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Kantapan J, Innuan P, Kongkarnka S, Sangthong P, Dechsupa N. Pentagalloyl Glucose from Bouea macrophylla Suppresses the Epithelial-Mesenchymal Transition and Synergizes the Doxorubicin-Induced Anticancer and Anti-Migration Effects in Triple-Negative Breast Cancer. Pharmaceuticals (Basel) 2024; 17:1729. [PMID: 39770571 PMCID: PMC11679756 DOI: 10.3390/ph17121729] [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: 11/25/2024] [Revised: 12/11/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Triple-negative breast cancer (TNBC) represents an aggressive form of breast cancer with few available therapeutic options. Chemotherapy, particularly with drugs like doxorubicin (DOX), remains the cornerstone of treatment for this challenging subtype. However, the clinical utility of DOX is hampered by adverse effects that escalate with higher doses and drug resistance, underscoring the need for alternative therapies. This study explored the efficacy of pentagalloyl glucose (PGG), a natural polyphenol derived from Bouea macrophylla, in enhancing DOX's anticancer effects and suppressing the epithelial-mesenchymal transition (EMT) in TNBC cells. Methods: This study employed diverse methodologies to assess the effects of PGG and DOX on TNBC cells. MDA-MB231 triple-negative breast cancer cells were used to evaluate cell viability, migration, invasion, apoptosis, mitochondrial membrane potential, and protein expression through techniques including MTT assays, wound healing assays, flow cytometry, Western blotting, and immunofluorescence. Results: Our findings demonstrate that PGG combined with DOX significantly inhibits TNBC cell proliferation, migration, and invasion. PGG enhances DOX-induced apoptosis by disrupting the mitochondrial membrane potential and activating caspase pathways; consequently, the activation of caspase-3 and the cleavage of PARP are increased. Additionally, the study shows that the combination treatment upregulates ERK signaling, further promoting apoptosis. Moreover, PGG reverses DOX-induced EMT by downregulating mesenchymal markers (vimentin and β-catenin) and upregulating epithelial markers (E-cadherin). Furthermore, it effectively inhibits STAT3 phosphorylation, associated with cell survival and migration. Conclusions: These results highlight the potential of PGG as an adjuvant therapy in TNBC treatment. PGG synergizes with DOX, which potentiates its anticancer effects while mitigating adverse reactions.
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Affiliation(s)
- Jiraporn Kantapan
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; (J.K.); (P.I.)
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Phattarawadee Innuan
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; (J.K.); (P.I.)
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Sarawut Kongkarnka
- Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Padchanee Sangthong
- Division of Biochemistry and Biochemical Innovation, Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; (J.K.); (P.I.)
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
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Moreira MP, Franco EP, Barros BAF, Anjos BRD, Almada DDG, Barbosa INT, Braga LDC, Cassali GD, Silva LM. Standard chemotherapy impacts on in vitro cellular heterogeneity in spheroids enriched with cancer stem cells (CSCs) derived from triple-negative breast cancer cell line. Biochem Biophys Res Commun 2024; 734:150765. [PMID: 39357337 DOI: 10.1016/j.bbrc.2024.150765] [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: 09/27/2024] [Accepted: 09/28/2024] [Indexed: 10/04/2024]
Abstract
Triple-negative breast cancer is a heterogeneous disease with high recurrence and mortality, linked to cancer stem cells (CSCs). Our study characterized distinct cell subpopulations and signaling pathways to explore chemoresistance. We observed cellular heterogeneity among and within the cells regarding phenotyping and drug response. In untreated BT-549 cells, we noted plasticity properties in both CD44+/CD24+/CD146+ hybrid cells and CD44-/CD24+/CD146+ epithelial cells, enabling phenotypic conversion into CD44+/CD24-/CD146- epithelial-mesenchymal transition (EMT)-like like breast CSCs (BCSCs). Additionally, non-BCSCs may give rise to ALDH+ epithelial-like BCSCs. Enriched BCSCs demonstrated the potential to differentiation into CD44-/CD24-/CD146- cells and exhibited self-renewal capabilities. Similar phenotypic plasticity was not observed in untreated Hs 578T and HMT-3522 S1 cells. BT-549 cells were more resistant to paclitaxel/PTX than to doxorubicin/DOX, a phenomenon potentially linked to the presence of CD24+ cells prior to treatment. Under the CSCs-enriched spheroids model, BT-549 demonstrated extreme resistance to DOX, likely due to the enrichment of BCSCs CD44+/CD24-/CD146- and the tumor cells CD44-/CD24-/CD146-. Additionally, DOX treatment induced the enrichment of plastic and chemoresistant cells, further exacerbating resistance mechanisms. BT-549 exhibited high heterogeneity, leading to significant alterations in cell subpopulations under BCSCs enrichment, demonstrating increased phenotypic plasticity during EMT. This phenomenon appears to play a major role in DOX resistance, as indicated by the presence of the refractory cells CD44+/CD24-/CD146- BCSCs EMT-like, CD44-/CD24-/CD146- tumor cells, and elevated STAT3 expression. Gene expression data from BT-549 CSCs-enriched spheroids suggests that ferroptosis may be occurring via autophagic regulation triggered by RAB7A, highlighting this gene as a potential therapeutic target.
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Affiliation(s)
- Milene Pereira Moreira
- Serviço de Biologia Celular, Diretoria de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias - Rua Conde Pereira Carneiro 80, Gameleira, Belo Horizonte, Minas Gerais, 30510-010, Brazil.
| | - Eliza Pereira Franco
- Serviço de Biologia Celular, Diretoria de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias - Rua Conde Pereira Carneiro 80, Gameleira, Belo Horizonte, Minas Gerais, 30510-010, Brazil
| | - Bárbara Avelar Ferreira Barros
- Serviço de Biologia Celular, Diretoria de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias - Rua Conde Pereira Carneiro 80, Gameleira, Belo Horizonte, Minas Gerais, 30510-010, Brazil; Programa de Pós-Graduação em Genética, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais - Avenida Presidente Antônio Carlos 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil
| | - Bianca Rocha Dos Anjos
- Serviço de Biologia Celular, Diretoria de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias - Rua Conde Pereira Carneiro 80, Gameleira, Belo Horizonte, Minas Gerais, 30510-010, Brazil; Programa de Pós-Graduação em Genética, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais - Avenida Presidente Antônio Carlos 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil
| | - Daniela de Gouvêa Almada
- Serviço de Biologia Celular, Diretoria de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias - Rua Conde Pereira Carneiro 80, Gameleira, Belo Horizonte, Minas Gerais, 30510-010, Brazil
| | - Isabela Nery Tavares Barbosa
- Serviço de Biologia Celular, Diretoria de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias - Rua Conde Pereira Carneiro 80, Gameleira, Belo Horizonte, Minas Gerais, 30510-010, Brazil
| | - Letícia da Conceição Braga
- Serviço de Biologia Celular, Diretoria de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias - Rua Conde Pereira Carneiro 80, Gameleira, Belo Horizonte, Minas Gerais, 30510-010, Brazil
| | - Geovanni Dantas Cassali
- Laboratório de Patologia Comparada, Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais - Avenida Presidente Antônio Carlos 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil
| | - Luciana Maria Silva
- Serviço de Biologia Celular, Diretoria de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias - Rua Conde Pereira Carneiro 80, Gameleira, Belo Horizonte, Minas Gerais, 30510-010, Brazil
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3
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Kaushal S, Gupta S, Shefrin S, Vora DS, Kaul SC, Sundar D, Wadhwa R, Dhanjal JK. Synthetic and Natural Inhibitors of Mortalin for Cancer Therapy. Cancers (Basel) 2024; 16:3470. [PMID: 39456564 PMCID: PMC11506508 DOI: 10.3390/cancers16203470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 10/08/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Upregulation of stress chaperone Mortalin has been closely linked to the malignant transformation of cells, tumorigenesis, the progression of tumors to highly aggressive stages, metastasis, drug resistance, and relapse. Various in vitro and in vivo assays have provided evidence of the critical role of Mortalin upregulation in promoting cancer cell characteristics, including proliferation, migration, invasion, and the inhibition of apoptosis, a consistent feature of most cancers. Given its critical role in several steps in oncogenesis and multi-modes of action, Mortalin presents a promising target for cancer therapy. Consequently, Mortalin inhibitors are emerging as potential anti-cancer drugs. In this review, we discuss various inhibitors of Mortalin (peptides, small RNAs, natural and synthetic compounds, and antibodies), elucidating their anti-cancer potentials.
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Affiliation(s)
- Shruti Kaushal
- Department of Computational Biology, Indraprastha Institute of Information Technology (IIIT) Delhi, Okhla Industrial Estate, Phase III, New Delhi 110020, India; (S.K.); (S.G.); (D.S.V.)
| | - Samriddhi Gupta
- Department of Computational Biology, Indraprastha Institute of Information Technology (IIIT) Delhi, Okhla Industrial Estate, Phase III, New Delhi 110020, India; (S.K.); (S.G.); (D.S.V.)
| | - Seyad Shefrin
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, New Delhi 110016, India; (S.S.); (D.S.)
| | - Dhvani Sandip Vora
- Department of Computational Biology, Indraprastha Institute of Information Technology (IIIT) Delhi, Okhla Industrial Estate, Phase III, New Delhi 110020, India; (S.K.); (S.G.); (D.S.V.)
| | - Sunil C. Kaul
- AIST-INDIA DAILAB, National Institute of Advanced Industrial Science & Technology (AIST), Central 4-1, Tsukuba 305-8565, Japan;
| | - Durai Sundar
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, New Delhi 110016, India; (S.S.); (D.S.)
- Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru 560100, India
| | - Renu Wadhwa
- AIST-INDIA DAILAB, National Institute of Advanced Industrial Science & Technology (AIST), Central 4-1, Tsukuba 305-8565, Japan;
| | - Jaspreet Kaur Dhanjal
- Department of Computational Biology, Indraprastha Institute of Information Technology (IIIT) Delhi, Okhla Industrial Estate, Phase III, New Delhi 110020, India; (S.K.); (S.G.); (D.S.V.)
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Wang C, Bai C, Zhang Z, Zhou H, Gao H, Wang S, Yuan Y. UGT1A7 altered HER2-positive breast cancer response to trastuzumab by affecting epithelial-to-mesenchymal transition: A potential biomarker to identify patients resistant to trastuzumab treatment. Cancer Gene Ther 2024; 31:1525-1535. [PMID: 39122832 DOI: 10.1038/s41417-024-00819-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 07/27/2024] [Accepted: 07/31/2024] [Indexed: 08/12/2024]
Abstract
HER2-positive (HER2+) breast cancer accounts for 20-30% of all breast cancers. Although trastuzumab has significantly improved the survival of patients with HER2+ breast cancer, more than 70% of patients develop drug resistance within one year of treatment. Differential-gene-expression analysis of trastuzumab-sensitive and resistant HER2+ breast cancer cell lines from GSE15043 was performed to identify the biomarkers associated with trastuzumab resistance. Differential biomarker expression was confirmed in FFPE tissues collected from clinical HER2+ breast cancer tumor samples that were sensitive or resistant to trastuzumab treatment. UGT1A7, a member of the uronic acid transferase family, was associated with trastuzumab resistance. UGT1A7 expression was downregulated in trastuzumab-resistant tumor tissues and in a cell line that developed trastuzumab resistance (BT474TR). Overexpressing UGT1A7 in BT474TR restored their sensitivity to trastuzumab treatment, whereas downregulating UGT1A7 expression in parental cells led to trastuzumab resistance. Importantly, UGT1A7 localized to the endoplasmic reticulum and altered stress responses. Furthermore, downregulating UGT1A7 expression promoted epithelial-to-mesenchymal transition (EMT) by affecting TWIST, SNAIL, and GRP78 expression and the AMP-activated protein kinase signaling pathway, thus contributing to trastuzumab resistance. This study demonstrated the important role and novel mechanisms of UGT1A7 in tumor responses to trastuzumab. Low UGT1A7 expression plays an important role in EMT and contributes to trastuzumab resistance. UGT1A7 has the potential to be developed as a biomarker for identifying patients who are resistant to trastuzumab treatment.
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Affiliation(s)
- Cong Wang
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Chenguang Bai
- Department of Radiology, Jiangsu Cancer Hospital &Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Zhe Zhang
- Department of Pathology, Jiangsu Cancer Hospital &Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Zhou
- Department of Chemotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Huanyao Gao
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Siwei Wang
- Department of Thoracic Surgery, Jiangsu Cancer Hospital &Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Yuan Yuan
- Department of Chemotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
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5
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Thakur C, Qiu Y, Pawar A, Chen F. Epigenetic regulation of breast cancer metastasis. Cancer Metastasis Rev 2024; 43:597-619. [PMID: 37857941 DOI: 10.1007/s10555-023-10146-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 10/02/2023] [Indexed: 10/21/2023]
Abstract
Breast cancer is the most frequently diagnosed malignancy and the second leading cause of cancer-related mortality among women worldwide. Recurrent metastasis is associated with poor patient outcomes and poses a significant challenge in breast cancer therapies. Cancer cells adapting to a new tissue microenvironment is the key event in distant metastasis development, where the disseminating tumor cells are likely to acquire genetic and epigenetic alterations during the process of metastatic colonization. Despite several decades of research in this field, the exact mechanisms governing metastasis are not fully understood. However, emerging body of evidence indicates that in addition to genetic changes, epigenetic reprogramming of cancer cells and the metastatic niche are paramount toward successful metastasis. Here, we review and discuss the latest knowledge about the salient attributes of metastasis and epigenetic regulation in breast cancer and crucial research domains that need further investigation.
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Affiliation(s)
- Chitra Thakur
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA.
| | - Yiran Qiu
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA
| | - Aashna Pawar
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA
| | - Fei Chen
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA.
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6
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Abdullaev B, Rasyid SA, Ali E, Al-Dhalimy AMB, Mustafa YF, Fenjan MN, Misra N, Al-Musawi SG, Alawadi A, Alsalamy A. Effective exosomes in breast cancer: focusing on diagnosis and treatment of cancer progression. Pathol Res Pract 2024; 253:154995. [PMID: 38113765 DOI: 10.1016/j.prp.2023.154995] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/17/2023] [Accepted: 11/27/2023] [Indexed: 12/21/2023]
Abstract
Breast cancer (BC) is the most prevalent aggressive malignant tumor in women worldwide and develops from breast tissue. Although cutting-edge treatment methods have been used and current mortality rates have decreased, BC control is still not satisfactory. Clarifying the underlying molecular mechanisms will help clinical options. Extracellular vesicles known as exosomes mediate cellular communication by delivering a variety of biomolecules, including proteins, oncogenes, oncomiRs, and even pharmacological substances. These transferable bioactive molecules can alter the transcriptome of target cells and affect signaling pathways that are related to tumors. Numerous studies have linked exosomes to BC biology, including therapeutic resistance and the local microenvironment. Exosomes' roles in tumor treatment resistance, invasion, and BC metastasis are the main topics of discussion in this review.
