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Tabaa MME, Harty MEE, Mohsen M, Rashad E, Negm WA, Elmorshedy K, Abu-Risha SE. Integrating network pharmacology and in vivo pharmacological validation to explore the gastroprotective mechanism of Sotetsuflavone against indomethacin-induced gastric ulcer in rats: Involvement of JAK2/STAT3 pathway. J Nutr Biochem 2025; 142:109934. [PMID: 40258498 DOI: 10.1016/j.jnutbio.2025.109934] [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: 01/19/2025] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 04/23/2025]
Abstract
Sotetsuflavone (SF) is an antioxidant flavonoid derived from the Cycas thouarsii R.Br. plant. Although SF regulates numerous cellular pathways influencing inflammation, its antiinflammatory benefits against gastric ulcers are less well-studied. Hence, it is imperative to thoroughly understand the potential gastroprotective mechanisms of SF. This study aimed to explore the effectiveness of SF against indomethacin (IND)-induced gastric ulcers. Network analysis and molecular docking were used to identify the specific targets and pathways related to SF and stomach ulcers. To validate the in vivo pharmacological action of SF, 36 rats were divided into six groups. Ulcer index (UI), protective percentage (PP), gastric mucosal mediators, oxidant/antioxidant status, and inflammatory markers (MIF, M-CSF, and AIF-1) were assessed. Additionally, the expression of PI3K, Akt, Siah2, SOCS3, JAK2, and STAT3 was determined. Stomach histopathology and immunohistochemistry were done. Network pharmacology detected 46 overlapping targets between SF and stomach ulcers, with HIF1A as the primary target among the top hubs. The network also revealed that JAK/STAT, PI3K/Akt, and HIF-1A signaling are among the top 50 markedly enriched KEGG pathways. Furthermore, docking results confirmed that SF has a strong binding affinity towards SOCS3, JAK2, STAT3, M-CSF (CSF-1), and AIF-1. Therefore, we hypothesized that the JAK2/STAT3 pathway may be primarily responsible for SF antiinflammatory action. Through up-regulating SOCS3, SF altered the PI3K/Akt pathway, mitigating oxidative stress, blocking the outflow of inflammatory mediators, and impeding gastric ulcer development. Overall, SF, by the SOCS3-mediated JAK2/STAT3 suppression, might considerably reduce oxidative stress, inflammation, and ulceration caused by indomethacin in the stomach.
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Affiliation(s)
- Manar M El Tabaa
- Pharmacology & Environmental Toxicology, Environmental Studies & Research Institute (ESRI), University of Sadat City, Sadat City, Menoufia, Egypt.
| | - Mohammed E El Harty
- Pharmacology & Environmental Toxicology, Environmental Studies & Research Institute (ESRI), University of Sadat City, Sadat City, Menoufia, Egypt
| | - Mohamed Mohsen
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Eman Rashad
- Cytology and Histology Department, Faculty of Veterinary Medicine, Cairo University, Egypt
| | - Walaa A Negm
- Pharmacognosy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | | | - Sally E Abu-Risha
- Pharmacology & Toxicology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
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De L, Xing N, Du Q, Guo S, Wang S. Investigating the anti-lung cancer properties of Zhuang medicine Cycas revoluta Thunb. leaves targeting ion channels and transporters through a comprehensive strategy. Comput Biol Chem 2024; 112:108156. [PMID: 39067352 DOI: 10.1016/j.compbiolchem.2024.108156] [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: 04/16/2024] [Revised: 06/24/2024] [Accepted: 07/16/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Cycas revoluta Thunb., known for its ornamental, economic, and medicinal value, has leaves often discarded as waste. However, in ethnic regions of China, the leaves (CRL) are used in folk medicine for anti-tumor properties, particularly for regulating pathways related to cancer. Recent studies on ion channels and transporters (ICTs) highlight their therapeutic potential against cancer, making it vital to identify CRL's active constituents targeting ICTs in lung cancer. PURPOSE This study aims to uncover bioactive substances in CRL and their mechanisms in regulating ICTs for lung cancer treatment using network pharmacology, bioinformatics, molecular docking, molecular dynamics (MD) simulations, in vitro cell assays and HPLC. METHODS We analyzed 62 CRL compounds, predicted targets using PubChem and SwissTargetPrediction, identified lung cancer and ICT targets via GeneCards, and visualized overlaps with R software. Interaction networks were constructed using Cytoscape and STRING. Gene expression, GO, and KEGG analyses were performed using R software. TCGA data provided insights into differential, correlation, survival, and immune analyses. Key interactions were validated through molecular docking and MD simulations. Main biflavonoids were quantified using HPLC, and in vitro cell viability assays were conducted for key biflavonoids. RESULTS Venn diagram analysis identified 52 intersecting targets and ten active CRL compounds. The PPI network highlighted seven key targets. GO and KEGG analysis showed CRL-targeted ICTs involved in synaptic transmission, GABAergic synapse, and proteoglycans in cancer. Differential expression and correlation analysis revealed significant differences in five core targets in lung cancer tissues. Survival analysis linked EGFR and GABRG2 with overall survival, and immune infiltration analysis associated the core targets with most immune cell types. Molecular docking indicated strong binding of CRL ingredients to core targets. HPLC revealed amentoflavone as the most abundant biflavonoid, followed by hinokiflavone, sciadopitysin, and podocarpusflavone A. MD simulations showed that podocarpusflavone A and amentoflavone had better binding stability with GABRG2, and the cell viability assay also proved that they had better anti-lung cancer potential. CONCLUSIONS This study identified potential active components, targets, and pathways of CRL-targeted ICTs for lung cancer treatment, suggesting CRL's utility in drug development and its potential beyond industrial waste.
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Affiliation(s)
- Luo De
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Meishan Traditional Chinese Medicine Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Nan Xing
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Qinyun Du
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Sa Guo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Shaohui Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Meishan Traditional Chinese Medicine Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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Ma Q, Hao S, Hong W, Tergaonkar V, Sethi G, Tian Y, Duan C. Versatile function of NF-ĸB in inflammation and cancer. Exp Hematol Oncol 2024; 13:68. [PMID: 39014491 PMCID: PMC11251119 DOI: 10.1186/s40164-024-00529-z] [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: 11/20/2023] [Accepted: 06/06/2024] [Indexed: 07/18/2024] Open
Abstract
Nuclear factor-kappaB (NF-ĸB) plays a crucial role in both innate and adaptive immune systems, significantly influencing various physiological processes such as cell proliferation, migration, differentiation, survival, and stemness. The function of NF-ĸB in cancer progression and response to chemotherapy has gained increasing attention. This review highlights the role of NF-ĸB in inflammation control, biological mechanisms, and therapeutic implications in cancer treatment. NF-ĸB is instrumental in altering the release of inflammatory factors such as TNF-α, IL-6, and IL-1β, which are key in the regulation of carcinogenesis. Specifically, in conditions including colitis, NF-ĸB upregulation can intensify inflammation, potentially leading to the development of colorectal cancer. Its pivotal role extends to regulating the tumor microenvironment, impacting components such as macrophages, fibroblasts, T cells, and natural killer cells. This regulation influences tumorigenesis and can dampen anti-tumor immune responses. Additionally, NF-ĸB modulates cell death mechanisms, notably by inhibiting apoptosis and ferroptosis. It also has a dual role in stimulating or suppressing autophagy in various cancers. Beyond these functions, NF-ĸB plays a role in controlling cancer stem cells, fostering angiogenesis, increasing metastatic potential through EMT induction, and reducing tumor cell sensitivity to chemotherapy and radiotherapy. Given its oncogenic capabilities, research has focused on natural products and small molecule compounds that can suppress NF-ĸB, offering promising avenues for cancer therapy.
