, Doha, Qatar
- Biomedical and Pharmaceutical Research Unit, Qatar University Health, Qatar University, Doha, Qatar
- Biomedical Research Centre, Qatar University, Doha, Qatar
| | - Ayesha Jabeen
- College of Medicine, Qatar University Health, Qatar University, Doha, Qatar
- Biomedical and Pharmaceutical Research Unit, Qatar University Health, Qatar University, Doha, Qatar
- Biomedical Research Centre, Qatar University, Doha, Qatar
| | - Semir Vranic
- College of Medicine, Qatar University Health, Qatar University, Doha, Qatar
- Biomedical and Pharmaceutical Research Unit, Qatar University Health, Qatar University, Doha, Qatar
| | - Ala-Eddin Al Moustafa
- College of Medicine, Qatar University Health, Qatar University, Doha, Qatar
- Biomedical and Pharmaceutical Research Unit, Qatar University Health, Qatar University, Doha, Qatar
- Biomedical Research Centre, Qatar University, Doha, Qatar
| | - Hamda Al-Thawadi
- College of Medicine, Qatar University Health, Qatar University, Doha, Qatar
- Biomedical and Pharmaceutical Research Unit, Qatar University Health, Qatar University, Doha, Qatar
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30
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Koleckova M, Ehrmann J, Bouchal J, Janikova M, Brisudova A, Srovnal J, Staffova K, Svoboda M, Slaby O, Radova L, Vomackova K, Melichar B, Veverkova L, Kolar Z. Epithelial to mesenchymal transition and microRNA expression are associated with spindle and apocrine cell morphology in triple-negative breast cancer. Sci Rep 2021; 11:5145. [PMID: 33664322 PMCID: PMC7933252 DOI: 10.1038/s41598-021-84350-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
Triple negative breast cancers (TNBC) are a morphologically and genetically heterogeneous group of breast cancers with uncertain prediction of biological behavior and response to therapy. Epithelial to mesenchymal transition (EMT) is a dynamic process characterized by loss of typical epithelial phenotype and acquisition of mesenchymal characteristics. Aberrant activation of EMT can aggravate the prognosis of patients with cancer, however, the mechanisms of EMT and role of microRNAs (miRNAs) in EMT activation is still unclear. The aim of our study was to analyze miRNA expression within areas of TNBCs with cellular morphology that may be related to the EMT process and discuss possible associations. Out of all 3953 re-examined breast cancers, 460 breast cancers were diagnosed as TNBC (11.64%). With regard to complete tumor morphology preservation, the tissue samples obtained from core—cut biopsies and influenced by previous neoadjuvant therapy were excluded. We assembled a set of selected 25 cases to determine miRNA expression levels in relation to present focal spindle cell and apocrine cell morphology within individual TNBCs. We used descriptive (histological typing and morphology), morphometric, molecular (microdissection of tumor and non-tumor morphologies, RNA isolation and purification, microchip analysis) and bioinformatic analysis (including pathway analysis). The results were verified by quantitative real-time PCR (RT-qPCR) on an extended set of 70 TNBCs. The majority of TNBCs were represented by high—grade invasive carcinomas of no special type (NST) with medullary features characterized by well-circumscribed tumors with central necrosis or fibrosis and frequent tendency to spindle-cell and/or apocrine cell transformation. Apocrine and spindle cell transformation showed a specific miRNA expression profile in comparison to other tumor parts, in situ carcinoma or non-tumor structures, particularly down-regulated expression of hsa-miRNA-143-3p and hsa-miRNA-205-5p and up-regulated expression of hsa-miR-22-3p, hsa-miRNA-185-5p, and hsa-miR-4443. Apocrine cell tumor morphology further revealed decreased expression of hsa-miR-145-5p and increased expression of additional 14 miRNAs (e.g. hsa-miR-182-5p, hsa-miR-3135b and hsa-miR-4417). Pathway analysis for target genes of these miRNAs revealed several shared biological processes (i.e. Wnt signaling, ErbB signaling, MAPK signaling, endocytosis and axon guidance), which may in part contribute to the EMT and tumor progression. We provide the first miRNA expression profiling of specific tissue morphologies in TNBC. Our results demonstrate a specific miRNA expression profile of apocrine and spindle cell morphology which can exhibit a certain similarity with the EMT process and may also be relevant for prognosis and therapy resistance of TNBC.
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Affiliation(s)
- Marketa Koleckova
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic
| | - Jiri Ehrmann
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic
| | - Jan Bouchal
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic. .,Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic.
| | - Maria Janikova
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic
| | - Aneta Brisudova
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic
| | - Josef Srovnal
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic
| | - Katerina Staffova
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic
| | - Marek Svoboda
- Central European Institute of Technology, Masaryk University, 625 00, Brno, Czech Republic
| | - Ondrej Slaby
- Central European Institute of Technology, Masaryk University, 625 00, Brno, Czech Republic
| | - Lenka Radova
- Central European Institute of Technology, Masaryk University, 625 00, Brno, Czech Republic
| | - Katherine Vomackova
- Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic
| | - Bohuslav Melichar
- Department of Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic
| | - Lucia Veverkova
- Department of Radiology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic
| | - Zdenek Kolar
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic. .,Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 775 15, Olomouc, Czech Republic.