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Affiliation(s)
- Bekhzod Abdullaev
- Research Department of Biotechnology, New Uzbekistan University, Tashkent, Uzbekistan; Department of Oncology, School of Medicine, Central Asian University, Tashkent, Uzbekistan.
| | - Sri Anggarini Rasyid
- Faculty of Science and Technology, Mandala Waluya University, Kendari, South East Sulawesi, Indonesia.
| | - Eyhab Ali
- college of chemistry, Al-Zahraa University for Women, Karbala, Iraq
| | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Iraq
| | - Mohammed N Fenjan
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | - Neeti Misra
- Department of Management, Uttaranchal Institute of Management, Uttaranchal University, India
| | | | - Ahmed Alawadi
- College of technical engineering, the Islamic University, Najaf, Iraq; College of technical engineering, the Islamic University of Al Diwaniyah, Iraq; College of technical engineering, the Islamic University of Babylon, Iraq
| | - Ali Alsalamy
- College of technical engineering, Imam Ja'afar Al-Sadiq University, Iraq
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Wang X, Song Y, Yu L, Xue X, Pang M, Li Y, Luo X, Hua Z, Lu C, Lu A, Liu Y. Co-Delivery of Hesperetin and Cisplatin via Hyaluronic Acid-Modified Liposome for Targeted Inhibition of Aggression and Metastasis of Triple-Negative Breast Cancer. ACS APPLIED MATERIALS & INTERFACES 2023; 15:34360-34377. [PMID: 37432741 DOI: 10.1021/acsami.3c03233] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/12/2023]
Abstract
Having no specific therapy for triple-negative breast cancer (TNBC), this subtype has the lowest survival rate and highest metastatic risk of breast cancer since the tumor inflammatory microenvironment mainly accounts for heterogeneity-induced insensitivity to chemotherapy and epithelial-mesenchymal transition (EMT). This study reports hyaluronic acid (HA)-modified liposomes loaded with cisplatin (CDDP) and hesperetin (Hes) (CDDP-HA-Lip/Hes) for active targeting to relieve systematic toxicity and effective anti-tumor/anti-metastasis ability of TNBC. Our results revealed that HA modification promoted the cellular uptake of the synthesized CDDP-HA-Lip/Hes nanoparticles in MDA-MB-231 cells and accumulation in tumor sites in vivo, indicating deeper tumor penetration. Importantly, CDDP-HA-Lip/Hes inhibited the PI3K/Akt/mTOR pathway to alleviate the inflammation in the tumor and with a crosstalk to suppress the process of the EMT, increasing the chemosensitivity and inhibiting tumor metastasis. Meanwhile, CDDP-HA-Lip/Hes could significantly inhibit the aggression and metastasis of TNBC with less side effects on normal tissues. Overall, this study provides a tumor-targeting drug delivery system with great potential for treating TNBC and its lung metastasis robustly.
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Affiliation(s)
- Xiangpeng Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yurong Song
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Liuchunyang Yu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xiaoxia Xue
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Mingshi Pang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yang Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xinyi Luo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zhenglai Hua
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Aiping Lu
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong
| | - Yuanyan Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
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Lenda B, Żebrowska-Nawrocka M, Turek G, Balcerczak E. Zinc Finger E-Box Binding Homeobox Family: Non-Coding RNA and Epigenetic Regulation in Gliomas. Biomedicines 2023; 11:biomedicines11051364. [PMID: 37239035 DOI: 10.3390/biomedicines11051364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/26/2023] [Accepted: 05/03/2023] [Indexed: 05/28/2023] Open
Abstract
Gliomas are the most common malignant brain tumours. Among them, glioblastoma (GBM) is a grade four tumour with a median survival of approximately 15 months and still limited treatment options. Although a classical epithelial to mesenchymal transition (EMT) is not the case in glioma due to its non-epithelial origin, the EMT-like processes may contribute largely to the aggressive and highly infiltrative nature of these tumours, thus promoting invasive phenotype and intracranial metastasis. To date, many well-known EMT transcription factors (EMT-TFs) have been described with clear, biological functions in glioma progression. Among them, EMT-related families of molecules such as SNAI, TWIST and ZEB are widely cited, well-established oncogenes considering both epithelial and non-epithelial tumours. In this review, we aimed to summarise the current knowledge with a regard to functional experiments considering the impact of miRNA and lncRNA as well as other epigenetic modifications, with a main focus on ZEB1 and ZEB2 in gliomas. Although we explored various molecular interactions and pathophysiological processes, such as cancer stem cell phenotype, hypoxia-induced EMT, tumour microenvironment and TMZ-resistant tumour cells, there is still a pressing need to elucidate the molecular mechanisms by which EMT-TFs are regulated in gliomas, which will enable researchers to uncover novel therapeutic targets as well as improve patients' diagnosis and prognostication.
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Affiliation(s)
- Bartosz Lenda
- Laboratory of Molecular Diagnostics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, BRaIN Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
| | - Marta Żebrowska-Nawrocka
- Laboratory of Molecular Diagnostics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, BRaIN Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
| | - Grzegorz Turek
- Department of Neurosurgery, Bródnowski Masovian Hospital, Kondratowicza 8, 03-242 Warsaw, Poland
| | - Ewa Balcerczak
- Laboratory of Molecular Diagnostics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, BRaIN Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
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9
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Loric S, Denis JA, Desbene C, Sabbah M, Conti M. Extracellular Vesicles in Breast Cancer: From Biology and Function to Clinical Diagnosis and Therapeutic Management. Int J Mol Sci 2023; 24:7208. [PMID: 37108371 PMCID: PMC10139222 DOI: 10.3390/ijms24087208] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/03/2023] [Accepted: 04/09/2023] [Indexed: 04/29/2023] Open
Abstract
Breast cancer (BC) is the first worldwide most frequent cancer in both sexes and the most commonly diagnosed in females. Although BC mortality has been thoroughly declining over the past decades, there are still considerable differences between women diagnosed with early BC and when metastatic BC is diagnosed. BC treatment choice is widely dependent on precise histological and molecular characterization. However, recurrence or distant metastasis still occurs even with the most recent efficient therapies. Thus, a better understanding of the different factors underlying tumor escape is mainly mandatory. Among the leading candidates is the continuous interplay between tumor cells and their microenvironment, where extracellular vesicles play a significant role. Among extracellular vesicles, smaller ones, also called exosomes, can carry biomolecules, such as lipids, proteins, and nucleic acids, and generate signal transmission through an intercellular transfer of their content. This mechanism allows tumor cells to recruit and modify the adjacent and systemic microenvironment to support further invasion and dissemination. By reciprocity, stromal cells can also use exosomes to profoundly modify tumor cell behavior. This review intends to cover the most recent literature on the role of extracellular vesicle production in normal and cancerous breast tissues. Specific attention is paid to the use of extracellular vesicles for early BC diagnosis, follow-up, and prognosis because exosomes are actually under the spotlight of researchers as a high-potential source of liquid biopsies. Extracellular vesicles in BC treatment as new targets for therapy or efficient nanovectors to drive drug delivery are also summarized.
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Affiliation(s)
- Sylvain Loric
- INSERM U538, CRSA, Saint-Antoine University Hospital, 75012 Paris, France; (J.A.D.)
| | | | - Cédric Desbene
- INSERM U538, CRSA, Saint-Antoine University Hospital, 75012 Paris, France; (J.A.D.)
| | - Michèle Sabbah
- INSERM U538, CRSA, Saint-Antoine University Hospital, 75012 Paris, France; (J.A.D.)
| | - Marc Conti
- INSERM U538, CRSA, Saint-Antoine University Hospital, 75012 Paris, France; (J.A.D.)
- INTEGRACELL SAS, 91160 Longjumeau, France
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Mui CW, Chan WN, Chen B, Cheung AHK, Yu J, Lo KW, Ke H, Kang W, To KF. Targeting YAP1/TAZ in nonsmall-cell lung carcinoma: From molecular mechanisms to precision medicine. Int J Cancer 2023; 152:558-571. [PMID: 35983734 DOI: 10.1002/ijc.34249] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/28/2022] [Accepted: 08/08/2022] [Indexed: 02/01/2023]
Abstract
Accumulating evidence has underscored the importance of the Hippo-YAP1 signaling in lung tissue homeostasis, whereas its deregulation induces tumorigenesis. YAP1 and its paralog TAZ are the key downstream effectors tightly controlled by the Hippo pathway. YAP1/TAZ exerts oncogenic activities by transcriptional regulation via physical interaction with TEAD transcription factors. In solid tumors, Hippo-YAP1 crosstalks with other signaling pathways such as Wnt/β-catenin, receptor tyrosine kinase cascade, Notch and TGF-β to synergistically drive tumorigenesis. As YAP1/TAZ expression is significantly correlated with unfavorable outcomes for the patients, small molecules have been developed for targeting YAP1/TAZ to get a therapeutic effect. In this review, we summarize the recent findings on the deregulation of Hippo-YAP1 pathway in nonsmall cell lung carcinoma, discuss the molecular mechanisms of its dysregulation in leading to tumorigenesis, explore the therapeutic strategies for targeting YAP1/TAZ, and provide the research directions for deep investigation. We believe that detailed delineation of Hippo-YAP1 regulation in tumorigenesis provides novel insight for accurate therapeutic intervention.
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Affiliation(s)
- Chun Wai Mui
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Wai Nok Chan
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Bonan Chen
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Alvin Ho-Kwan Cheung
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Jun Yu
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Kwok Wai Lo
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Huixing Ke
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
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11
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Zhou H, Yun X, Shu Y, Xu K. Aspirin increases the efficacy of gemcitabine in pancreatic cancer by modulating the PI3K/AKT/mTOR signaling pathway and reversing epithelial‑mesenchymal transition. Oncol Lett 2023; 25:101. [PMID: 36817049 PMCID: PMC9932045 DOI: 10.3892/ol.2023.13687] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 11/15/2022] [Indexed: 02/04/2023] Open
Abstract
Gemcitabine is regarded as a standard medication for patients with pancreatic cancer. The aim of the present study was to investigate the impact of aspirin (ASA) on the efficacy of gemcitabine in pancreatic cancer and the potential mechanism. The SW1990 and BxPC-3 human pancreatic cell lines were treated with 2 mmol/l ASA and/or 1 mg/l gemcitabine. The effects of the treatments were tested on the viability, migration and invasion of the cells using MTT, wound healing and Transwell invasion assays. In addition, cell apoptosis was evaluated via flow cytometry with Annexin V-FITC/PI and the western blotting of Bax and Bcl-2. The expression of epithelial-mesenchymal transition (EMT)-associated proteins and activation of the PI3K/AKT/mTOR pathway were also assessed using western blotting. The results reveal that ASA increased the efficacy of gemcitabine in reducing the proliferation, migration and invasion of pancreatic cancer cells and increasing their apoptosis. These effects are associated with inhibition of the PI3K/AKT/mTOR pathway and the reversal of EMT. Thus, the combined use of ASA and gemcitabine is suggested to be a potential therapeutic strategy for patients with pancreatic cancer.
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Affiliation(s)
- Hanyu Zhou
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China,Department of Oncology, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215006, P.R. China,Department of Oncology, Suzhou Municipal Hospital, Suzhou, Jiangsu 215001, P.R. China,Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China
| | - Xiao Yun
- Department of General Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China,Department of Oncology, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215006, P.R. China,Department of Oncology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China,Dr Yongqian Shu, Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Gulou, Nanjing, Jiangsu 210029, P.R. China, E-mail:
| | - Kequn Xu
- Department of Oncology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China,Correspondence to: Dr Kequn Xu, Department of Oncology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, 29 Xinglong Lane, Tianning, Changzhou, Jiangsu 213003, P.R. China, E-mail:
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12
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Exosomes derived from MDR cells induce cetuximab resistance in CRC via PI3K/AKT signaling‑mediated Sox2 and PD‑L1 expression. Exp Ther Med 2023; 25:86. [PMID: 36741914 PMCID: PMC9852420 DOI: 10.3892/etm.2023.11785] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 07/11/2022] [Indexed: 01/05/2023] Open
Abstract
The anti-EGFR antibody cetuximab is used as a first-line targeted therapeutic drug in colorectal cancer. It has previously been reported that the efficacy of the EGFR antibody cetuximab is limited by the emergence of acquired drug resistance. In our previous study the transmissibility effect of exosomes from drug resistant tumor cells to sensitive tumor cells was identified. It can therefore be hypothesized that drug resistant cells might affect neighboring and distant cells via regulation of exosome composition and behavior. However, the mechanism of exosomes in KRAS-wild-type colorectal cancer (CRC) remains unknown. In the present study, functional analysis of overall survival post-diagnosis in patients with KRAS wild-type and those with mutant CRC was performed using human CRC specimens. Furthermore, it was demonstrated that multidrug resistance (MDR) cancer cell-derived exosomes were potentially a key factor, which promoted cetuximab-resistance in CRC cells and reduced the inhibitory effect of cetuximab in CRC xenograft models. The Cell Counting Kit-8 and colony formation assays were performed to assess the effects of exosomes derived from CRC/MDR cells on cetuximab resistance. Sphere formation assay results demonstrated that exosomes derived from CRC/MDR cells altered the self-renewal and multipotential ability of stem-cell-associated markers and facilitated resistance to cetuximab in cetuximab-sensitive cells. Furthermore, exosomes derived from CRC/MDR cells decreased sensitivity to cetuximab via the activation of PI3K/AKT signaling, which promoted Sox2 and programmed death-ligand 1 (PD-L1) mRNA and protein expression according to reverse transcription-quantitative PCR, western blotting and immunohistochemistry analyses, as well as apoptosis resistance both in vitro and in vivo according to a TUNEL assay. In conclusion, the results of the present study demonstrated that exosomes derived from CRC/MDR cells may promote cetuximab resistance in KRAS wild-type cells via activation of the PI3K/AKT signaling pathway-mediated expression of Sox2 and PD-L1, which will be useful for investigating a potential clinical target in predicting cetuximab resistance.