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Affiliation(s)
- Qiang Ma
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230022, P.R. China
| | - Shuai Hao
- Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
- Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, P.R. China
| | - Weilong Hong
- Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Gautam Sethi
- Department of Pharmacology and NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
| | - Yu Tian
- School of Public Health, Benedictine University, Lisle, 60532, USA.
| | - Chenyang Duan
- Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China.
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Verma S, Magazzù G, Eftekhari N, Lou T, Gilhespy A, Occhipinti A, Angione C. Cross-attention enables deep learning on limited omics-imaging-clinical data of 130 lung cancer patients. CELL REPORTS METHODS 2024; 4:100817. [PMID: 38981473 PMCID: PMC11294841 DOI: 10.1016/j.crmeth.2024.100817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 04/18/2024] [Accepted: 06/17/2024] [Indexed: 07/11/2024]
Abstract
Deep-learning tools that extract prognostic factors derived from multi-omics data have recently contributed to individualized predictions of survival outcomes. However, the limited size of integrated omics-imaging-clinical datasets poses challenges. Here, we propose two biologically interpretable and robust deep-learning architectures for survival prediction of non-small cell lung cancer (NSCLC) patients, learning simultaneously from computed tomography (CT) scan images, gene expression data, and clinical information. The proposed models integrate patient-specific clinical, transcriptomic, and imaging data and incorporate Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway information, adding biological knowledge within the learning process to extract prognostic gene biomarkers and molecular pathways. While both models accurately stratify patients in high- and low-risk groups when trained on a dataset of only 130 patients, introducing a cross-attention mechanism in a sparse autoencoder significantly improves the performance, highlighting tumor regions and NSCLC-related genes as potential biomarkers and thus offering a significant methodological advancement when learning from small imaging-omics-clinical samples.
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Affiliation(s)
- Suraj Verma
- School of Computing, Engineering and Digital Technologies, Teesside University, Middlesbrough, UK
| | | | | | - Thai Lou
- Gateshead Health NHS Foundation Trust, Gateshead, UK
| | - Alex Gilhespy
- South Tyneside and Sunderland NHS Foundation Trust, Sunderland, UK
| | - Annalisa Occhipinti
- School of Computing, Engineering and Digital Technologies, Teesside University, Middlesbrough, UK; Centre for Digital Innovation, Teesside University, Middlesbrough, UK; National Horizons Centre, Teesside University, Darlington, UK
| | - Claudio Angione
- School of Computing, Engineering and Digital Technologies, Teesside University, Middlesbrough, UK; Centre for Digital Innovation, Teesside University, Middlesbrough, UK; National Horizons Centre, Teesside University, Darlington, UK.
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Ginovyan M, Javrushyan H, Hovhannisyan S, Nadiryan E, Sevoyan G, Harutyunyan T, Gevorgyan S, Karabekian Z, Maloyan A, Avtandilyan N. 5-fluorouracil and Rumex obtusifolius extract combination trigger A549 cancer cell apoptosis: uncovering PI3K/Akt inhibition by in vitro and in silico approaches. Sci Rep 2024; 14:14676. [PMID: 38918540 PMCID: PMC11199614 DOI: 10.1038/s41598-024-65816-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 06/24/2024] [Indexed: 06/27/2024] Open
Abstract
The continuous increase in cancer rates, failure of conventional chemotherapies to control the disease, and excessive toxicity of chemotherapies clearly demand alternative approaches. Natural products contain many constituents that can act on various bodily targets to induce pharmacodynamic responses. This study aimed to explore the combined anticancer effects of Rumex obtusifolius (RO) extract and the chemotherapeutic agent 5-fluorouracil (5-FU) on specific molecular targets involved in cancer progression. By focusing on the PI3K/Akt signaling pathway and its related components, such as cytokines, growth factors (TNFa, VEGFa), and enzymes (Arginase, NOS, COX-2, MMP-2), this research sought to elucidate the molecular mechanisms underlying the anticancer effects of RO extract, both independently and in combination with 5-FU, in non-small lung adenocarcinoma A549 cells. The study also investigated the potential interactions of compounds identified by HPLC/MS/MS of RO on PI3K/Akt in the active site pocket through an in silico analysis. The ultimate goal was to identify potent therapeutic combinations that effectively inhibit, prevent or delay cancer development with minimal side effects. The results revealed that the combined treatment of 5-FU and RO demonstrated a significant reduction in TNFa levels, comparable to the effect observed with RO alone. RO modulated the PI3K/Akt pathway, influencing the phosphorylated and total amounts of these proteins during the combined treatment. Notably, COX-2, a key player in inflammatory processes, substantially decreased with the combination treatment. Caspase-3 activity, indicative of apoptosis, increased by 1.8 times in the combined treatment compared to separate treatments. In addition, the in silico analyses explored the binding affinities and interactions of RO's major phytochemicals with intracellular targets, revealing a high affinity for PI3K and Akt. These findings suggest that the combined treatment induces apoptosis in A549 cells by regulating the PI3K/Akt pathway.
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Affiliation(s)
- Mikayel Ginovyan
- Research Institute of Biology, Yerevan State University, 1 Alex Manoogian, 0025, Yerevan, RA, Armenia
| | - Hayarpi Javrushyan
- Research Institute of Biology, Yerevan State University, 1 Alex Manoogian, 0025, Yerevan, RA, Armenia
| | - Svetlana Hovhannisyan
- Research Institute of Biology, Yerevan State University, 1 Alex Manoogian, 0025, Yerevan, RA, Armenia
| | - Edita Nadiryan
- Research Institute of Biology, Yerevan State University, 1 Alex Manoogian, 0025, Yerevan, RA, Armenia
| | - Gohar Sevoyan
- Laboratory of Immunology and Tissue Engineering, L.A. Orbeli Institute of Physiology NAS RA, Yerevan, Armenia
| | - Tigran Harutyunyan
- Department of Genetics and Cytology, Yerevan State University, Yerevan, Armenia
| | | | - Zaruhi Karabekian
- Laboratory of Immunology and Tissue Engineering, L.A. Orbeli Institute of Physiology NAS RA, Yerevan, Armenia
| | - Alina Maloyan
- Center for Developmental Health, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, USA
| | - Nikolay Avtandilyan
- Research Institute of Biology, Yerevan State University, 1 Alex Manoogian, 0025, Yerevan, RA, Armenia.