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31
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Sabtu SN, Sani SFA, Looi LM, Chiew SF, Pathmanathan D, Bradley DA, Osman Z. Indication of high lipid content in epithelial-mesenchymal transitions of breast tissues. Sci Rep 2021; 11:3250. [PMID: 33547362 PMCID: PMC7864999 DOI: 10.1038/s41598-021-81426-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 12/21/2020] [Indexed: 02/06/2023] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a crucial process in cancer progression and metastasis. Study of metabolic changes during the EMT process is important in seeking to understand the biochemical changes associated with cancer progression, not least in scoping for therapeutic strategies aimed at targeting EMT. Due to the potential for high sensitivity and specificity, Raman spectroscopy was used here to study the metabolic changes associated with EMT in human breast cancer tissue. For Raman spectroscopy measurements, tissue from 23 patients were collected, comprising non-lesional, EMT and non-EMT formalin-fixed and paraffin embedded breast cancer samples. Analysis was made in the fingerprint Raman spectra region (600-1800 cm-1) best associated with cancer progression biochemical changes in lipid, protein and nucleic acids. The ANOVA test followed by the Tukey's multiple comparisons test were conducted to see if there existed differences between non-lesional, EMT and non-EMT breast tissue for Raman spectroscopy measurements. Results revealed that significant differences were evident in terms of intensity between the non-lesional and EMT samples, as well as the EMT and non-EMT samples. Multivariate analysis involving independent component analysis, Principal component analysis and non-negative least square were used to analyse the Raman spectra data. The results show significant differences between EMT and non-EMT cancers in lipid, protein, and nucleic acids. This study demonstrated the capability of Raman spectroscopy supported by multivariate analysis in analysing metabolic changes in EMT breast cancer tissue.
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Affiliation(s)
- Siti Norbaini Sabtu
- Department of Physics, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - S F Abdul Sani
- Department of Physics, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia.
| | - L M Looi
- Department of Pathology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - S F Chiew
- Department of Pathology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Dharini Pathmanathan
- Institute of Mathematical Sciences, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - D A Bradley
- Centre for Biomedical Physics, Sunway University, Jalan Universiti, 46150, Petaling Jaya, Malaysia
- Department of Physics, University of Surrey, Guildford, GU2 7XH, UK
| | - Z Osman
- Department of Physics, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia
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32
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Qi T, Qu Q, Li G, Wang J, Zhu H, Yang Z, Sun Y, Lu Q, Qu J. Function and regulation of the PEA3 subfamily of ETS transcription factors in cancer. Am J Cancer Res 2020; 10:3083-3105. [PMID: 33163259 PMCID: PMC7642666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 09/17/2020] [Indexed: 06/11/2023] Open
Abstract
The PEA3 subfamily is a subgroup of the E26 transformation-specific (ETS) family. Its members, ETV1, ETV4, and ETV5, have been found to be overexpressed in multiple cancers. The deregulation of ETV1, ETV4, and ETV5 induces cell growth, invasion, and migration in various tumor cells, leading to tumor progression, metastasis, and drug resistance. Therefore, exploring drugs or therapeutic targets that target the PEA3 subfamily may contribute to the clinical treatment of tumor patients. In this review, we introduce the structures and functions of the PEA3 subfamily members, systematically review their main roles in various tumor cells, analyze their prognostic and diagnostic value, and, finally, introduce several molecular targets and therapeutic drugs targeting ETV1, ETV4, and ETV5. We conclude that targeting a series of upstream regulators and downstream target genes of the PEA3 subfamily may be an effective strategy for the treatment of ETV1/ETV4/ETV5-overexpressing tumors.