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13
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Li Y, Liu R, Han X, Xu W, Liu Y. PLAGL2 increases adriamycin resistance and EMT in breast cancer cells by activating the Wnt pathway. Genes Genomics 2023; 45:49-57. [PMID: 36399309 DOI: 10.1007/s13258-022-01330-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 10/14/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Adriamycin (ADR) is an effective treatment for breast cancer; nevertheless, it is often linked with acquired resistance in breast cancer cells, reducing ADR's therapeutic efficacy and increasing the risk of recurrence and poor prognosis. It has been revealed that the zinc-finger transcription factor pleomorphic adenoma gene like-2 (PLAGL2) is required for epithelial to mesenchymal transition (EMT) in cancer cells. Recent data indicates that PLAGL2 is also involved in regulating chemotherapeutic drug resistance, albeit the exact mechanism by which this happens remains unknown. OBJECTIVE This study examines the effect of PLAGL2 on adriamycin resistance and EMT in breast cancer cells. METHODS The small interfering RNA (siRNA) targeting PLAGL2 was transfected to breast cancer cells to alter PLAGL2 expression. Cell counting kit-8 (CCK-8) and colony formation assay detected cell growth and proliferation rate. Moreover, wound-healing and transwell assays were conducted to evaluate migration and invasion. Western blot (WB) checked the apoptosis and EMT-associated proteins. RESULTS PLAGL2 expression is associated with breast cancer cells' acquired resistance to ADR in this investigation. Additionally, deletion of PLAGL2 was associated with enhanced sensitivity to ADR, reduced proliferation, migration, and invasion capabilities, increased E-cadherin levels, and reduced Wnt6, β-catenin, and DVL1 levels in ADR-resistant breast cancer cells (MCF-7/ADR and MDA-MB-231/ADR cells). PLAGL2 could bind to the promoter region of Wnt6 and promote its expression. Additionally, the results of this research established that Wnt signaling is implicated in breast cancer cells' resistance to ADR since BML-284, a Wnt signaling activator partly restored the sensitivity of MCF-7/ADR and MDA-MB-231/ADR cells to ADR. CONCLUSION PLAGL2 promotes adriamycin resistance and cell aggressiveness in breast cancer cells via activating the Wnt signaling pathway.
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Affiliation(s)
- Yuxiao Li
- Department of Basic Teaching, Zhuhai Campus of Zunyi Medical University, 368 Jinwan Road, Zhuhai, 519041, Guangdong, China
| | - Ruolin Liu
- College of Basic Medicine, Hebei Medical University, Shijiazhuang, 050000, China
| | - Xingzhao Han
- Department of Basic Teaching, Zhuhai Campus of Zunyi Medical University, 368 Jinwan Road, Zhuhai, 519041, Guangdong, China
| | - Wei Xu
- Business School of International Medicine, China Pharmaceutical University, Nanjing, 210009, China
| | - Yahui Liu
- Department of Basic Teaching, Zhuhai Campus of Zunyi Medical University, 368 Jinwan Road, Zhuhai, 519041, Guangdong, China.
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14
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Hagag S, Kodous A, Shaaban HA. Molecular and Immunohistochemical Alterations in Breast Cancer Patients in Upper Egypt. Rep Biochem Mol Biol 2023; 11:532-546. [PMID: 37131903 PMCID: PMC10149126 DOI: 10.52547/rbmb.11.4.532] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/30/2022] [Indexed: 05/04/2023]
Abstract
Background Breast cancer (BC) plays a major public health in Egyptian woman. In Upper Egypt, there is an increase in incidence of BC compared to other Egyptian areas. Triple-negative BC, estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-neu-negative, is a high-risk BC that lacks the benefit of specific therapy that targets these proteins. Accurate determination of Caveolin-1(Cav-1), Caveolin-2 (Cav-2) and HER-2/neu status have become of major clinical significance in BC by focusing about its role as a tumor marker for response to different therapies. Methods The present study was performed on 73 female BC patients in the South Egypt Cancer Institute. Blood samples were used for Cav-1, Cav-2, and HER-2/neu genes amplification and expression. In addition, immunohistological analysis of mammaglobin, GATA3, ER, PR, and HER-2/neu was done. Results There was a statistically significant association between Cav-1, 2 and HER-2/neu genes expression and the age of patients (P< 0.001). There are increase in the level of Cav-1, 2 and increase in HER-2/neu mRNA expression in groups treated with chemotherapy and group treated with both chemotherapy and radiotherapy compared to each group baseline level of genes mRNA expression before treatment. On the contrary, the group treated with chemotherapy, radiotherapy and hormonal therapy revealed increase on the level of Cav-1, 2 and HER-2/neu mRNA expression when compared with their baseline for the same patients before treatment. Conclusions Noninvasive molecular biomarkers such as Cav-1 and Cav-2 have been proposed for use in the diagnosis and prognosis for women with BC.
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Affiliation(s)
- Sanaa Hagag
- Radiation Biology department, National Center for Radiation Research & Technology, Egyptian Atomic Energy Authority, Nasr City, 8029, Cairo, Egypt.
| | - Ahmad Kodous
- Radiation Biology department, National Center for Radiation Research & Technology, Egyptian Atomic Energy Authority, Nasr City, 8029, Cairo, Egypt.
- Corresponding author: Ahmad Kodous; Tel: +20 1144496363; E-mail:
| | - Hebat Aallh Shaaban
- Pathology department, National Cancer Institute, Cairo University, Giza, Egypt.
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15
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Inoue S, Imanishi M, Kanzaki A, Fujimoto A, Maeyama M, Okamoto A, Matsuda H, Yoshikawa K, Takahashi R. Role of Cancer Stem-like Cells in the Process of Invasion and Mesenchymal Transformation by a Reconstituted Triple-negative Breast Cancer Cell Population Resistant to p53-induced Apoptosis. Acta Histochem Cytochem 2022; 55:169-184. [PMID: 36405550 PMCID: PMC9631983 DOI: 10.1267/ahc.22-00076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 09/06/2022] [Indexed: 09/09/2023] Open
Abstract
We investigated the role of cancer stem cells (CSCs) in a population of triple-negative breast cancer (TNBC) cells that are resistant to apoptosis. A human breast cancer cell population capable of inducing p53 expression with doxycycline (Dox) was created and used as an untreated control (UT). After the addition of Dox to UT for 5 days, the cell population reconstituted with cells showing resistance to apoptosis was named RE. Fluorescence-activated cell sorting (FACS) and immunostaining revealed that after the addition of Dox, the ratio of cells in the S and G2/M phases decreased in UT as apoptosis proceeded, but did not markedly change in apoptosis-resistant RE. CSC-like cells in RE exhibited a cell morphology with a larger ratio of the major/minor axis than UT. FACS showed that RE had a higher proportion of CSC-like cells and contained more CD44+CD24- mesenchymal CSCs than ALDH1A3+ epithelial-like CSCs. In a Matrigel invasion assay, UT was more likely to form a three-dimensional cell population, whereas RE exhibited a planar population, higher migration ability, and the up-regulated expression of epithelial-mesenchymal transition-related genes. These results provide insights into the mechanisms by which TNBC cells acquire treatment resistance at the time of recurrence.
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Affiliation(s)
- Sana Inoue
- Graduate School of Pharmaceutical Sciences Doshisha Women’s College of Liberal Arts, Kyoto, Japan
- Faculty of Pharmaceutical Sciences Doshisha Women’s College of Liberal Arts, Kyoto, Japan
| | - Miki Imanishi
- Faculty of Pharmaceutical Sciences Doshisha Women’s College of Liberal Arts, Kyoto, Japan
| | - Ai Kanzaki
- Faculty of Pharmaceutical Sciences Doshisha Women’s College of Liberal Arts, Kyoto, Japan
| | - Atsumi Fujimoto
- Faculty of Pharmaceutical Sciences Doshisha Women’s College of Liberal Arts, Kyoto, Japan
| | - Marina Maeyama
- Faculty of Pharmaceutical Sciences Doshisha Women’s College of Liberal Arts, Kyoto, Japan
| | - Ayaka Okamoto
- Faculty of Pharmaceutical Sciences Doshisha Women’s College of Liberal Arts, Kyoto, Japan
| | - Hiroka Matsuda
- Faculty of Pharmaceutical Sciences Doshisha Women’s College of Liberal Arts, Kyoto, Japan
| | - Kiyotsugu Yoshikawa
- Faculty of Pharmaceutical Sciences Doshisha Women’s College of Liberal Arts, Kyoto, Japan
| | - Rei Takahashi
- Graduate School of Pharmaceutical Sciences Doshisha Women’s College of Liberal Arts, Kyoto, Japan
- Faculty of Pharmaceutical Sciences Doshisha Women’s College of Liberal Arts, Kyoto, Japan
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16
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Thakur C, Carruthers NJ, Zhang Q, Xu L, Fu Y, Bi Z, Qiu Y, Zhang W, Wadgaonkar P, Almutairy B, Guo C, Stemmer PM, Chen F. Depletion of Mdig Changes Proteomic Profiling in Triple Negative Breast Cancer Cells. Biomedicines 2022; 10:2021. [PMID: 36009568 PMCID: PMC9405604 DOI: 10.3390/biomedicines10082021] [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] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
Triple-negative breast cancers are highly aggressive with an overall poor prognosis and limited therapeutic options. We had previously investigated the role of mdig, an oncogenic gene induced by some environmental risk factors, on the pathogenesis of breast cancer. However, a comprehensive analysis of the proteomic profile affected by mdig in triple-negative breast cancer has not been determined yet. Using label-free bottom-up quantitative proteomics, we compared wildtype control and mdig knockout MDA-MB-231 cells and identified the proteins and pathways that are significantly altered with mdig deletion. A total of 904 differentially expressed (p < 0.005) proteins were identified in the KO cells. Approximately 30 pathways and networks linked to the pathogenicity of breast cancer were either up- or downregulated, such as EIF2 signaling, the unfolded protein response, and isoleucine degradation I. Ingenuity Pathway Analysis established that the differentially expressed proteins have relevant biological actions in cell growth, motility, and malignancy. These data provide the first insight into protein expression patterns in breast cancer associated with a complete disruption of the mdig gene and yielded substantial information on the key proteins, biological processes, and pathways modulated by mdig that contribute to breast cancer tumorigenicity and invasiveness.
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Affiliation(s)
- Chitra Thakur
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, The State University of New York, Lauterbur Drive, Stony Brook, NY 11794, USA
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, 101 Nicolls Road, Stony Brook, NY 11794, USA
| | - Nicholas J. Carruthers
- Institute of Environmental Health Sciences, Wayne State University, 2309 Scott Hall, 540 E Canfield Ave, Detroit, MI 48202, USA
| | - Qian Zhang
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Liping Xu
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Yao Fu
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, The State University of New York, Lauterbur Drive, Stony Brook, NY 11794, USA
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Zhuoyue Bi
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, The State University of New York, Lauterbur Drive, Stony Brook, NY 11794, USA
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Yiran Qiu
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, The State University of New York, Lauterbur Drive, Stony Brook, NY 11794, USA
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Wenxuan Zhang
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, The State University of New York, Lauterbur Drive, Stony Brook, NY 11794, USA
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Priya Wadgaonkar
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Bandar Almutairy
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Chunna Guo
- Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201, USA
| | - Paul M. Stemmer
- Institute of Environmental Health Sciences, Wayne State University, 2309 Scott Hall, 540 E Canfield Ave, Detroit, MI 48202, USA
| | - Fei Chen
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, The State University of New York, Lauterbur Drive, Stony Brook, NY 11794, USA
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, 101 Nicolls Road, Stony Brook, NY 11794, USA
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17
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Javdani H, Mollaei H, Karimi F, Mahmoudi S, Farahi A, Mirzaei-Parsa MJ, Shahabi A. Review article epithelial to mesenchymal transition‑associated microRNAs in breast cancer. Mol Biol Rep 2022; 49:9963-9973. [PMID: 35716288 DOI: 10.1007/s11033-022-07553-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 04/27/2022] [Accepted: 05/03/2022] [Indexed: 10/18/2022]
Abstract
Despite major advances, breast cancer (BC) is the most commonly diagnosed carcinoma and remains a deadly disease among women worldwide. Many researchers point toward an important role of an epithelial to mesenchymal transition (EMT) in BC development and promoting metastasis. Here, will be discussed that how functional changes of transcription factors, signaling pathways, and microRNAs (miRNA) in BC promote EMT. A thorough understanding the EMT biology can be important to determine reversing the process and design treatment approaches. There are frequent debates as to whether EMT is really relevant to BC in vivo, in which due to the intrinsic heterogeneity and tumor microenvironment. Nevertheless, given the importance of EMT in cancer progression and metastasis, the implementation of therapies against cancer-associated EMT will continue to help us develop and test potential treatments.
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Affiliation(s)
- Hossein Javdani
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Homa Mollaei
- Department of Biology, Faculty of Sciences, University of Birjand, Birjand, Iran
| | - Farzaneh Karimi
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Shiva Mahmoudi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Farahi
- Student Research Committee, Department of Molecular Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohamad Javad Mirzaei-Parsa
- Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Arman Shahabi
- Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran. .,Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, P. O. Box: 7618747653, Kerman, Iran.
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18
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Ye HS, Gao HF, Li H, Nie JH, Li TT, Lu MD, Wu ML, Liu J, Wang K. Higher efficacy of resveratrol against advanced breast cancer organoids: A comparison with that of clinically relevant drugs. Phytother Res 2022; 36:3313-3324. [PMID: 35649509 DOI: 10.1002/ptr.7515] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/13/2022] [Accepted: 05/10/2022] [Indexed: 12/24/2022]
Abstract
The lack of reliable drugs is a therapeutic challenge of advanced breast cancers (ABCs). Resveratrol (Res) exerts inhibitory effects on breast cancer cell lines and animal models, while its efficacy against individual breast cancer cases remains unknown. This study aims to use ABC-derived organoids (ABCOs) as the ex vivo therapeutic platform to clarify the effectiveness of resveratrol against different ABC subtypes. Immunohistochemical staining confirmed that the ABCOs maintained their original tumors' ER, PR, HER2, and Ki67 expression patterns. ABCO proliferation and viability tests showed >50% cell death rates in 79.2% (19/24) of Res-treated, 28.6% (2/7) fulvestrant-treated, 66.7% (4/6) paclitaxel-treated, and 66.7% (6/9) gemcitabine-treated ABCOs. pSTAT3 nuclear translocation was more frequent in Res-sensitive (17/19; 89.47%) than that (1/5; 20%) of Res-insensitive ABCOs, which were suppressed upon Res treatment. Statistical analysis revealed a close correlation of STAT3 activation with the efficacy of Res, but not related to tumor receptor expression patterns (ER, PR, HER2) and pathological classification. We demonstrate for the first time the higher efficacy and broader spectrum of Res against different subtypes of ABCOs in comparison with that of conventional antibreast cancer drugs, providing an alternative approach for better management of ABCs.