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Du Q, Xing N, Guo S, Li R, Meng X, Wang S. Cycads: A comprehensive review of its botany, traditional uses, phytochemistry, pharmacology and toxicology. PHYTOCHEMISTRY 2024; 220:114001. [PMID: 38286200 DOI: 10.1016/j.phytochem.2024.114001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 01/21/2024] [Accepted: 01/22/2024] [Indexed: 01/31/2024]
Abstract
Cycads, which primarily consist of the families Cycadaceae and Zamiaceae, possess intrinsic therapeutic attributes that are prominently expressed across their morphological spectrum, including roots, leaves, flowers, and seeds. In Chinese traditional medicine, the leaves of cycads are particularly revered for their profound healing capabilities. This meticulous review engages with existing literature on cycads and presents insightful avenues for future research. Over 210 phytoconstituents have been isolated and identified from various cycad tissues, including flavonoids, azoxy metabolites, sterols, lignans, non-proteogenic amino acids, terpenoids, and other organic constituents. The contemporary pharmacological discourse highlights the antineoplastic, antimicrobial, and antidiabetic activities inherent in these ancient plants, which are of particular importance to the field of oncology. Despite the prevalent focus on crude extracts and total flavonoid content, our understanding of the nuanced pharmacodynamics of cycads lags considerably behind. The notoriety of cycads derived toxicity, notably within the context of Guam's neurological disease cluster, has precipitated an established emphasis on toxicological research within this field. As such, this critical review emphasizes nascent domains deserving of academic and clinical pursuit, whilst nested within the broader matrix of current scientific understanding. The systematic taxonomy, traditional applications, phytochemical composition, therapeutic potential, and safety profile of cycads are holistically interrogated, assimilating an indispensable repository for future scholarly inquiries. In conclusion, cycads stand as a veritable treasure trove of pharmacological virtue, displaying remarkable therapeutic prowess and holding vast promise for ongoing scientific discovery and clinical utilization.
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Affiliation(s)
- Qinyun Du
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Nan Xing
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Sa Guo
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Rui Li
- Meishan Hospital of Chengdu University of Traditional Chinese Medicine, Meishan, 620010, China
| | - Xianli Meng
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Shaohui Wang
- Meishan Hospital of Chengdu University of Traditional Chinese Medicine, Meishan, 620010, China; School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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Wei Q, Zhang YH. Flavonoids with Anti-Angiogenesis Function in Cancer. Molecules 2024; 29:1570. [PMID: 38611849 PMCID: PMC11013936 DOI: 10.3390/molecules29071570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 03/23/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
The formation of new blood vessels, known as angiogenesis, significantly impacts the development of multiple types of cancer. Consequently, researchers have focused on targeting this process to prevent and treat numerous disorders. However, most existing anti-angiogenic treatments rely on synthetic compounds and humanized monoclonal antibodies, often expensive or toxic, restricting patient access to these therapies. Hence, the pursuit of discovering new, affordable, less toxic, and efficient anti-angiogenic compounds is imperative. Numerous studies propose that natural plant-derived products exhibit these sought-after characteristics. The objective of this review is to delve into the anti-angiogenic properties exhibited by naturally derived flavonoids from plants, along with their underlying molecular mechanisms of action. Additionally, we summarize the structure, classification, and the relationship between flavonoids with their signaling pathways in plants as anti-angiogenic agents, including main HIF-1α/VEGF/VEGFR2/PI3K/AKT, Wnt/β-catenin, JNK1/STAT3, and MAPK/AP-1 pathways. Nonetheless, further research and innovative approaches are required to enhance their bioavailability for clinical application.
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Affiliation(s)
- Qiang Wei
- School of Medicine, Anhui Xinhua University, 555 Wangjiang West Road, Hefei 230088, China;
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Günaydın Ş, Sulukoğlu EK, Kalın ŞN, Altay A, Budak H. Diffractaic acid exhibits thioredoxin reductase 1 inhibition in lung cancer A549 cells. J Appl Toxicol 2023; 43:1676-1685. [PMID: 37329199 DOI: 10.1002/jat.4505] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/24/2023] [Accepted: 05/29/2023] [Indexed: 06/18/2023]
Abstract
Lung cancer is the leading cause of cancer-related deaths all over the world. Therefore, it has gained importance in the development of new chemotherapeutic strategies to identify anticancer agents with low side effects, reliable, high anticancer potential, and specific to lung cancer cells. Thioredoxin reductase 1 (TrxR1) is an important therapeutic target for lung cancer treatment because of its overexpression in tumor cells. Here, we aimed to examine the anticancer effect of diffractaic acid, a lichen secondary metabolite, in A549 cells by comparing it with the commercial chemotherapeutic drug carboplatin and also to investigate whether the anticancer effect of diffractaic acid occurs via TrxR1-targeting. The IC50 value of diffractaic acid on A549 cells was determined as 46.37 μg/mL at 48 h, and diffractaic acid had stronger cytotoxicity than carboplatin in A549 cells. qPCR results revealed that diffractaic acid promoted the intrinsic apoptotic pathway through the upregulation of the BAX/BCL2 ratio and P53 gene in A549 cells, which is consistent with the flow cytometry results. Furthermore, migration analysis results indicated that diffractaic acid impressively suppressed the migration of A549 cells. While the enzymatic activity of TrxR1 was inhibited by diffractaic acid in A549 cells, no changes were seen in the quantitative expression levels of gene and protein. These findings provide fundamental data on the anticancer effect of diffractaic acid on A549 cells targeting TrxR1 activity, suggesting that it could be considered a chemotherapeutic agent for lung cancer therapy.
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Affiliation(s)
- Şükran Günaydın
- Science Faculty, Department of Molecular Biology and Genetics, Atatürk University, Erzurum, Turkey
- East Anatolia High Technology Application and Research Center, Atatürk University, Erzurum, Turkey
| | - Emine Karaca Sulukoğlu
- Science Faculty, Department of Molecular Biology and Genetics, Atatürk University, Erzurum, Turkey
- Science Faculty, Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, Turkey
| | - Şeyda Nur Kalın
- Science Faculty, Department of Molecular Biology and Genetics, Atatürk University, Erzurum, Turkey
- East Anatolia High Technology Application and Research Center, Atatürk University, Erzurum, Turkey
| | - Ahmet Altay
- Faculty of Science and Arts, Department of Chemistry, Erzincan Binali Yıldırım University, Erzincan, Turkey
| | - Harun Budak
- Science Faculty, Department of Molecular Biology and Genetics, Atatürk University, Erzurum, Turkey
- East Anatolia High Technology Application and Research Center, Atatürk University, Erzurum, Turkey
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Wang D, Zhang L, Sun Z, Jiang H, Zhang J. A radiomics signature associated with underlying gene expression pattern for the prediction of prognosis and treatment response in hepatocellular carcinoma. Eur J Radiol 2023; 167:111086. [PMID: 37708675 DOI: 10.1016/j.ejrad.2023.111086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/13/2023] [Accepted: 09/04/2023] [Indexed: 09/16/2023]
Abstract
PURPOSE Identifying robust prognosis and treatment efficiency predictive biomarkers of hepatocellular carcinoma (HCC) is challenging. The purpose of this study is to develop a radiomics approach for predicting the overall survival (OS) based on pretreatment CT images and to explore the radiomic-associated key genes. METHODS Patients with pathologically or clinically proven HCC from three data sets were retrospectively included in this study. The institute internal data that received transarterial chemoembolization (TACE) treatment was used as the training set to construct the radiomics signature to predict OS by the least absolute shrinkage and selection operator COX (LASSO-COX) regression algorithms. The model was externally tested in 41 patients from The Cancer Genome Atlas (TCGA) with available CT images. Area under the receiver operating characteristics curve (AUC) and the log-rank test were used for survival analysis based on high versus low radiomics score. RNA sequencing data of TCGA and Gene Expression Omnibus (GEO) public database were used for gene expression analysis. RESULTS A total of 752 patients were divided into the Radiomics cohort (n = 267), the TCGA cohort (n = 338) and GEO cohort (n = 147). The rad-score divided patients into high and low risk groups, with significant survival differences (P < 0.0001 and P = 0.0055) in the training and external test set. The AUC for 5 years' OS were 0.730 and 0.695, respectively. Seven OS-related genes (SPP1, GJA5, GJA4, INMT, PDZD4, ALDOA and MAFG) were identified, all of which were related with TACE efficiency, except for MAFG (P greater than 0.05). CONCLUSIONS CT-radiomics signature could effectively predict the prognosis and treatment response of HCC, which were also associated with the tumor microenvironment heterogeneity.