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Affiliation(s)
- Tingting Qi
- Department of Pharmacy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, PR China
- Institute of Clinical Pharmacy, Central South UniversityChangsha 410011, PR China
| | - Qiang Qu
- Department of Pharmacy, Xiangya Hospital, Central South UniversityChangsha 410007, PR China
| | - Guohua Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, PR China
- Institute of Clinical Pharmacy, Central South UniversityChangsha 410011, PR China
| | - Jiaojiao Wang
- Department of Pharmacy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, PR China
- Institute of Clinical Pharmacy, Central South UniversityChangsha 410011, PR China
| | - Haihong Zhu
- Department of Pharmacy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, PR China
- Institute of Clinical Pharmacy, Central South UniversityChangsha 410011, PR China
| | - Zhi Yang
- Department of General Surgery, Xiangya Hospital, Central South UniversityChangsha 410007, PR China
| | - Yuesheng Sun
- Department of General Surgery, The Third Clinical College of Wenzhou Medical University, Wenzhou People’s HospitalWenzhou 325000, PR China
| | - Qiong Lu
- Department of Pharmacy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, PR China
- Institute of Clinical Pharmacy, Central South UniversityChangsha 410011, PR China
| | - Jian Qu
- Department of Pharmacy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, PR China
- Institute of Clinical Pharmacy, Central South UniversityChangsha 410011, PR China
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33
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Van Bockstal MR, Noel F, Guiot Y, Duhoux FP, Mazzeo F, Van Marcke C, Fellah L, Ledoux B, Berlière M, Galant C. Predictive markers for pathological complete response after neo-adjuvant chemotherapy in triple-negative breast cancer. Ann Diagn Pathol 2020; 49:151634. [PMID: 32987254 DOI: 10.1016/j.anndiagpath.2020.151634] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 09/14/2020] [Indexed: 12/21/2022]
Abstract
A combination of Sox10 and GATA3 was previously identified as a marker for metastatic triple-negative breast cancer (TNBC), but it is uncertain whether their expression is associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). This study investigates the predictive value of clinicopathological characteristics, as well as protein expression of Sox10, GATA3, p53 and p63, in a consecutive series of TNBC patients treated with NAC. Archived hematoxylin & eosin stained slides of core biopsies and resection specimens from 35 TNBC patients were reviewed. The following clinicopathological characteristics were determined at the biopsy level: age at diagnosis, cancer type, Nottingham grade, lympho-vascular invasion, syncytial growth, necrosis, clear cell differentiation, myxoid peritumor stroma, stromal tumor-infiltrating lymphocytes (sTILs) and presence of an in situ component. The MD Anderson residual cancer burden (RCB) score and corresponding RCB class were determined. Immunohistochemistry for Sox10, p53, GATA3 and p63 was performed at the biopsy level. sTILs, either as a continuous or as a dichotomous variable, were the only parameter that was significantly associated with pCR in univariable and multivariable analyses. Assessment of sTILs showed moderate to good interobserver agreement. High sTILs (≥40%) were significantly associated with increased pCR rates, and this association was observer-independent. This retrospective study of a consecutive community-based cohort of TNBC patients confirms that sTILs are a robust, observer-independent predictor for therapeutic response after NAC. The combination of Sox10, GATA3 and p53 immunoreactivity is unlikely to harbor any predictive value for pCR in TNBC.
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Affiliation(s)
- Mieke R Van Bockstal
- Department of Pathology, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium; Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium; Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium.
| | - Fanchon Noel
- Department of Pathology, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium
| | - Yves Guiot
- Department of Pathology, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium
| | - Francois P Duhoux
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium; Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium; Department of Medical Oncology, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium
| | - Filomena Mazzeo
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium; Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium; Department of Medical Oncology, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium
| | - Cédric Van Marcke
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium; Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium; Department of Medical Oncology, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium
| | - Latifa Fellah
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium; Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium; Department of Radiology, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium
| | - Benjamin Ledoux
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium; Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium; Department of Oncologic Radiotherapy, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium
| | - Martine Berlière
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium; Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium
| | - Christine Galant
- Department of Pathology, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium; Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium; Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium
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A four-gene signature in the tumor microenvironment that significantly associates with the prognosis of patients with breast cancer. Gene 2020; 761:145049. [PMID: 32791092 DOI: 10.1016/j.gene.2020.145049] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/27/2020] [Accepted: 08/07/2020] [Indexed: 12/15/2022]
Abstract
Breast cancer (BRCA) is a highly heterogeneous disease due to the complicated microenvironment in the tumor, making the treatment benefits varied. Therefore, this study aims to identify a gene signature in the tumor microenvironment (TME) associated with the prognosis of BRCA patients. We downloaded the immune, stromal, and proliferation (ISP)-associated genes from the literature on BRCA. mRNA expression and clinical information obtained from The Cancer Genome Atlas (TCGA) were performed to identify the initial biomarker. Furthermore, we validated the robustness of the gene signature in the independent validation data set GSE20685. A four-gene signature in TME, including CD74, MMP9, RPA3, and SHCBP1, was constructed to predict the overall survival of BRCA. The survival time of the high-risk group was significantly worse than that of the low-risk group. Univariate and multivariate Cox regression analysis showed that our four-gene ISP signature was an independent prognostic factor in TCGA and GSE20685 data sets. The AUC suggested that our four-gene ISP signature was comparable to TNM classification at predicting the overall survival of BRCA patients. Interestingly, BRCA patients with high-risk scores were more likely to be associated with stromal and proliferation of cancer. In contrast, those with high-risk scores were more likely to be associated with tumor immunity-related pathway. We found an innovative biomarker in TME to predict the prognosis of BRCA. This signal might reflect the imbalance of TME and provide potential biomarkers for the individualized and precise treatment of BRCA.
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