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Affiliation(s)
- Hai-Shan Ye
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Hong-Fei Gao
- Breast Cancer Department, Cancer Center, Guangdong Provincial People's Hospital Affiliated to South China University of Technology School of Medicine, Guangzhou, China
| | - Hong Li
- BioMed Laboratory, Jingke Biotechnology Group, Guangzhou, China.,Liaoning Laboratory of Cancer Genetics and Epigenetics, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Jun-Hua Nie
- School of Medicine, South China University of Technology, Guangzhou, China.,BioMed Laboratory, Jingke Biotechnology Group, Guangzhou, China
| | - Ting-Ting Li
- BioMed Laboratory, Jingke Biotechnology Group, Guangzhou, China
| | - Meng-Di Lu
- School of Medicine, South China University of Technology, Guangzhou, China.,BioMed Laboratory, Jingke Biotechnology Group, Guangzhou, China
| | - Mo-Li Wu
- Liaoning Laboratory of Cancer Genetics and Epigenetics, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Jia Liu
- School of Medicine, South China University of Technology, Guangzhou, China.,Liaoning Laboratory of Cancer Genetics and Epigenetics, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Kun Wang
- Breast Cancer Department, Cancer Center, Guangdong Provincial People's Hospital Affiliated to South China University of Technology School of Medicine, Guangzhou, China
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19
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Saini G, Joshi S, Garlapati C, Li H, Kong J, Krishnamurthy J, Reid MD, Aneja R. Polyploid giant cancer cell characterization: New frontiers in predicting response to chemotherapy in breast cancer. Semin Cancer Biol 2022; 81:220-231. [PMID: 33766651 PMCID: PMC8672208 DOI: 10.1016/j.semcancer.2021.03.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/19/2021] [Accepted: 03/20/2021] [Indexed: 02/07/2023]
Abstract
Although polyploid cells were first described nearly two centuries ago, their ability to proliferate has only recently been demonstrated. It also becomes increasingly evident that a subset of tumor cells, polyploid giant cancer cells (PGCCs), play a critical role in the pathophysiology of breast cancer (BC), among other cancer types. In BC, PGCCs can arise in response to therapy-induced stress. Their progeny possess cancer stem cell (CSC) properties and can repopulate the tumor. By modulating the tumor microenvironment (TME), PGCCs promote BC progression, chemoresistance, metastasis, and relapse and ultimately impact the survival of BC patients. Given their pro- tumorigenic roles, PGCCs have been proposed to possess the ability to predict treatment response and patient prognosis in BC. Traditionally, DNA cytometry has been used to detect PGCCs.. The field will further derive benefit from the development of approaches to accurately detect PGCCs and their progeny using robust PGCC biomarkers. In this review, we present the current state of knowledge about the clinical relevance of PGCCs in BC. We also propose to use an artificial intelligence-assisted image analysis pipeline to identify PGCC and map their interactions with other TME components, thereby facilitating the clinical implementation of PGCCs as biomarkers to predict treatment response and survival outcomes in BC patients. Finally, we summarize efforts to therapeutically target PGCCs to prevent chemoresistance and improve clinical outcomes in patients with BC.
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Affiliation(s)
- Geetanjali Saini
- Department of Biology, Georgia State University, Atlanta, GA, USA
| | - Shriya Joshi
- Department of Biology, Georgia State University, Atlanta, GA, USA
| | | | - Hongxiao Li
- Department of Mathematics and Statistics, Georgia State University, Atlanta, GA, USA; Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jun Kong
- Department of Mathematics and Statistics, Georgia State University, Atlanta, GA, USA; Department of Computer Science, Georgia State University, Atlanta, GA, USA; Department of Computer Science, Emory University, Atlanta, GA, USA
| | | | - Michelle D Reid
- Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Ritu Aneja
- Department of Biology, Georgia State University, Atlanta, GA, USA.
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20
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Huang Y, Jia M, Yang X, Han H, Hou G, Bi L, Yang Y, Zhang R, Zhao X, Peng C, Ouyang X. Annexin A2: The Diversity of Pathological Effects in Tumorigenesis and Immune Response. Int J Cancer 2022; 151:497-509. [PMID: 35474212 DOI: 10.1002/ijc.34048] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 04/12/2022] [Accepted: 04/14/2022] [Indexed: 11/11/2022]
Abstract
Annexin A2 (ANXA2) is widely used as a marker in a variety of tumors. By regulating multiple signal pathways, ANXA2 promotes the epithelial-mesenchymal transition, which can cause tumorigenesis and accelerate thymus degeneration. The elevated ANXA2 heterotetramer facilitates the production of plasmin, which participates in pathophysiologic processes such as tumor cell invasion and metastasis, bleeding diseases, angiogenesis, inducing the expression of inflammatory factors. In addition, the ANXA2 on the cell membrane mediates immune response via its interaction with surface proteins of pathogens, C1q, toll-like receptor 2, anti-dsDNA antibodies and immunoglobulins. Nuclear ANXA2 plays a role as part of a primer recognition protein complex that enhances DNA synthesis and cells proliferation by acting on the G1-S phase of the cell. ANXA2 reduction leads to the inhibition of invasion and metastasis in multiple tumor cells, bleeding complications in acute promyelocytic leukemia, retinal angiogenesis, autoimmunity response and tumor drug resistance. In this review, we provide an update on the pathological effects of ANXA2 in both tumorigenesis and the immune response. We highlight ANXA2 as a critical protein in numerous malignancies and the immune host response.
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Affiliation(s)
- Yanjie Huang
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China.,Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, China
| | - Mengzhen Jia
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xiaoqing Yang
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, China
| | - Hongyan Han
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Gailing Hou
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Liangliang Bi
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, China
| | - Yueli Yang
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, China
| | - Ruoqi Zhang
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xueru Zhao
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Chaoqun Peng
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xinshou Ouyang
- Department of Internal Medicine, Digestive Disease Section, Yale University, New Haven, Ct, USA
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21
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Mesenchymal Stem Cell-Derived Extracellular Vesicles: Pleiotropic Impacts on Breast Cancer Occurrence, Development, and Therapy. Int J Mol Sci 2022; 23:ijms23062927. [PMID: 35328347 PMCID: PMC8954385 DOI: 10.3390/ijms23062927] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/03/2022] [Accepted: 03/06/2022] [Indexed: 01/27/2023] Open
Abstract
Breast cancer (BC) is one of the most devastating cancers, with high morbidity and mortality, among the female population worldwide. In BC, mesenchymal stem cells (MSCs), as pluripotent stromal stem cells, play a significant role in TME formation and tumor progression. Recently, an increasing number of studies have demonstrated that extracellular vesicles (EVs) are essential for the crosstalk between MSCs and BC cells. MSC-derived EVs (MSC-EVs) can deliver a diversity of molecules, including lipids, proteins, and nucleic acids, etc., to target cells, and produce corresponding effects. Studies have demonstrated that MSC-EVs exert both inhibitory and promotive effects in different situations and different stages of BC. Meanwhile, MSC-EVs provide novel therapeutic options for BC, such as EVs as carriers for drug delivery. Therefore, in this review, we summarize the role of MSC-EVs in BC progression and application in clinical treatment, in the hope of providing a basis for further research.
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22
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Integrating mutational and nonmutational mechanisms of acquired therapy resistance within the Darwinian paradigm. Trends Cancer 2022; 8:456-466. [DOI: 10.1016/j.trecan.2022.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 02/07/2023]
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23
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Cao L, Bridle KR, Shrestha R, Prithviraj P, Crawford DHG, Jayachandran A. CD73 and PD-L1 as Potential Therapeutic Targets in Gallbladder Cancer. Int J Mol Sci 2022; 23:ijms23031565. [PMID: 35163489 PMCID: PMC8836068 DOI: 10.3390/ijms23031565] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/21/2022] [Accepted: 01/28/2022] [Indexed: 12/24/2022] Open
Abstract
Gallbladder cancer (GBC) is one of the most common and aggressive biliary tract cancers with a dismal prognosis. Ongoing clinical trials are evaluating a few selected immune checkpoint inhibitors (ICIs) as monotherapy for the treatment of GBC patients. However, only a subset of patients benefits from these treatments. To improve ICI therapy response, molecular mechanisms that confer resistance to immune checkpoint (IC) blockade needs to be explored. Epithelial-to-mesenchymal transition (EMT) program and cancer stem cells (CSCs) have been implicated as key processes that confer ICI treatment resistance. However, in GBC the EMT-CSC-IC axis has not yet been clearly elucidated. This study aims to examine the aberrant expression of ICs associated with CSC and EMT. We successfully enriched CSCs by utilizing a 3-dimensional culture system and established a reversible EMT model with human GBC NOZ cell line. Notably, ICs CD73 and PD-L1 were closely associated with both CSC and EMT phenotypes. Knockdown of CD73 or PD-L1 reduced the proliferative and motile abilities of both adherent monolayers and anchorage-free spheroids. In conclusion, blocking CD73 and PD-L1 offer a promising therapeutic strategy for targeting highly aggressive populations with CSC and EMT phenotype to improve GBC patient prognosis.
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Affiliation(s)
- Lu Cao
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (L.C.); (K.R.B.); (R.S.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Kim R. Bridle
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (L.C.); (K.R.B.); (R.S.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Ritu Shrestha
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (L.C.); (K.R.B.); (R.S.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | | | - Darrell H. G. Crawford
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (L.C.); (K.R.B.); (R.S.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Aparna Jayachandran
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (L.C.); (K.R.B.); (R.S.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia;
- Correspondence:
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24
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Naranjo AI, González-Gómez MJ, Baladrón V, Laborda J, Nueda ML. Different Expression Levels of DLK2 Inhibit NOTCH Signaling and Inversely Modulate MDA-MB-231 Breast Cancer Tumor Growth In Vivo. Int J Mol Sci 2022; 23:1554. [PMID: 35163478 PMCID: PMC8836183 DOI: 10.3390/ijms23031554] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/21/2022] [Accepted: 01/27/2022] [Indexed: 11/22/2022] Open
Abstract
NOTCH signaling is implicated in the development of breast cancer tumors. DLK2, a non-canonical inhibitor of NOTCH signaling, was previously shown to be involved in skin and breast cancer. In this work, we studied whether different levels of DLK2 expression influenced the breast cancer characteristics of MDA-MB-231 cells. We found that DLK2 overexpression inhibited NOTCH activation in a dose-dependent manner. Moreover, depending on the level of inhibition of NOTCH1 activation generated by different levels of DLK2 expression, cell proliferation, cell cycle dynamics, cell apoptosis, cell migration, and tumor growth in vivo were affected in opposite directions. Low levels of DLK2 expression produced a slight inhibition of NOTCH1 activation, and enhanced MDA-MB-231 cell invasion in vitro and cell proliferation both in vitro and in vivo. In contrast, MDA-MB-231 cells expressing elevated levels of DLK2 showed a strong inhibition of NOTCH1 activation, decreased cell proliferation, increased cell apoptosis, and were unable to generate tumors in vivo. In addition, DLK2 expression levels also affected some members of other cell signaling pathways implicated in cancer, such as ERK1/2 MAPK, AKT, and rpS6 kinases. Our data support an important role of DLK2 as a protein that can finely regulate NOTCH signaling and affect the tumor properties and growth dynamics of MDA-MB-231 breast cancer cells.
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Affiliation(s)
- Ana-Isabel Naranjo
- Biochemistry and Molecular Biology Branch, Medical School/CRIB/Biomedicine Unit, Department of Inorganic and Organic Chemistry and Biochemistry, University of Castilla-La Mancha (UCLM)/CSIC, 02008 Albacete, Spain; (A.-I.N.); (V.B.)
| | - María-Julia González-Gómez
- Biochemistry and Molecular Biology Branch, Higher Technical School of Agricultural and Forestry Engineering/CRIB/Biomedicine Unit, Department of Inorganic and Organic Chemistry and Biochemistry, University of Castilla-La Mancha (UCLM)/CSIC, 02008 Albacete, Spain;
| | - Victoriano Baladrón
- Biochemistry and Molecular Biology Branch, Medical School/CRIB/Biomedicine Unit, Department of Inorganic and Organic Chemistry and Biochemistry, University of Castilla-La Mancha (UCLM)/CSIC, 02008 Albacete, Spain; (A.-I.N.); (V.B.)
| | - Jorge Laborda
- Biochemistry and Molecular Biology Branch, School of Pharmacy/CRIB/Biomedicine Unit, Department of Inorganic and Organic Chemistry and Biochemistry, University of Castilla-La Mancha (UCLM)/CSIC, 02008 Albacete, Spain
| | - María-Luisa Nueda
- Biochemistry and Molecular Biology Branch, School of Pharmacy/CRIB/Biomedicine Unit, Department of Inorganic and Organic Chemistry and Biochemistry, University of Castilla-La Mancha (UCLM)/CSIC, 02008 Albacete, Spain
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25
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Ermis M, Antmen E, Kuren O, Demirci U, Hasirci V. A Cell Culture Chip with Transparent, Micropillar-Decorated Bottom for Live Cell Imaging and Screening of Breast Cancer Cells. MICROMACHINES 2022; 13:mi13010093. [PMID: 35056257 PMCID: PMC8779566 DOI: 10.3390/mi13010093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 12/31/2021] [Accepted: 01/04/2022] [Indexed: 12/30/2022]
Abstract
In the recent years, microfabrication technologies have been widely used in cell biology, tissue engineering, and regenerative medicine studies. Today, the implementation of microfabricated devices in cancer research is frequent and advantageous because it enables the study of cancer cells in controlled microenvironments provided by the microchips. Breast cancer is one of the most common cancers in women, and the way breast cancer cells interact with their physical microenvironment is still under investigation. In this study, we developed a transparent cell culture chip (Ch-Pattern) with a micropillar-decorated bottom that makes live imaging and monitoring of the metabolic, proliferative, apoptotic, and morphological behavior of breast cancer cells possible. The reason for the use of micropatterned surfaces is because cancer cells deform and lose their shape and acto-myosin integrity on micropatterned substrates, and this allows the quantification of the changes in morphology and through that identification of the cancerous cells. In the last decade, cancer cells were studied on micropatterned substrates of varying sizes and with a variety of biomaterials. These studies were conducted using conventional cell culture plates carrying patterned films. In the present study, cell culture protocols were conducted in the clear-bottom micropatterned chip. This approach adds significantly to the current knowledge and applications by enabling low-volume and high-throughput processing of the cell behavior, especially the cell–micropattern interactions. In this study, two different breast cancer cell lines, MDA-MB-231 and MCF-7, were used. MDA-MB-231 cells are invasive and metastatic, while MCF-7 cells are not metastatic. The nuclei of these two cell types deformed to distinctly different levels on the micropatterns, had different metabolic and proliferation rates, and their cell cycles were affected. The Ch-Pattern chips developed in this study proved to have significant advantages when used in the biological analysis of live cells and highly beneficial in the study of screening breast cancer cell–substrate interactions in vitro.