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Affiliation(s)
- Dandan Wang
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Linhan Zhang
- Department of PET/CT, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhongqi Sun
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Huijie Jiang
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Jinfeng Zhang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
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Li J, Jiang JL, Chen YM, Lu WQ. KLF2 inhibits colorectal cancer progression and metastasis by inducing ferroptosis via the PI3K/AKT signaling pathway. J Pathol Clin Res 2023; 9:423-435. [PMID: 37147883 PMCID: PMC10397377 DOI: 10.1002/cjp2.325] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/26/2023] [Accepted: 04/16/2023] [Indexed: 05/07/2023]
Abstract
Krüppel-like factor 2 (KLF2) belongs to the zinc finger family and is thought to be a tumor suppressor gene due to its low expression in various cancer types. However, its functional role and molecular pathway involvement in colorectal cancer (CRC) are not well defined. Herein, we investigated the potential mechanism of KLF2 in CRC cell invasion, migration, and epithelial-mesenchymal transition (EMT). We utilized the TCGA and GEPIA databases to analyze the expression of KLF2 in CRC patients and its correlation with different CRC stages and CRC prognosis. RT-PCR, western blot, and immunohistochemistry assays were used to measure KLF2 expression. Gain-of-function assays were performed to evaluate the role of KLF2 in CRC progression. Moreover, mechanistic experiments were conducted to investigate the molecular mechanism and involved signaling pathways regulated by KLF2. Additionally, we also conducted a xenograft tumor assay to evaluate the role of KLF2 in tumorigenesis. KLF2 expression was low in CRC patient tissues and cell lines, and low expression of KLF2 was associated with poor CRC prognosis. Remarkably, overexpressing KLF2 significantly inhibited the invasion, migration, and EMT capabilities of CRC cells, and tumor growth in xenografts. Mechanistically, KLF2 overexpression induced ferroptosis in CRC cells by regulating glutathione peroxidase 4 expression. Moreover, this KLF2-dependent ferroptosis in CRC cells was mediated by inhibiting the PI3K/AKT signaling pathway that resulted in the suppression of invasion, migration, and EMT of CRC cells. We report for the first time that KLF2 acts as a tumor suppressor in CRC by inducing ferroptosis via inhibiting the PI3K/AKT signaling pathway, thus providing a new direction for CRC prognosis assessment and targeted therapy.
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Affiliation(s)
- Jia Li
- Department of General SurgeryShenzhen Traditional Chinese Medicine HospitalShenzhenPR China
| | - Ji Ling Jiang
- Department of General SurgeryShenzhen Traditional Chinese Medicine HospitalShenzhenPR China
| | - Yi Mei Chen
- Department of Breast SurgeryShenzhen Women & Children's Health Care HospitalShenzhenPR China
| | - Wei Qi Lu
- Department of Gastrointestinal SurgeryFirst Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhouPR China
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Ren M, Li S, Gao Q, Qiao L, Cao Q, Yang Z, Chen C, Jiang Y, Wang G, Fu S. Advances in the Anti-Tumor Activity of Biflavonoids in Selaginella. Int J Mol Sci 2023; 24:ijms24097731. [PMID: 37175435 PMCID: PMC10178260 DOI: 10.3390/ijms24097731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 04/16/2023] [Accepted: 04/18/2023] [Indexed: 05/15/2023] Open
Abstract
Despite the many strategies employed to slow the spread of cancer, the development of new anti-tumor drugs and the minimization of side effects have been major research hotspots in the anti-tumor field. Natural drugs are a huge treasure trove of drug development, and they have been widely used in the clinic as anti-tumor drugs. Selaginella species in the family Selaginellaceae are widely distributed worldwide, and they have been well-documented in clinical practice for the prevention and treatment of cancer. Biflavonoids are the main active ingredients in Selaginella, and they have good biological and anti-tumor activities, which warrant extensive research. The promise of biflavonoids from Selaginella (SFB) in the field of cancer therapy is being realized thanks to new research that offers insights into the multi-targeting therapeutic mechanisms and key signaling pathways. The pharmacological effects of SFB against various cancers in vitro and in vivo are reviewed in this review. In addition, the types and characteristics of biflavonoid structures are described in detail; we also provide a brief summary of the efforts to develop drug delivery systems or combinations to enhance the bioavailability of SFB monomers. In conclusion, SFB species have great potential to be developed as adjuvant or even primary therapeutic agents for cancer, with promising applications.
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Affiliation(s)
- Mengdie Ren
- School of Pharmacy, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi 563003, China
| | - Sihui Li
- School of Pharmacy, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi 563003, China
| | - Qiong Gao
- School of Pharmacy, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi 563003, China
| | - Lei Qiao
- School of Pharmacy, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi 563003, China
| | - Qianping Cao
- School of Pharmacy, Zunyi Medical University, Zunyi 563000, China
| | - Ze Yang
- School of Pharmacy, Zunyi Medical University, Zunyi 563000, China
| | - Chaoqiang Chen
- School of Pharmacy, Zunyi Medical University, Zunyi 563000, China
| | - Yongmei Jiang
- School of Pharmacy, Zunyi Medical University, Zunyi 563000, China
| | - Gang Wang
- School of Pharmacy, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi 563003, China
| | - Shaobin Fu
- School of Pharmacy, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi 563003, China
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12
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Therapeutic Properties of Flavonoids in Treatment of Cancer through Autophagic Modulation: A Systematic Review. Chin J Integr Med 2023; 29:268-279. [PMID: 35809179 PMCID: PMC9282630 DOI: 10.1007/s11655-022-3674-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/02/2022] [Indexed: 01/18/2023]
Abstract
Cancers have high morbidity and mortality rates worldwide. Current anticancer therapies have demonstrated specific signaling pathways as a target in the involvement of carcinogenesis. Autophagy is a quality control system for proteins and plays a fundamental role in cancer carcinogenesis, exerting an anticarcinogenic role in normal cells and can inhibit the transformation of malignant cells. Therefore, drugs aimed at autophagy can function as antitumor agents. Flavonoids are a class of polyphenolic secondary metabolites commonly found in plants and, consequently, consumed in diets. In this review, the systematic search strategy was used, which included the search for descriptors "flavonoids" AND "mTOR pathway" AND "cancer" AND "autophagy", in the electronic databases of PubMed, Cochrane Library, Web of Science and Scopus, from January 2011 to January 2021. The current literature demonstrates that flavonoids have anticarcinogenic properties, including inhibition of cell proliferation, induction of apoptosis, autophagy, necrosis, cell cycle arrest, senescence, impaired cell migration, invasion, tumor angiogenesis and reduced resistance to multiple drugs in tumor cells. We demonstrate the available evidence on the roles of flavonoids and autophagy in cancer progression and inhibition. (Registration No. CRD42021243071 at PROSPERO).