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Affiliation(s)
- Menekse Ermis
- BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University, Ankara 06800, Turkey; (M.E.); (E.A.); (O.K.)
| | - Ezgi Antmen
- BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University, Ankara 06800, Turkey; (M.E.); (E.A.); (O.K.)
| | - Ozgur Kuren
- BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University, Ankara 06800, Turkey; (M.E.); (E.A.); (O.K.)
| | - Utkan Demirci
- Canary Center for Cancer Early Detection, Department of Radiology, Electrical Engineering Department, Stanford University, Palo Alto, CA 94305, USA;
| | - Vasif Hasirci
- BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University, Ankara 06800, Turkey; (M.E.); (E.A.); (O.K.)
- Department of Medical Engineering, Acibadem Mehmet Ali Aydinlar University, Istanbul 34684, Turkey
- ACU Biomaterials Center, Acibadem Mehmet Ali Aydinlar University, Istanbul 34684, Turkey
- Correspondence:
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26
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Crosstalk between non-coding RNAs expression profile, drug resistance and immune response in breast cancer. Pharmacol Res 2021; 176:106041. [PMID: 34952200 DOI: 10.1016/j.phrs.2021.106041] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/15/2021] [Accepted: 12/19/2021] [Indexed: 12/18/2022]
Abstract
Drug resistance is one of the most critical challenges facing researchers in treating breast cancer. Despite numerous treatments for breast cancer, including conventional chemical drugs, monoclonal antibodies, and immunotherapeutic drugs known as immune checkpoint inhibitors (ICI), many patients resist various approaches. In recent years, the relationship between gene expression profiles and drug resistance phenotypes has attracted much attention. Non-coding RNAs (ncRNAs) are regulatory molecules that have been shown to regulate gene expression and cell transcriptome. Two categories, microRNAs and long non-coding RNAs have been more considered and studied among these ncRNAs. Studying the role of different ncRNAs in chemical drug resistance and ICI resistance together can be beneficial in selecting more effective treatments for breast cancer. Changing the expression and action mechanism of these regulatory molecules on drug resistance phenotypes is the main topic of this review article.
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27
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Garrido-Cano I, Pattanayak B, Adam-Artigues A, Lameirinhas A, Torres-Ruiz S, Tormo E, Cervera R, Eroles P. MicroRNAs as a clue to overcome breast cancer treatment resistance. Cancer Metastasis Rev 2021; 41:77-105. [PMID: 34524579 PMCID: PMC8924146 DOI: 10.1007/s10555-021-09992-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 09/02/2021] [Indexed: 12/31/2022]
Abstract
Breast cancer is the most frequent cancer in women worldwide. Despite the improvement in diagnosis and treatments, the rates of cancer relapse and resistance to therapies remain higher than desirable. Alterations in microRNAs have been linked to changes in critical processes related to cancer development and progression. Their involvement in resistance or sensitivity to breast cancer treatments has been documented by different in vivo and in vitro experiments. The most significant microRNAs implicated in modulating resistance to breast cancer therapies are summarized in this review. Resistance to therapy has been linked to cellular processes such as cell cycle, apoptosis, epithelial-to-mesenchymal transition, stemness phenotype, or receptor signaling pathways, and the role of microRNAs in their regulation has already been described. The modulation of specific microRNAs may modify treatment response and improve survival rates and cancer patients' quality of life. As a result, a greater understanding of microRNAs, their targets, and the signaling pathways through which they act is needed. This information could be useful to design new therapeutic strategies, to reduce resistance to the available treatments, and to open the door to possible new clinical approaches.
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Affiliation(s)
| | | | | | - Ana Lameirinhas
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain
| | | | - Eduardo Tormo
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain.,Center for Biomedical Network Research On Cancer, CIBERONC-ISCIII, 28029, Madrid, Spain
| | | | - Pilar Eroles
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain. .,Center for Biomedical Network Research On Cancer, CIBERONC-ISCIII, 28029, Madrid, Spain. .,Department of Physiology, University of Valencia, 46010, Valencia, Spain.
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28
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Parfenyev SE, Shabelnikov SV, Pozdnyakov DY, Gnedina OO, Adonin LS, Barlev NA, Mittenberg AG. Proteomic Analysis of Zeb1 Interactome in Breast Carcinoma Cells. Molecules 2021; 26:molecules26113143. [PMID: 34074001 PMCID: PMC8197395 DOI: 10.3390/molecules26113143] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 11/16/2022] Open
Abstract
Breast cancer is the most frequently diagnosed malignant neoplasm and the second leading cause of cancer death among women. Epithelial-to-mesenchymal Transition (EMT) plays a critical role in the organism development, providing cell migration and tissue formation. However, its erroneous activation in malignancies can serve as the basis for the dissemination of cancer cells and metastasis. The Zeb1 transcription factor, which regulates the EMT activation, has been shown to play an essential role in malignant transformation. This factor is involved in many signaling pathways that influence a wide range of cellular functions via interacting with many proteins that affect its transcriptional functions. Importantly, the interactome of Zeb1 depends on the cellular context. Here, using the inducible expression of Zeb1 in epithelial breast cancer cells, we identified a substantial list of novel potential Zeb1 interaction partners, including proteins involved in the formation of malignant neoplasms, such as ATP-dependent RNA helicase DDX17and a component of the NURD repressor complex, CTBP2. We confirmed the presence of the selected interactors by immunoblotting with specific antibodies. Further, we demonstrated that co-expression of Zeb1 and CTBP2 in breast cancer patients correlated with the poor survival prognosis, thus signifying the functionality of the Zeb1–CTBP2 interaction.
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Affiliation(s)
- Sergey E. Parfenyev
- Institute of Cytology of the Russian Academy of Sciences, 194064 St. Petersburg, Russia; (S.E.P.); (S.V.S.); (D.Y.P.); (O.O.G.); (N.A.B.)
| | - Sergey V. Shabelnikov
- Institute of Cytology of the Russian Academy of Sciences, 194064 St. Petersburg, Russia; (S.E.P.); (S.V.S.); (D.Y.P.); (O.O.G.); (N.A.B.)
| | - Danila Y. Pozdnyakov
- Institute of Cytology of the Russian Academy of Sciences, 194064 St. Petersburg, Russia; (S.E.P.); (S.V.S.); (D.Y.P.); (O.O.G.); (N.A.B.)
| | - Olga O. Gnedina
- Institute of Cytology of the Russian Academy of Sciences, 194064 St. Petersburg, Russia; (S.E.P.); (S.V.S.); (D.Y.P.); (O.O.G.); (N.A.B.)
| | - Leonid S. Adonin
- Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Russia;
| | - Nickolai A. Barlev
- Institute of Cytology of the Russian Academy of Sciences, 194064 St. Petersburg, Russia; (S.E.P.); (S.V.S.); (D.Y.P.); (O.O.G.); (N.A.B.)
- Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Russia;
| | - Alexey G. Mittenberg
- Institute of Cytology of the Russian Academy of Sciences, 194064 St. Petersburg, Russia; (S.E.P.); (S.V.S.); (D.Y.P.); (O.O.G.); (N.A.B.)
- Correspondence: or
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29
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Messeha SS, Zarmouh NO, Soliman KFA. Polyphenols Modulating Effects of PD-L1/PD-1 Checkpoint and EMT-Mediated PD-L1 Overexpression in Breast Cancer. Nutrients 2021; 13:nu13051718. [PMID: 34069461 PMCID: PMC8159140 DOI: 10.3390/nu13051718] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/11/2021] [Accepted: 05/17/2021] [Indexed: 12/12/2022] Open
Abstract
Investigating dietary polyphenolic compounds as antitumor agents are rising due to the growing evidence of the close association between immunity and cancer. Cancer cells elude immune surveillance for enhancing their progression and metastasis utilizing various mechanisms. These mechanisms include the upregulation of programmed death-ligand 1 (PD-L1) expression and Epithelial-to-Mesenchymal Transition (EMT) cell phenotype activation. In addition to its role in stimulating normal embryonic development, EMT has been identified as a critical driver in various aspects of cancer pathology, including carcinogenesis, metastasis, and drug resistance. Furthermore, EMT conversion to another phenotype, Mesenchymal-to-Epithelial Transition (MET), is crucial in developing cancer metastasis. A central mechanism in the upregulation of PD-L1 expression in various cancer types is EMT signaling activation. In breast cancer (BC) cells, the upregulated level of PD-L1 has become a critical target in cancer therapy. Various signal transduction pathways are involved in EMT-mediated PD-L1 checkpoint overexpression. Three main groups are considered potential targets in EMT development; the effectors (E-cadherin and Vimentin), the regulators (Zeb, Twist, and Snail), and the inducers that include members of the transforming growth factor-beta (TGF-β). Meanwhile, the correlation between consuming flavonoid-rich food and the lower risk of cancers has been demonstrated. In BC, polyphenols were found to downregulate PD-L1 expression. This review highlights the effects of polyphenols on the EMT process by inhibiting mesenchymal proteins and upregulating the epithelial phenotype. This multifunctional mechanism could hold promises in the prevention and treating breast cancer.
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Affiliation(s)
- Samia S. Messeha
- Division of Pharmaceutical Sciences, College of Pharmacy & Pharmaceutical Sciences, Institute of Public Health Florida A&M University, Tallahassee, FL 32307, USA;
| | - Najla O. Zarmouh
- Faculty of Medical Technology-Misrata, Libyan National Board for Technical & Vocational Education, Misrata LY72, Libya;
| | - Karam F. A. Soliman
- Division of Pharmaceutical Sciences, College of Pharmacy & Pharmaceutical Sciences, Institute of Public Health Florida A&M University, Tallahassee, FL 32307, USA;
- Correspondence: ; Tel.: +1-850-599-3306; Fax: +1-850-599-3667
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30
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Mo G, Zhang B, Jiang Q. Role of ARK5 in cancer and other diseases (Review). Exp Ther Med 2021; 22:697. [PMID: 33986861 PMCID: PMC8112134 DOI: 10.3892/etm.2021.10129] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 06/20/2020] [Indexed: 12/14/2022] Open
Abstract
Malignant tumors are often exposed to hypoxic and glucose-starved microenvironments. AMP-activated protein kinase (AMPK) is an energy sensor that is stimulated during energy-deficient conditions and protects cells from hypoxic injury by regulating metabolism. AMPK-related protein kinase 5 (ARK5) is a member of the catalytic sub-unit of the AMPK family and has an important role in energy regulation and hypoxia. ARK5 is regulated by Akt and liver kinase B1 and is associated with numerous tumor-related molecules to exert the negative effects of tumors. Studies have revealed ARK5 overexpression in cases of tumor invasion and metastasis and a positive association with the degree of cancer cell malignancy, which is regarded as a key element in determining cancer prognosis. Furthermore, ARK5 downregulation improves drug sensitivity through the epithelial-mesenchymal transition pathway, indicating that it may be a potential therapeutic target. In other non-cancer conditions, ARK5 has various roles in neurodegenerative diseases (Alzheimer's and Huntington's disease), renal disorders (diabetic nephropathy and renal fibrosis) and physiological processes (striated muscle generation). In the present review, the upstream and downstream molecular pathways of ARK5 in cancer and other diseases are described and potential therapeutic strategies are discussed.
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Affiliation(s)
- Guoheng Mo
- Department of Neurosurgery, Queen Mary College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Bohan Zhang
- First Clinical Medical College, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Qunguang Jiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Tan C, Sun W, Xu Z, Zhu S, Hu W, Wang X, Zhang Y, Zhang G, Wang Z, Xu Y, Tang J. Small extracellular vesicles deliver TGF-β1 and promote adriamycin resistance in breast cancer cells. Mol Oncol 2021; 15:1528-1542. [PMID: 33508878 PMCID: PMC8096780 DOI: 10.1002/1878-0261.12908] [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: 07/13/2020] [Revised: 09/27/2020] [Accepted: 01/26/2021] [Indexed: 12/17/2022] Open
Abstract
Chemotherapeutic resistance is a major obstacle in the control of advanced breast cancer (BCa). We have previously shown that small extracellular vesicles (sEVs) can transmit adriamycin resistance between BCa cells. Here, we describe that sEV-mediated TGF-β1 intercellular transfer is involved in the drug-resistant transmission. sEVs were isolated and characterized from both sensitive and resistant cells. sEVs derived from the resistant cells were incubated with the sensitive cells and resulted in transmitting the resistant phenotype to the recipient cells. Cytokine antibody microarray revealed that most metastasis-associated cytokines present at the high levels in sEVs from the resistant cells compared with their levels in sEVs from the sensitive cells, particularly TGF-β1 is enriched in sEVs from the resistant cells. The sEV-mediated TGF-β1 intercellular transfer led to increasing Smad2 phosphorylation and improving cell survival by suppressing apoptosis and enhancing cell mobility. Furthermore, sEV-mediated drug-resistant transmission by delivering TGF-β1 was validated using a zebrafish xenograft tumor model. These results elaborated that sEV-mediated TGF-β1 intercellular transfer contributes to adriamycin resistance in BCa.