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13
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Flavonoid Components, Distribution, and Biological Activities in Taxus: A review. Molecules 2023; 28:molecules28041713. [PMID: 36838700 PMCID: PMC9959731 DOI: 10.3390/molecules28041713] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 01/29/2023] [Accepted: 02/02/2023] [Indexed: 02/16/2023] Open
Abstract
Taxus, also known as "gold in plants" because of the famous agents with emphases on Taxol and Docetaxel, is a genus of the family Taxaceae, distributed almost around the world. The plants hold an important place in traditional medicine in China, and its products are used for treating treat dysuria, swelling and pain, diabetes, and irregular menstruation in women. In order to make a further study and better application of Taxus plants for the future, cited references from between 1958 and 2022 were collected from the Web of Science, the China National Knowledge Internet (CNKI), SciFinder, and Google Scholar, and the chemical structures, distribution, and bioactivity of flavonoids identified from Taxus samples were summed up in the research. So far, 59 flavonoids in total with different skeletons were identified from Taxus plants, presenting special characteristics of compound distribution. These compounds have been reported to display significant antibacterial, antiaging, anti-Alzheimer's, antidiabetes, anticancer, antidepressant, antileishmaniasis, anti-inflammatory, antinociceptive and antiallergic, antivirus, antilipase, neuronal protective, and hepatic-protective activities, as well as promotion of melanogenesis. Flavonoids represent a good example of the utilization of the Taxus species. In the future, further pharmacological and clinical experiments for flavonoids could be accomplished to promote the preparation of relative drugs.
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14
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Ramalingam V, Varunkumar K, Ravikumar V, Rajaram R. N-(2-hydroxyphenyl)-2-phenazinamine from Nocardiopsis exhalans induces p53-mediated intrinsic apoptosis signaling in lung cancer cell lines. Chem Biol Interact 2023; 369:110282. [PMID: 36427553 DOI: 10.1016/j.cbi.2022.110282] [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: 09/08/2022] [Revised: 11/14/2022] [Accepted: 11/22/2022] [Indexed: 11/24/2022]
Abstract
The present study aims to investigate the effect and the molecular mechanism of N-(2-hydroxyphenyl)-2-phenazinamine (NHP) isolated from Nocardiopsis exhalans against the proliferation of human lung cancer cells. The cytotoxic activity of NHP against A549 and H520 cells was determined using MTT assay. The cytotoxic activity of NHP against A549 and H520 lung cancer cells showed excellent activity at 75 μg/mL and damage the mitochondrial membrane and nucleus by generating oxidative stress. NHP causes nuclear condensation and induces apoptosis which was confirmed using AO/EB and PI/DAPI dual staining assay. Moreover, the NHP downregulates the oncogenic genes such as IL-8, TNFα, MMPs and BcL2 and also upregulates the expression of apoptosis marker genes such as Cyto C, p53, p21, caspase 9/3 in A549 and H520 human lung cancer cells. Considering the strong anticancer activity of NHP against lung cancer, NHP may be further evaluated as a potential anticancer drug for the treatment of lung cancer.
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Affiliation(s)
- Vaikundamoorthy Ramalingam
- Centre for Natural Products and Traditional Knowledge, Indian Institute of Chemical Technology, Hyderabad, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, India.
| | | | | | - Rajendran Rajaram
- Department of Marine Science, Bharathidasan University, Tiruchirappalli, India.
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15
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Ghareghomi S, Atabaki V, Abdollahzadeh N, Ahmadian S, Hafez Ghoran S. Bioactive PI3-kinase/Akt/mTOR Inhibitors in Targeted Lung Cancer Therapy. Adv Pharm Bull 2023; 13:24-35. [PMID: 36721812 PMCID: PMC9871280 DOI: 10.34172/apb.2023.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/27/2021] [Accepted: 09/28/2021] [Indexed: 02/03/2023] Open
Abstract
One of the central signaling pathways with a regulatory effect on cell proliferation and survival is Akt/mTOR. In many human cancer types, for instance, lung cancer, the overexpression of Akt/mTOR has been reported. For this reason, either targeting cancer cells by synthetic or natural products affecting the Akt/mTOR pathway down-regulation is a useful strategy in cancer therapy. Direct inhibition of the signaling pathway or modulation of each related molecule could have significant feedback on the growth and proliferation of cancer cells. A variety of secondary metabolites has been identified to directly inhibit the AKT/mTOR signaling, which is important in the field of drug discovery. Naturally occurring nitrogenous and phenolic compounds can emerge as two pivotal classes of natural products possessing anticancer abilities. Herein, we have summarized the alkaloids and flavonoids for lung cancer treatment together with all the possible mechanisms of action relying on the Akt/mTOR pathway down-regulation. This review suggested that in search of new drugs, phytochemicals could be considered as promising scaffolds to be developed into efficient drugs for the treatment of cancer. In this review, the terms "Akt/mTOR", "Alkaloid", "flavonoid", and "lung cancer" were searched without any limitation in search criteria in Scopus, PubMed, Web of Science, and Google scholar engines.
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Affiliation(s)
- Somayyeh Ghareghomi
- Department of Biochemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Vahideh Atabaki
- Department of Pharmacognosy and Pharmaceutical Biotechnology, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Naseh Abdollahzadeh
- Neurophysiology Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Shahin Ahmadian
- Department of Biochemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran.,Corresponding Authors: Salar Hafez Ghoran and Shahin Ahmadian, and
| | - Salar Hafez Ghoran
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.,Corresponding Authors: Salar Hafez Ghoran and Shahin Ahmadian, and
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16
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Berberine: An Important Emphasis on Its Anticancer Effects through Modulation of Various Cell Signaling Pathways. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27185889. [PMID: 36144625 PMCID: PMC9505063 DOI: 10.3390/molecules27185889] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 08/31/2022] [Accepted: 09/06/2022] [Indexed: 11/27/2022]
Abstract
Cancer is the most commonly diagnosed type of disease and a major cause of death worldwide. Despite advancement in various treatment modules, there has been little improvement in survival rates and side effects associated with this disease. Medicinal plants or their bioactive compounds have been extensively studied for their anticancer potential. Novel drugs based on natural products are urgently needed to manage cancer through attenuation of different cell signaling pathways. In this regard, berberine is a bioactive alkaloid that is found in variety of plants, and an inverse association has been revealed between its consumption and cancer. Berberine exhibits an anticancer role through scavenging free radicals, induction of apoptosis, cell cycle arrest, inhibition of angiogenesis, inflammation, PI3K/AKT/mammalian target of rapamycin (mTOR), Wnt/β-catenin, and the MAPK/ERK signaling pathway. In addition, synergistic effects of berberine with anticancer drugs or natural compounds have been proven in several cancers. This review outlines the anticancer effects and mechanisms of action of berberine in different cancers through modulation of various cell signaling pathways. Moreover, the recent developments in the drug delivery systems and synergistic effect of berberine are explained.
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17
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Wang S, Xing N, Meng X, Xiang L, Zhang Y. Comprehensive bioinformatics analysis to identify a novel cuproptosis-related prognostic signature and its ceRNA regulatory axis and candidate traditional Chinese medicine active ingredients in lung adenocarcinoma. Front Pharmacol 2022; 13:971867. [PMID: 36110528 PMCID: PMC9468865 DOI: 10.3389/fphar.2022.971867] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/08/2022] [Indexed: 01/10/2023] Open
Abstract
Lung adenocarcinoma (LUAD) is the most ordinary histological subtype of lung cancer, and regulatory cell death is an attractive target for cancer therapy. Recent reports suggested that cuproptosis is a novel copper-dependent modulated form of cell death dependent on mitochondrial respiration. However, the role of cuproptosis-related genes (CRGs) in the LUAD process is unclear. In the current study, we found that DLD, LIAS, PDHB, DLAT and LIPA1 in 10 differentially expressed CRGs were central genes. GO and KEGG enrichment results showed that these 10 CRGs were mainly enriched in acetyl-CoA biosynthetic process, mitochondrial matrix, citrate cycle (TCA cycle) and pyruvate metabolism. Furthermore, we constructed a prognostic gene signature model based on the six prognostic CRGs, which demonstrated good predictive potential. Excitedly, we found that these six prognostic CRGs were significantly associated with most immune cell types, with DLD being the most significant (19 types). Significant correlations were noted between some prognostic CRGs and tumor mutation burden and microsatellite instability. Clinical correlation analysis showed that DLD was related to the pathological stage, T stage, and M stage of patients with LUAD. Lastly, we constructed the lncRNA UCA1/miR-1-3p/DLD axis that may play a key role in the progression of LUAD and screened nine active components of traditional Chinese medicine (TCM) that may regulate DLD. Further, in vitro cell experiments and molecular docking were used to verify this. In conclusion, we analyzed the potential value of CRGs in the progression of LUAD, constructed the potential regulatory axis of ceRNA, and obtained the targeted regulatory TCM active ingredients through comprehensive bioinformatics combined with experimental validation strategies. This work not only provides new insights into the treatment of LUAD but also includes a basis for the development of new immunotherapy drugs that target cuproptosis.
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Affiliation(s)
- Shaohui Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Nan Xing
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xianli Meng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Xiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Yi Zhang, ; Li Xiang,
| | - Yi Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Yi Zhang, ; Li Xiang,
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18
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Liu F, Liang Y, Sun R, Yang W, Liang Z, Gu J, Zhao F, Tang D. Astragalus mongholicus Bunge and Curcuma aromatica Salisb. inhibits liver metastasis of colon cancer by regulating EMT via the CXCL8/CXCR2 axis and PI3K/AKT/mTOR signaling pathway. Chin Med 2022; 17:91. [PMID: 35922850 PMCID: PMC9351103 DOI: 10.1186/s13020-022-00641-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 07/04/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND One of the most challenging aspects of colon cancer (CC) prognosis and treatment is liver-tropic metastasis. Astragalus mongholicus Bunge-Curcuma aromatica Salisb. (AC) is a typical medication combination for the therapy of many malignancies. Our previous studies found that AC intervention inhibits liver metastasis of colon cancer (LMCC). Nevertheless, the comprehensive anti-metastasis mechanisms of AC have not been uncovered. METHODS In bioinformatics analysis, RNA-seq data of CC and LMCC patients were collected from TCGA and GEO databases, and differentially expressed genes (DEGs) were identified. The biological processes and signaling pathways involved in DEGs were enriched by GO and KEGG. The protein-protein interaction (PPI) network of DEGs was established and visualized using the Cytocape software, followed by screening Hub genes in the PPI network using Degree value as the criterion. Subsequently, the expression and survival relevance of Hub gene in COAD patients were verified. In the experimental study, the effects of AC on the inhibition of colon cancer growth and liver metastasis were comprehensively evaluated by cellular and animal models. Finally, based on the results of bioinformatics analysis, the possible mechanisms of AC inhibition of colon cancer EMT and liver metastasis were explored by in vivo and in vitro pharmacological experiments. RESULTS In this study, we obtained 2386 DEGs relevant to LMCC from the COAD (colon adenocarcinoma) and GSE38174 datasets. Results of GO gene function and KEGG signaling pathway enrichment analysis suggested that cellular EMT (Epithelial-mesenchymal transition) biological processes, Cytokine-cytokine receptor interaction and PI3K/Akt signaling pathways might be closely related to LMCC mechanism. We then screened for CXCL8, the core hub gene with the highest centrality within the PPI network of DEGs, and discovered that CXCL8 expression was negatively correlated with the prognosis of COAD patients. In vitro and in vivo experimental evidence presented that AC significantly inhibited colon cancer cell proliferation, migration and invasion ability, and suppressed tumor growth and liver metastasis in colon cancer orthotopic transplantation mice models. Concomitantly, AC significantly reduced CXCL8 expression levels in cell supernatants and serum. Moreover, AC reduced the expression and transcription of genes related to the PI3K/AKT pathway while suppressing the EMT process in colon cancer cells and model mice. CONCLUSIONS In summary, our research predicted the potential targets and pathways of LMCC, and experimentally demonstrated that AC might inhibit the growth and liver metastasis in colon cancer by regulating EMT via the CXCL8/CXCR2 axis and PI3K/AKT/mTOR signaling pathway, which may facilitate the discovery of mechanisms and new therapeutic strategies for LMCC.
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Affiliation(s)
- Fuyan Liu
- School of Traditional Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yan Liang
- School of Traditional Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ruolan Sun
- School of Traditional Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Weicheng Yang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhongqing Liang
- School of Traditional Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Junfei Gu
- School of Traditional Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Fan Zhao
- School of Traditional Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Decai Tang
- School of Traditional Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
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19
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Sun J, Zhao X, Jiang H, Yang T, Li D, Yang X, Jia A, Ma Y, Qian Z. ARHGAP9 inhibits colorectal cancer cell proliferation, invasion and EMT via targeting PI3K/AKT/mTOR signaling pathway. Tissue Cell 2022; 77:101817. [DOI: 10.1016/j.tice.2022.101817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/02/2022] [Accepted: 05/04/2022] [Indexed: 11/30/2022]
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20
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Ma Y, Liu J, Cui X, Hou J, Yu F, Wang J, Wang X, Chen C, Tong L. Hyaluronic Acid Modified Nanostructured Lipid Carrier for Targeting Delivery of Kaempferol to NSCLC: Preparation, Optimization, Characterization, and Performance Evaluation In Vitro. Molecules 2022; 27:4553. [PMID: 35889427 PMCID: PMC9318624 DOI: 10.3390/molecules27144553] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 07/06/2022] [Accepted: 07/15/2022] [Indexed: 12/18/2022] Open
Abstract
Lung cancer seriously threatens the health of human beings, with non-small cell lung cancer (NSCLC) accounting for 80%. Nowadays, the potential position of nano-delivery in treating cancer has been the subject of continuous research. The present research aimed to prepare two molecular weight hyaluronic acid (HA)-modified kaempferol (KA)-loaded nanostructured lipid carriers (HA-KA-NLCs) by the method of melting ultrasonic and electrostatic adsorption, and to assess the antitumor effect of the preparations on A549 cells. The characterization and safety evaluation of the preparations illustrated that they are acceptable for drug delivery for cancer. Subsequently, differential scanning calorimetry (DSC) curve and transmission electron microscopy (TEM) images indicated that the drug was adequately incorporated in the carrier, and the particle appeared as a sphere. Moreover, HA-KA-NLC showed predominant in vitro antitumor effects, inhibiting proliferation, migration, and invasion, promoting apoptosis and increasing cellular uptake of A549 cells. Otherwise, the Western blot assay revealed that preparations could activate epithelial-mesenchymal transition (EMT)-related signaling pathways and modulate the expression of E-cadherin, N-cadherin, and Vimentin in A549 cells. Our present findings demonstrated that HA-KA-NLC could be considered as a secure and effective carrier for targeted tumor delivery and may have potential application prospects in future clinic therapy of NSCLC.