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Affiliation(s)
- Chunli Tan
- Jiangsu Institute of Cancer ResearchJiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityChina
- Department of General Surgerythe First Affiliated Hospital with Nanjing Medical UniversityChina
- Department of PharmacyThe People's Hospital of Guangxi Zhuang Autonomous RegionNanningChina
| | - Wenbo Sun
- Jiangsu Institute of Cancer ResearchJiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityChina
| | - Zhi Xu
- Department of General Surgerythe First Affiliated Hospital with Nanjing Medical UniversityChina
| | - Shuyi Zhu
- Jiangsu Institute of Cancer ResearchJiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityChina
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and TreatmentNanjing Medical UniversityChina
| | - Weizi Hu
- Jiangsu Institute of Cancer ResearchJiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityChina
- Department of General Surgerythe First Affiliated Hospital with Nanjing Medical UniversityChina
| | - Xiumei Wang
- Jiangsu Institute of Cancer ResearchJiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityChina
| | - Yanyan Zhang
- Jiangsu Institute of Cancer ResearchJiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityChina
| | - Guangqin Zhang
- School of Basic Medicine and Clinical PharmacyChina Pharmaceutical UniversityNanjingChina
| | - Zibin Wang
- Analysis and Test CenterNanjing Medical UniversityChina
| | - Yong Xu
- Jiangsu Institute of Cancer ResearchJiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityChina
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and TreatmentNanjing Medical UniversityChina
| | - Jinhai Tang
- Department of General Surgerythe First Affiliated Hospital with Nanjing Medical UniversityChina
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Chen C, Hou J, Yu S, Li W, Wang X, Sun H, Qin T, Claret FX, Guo H, Liu Z. Role of cancer-associated fibroblasts in the resistance to antitumor therapy, and their potential therapeutic mechanisms in non-small cell lung cancer. Oncol Lett 2021; 21:413. [PMID: 33841574 PMCID: PMC8020389 DOI: 10.3892/ol.2021.12674] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 02/26/2021] [Indexed: 12/13/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality rates, which seriously endangers human health. Although treatment methods continue to evolve, the emergence of drug resistance is inevitable and seriously hinders the treatment of NSCLC. The tumor microenvironment (TME) protects tumor cells from the effects of chemotherapeutic drugs, which can lead to drug resistance. Cancer-associated fibroblasts (CAFs) are an important component of the TME, and various studies have demonstrated that CAFs play a crucial role in drug resistance in NSCLC. However, the drug resistance mechanism of CAFs and whether CAFs can be used as a target to reverse the resistance of tumor cells remain unclear. The present review discusses this issue and describes the heterogeneity of CAF markers, as well as their origins and resident organs, and the role and mechanism of this heterogeneity in NSCLC progression. Furthermore, the mechanism of CAF-mediated NSCLC resistance to chemotherapy, targeted therapy and immunotherapy is introduced, and strategies to reverse this resistance are described.
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Affiliation(s)
- Congcong Chen
- School of Life Science, Northwest University, Xi'an, Shaanxi 710069, P.R. China
| | - Jia Hou
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Sizhe Yu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Wenyuan Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiao Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Hong Sun
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Tianjie Qin
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Francois X. Claret
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston TX77030, USA
| | - Hui Guo
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaanxi 710061, P.R. China
| | - Zhiyan Liu
- School of Life Science, Northwest University, Xi'an, Shaanxi 710069, P.R. China
- Department of Respiratory and Critical Care Medicine, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi 710018, P.R. China
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Tu J, Yao Z, Wu W, Ju J, Xu Y, Liu Y. Perineural Invasion Is a Strong Prognostic Factor but Not a Predictive Factor of Response to Adjuvant Chemotherapy in Node-Negative Colon Cancer. Front Oncol 2021; 11:663154. [PMID: 33859950 PMCID: PMC8042311 DOI: 10.3389/fonc.2021.663154] [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: 02/02/2021] [Accepted: 03/04/2021] [Indexed: 12/19/2022] Open
Abstract
Purpose To validate the prognostic value and evaluate the predictive value of response to adjuvant chemotherapy of perineural invasion (PNI) in node-negative colon cancer using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 18 tumor registry database. Methods Patients diagnosed with colon cancer from the SEER database between January 1, 2010 and December 31, 2015 were identified. Chi-square analysis was performed to evaluate different demographic and clinical features of patients between PNI-negative (PNI (-)) and PNI-positive (PNI (+)) groups. Univariate and multivariate Cox proportional hazard regression models were built to examine the relationship of demographic and clinical features and survival outcomes with the hazard ratios (HRs) and 95% confidence intervals (CIs). Results In total, 57,255 node-negative colon cancer patients were extracted from the SEER database. The receipt of chemotherapy was not an independent prognostic factor for CSS in T3 colon cancer with or without the presence of PNI (P >0.05). The receipt of chemotherapy was independently associated with 34.0% decreased risk of cancer-specific mortality compared with those without the receipt of chemotherapy in T4 colon cancer without the presence of PNI (HR = 0.660, 95%CI = 0.559-0.779, P <0.001); the receipt of chemotherapy was independently associated with 36.0% decreased risk of cancer-specific mortality compared with those without the receipt of chemotherapy in T4 colon cancer with the presence of PNI (HR = 0.640, 95%CI = 0.438-0.935, P = 0.021). Conclusions The present study demonstrated the poor prognosis of PNI (+) in both stage I and II colon cancer. However, the presence of PNI was not a predictive factor of response to adjuvant chemotherapy in node-negative colon cancer.
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Affiliation(s)
- Junhao Tu
- Department of General Surgery, Suzhou Wuzhong People's Hospital, Suzhou, China
| | - Zongxi Yao
- Department of General Surgery, Suzhou Wuzhong People's Hospital, Suzhou, China
| | - Wenqing Wu
- Department of General Surgery, Suzhou Wuzhong People's Hospital, Suzhou, China
| | - Jianxiang Ju
- Department of General Surgery, Suzhou Wuzhong People's Hospital, Suzhou, China
| | - Yinkai Xu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yulin Liu
- Department of General Surgery, Suzhou Wuzhong People's Hospital, Suzhou, China
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The role of epithelial-mesenchymal transition-regulating transcription factors in anti-cancer drug resistance. Arch Pharm Res 2021; 44:281-292. [PMID: 33768509 PMCID: PMC8009775 DOI: 10.1007/s12272-021-01321-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 03/14/2021] [Indexed: 12/16/2022]
Abstract
The complex orchestration of gene expression that mediates the transition of epithelial cells into mesenchymal cells is implicated in cancer development and metastasis. As the primary regulator of the process, epithelial-mesenchymal transition-regulating transcription factors (EMT-TFs) play key roles in metastasis. They are also highlighted in recent preclinical studies on resistance to cancer therapy. This review describes the role of three main EMT-TFs, including Snail, Twist1, and zinc-finger E homeobox-binding 1 (ZEB1), relating to drug resistance and current possible approaches for future challenges targeting EMT-TFs.
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Wan X, Hou J, Liu S, Zhang Y, Li W, Zhang Y, Ding Y. Estrogen Receptor α Mediates Doxorubicin Sensitivity in Breast Cancer Cells by Regulating E-Cadherin. Front Cell Dev Biol 2021; 9:583572. [PMID: 33614637 PMCID: PMC7889969 DOI: 10.3389/fcell.2021.583572] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 01/11/2021] [Indexed: 12/31/2022] Open
Abstract
Anthracyclines resistance is commonly seen in patients with estrogen receptor α (ERα) positive breast cancer. Epithelial-mesenchymal transition (EMT), which is characterized with the loss of epithelial cell polarity, cell adhesion and acquisition of new invasive property, is considered as one of the mechanisms of chemotherapy-induced drug resistance. In order to identify factors that associated with doxorubicin resistance, we performed in vitro and in vivo experiments using human and mouse breast cancer cell lines with different ERα status. Cell survival experiments revealed that ERα-positive cells (MCF-7 and MCF-7/ADR cell lines), were less sensitive to doxorubicin than ERα-negative (MDA-MB-231, MDA-MB-468) cells, and mouse mammary carcinoma cells (4T-1). The expression of E-cadherin reduced in low-invasive ERα-positive MCF-7 cells after treatment with doxorubicin, indicating epithelial mesenchymal transition. In contrast, the expression of E-cadherin was upregulated in high-invasive ERα-negative cells, showing mesenchymal-epithelial transition (MET). Moreover, it was found that the growth inhibition of 4T-1 cells by doxorubicin was positively correlated with the expression of E-cadherin. In a mouse breast cancer xenograft model, E-cadherin was overexpressed in the primary tumor tissues of the doxorubicin-treated mice. In ERα-positive MCF-7 cells, doxorubicin treatment upregulated the expression of EMT-related transcription factors Snail and Twist, that regulate the expression of E-cadherin. Following overexpression of ERα in ERα-negative cells (MDA-MB-231 and MDA-MB-468), doxorubicin enhanced the upregulation of Snail and Twist, decreased expression of E-cadherin, and decreased the sensitivity of cells to doxorubicin. In contrast, inhibition of ERα activity increased the sensitivity to doxorubicin in ERα-positive MCF-7 cells. These data suggest that the regulation of Snail and/or Twist varies depends on different ERα status. Therefore, doxorubicin combined with anti-estrogen receptor α therapy could improve the treatment efficacy of doxorubicin in ERα-positive breast cancer.
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Affiliation(s)
- Xiaoqing Wan
- Laboratory of Molecular Oncology, Weifang Medical University, Weifang, China.,Department of Pathophysiology, Weifang Medical University, Weifang, China
| | - Jiaxin Hou
- School of Physical Education & Sports Science, Qufu Normal University, Qufu, China
| | - Shurong Liu
- Laboratory of Molecular Oncology, Weifang Medical University, Weifang, China
| | - Yanli Zhang
- Department of Pathophysiology, Weifang Medical University, Weifang, China
| | - Wenqing Li
- Laboratory of Molecular Oncology, Weifang Medical University, Weifang, China
| | - Yanru Zhang
- Laboratory of Molecular Oncology, Weifang Medical University, Weifang, China
| | - Yi Ding
- Department of Pathophysiology, Weifang Medical University, Weifang, China.,Key Laboratory of Applied Pharmacology, Weifang Medical University, Weifang, China
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Feng Y, Yang Z, Zhang C, Che N, Liu X, Xuan Y. B7-H4 induces epithelial-mesenchymal transition and promotes colorectal cancer stemness. Pathol Res Pract 2021; 218:153323. [PMID: 33429327 DOI: 10.1016/j.prp.2020.153323] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 12/13/2020] [Accepted: 12/15/2020] [Indexed: 12/22/2022]
Abstract
B7-H4 is a unique negative regulator of T cells that is typically significantly overexpressed in various carcinomas and is associated with poor prognosis. However, the effects of B7-H4 expression on epithelial-mesenchymal transition (EMT) and cancer stemness of colorectal cancer (CRC) are not entirely clear. In the present study, we used tissue samples from 98 patients with CRC and CRC cell lines to determine the clinicopathological significance of B7-H4 in CRC and its effects on CRC stemness. We performed immunohistochemical staining; immunofluorescence imaging; western blotting; and tumor sphere formation, wound healing, transwell migration, and in vivo tumorigenesis assays. B7-H4 expression was upregulated in CRC tissues and was associated with lymph node metastasis, distant metastasis, clinical stage, a shorter overall survival rate, and disease-free survival rate. Cox regression analyses indicated that B7-H4 is an independent poor prognostic factor for CRC. In addition, B7-H4 expression was correlated with the expression of EMT-related proteins and cancer stemness-related proteins. Moreover, immunohistochemical and immunofluorescence analyses revealed that B7-H4 was correlated with CD133 and CD44 expression levels in both CRC tissues and HT29 and HCT116 cell lines. Conversely, B7-H4 knockdown downregulated the expression of EMT- and cancer stemness-related proteins, while inhibiting tumor spheroid formation, cell migration, and invasion of CRC cell lines. These results indicate that B7-H4 can promote EMT and may be a novel stem cell marker, suggesting its potential as a prognostic biomarker for CRC.
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Affiliation(s)
- Ying Feng
- Department of Pathology, Yanbian University College of Medicine, Yanji, China; Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, China
| | - Zhaoting Yang
- Department of Pathology, Yanbian University College of Medicine, Yanji, China; Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, China
| | - Chengye Zhang
- Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, China
| | - Nan Che
- Department of Pathology, Yanbian University College of Medicine, Yanji, China; Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, China
| | - Xingzhe Liu
- Department of Pathology, Yanbian University College of Medicine, Yanji, China; Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, China
| | - Yanhua Xuan
- Department of Pathology, Yanbian University College of Medicine, Yanji, China; Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, China.
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Pan G, Liu Y, Shang L, Zhou F, Yang S. EMT-associated microRNAs and their roles in cancer stemness and drug resistance. Cancer Commun (Lond) 2021; 41:199-217. [PMID: 33506604 PMCID: PMC7968884 DOI: 10.1002/cac2.12138] [Citation(s) in RCA: 211] [Impact Index Per Article: 52.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/30/2020] [Accepted: 01/18/2021] [Indexed: 12/15/2022] Open
Abstract
Epithelial‐to‐mesenchymal transition (EMT) is implicated in a wide array of malignant behaviors of cancers, including proliferation, invasion, and metastasis. Most notably, previou studies have indicated that both cancer stem‐like properties and drug resistance were associated with EMT. Furthermore, microRNAs (miRNAs) play a pivotal role in the regulation of EMT phenotype, as a result, some miRNAs impact cancer stemness and drug resistance. Therefore, understanding the relationship between EMT‐associated miRNAs and cancer stemness/drug resistance is beneficial to both basic research and clinical treatment. In this review, we preliminarily looked into the various roles that the EMT‐associated miRNAs play in the stem‐like nature of malignant cells. Then, we reviewed the interaction between EMT‐associated miRNAs and the drug‐resistant complex signaling pathways of multiple cancers including lung cancer, gastric cancer, gynecologic cancer, breast cancer, liver cancer, colorectal cancer, pancreatic cancer, esophageal cancer, and nasopharyngeal cancer. We finally discussed the relationship between EMT, cancer stemness, and drug resistance, as well as looked forward to the potential applications of miRNA therapy for malignant tumors.
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Affiliation(s)
- Guangtao Pan
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P. R. China
| | - Yuhan Liu
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P. R. China
| | - Luorui Shang
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P. R. China
| | - Fangyuan Zhou
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P. R. China
| | - Shenglan Yang
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P. R. China
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Liu C, Billet S, Choudhury D, Cheng R, Haldar S, Fernandez A, Biondi S, Liu Z, Zhou H, Bhowmick NA. Bone marrow mesenchymal stem cells interact with head and neck squamous cell carcinoma cells to promote cancer progression and drug resistance. Neoplasia 2021; 23:118-128. [PMID: 33310208 PMCID: PMC7732973 DOI: 10.1016/j.neo.2020.11.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/19/2020] [Accepted: 11/25/2020] [Indexed: 02/05/2023]
Abstract
Head and neck cancers are often diagnosed at later stages with poor outcomes. Mesenchymal stem cells (MSC) are recruited to primary tumor sites where they can have pro- and antitumorigenic influence. In trying to better understand the dynamics between MSC and cancer cells, we found that head and neck cancer-MSC exposure resulted in mesenchymal features, elevated proliferation rate, and were more motile, like the same cells that fused with MSC. We orthotopically grafted the parental head and neck cancer cells, those fused with MSC, or those exposed to MSC into the tongues of mice. The cancer cells originally incubated with MSC developed larger more aggressive tumors compared to the parental cell line. RNA sequencing analysis revealed the expression of genes associated with drug resistance in the cancer cells exposed to MSC compared to parental cancer cells. Strikingly, MSC exposed cancer cell lines developed paclitaxel resistance that could be maintained up to 30 d after the initial co-incubation period. The secretory profile of the MSC suggested IL-6 to be a potential mediator of epigenetic imprinting on the head and neck cancer cells. When the MSC-imprinted cancer cells were exposed to the demethylation agent, 5-aza-2'deoxycytidine, it restored the expression of the drug resistance genes to that of parental cells. This study demonstrated that the recognized recruitment of MSC to tumors could impart multiple protumorigenic properties including chemotherapy resistance like that observed in the relatively rare event of cancer/MSC cell fusion.
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Affiliation(s)
- Chuanxia Liu
- State Key Laboratory of Oral Diseases, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; The Affiliated Stomatology Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Sandrine Billet
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Diptiman Choudhury
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ran Cheng
- State Key Laboratory of Oral Diseases, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Subhash Haldar
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ana Fernandez
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Shea Biondi
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Zhenqiu Liu
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Hongmei Zhou
- State Key Laboratory of Oral Diseases, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
| | - Neil A Bhowmick
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
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Zielinska HA, Daly CS, Alghamdi A, Bahl A, Sohail M, White P, Dean SR, Holly JMP, Perks CM. Interaction between GRP78 and IGFBP-3 Affects Tumourigenesis and Prognosis in Breast Cancer Patients. Cancers (Basel) 2020; 12:E3821. [PMID: 33352865 PMCID: PMC7767108 DOI: 10.3390/cancers12123821] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/26/2020] [Accepted: 12/15/2020] [Indexed: 01/09/2023] Open
Abstract
Insulin-like growth factor binding protein 3 (IGFBP-3) plays a key role in breast cancer progression and was recently shown to bind to the chaperone protein glucose-regulated protein 78 (GRP78); however, the clinical significance of this association remains poorly investigated. Here we report a direct correlation between the expression of GRP78 and IGFBP-3 in breast cancer cell lines and tumour sections. Kaplan-Meier survival plots revealed that patients with low GRP78 expression that are positive for IGFBP-3 had poorer survival rates than those with low IGFBP-3 levels, and we observed a similar trend in the publicly available METABRIC gene expression database. With breast cancer cells, in vitro IGFBP-3 enhanced induced apoptosis, however when GRP78 expression was silenced the actions of IGFBP-3 were switched from increasing to inhibiting ceramide (C2)-induced cell death and promoted cell invasion. Using immunofluorescence and cell surface biotinylation, we showed that knock-down of GRP78 negated the entry of IGFBP-3 into the cells. Together, our clinical and experimental results suggest that loss of GRP78 reduces IGFBP-3 entry into cells switching its actions to promote tumorigenesis and predicts a poor prognosis in breast cancer patients.
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Affiliation(s)
- Hanna A. Zielinska
- IGFs & Metabolic Endocrinology Group, Bristol Medical School, Translational Health Sciences, University of Bristol, Southmead Hospital, Bristol BS10 5NB, UK; (H.A.Z.); (A.A.); (J.M.P.H.)
| | - Carl S. Daly
- Faculty of Health Sciences, University of the West England, Bristol BS16 1QY, UK; (C.S.D.); (P.W.); (S.R.D.)
| | - Ahmad Alghamdi
- IGFs & Metabolic Endocrinology Group, Bristol Medical School, Translational Health Sciences, University of Bristol, Southmead Hospital, Bristol BS10 5NB, UK; (H.A.Z.); (A.A.); (J.M.P.H.)
- Faculty of Applied medical Sciences, Taif University, Taif, Saudi Arabia
| | - Amit Bahl
- Bristol Haematology and Oncology Centre, Department of Clinical Oncology, University Hospitals Bristol, Bristol BS2 8ED, UK;
| | - Muhammed Sohail
- Faculty of Life Sciences, School of Cellular and Molecular Medicine, Bristol University, Bristol BS8 1TD, UK;
| | - Paul White
- Faculty of Health Sciences, University of the West England, Bristol BS16 1QY, UK; (C.S.D.); (P.W.); (S.R.D.)
| | - Sarah R. Dean
- Faculty of Health Sciences, University of the West England, Bristol BS16 1QY, UK; (C.S.D.); (P.W.); (S.R.D.)
| | - Jeff M. P. Holly
- IGFs & Metabolic Endocrinology Group, Bristol Medical School, Translational Health Sciences, University of Bristol, Southmead Hospital, Bristol BS10 5NB, UK; (H.A.Z.); (A.A.); (J.M.P.H.)
| | - Claire M. Perks
- IGFs & Metabolic Endocrinology Group, Bristol Medical School, Translational Health Sciences, University of Bristol, Southmead Hospital, Bristol BS10 5NB, UK; (H.A.Z.); (A.A.); (J.M.P.H.)
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Taurin S, Alkhalifa H. Breast cancers, mammary stem cells, and cancer stem cells, characteristics, and hypotheses. Neoplasia 2020; 22:663-678. [PMID: 33142233 PMCID: PMC7586061 DOI: 10.1016/j.neo.2020.09.009] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/25/2020] [Accepted: 09/27/2020] [Indexed: 12/12/2022]
Abstract
The cellular heterogeneity of breast cancers still represents a major therapeutic challenge. The latest genomic studies have classified breast cancers in distinct clusters to inform the therapeutic approaches and predict clinical outcomes. The mammary epithelium is composed of luminal and basal cells, and this seemingly hierarchical organization is dependent on various stem cells and progenitors populating the mammary gland. Some cancer cells are conceptually similar to the stem cells as they can self-renew and generate bulk populations of nontumorigenic cells. Two models have been proposed to explain the cell of origin of breast cancer and involve either the reprogramming of differentiated mammary cells or the dysregulation of mammary stem cells or progenitors. Both hypotheses are not exclusive and imply the accumulation of independent mutational events. Cancer stem cells have been isolated from breast tumors and implicated in the development, metastasis, and recurrence of breast cancers. Recent advances in single-cell sequencing help deciphering the clonal evolution within each breast tumor. Still, few clinical trials have been focused on these specific cancer cell populations.
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Affiliation(s)
- Sebastien Taurin
- Department of Molecular Medicine, College of Medicine and Medical Sciences, Princess Al-Jawhara Center for Molecular Medicine and Inherited Disorders, Arabian Gulf University, Manama, Bahrain.
| | - Haifa Alkhalifa
- New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
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Koual M, Tomkiewicz C, Cano-Sancho G, Antignac JP, Bats AS, Coumoul X. Environmental chemicals, breast cancer progression and drug resistance. Environ Health 2020; 19:117. [PMID: 33203443 PMCID: PMC7672852 DOI: 10.1186/s12940-020-00670-2] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 10/21/2020] [Indexed: 05/04/2023]
Abstract
Breast cancer (BC) is one of the most common causes of cancer in the world and the second leading cause of cancer deaths among women. Mortality is associated mainly with the development of metastases. Identification of the mechanisms involved in metastasis formation is, therefore, a major public health issue. Among the proposed risk factors, chemical environment and pollution are increasingly suggested to have an effect on the signaling pathways involved in metastatic tumor cells emergence and progression. The purpose of this article is to summarize current knowledge about the role of environmental chemicals in breast cancer progression, metastasis formation and resistance to chemotherapy. Through a scoping review, we highlight the effects of a wide variety of environmental toxicants, including persistent organic pollutants and endocrine disruptors, on invasion mechanisms and metastatic processes in BC. We identified the epithelial-to-mesenchymal transition and cancer-stemness (the stem cell-like phenotype in tumors), two mechanisms suspected of playing key roles in the development of metastases and linked to chemoresistance, as potential targets of contaminants. We discuss then the recently described pro-migratory and pro-invasive Ah receptor signaling pathway and conclude that his role in BC progression is still controversial. In conclusion, although several pertinent pathways for the effects of xenobiotics have been identified, the mechanisms of actions for multiple other molecules remain to be established. The integral role of xenobiotics in the exposome in BC needs to be further explored through additional relevant epidemiological studies that can be extended to molecular mechanisms.
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Affiliation(s)
- Meriem Koual
- INSERM UMR-S1124, 3TS, Toxicologie Pharmacologie et Signalisation Cellulaire, Université de Paris, Paris, France.
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Service de Chirurgie Cancérologique Gynécologique et du Sein, Paris, France.
- Faculté de Médecine, Université de Paris, Paris, France.
| | - Céline Tomkiewicz
- INSERM UMR-S1124, 3TS, Toxicologie Pharmacologie et Signalisation Cellulaire, Université de Paris, Paris, France
- Faculté de Médecine, Université de Paris, Paris, France
| | | | | | - Anne-Sophie Bats
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Service de Chirurgie Cancérologique Gynécologique et du Sein, Paris, France
- Faculté de Médecine, Université de Paris, Paris, France
- INSERM UMR-S1147, Equipe labellisée Ligue Nationale Contre le Cancer, Université de Paris, Paris, France
| | - Xavier Coumoul
- INSERM UMR-S1124, 3TS, Toxicologie Pharmacologie et Signalisation Cellulaire, Université de Paris, Paris, France.
- Faculté de Médecine, Université de Paris, Paris, France.
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Yang Z, Zhang C, Che N, Feng Y, Li C, Xuan Y. Su(var)3-9, Enhancer of Zeste, and Trithorax Domain-Containing 5 Facilitates Tumor Growth and Pulmonary Metastasis through Up-Regulation of AKT1 Signaling in Breast Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 191:180-193. [PMID: 33129761 DOI: 10.1016/j.ajpath.2020.10.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 09/11/2020] [Accepted: 10/06/2020] [Indexed: 12/20/2022]
Abstract
Several studies have confirmed the function of Su(var)3-9, Enhancer of zeste, and Trithorax (SET) domain-containing 5 (SETD5) in post-translational modifications of nonhistone proteins. Mutation of the SETD5 gene has been implicated in the progression of many human cancers, such as breast cancer (BC), but its functional role in BC progression is still unknown. The current article investigates the clinical significance and the functional role of SETD5 in BC. Our studies show that SETD5 expression in BC was related to poor clinical outcomes, including lymph node metastasis and advanced clinical stage. SETD5 expression positively correlated with tumor-associated macrophages. SETD5 was an independent predictor of poor overall survival in BC. Furthermore, these studies show that down-regulation of SETD5 significantly decreased BC cell proliferation, metastasis, and angiogenesis, and increased apoptosis of BC cells. The mechanistic analysis showed that SETD5 contributes BC progression by interacting with AKT1 pathway. Also, in vivo experiments show that blocking of SETD5 expression significantly inhibited tumor growth and pulmonary metastasis of BC cells. These findings indicate that SETD5 is a potential prognosis marker and facilitates tumor progression of BC.
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Affiliation(s)
- Zhaoting Yang
- Department of Pathology, Yanbian University Medicine College, Yanji, China; Institute for Regenerative Medicine, Yanbian University Medicine College, Yanji, China
| | - Chengye Zhang
- Institute for Regenerative Medicine, Yanbian University Medicine College, Yanji, China; Air Force Medical Center of the Chinese People's Liberation Army, Beijing, China
| | - Nan Che
- Department of Pathology, Yanbian University Medicine College, Yanji, China; Institute for Regenerative Medicine, Yanbian University Medicine College, Yanji, China
| | - Ying Feng
- Department of Pathology, Yanbian University Medicine College, Yanji, China; Institute for Regenerative Medicine, Yanbian University Medicine College, Yanji, China
| | - Chao Li
- Institute for Regenerative Medicine, Yanbian University Medicine College, Yanji, China
| | - Yanhua Xuan
- Department of Pathology, Yanbian University Medicine College, Yanji, China; Institute for Regenerative Medicine, Yanbian University Medicine College, Yanji, China.
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Shi R, Liu L, Wang F, He Y, Niu Y, Wang C, Zhang X, Zhang X, Zhang H, Chen M, Wang Y. Downregulation of cytokeratin 18 induces cellular partial EMT and stemness through increasing EpCAM expression in breast cancer. Cell Signal 2020; 76:109810. [PMID: 33069797 DOI: 10.1016/j.cellsig.2020.109810] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 10/09/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023]
Abstract
Induction of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) characteristics underlie the development of metastasis, chemoresistance, and tumor recurrence in breast cancer. Downregulation of cytokeratin 18 (CK18) is a critical molecular event of EMT; however, its importance in the induction of EMT and CSC features has not been defined to date. This study aimed to investigate the biological significance and underlying molecular mechanisms of CK18 in inducing EMT phenotype and stemness properties of breast cancer cells. Three breast cancer cell lines (i.e., non-metastatic MCF-7, highly metastatic MDA-MB-231, and mitoxantrone (MX)-selected resistant MCF-7/MX cells) and two CK18-knockdown stable cell clones (MCF-7-shCK18-7D and 3C) were used to determine the association between CK18 and EMT and stemness. CK18 expression was extremely low in highly metastatic, resistant, and transforming growth factor (TGF)-β1/tumor necrosis factor (TNF)-α-treated breast cancer cells with mesenchymal phenotype and increased expression of CSC markers. Depletion of CK18 promoted partial EMT and the acquisition of stemness properties in breast cancer MCF-7 cells. Mechanistically, CK18 interference in MCF-7 cells activated the Wnt/β-catenin signaling, resulting in the up-regulation of epithelial cell adhesion molecule (EpCAM). Consistently, the stemness properties and metastasis can be attenuated by further knockdown of EpCAM in CK18-depleted cells. In conclusion, downregulation of CK18 promotes partial EMT and enhances breast cancer stemness by increasing EpCAM expression partly via the Wnt/β-catenin pathway. These findings indicate that CK18 may serve as a potential treatment target for advanced breast cancer.
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Affiliation(s)
- Ruizan Shi
- Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China.
| | - Linhong Liu
- Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China
| | - Fengge Wang
- Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China
| | - Yifan He
- Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China
| | - Yanan Niu
- Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China
| | - Chang Wang
- Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China
| | - Xuanping Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China
| | - Xiuli Zhang
- Technology Innovation Center, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Huifeng Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China
| | - Min Chen
- Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China
| | - Yan Wang
- Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China
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Cardamonin inhibits the proliferation and metastasis of non-small-cell lung cancer cells by suppressing the PI3K/Akt/mTOR pathway. Anticancer Drugs 2020; 30:241-250. [PMID: 30640793 DOI: 10.1097/cad.0000000000000709] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Cardamonin, a natural chalcone compound, has been reported to exert anticancer effects in several cancers. However, the specific pharmacological actions of cardamonin on human non-small-cell lung cancer (NSCLC) and the potential mechanisms still remain obscure. Here, we investigated the antineoplastic role of cardamonin in NSCLC both in vitro and in vivo. The proliferation of five NSCLC cell lines was inhibited in a dose-dependent and time-dependent manner with cardamonin treatment. In A549 and H460 cells, cardamonin induced apoptosis by activating caspase-3, upregulating Bax, and downregulating Bcl-2. In addition, cardamonin arrested cells in the G2/M phase and inhibited the expression levels of cyclin D1/CDK4. Moreover, cell migration and invasion were suppressed by reversing epithelial-mesenchymal transition with cardamonin treatment. Further study showed that cardamonin reduced the phosphorylation levels of the downstream effectors of phosphoinositide 3-kinase (PI3K), including protein kinase-B (Akt/PKB) and mammalian target of rapamycin (mTOR). Moreover, in the H460 xenograft model, cardamonin significantly retarded tumor growth. Also, in tumor tissues, we found that cardamonin treatment decreased the expression rates of Ki-67, p-Akt, and p-mTOR. These data suggest that cardamonin suppressed NSCLC cell proliferation and inhibited metastasis partly by restraining the PI3K/Akt/mTOR pathway and it might be an effective therapeutic compound for NSCLC in the future.