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Affiliation(s)
- Yufei Ma
- Department of Pharmacy, Mudanjiang Medical University, Mudanjiang 157000, China; (Y.M.); (J.H.); (F.Y.); (J.W.); (X.W.); (C.C.)
| | - Jinli Liu
- Department of Basic Medicine, Mudanjiang Medical University, Mudanjiang 157000, China;
| | - Xinyu Cui
- Department of Public Health, Mudanjiang Medical University, Mudanjiang 157000, China;
| | - Jiafu Hou
- Department of Pharmacy, Mudanjiang Medical University, Mudanjiang 157000, China; (Y.M.); (J.H.); (F.Y.); (J.W.); (X.W.); (C.C.)
| | - Fengbo Yu
- Department of Pharmacy, Mudanjiang Medical University, Mudanjiang 157000, China; (Y.M.); (J.H.); (F.Y.); (J.W.); (X.W.); (C.C.)
| | - Jinghua Wang
- Department of Pharmacy, Mudanjiang Medical University, Mudanjiang 157000, China; (Y.M.); (J.H.); (F.Y.); (J.W.); (X.W.); (C.C.)
| | - Xiaoxue Wang
- Department of Pharmacy, Mudanjiang Medical University, Mudanjiang 157000, China; (Y.M.); (J.H.); (F.Y.); (J.W.); (X.W.); (C.C.)
| | - Cong Chen
- Department of Pharmacy, Mudanjiang Medical University, Mudanjiang 157000, China; (Y.M.); (J.H.); (F.Y.); (J.W.); (X.W.); (C.C.)
| | - Lei Tong
- Department of Pharmacy, Mudanjiang Medical University, Mudanjiang 157000, China; (Y.M.); (J.H.); (F.Y.); (J.W.); (X.W.); (C.C.)
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Abstract
ABSTRACT The phosphosphatidylinositol-3-kinase (PI3K) signaling pathway is one of the most important intracellular signal transduction pathways affecting cell functions, such as apoptosis, translation, metabolism, and angiogenesis. Lung cancer is a malignant tumor with the highest morbidity and mortality rates in the world. It can be divided into two groups, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC accounts for >85% of all lung cancers. There are currently many clinical treatment options for NSCLC; however, traditional methods such as surgery, chemotherapy, and radiotherapy have not been able to provide patients with good survival benefits. The emergence of molecular target therapy has improved the survival and prognosis of patients with NSCLC. In recent years, there have been an increasing number of studies on NSCLC and PI3K signaling pathways. Inhibitors of various parts of the PI3K pathway have appeared in various phases of clinical trials with NSCLC as an indication. This article focuses on the role of the PI3K signaling pathway in the occurrence and development of NSCLC and summarizes the current clinical research progress and possible development strategies.
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22
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Mirzaei S, Saghari S, Bassiri F, Raesi R, Zarrabi A, Hushmandi K, Sethi G, Tergaonkar V. NF-κB as a regulator of cancer metastasis and therapy response: A focus on epithelial-mesenchymal transition. J Cell Physiol 2022; 237:2770-2795. [PMID: 35561232 DOI: 10.1002/jcp.30759] [Citation(s) in RCA: 127] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/24/2022] [Accepted: 04/19/2022] [Indexed: 12/13/2022]
Abstract
Metastasis of tumor cells is a complex challenge and significantly diminishes the overall survival and prognosis of cancer patients. The epithelial-to-mesenchymal transition (EMT) is a well-known mechanism responsible for the invasiveness of tumor cells. A number of molecular pathways can regulate the EMT mechanism in cancer cells and nuclear factor-kappaB (NF-κB) is one of them. The nuclear translocation of NF-κB p65 can induce the transcription of several genes involved in EMT induction. The present review describes NF-κB and EMT interaction in cancer cells and their association in cancer progression. Due to the oncogenic role NF-κB signaling, its activation enhances metastasis of tumor cells via EMT induction. This has been confirmed in various cancers including brain, breast, lung and gastric cancers, among others. The ZEB1/2, transforming growth factor-β, and Slug as inducers of EMT undergo upregulation by NF-κB to promote metastasis of tumor cells. After EMT induction driven by NF-κB, a significant decrease occurs in E-cadherin levels, while N-cadherin and vimentin levels undergo an increase. The noncoding RNAs can potentially also function as upstream mediators and modulate NF-κB/EMT axis in cancers. Moreover, NF-κB/EMT axis is involved in mediating drug resistance in tumor cells. Thus, suppressing NF-κB/EMT axis can also promote the sensitivity of cancer cells to chemotherapeutic agents.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Sam Saghari
- Department of Health Services Management, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Farzaneh Bassiri
- Department of Biology, Fars Science and Research Branch, Islamic Azad University, Fars, Iran.,Department of Biology, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Rasoul Raesi
- PhD in Health Services Management, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, Turkey
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology and Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Yong Loo Lin School of Medicine, NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore, Singapore
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology (IMCB), 61 Biopolis Drive, Proteos, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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23
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The Anticancer Mechanisms of Scutellaria barbata against Lung Squamous Cell Carcinoma. JOURNAL OF ONCOLOGY 2022. [DOI: 10.1155/2022/7529923] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Objective. Scutellaria barbata (S. barbata) is a Chinese traditional medicinal crop with anti-inflammatory as well as anticancer properties. To explore the anticancer mechanisms of functional monomers of S. barbata against lung squamous cell carcinoma (LUSC), a network pharmacology approach and molecular docking were utilized. Methods. The expression profile of genes encoding functional monomer components in S. barbata was obtained from the Traditional Chinese Medicine Systems Pharmacology platform (TCMSP) database. Expression data of LUSC-related genes were acquired from DisGeNET, GeneCards, OMIM, DrugBank, and TTD databases. The target genes of S. barbata that confer anticancer effects against LUSC were obtained by considering the intersecting genes between S. barbata target genes and LUSC-related genes. The potential regulatory pathways enriched in these intersected genes were identified using the KOBAS database, and Gene Ontology (GO) function enrichment analysis was performed using the online tool DAVID. The relationship network of S. barbata functional monomer components-action targets-disease-pathways was established using Cytoscape 3.8.2, and the protein-protein interaction network of those intersected genes was established using the STRING database. Finally, the hub genes were screened by using CytoNCA, a plug-in of Cytoscape, and hub gene expressions in LUSC were evaluated via the Gene Expression Profiling Interactive Analysis (GEPIA) database. AutoDockTools and PyMOL software were employed to verify the molecular docking on disease target proteins and drug functional molecules. Results. In S. barbata, 104 target genes and 20 hub genes encoding functional components against LUSC were screened out, six of which were significantly differentially expressed between LUSC samples and normal tissue samples in the GEPIA database. Here, GO analysis illustrated the involvement of these genes in the signal transduction and positive regulation of transcription from RNA polymerase II promoter and negative regulation of apoptosis, while KEGG pathway enrichment analysis demonstrated that these genes were mainly involved in several pathways, for instance, AGE-RAGE, PI3K-Akt, p53, and MAPK signaling pathway. There are four main functional components docking with six key target proteins, all of which have strong binding activity. Conclusions. We predicted the molecular mechanisms and signaling pathways of genes encoding functional components in S. barbata against LUSC. These discoveries offer novel understanding for further study, laying a scientific foundation for the production of synthetic monomer components of S. barbata.