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Luo H, Cong S, Dong J, Jin L, Jiang D, Wang X, Chen Q, Li F. Paired‑related homeobox 1 overexpression promotes multidrug resistance via PTEN/PI3K/AKT signaling in MCF‑7 breast cancer cells. Mol Med Rep 2020; 22:3183-3190. [PMID: 32945446 PMCID: PMC7453582 DOI: 10.3892/mmr.2020.11414] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 06/19/2020] [Indexed: 12/17/2022] Open
Abstract
Multidrug resistance (MDR) is a major cause of disease relapse and mortality in breast cancer. Paired‑related homeobox 1 (PRRX1) is associated with the epithelial‑mesenchymal transition (EMT), which is involved in tumor development, including cell invasion and MDR. However, the effect of PRRX1 on MDR had not clearly established. The present study investigated the influence of PRRX1 on MDR and the underlying molecular mechanisms in MCF‑7 breast cancer cells. MCF‑7 cells were divided into PRRX1+ group (cells transfected with a recombinant plasmid carrying the PRRX1 gene), negative control group (cells transfected with a blank vector) and blank group (untreated cells). It was found that the relative protein and mRNA expression levels of PRRX1, N‑cadherin, vimentin and P‑glycoprotein were significantly higher in PRRX1‑overexpressing MCF‑7 cells compared with those in control cells. The half‑maximal inhibitory concentration of three groups after treatment with docetaxel and cis‑platinum complexes were significantly higher in PRRX1‑overexpressing MCF‑7 cells compared with those in control cells. Furthermore, relative PTEN expression decreased significantly and levels of phosphorylated PI3K and AKT increased substantially in PRRX1‑overexpressing MCF‑7 cells. These results indicated that PRRX1 overexpression may induce MDR via PTEN/PI3K/AKT signaling in breast cancer. It is highly recommended that PRRX1 gene expression detection should be performed in patients with breast cancer to aid the selection of more appropriate treatments, which will lead to an improved prognosis in clinical practice.
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Affiliation(s)
- Haoyue Luo
- Department of Breast Disease Diagnosis, Treatment Centre, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Shaobo Cong
- Department of Biochemistry and Molecular Biology, Medical College of Qingdao University, Qingdao, Shandong 266021, P.R. China
| | - Jiaojiao Dong
- Department of Breast Disease Diagnosis, Treatment Centre, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Litao Jin
- Department of Breast Disease Diagnosis, Treatment Centre, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Dandan Jiang
- Department of Breast Disease Diagnosis, Treatment Centre, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Xingang Wang
- Department of Breast Disease Diagnosis, Treatment Centre, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Qingfeng Chen
- Department of Breast Disease Diagnosis, Treatment Centre, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Funian Li
- Department of Breast Disease Diagnosis, Treatment Centre, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
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Xue J, Li R, Gao D, Chen F, Xie H. CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer. Int J Nanomedicine 2020; 15:5701-5718. [PMID: 32848392 PMCID: PMC7426108 DOI: 10.2147/ijn.s257527] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 07/13/2020] [Indexed: 12/17/2022] Open
Abstract
Introduction Traditional chemotherapy for ovarian cancer is limited due to drug resistance and systemic side effects. Although various targeted drug delivery strategies have been designed to enhance drug accumulation at the tumor site, simply improvement of targeting capability has not consistently led to satisfactory outcomes. Herein, AMD3100 was selected as the targeting ligand because of its high affinity to chemokine receptor 4 (CXCR4), which was highly expressed on ovarian cancer cells. Moreover, the AMD3100 has been proved having blockage capability of stromal cell-derived factor 1 (SDF-1 or CXCL12)/CXCR4 axis and to be a sensitizer of chemotherapeutic therapy. We designed a dual-functional targeting delivery system by modifying paclitaxel (PTX)-loaded PEGylation bovine serum albumin (BSA) nanoparticles (NPs) with AMD3100 (AMD-NP-PTX), which can not only achieve specific tumor-targeting efficiency but also enhance the therapeutic outcomes. Methods AMD3100 was chemically modified to Mal-PEG-NHS followed by reacting with BSA, then AMD-NP-PTX was synthesized and characterized. The targeting efficiency of AMD-NP was evaluated both in vitro and in vivo. The anticancer effect of AMD-NP-PTX was determined on Caov3 cells and ovarian cancer-bearing nude mice. Finally, the potential therapeutic mechanism was studied. Results AMD-NP-PTX was synthesized successfully and well characterized. Cellular uptake assay and in vivo imaging experiments demonstrated that NPs could be internalized by Caov3 cells more efficiently after modification of AMD3100. Furthermore, the AMD-NP-PTX exhibited significantly enhanced inhibition effect on tumor growth and metastasis compared with PTX, NP-PTX and free AMD3100 plus NP-PTX both in vitro and in vivo, and demonstrated improved safety profile. We also confirmed that AMD-NP-PTX worked through targeting CXCL12/CXCR4 axis, thereby disturbing its downstream signaling pathways including epithelial–mesenchymal transition (EMT) processes and nuclear factor κB (NF-κB) pathway. Conclusion The AMD-NP-PTX we designed would open a new avenue for dual-functional NPs in ovarian cancer therapy.
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Affiliation(s)
- Jiyang Xue
- Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People's Republic of China
| | - Ruixiang Li
- Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People's Republic of China
| | - Dingding Gao
- Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People's Republic of China
| | - Fenghua Chen
- Department of Ultrasonography, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People's Republic of China
| | - Hongjuan Xie
- Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People's Republic of China
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Cao D, Zhu GY, Lu Y, Yang A, Chen D, Huang HJ, Peng SX, Chen LW, Li YW. Luteolin suppresses epithelial-mesenchymal transition and migration of triple-negative breast cancer cells by inhibiting YAP/TAZ activity. Biomed Pharmacother 2020; 129:110462. [PMID: 32768952 DOI: 10.1016/j.biopha.2020.110462] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 06/21/2020] [Accepted: 06/24/2020] [Indexed: 12/18/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly lethal subtype of breast cancer associated with early relapse and metastasis. Epithelial to mesenchymal transition (EMT) plays pivotal roles in the progression of TNBC, including inducing cancer stem cell (CSC) properties, chemoresistance, tumor metastasis, and recurrence. Abnormally activated YAP/TAZ induces EMT in TNBC, making it a promising target for drug development. Our goal is to identify potential YAP/TAZ inhibitors from naturally derivative molecules and further study its effects on inhibiting EMT and metastasis of TNBC. In the current study, we demonstrate that luteolin significantly inhibits YAP/TAZ activity by promoting YAP/TAZ degradation in TNBC cells. Luteolin treatment leads to a decrease of mesenchymal markers and an increase of epithelial markers in both TNBC cells and TAZ-induced mesenchymal cells. Consistently, luteolin treatment inhibits cell migration in TNBC cells. Additionally, luteolin inhibits tumor growth in mice xenografted with TNBC cells. Collectively, our results support luteolin as a novel YAP/TAZ inhibitor for development as a new agent for the treatment of TNBC.
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Affiliation(s)
- Dai Cao
- Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Guo-Yuan Zhu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China
| | - Yan Lu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Aiping Yang
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Die Chen
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Hui-Jie Huang
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Shu-Xian Peng
- Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Li-Wen Chen
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Ying-Wei Li
- Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
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Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance. Drug Resist Updat 2020; 53:100715. [PMID: 32679188 DOI: 10.1016/j.drup.2020.100715] [Citation(s) in RCA: 324] [Impact Index Per Article: 64.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 05/29/2020] [Accepted: 06/07/2020] [Indexed: 12/11/2022]
Abstract
It is well established that multifactorial drug resistance hinders successful cancer treatment. Tumor cell interactions with the tumor microenvironment (TME) are crucial in epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR). TME-induced factors secreted by cancer cells and cancer-associated fibroblasts (CAFs) create an inflammatory microenvironment by recruiting immune cells. CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) and inflammatory tumor associated macrophages (TAMs) are main immune cell types which further enhance chronic inflammation. Chronic inflammation nurtures tumor-initiating/cancer stem-like cells (CSCs), induces both EMT and MDR leading to tumor relapses. Pro-thrombotic microenvironment created by inflammatory cytokines and chemokines from TAMs, MDSCs and CAFs is also involved in EMT and MDR. MDSCs are the most common mediators of immunosuppression and are also involved in resistance to targeted therapies, e.g. BRAF inhibitors and oncolytic viruses-based therapies. Expansion of both cancer and stroma cells causes hypoxia by hypoxia-inducible transcription factors (e.g. HIF-1α) resulting in drug resistance. TME factors induce the expression of transcriptional EMT factors, MDR and metabolic adaptation of cancer cells. Promoters of several ATP-binding cassette (ABC) transporter genes contain binding sites for canonical EMT transcription factors, e.g. ZEB, TWIST and SNAIL. Changes in glycolysis, oxidative phosphorylation and autophagy during EMT also promote MDR. Conclusively, EMT signaling simultaneously increases MDR. Owing to the multifactorial nature of MDR, targeting one mechanism seems to be non-sufficient to overcome resistance. Targeting inflammatory processes by immune modulatory compounds such as mTOR inhibitors, demethylating agents, low-dosed histone deacetylase inhibitors may decrease MDR. Targeting EMT and metabolic adaptation by small molecular inhibitors might also reverse MDR. In this review, we summarize evidence for TME components as causative factors of EMT and anticancer drug resistance.
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Jing L, Feng L, Zhou Z, Shi S, Deng R, Wang Z, Zhang Y, Ren Z, Liu Y. TNNT2 as a potential biomarker for the progression and prognosis of colorectal cancer. Oncol Rep 2020; 44:628-636. [PMID: 32627044 PMCID: PMC7336514 DOI: 10.3892/or.2020.7637] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 02/26/2020] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. At present, there are limited effective biomarkers of CRC. The present study aimed to identify potential signatures associated with the tumorigenesis and prognosis of CRC using publicly available databases, and further validate the identified biomarkers in CRC cell lines. Identification of differentially expressed mRNAs between CRC and paracancerous samples was conducted based on data from The Cancer Genome Atlas (TCGA; 471 tumor samples and 41 normal samples). Survival analysis was performed to explore the prognostic value of troponin 2 (TNNT2) in the TCGA training set, which was further validated in an external dataset, GSE17531. Functional enrichment analysis was conducted to determine the possible biological functions using GSEA 3.0. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were utilized to detect the mRNA and protein expression levels of TNNT2 between CRC and normal colorectal cells. Immunohistochemistry was performed to detect the protein expression of TNNT2 in CRC and normal tissues. TNNT2 was significantly upregulated in CRC samples compared with adjacent normal samples in the TCGA dataset. Increased expression of TNNT2 was associated with inferior prognosis in the TCGA training dataset and GSE17531 validation dataset. Functional enrichment analysis revealed that the ErbB signaling pathway and glycerophospholipid metabolism pathway were significantly activated in the TNNT2 high expression group. Overexpression of TNNT2 mRNA and TNNT2 protein in CRC tumor cells was confirmed by RT-qPCR and western blotting, respectively. Immunohistochemistry indicated increased protein expression levels of TNNT2 in CRC tissues in comparison with normal tissues. TNNT2 was associated with the tumorigenesis and prognosis of CRC, which may be useful for novel biomarker identification and targeted therapeutic strategy development.
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Affiliation(s)
- Li Jing
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Li Feng
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Zhiguo Zhou
- Department of Radiotherapy, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Shuai Shi
- Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Ruoying Deng
- Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Zhicong Wang
- Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yi Zhang
- Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Zhixue Ren
- The Seven People's Hospital of Hebei Province, Dingzhou, Hebei 073000, P.R. China
| | - Yibing Liu
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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50
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Chen L, Zhang S, Shen Y, Qi L, Zhang Z, Tian H, Zou Z. Thymus‑expressed chemokine secreted by breast cancer cells promotes metastasis and inhibits apoptosis. Oncol Rep 2020; 43:1875-1884. [PMID: 32323823 PMCID: PMC7160534 DOI: 10.3892/or.2020.7575] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 03/10/2020] [Indexed: 12/12/2022] Open
Abstract
The aim of the present study was to investigate the underlying mechanisms of thymus‑expressed chemokine (TECK) autocrine signaling, and its effect on carcinogenesis and the development of breast cancer. The present study also assessed epithelial‑mensenchymal transition (EMT) and cell migration, invasion, proliferation and apoptosis. Breast cancer cell lines MCF‑7 and MDA‑MB‑231 were used in the present study, and TECK basic expression in cancer cells was investigated using western blotting (WB). EMT markers, Akt pathway molecules and apoptosis indicators were detected by reverse transcription‑quantitative PCR or WB. In order to assess migration and invasion, wound healing and Matrigel invasion assays were performed. Moreover, flow cytometry was used to assess the rate of proliferation and apoptosis. In vivo experiments were conducted in nude mice to assess cancer growth. It was revealed that breast cancer cells could secrete TECK in an autocrine manner. Furthermore, TECK could increase cell migration and invasion by promoting EMT and inhibit apoptosis via the Akt signaling pathway.
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Affiliation(s)
- Lu Chen
- Department of Anatomy, Histology and Embryology, School of Basic Medical Science, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Shuming Zhang
- Department of Radiotherapy, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong 250014, P.R. China
| | - Yaqian Shen
- Department of Anatomy, Histology and Embryology, School of Basic Medical Science, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Linzeng Qi
- Department of Anatomy, Histology and Embryology, School of Basic Medical Science, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Zhaolin Zhang
- Department of Special Examination, Penglai People's Hospital, Penglai, Shandong 265600, P.R. China
| | - Hua Tian
- Department of Anatomy, Histology and Embryology, School of Basic Medical Science, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Zhigeng Zou
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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