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LncCDH5-3:3 Regulates Apoptosis, Proliferation, and Aggressiveness in Human Lung Cancer Cells. Cells 2022; 11:cells11030378. [PMID: 35159188 PMCID: PMC8834634 DOI: 10.3390/cells11030378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/07/2022] [Accepted: 01/20/2022] [Indexed: 02/05/2023] Open
Abstract
(1) Lung cancer (both small cell and non-small cell) is the leading cause of new deaths associated with cancers globally in men and women. Long noncoding RNAs (lncRNAs) are associated with tumorigenesis in different types of tumors, including lung cancer. Herein, we discuss: (1) An examination of the expression profile of lncCDH5-3:3 in non-small cell lung cancer (NSCLC), and an evaluation of its functional role in lung cancer development and progression using in vitro models; (2) A quantitative real-time polymerase chain reaction assay that confirms lncCDH5-3:3 expression in tumor samples resected from 20 NSCLC patients, and that shows its statistically higher expression levels at stage III NSCLC, compared to stages I and II. Moreover, knockout (KO) and overexpression, as well as molecular and biochemical techniques, were used to investigate the biological functions of lncCDH5-3:3 in NSCLC cells, with a focus on the cells’ proliferation and migration; (3) The finding that lncCDH5-3:3 silencing promotes apoptosis and probably regulates the cell cycle and E-cadherin expression in adenocarcinoma cell lines. In comparison, lncCDH5-3:3 overexpression increases the expression levels of proliferation and epithelial-to-mesenchymal transition markers, such as EpCAM, Akt, and ERK1/2; however, at the same time, it also stimulates the expression of E-cadherin, which conversely inhibits the mobility capabilities of lung cancer cells; (4) The results of this study, which provide important insights into the role of lncRNAs in lung cancer. Our study shows that lncCDH5-3:3 affects important features of lung cancer cells, such as their viability and motility. The results support the idea that lncCDH5-3:3 is probably involved in the oncogenesis of NSCLC through the regulation of apoptosis and tumor cell metastasis formation.
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Yan S, Zhang B, Feng J, Wu H, Duan N, Zhu Y, Zhao Y, Shen S, Zhang K, Wu W, Liu N. FGFC1 Selectively Inhibits Erlotinib-Resistant Non-Small Cell Lung Cancer via Elevation of ROS Mediated by the EGFR/PI3K/Akt/mTOR Pathway. Front Pharmacol 2022; 12:764699. [PMID: 35126111 PMCID: PMC8807551 DOI: 10.3389/fphar.2021.764699] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 12/15/2021] [Indexed: 12/27/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been used as a first-line treatment for patients harboring with EGFR mutations in advanced NSCLC. Nevertheless, the drug resistance after continuous and long-term chemotherapies considerably limits its clinical efficacy. Therefore, it is of great importance to develop new chemotherapeutic agents and treatment strategies to conquer the drug resistance. FGFC1 (Fungi fibrinolytic compound 1), a type of bisindole alkaloid from a metabolite of the rare marine fungi Starchbotrys longispora. FG216, has exhibited excellent fibrinolytic and anti-inflammatory activity. However, the potent efficacy of FGFC1 in human cancer therapy requires further study. Herein, we demonstrated that FGFC1 selectively suppressed the growth of NSCLC cells with EGFR mutation. Mechanistically, FGFC1 treatment significantly induced the apoptosis of erlotinib-resistant NSCLC cells H1975 in a dose-dependent manner, which was proved to be mediated by mitochondrial dysfunction and elevated accumulation of intracellular reactive oxygen species (ROS). Scavenging ROS not only alleviated FGFC1-induced apoptosis but also relieved the decrease of phospho-Akt. We further confirmed that FGFC1 significantly decreased the phosphorylation of protein EGFR, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR) in H1975 cells. Notably, PI3K inhibitor (LY294002) could promote the accumulation of ROS and the expression levels of apoptosis-related proteins induced by FGFC1. Molecular dynamics simulations indicated that FGFC1 can inhibit EGFR and its downstream PI3K/Akt/mTOR pathway through directly binding to EGFR, which displayed a much higher binding affinity to EGFRT790M/L858R than EGFRWT. Additionally, FGFC1 treatment also inhibited the migration and invasion of H1975 cells. Finally, FGFC1 effectively inhibited tumor growth in the nude mice xenograft model of NSCLC. Taken together, our results indicate that FGFC1 may be a potential candidate for erlotinib-resistant NSCLC therapy.
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Affiliation(s)
- Shike Yan
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Bing Zhang
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Jingwen Feng
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Haigang Wu
- School of Life Sciences, Henan University, Kaifeng, China
| | - Namin Duan
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Yamin Zhu
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Yueliang Zhao
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Shuang Shen
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Kai Zhang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wenhui Wu
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
- Engineering Research Center of Aquatic-Product Processing & Preservation, Shanghai, China
| | - Ning Liu
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
- Engineering Research Center of Aquatic-Product Processing & Preservation, Shanghai, China
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26
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Liu W, Huang L, Zhang C, Liu Z. Effect of Nerve Training Technology on Apoptosis of Cartilage and Osteoblasts and Expression of Aggrecan Protein in Osteoporotic Arthritis. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.2880] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Arthritis and osteoporosis are two common disorders in the world, especially for the elder, but the current treatments have limited efficacy. Herein, we aimed to determine whether the novel technique, neurological training can alleviate osteoporosis complicated with arthritis in rat
model. Thirty rats were assigned into normal group, model group, and treatment group (treated with forsythin and neurological training) (n = 10) followed by assessment of chondrocytes and osteoblasts using Mankin score, apoptosis by TUNEL and flow cytometry, and IL-1β, TNF-α,
and Aggrecan levels. Apoptotic chondrocytes of treatment group (27.43±1.34) was lower than model group (p < 0.05), whereas amount of osteoblast was increased upon forsythin and neurological training, with lower Mankin’s score (6.38±0.76). Besides, the content
of IL-1β and TNF-α of treatment group was significantly lower but Aggrecan mRNA and protein expression was significantly higher. In conclusion, neurological training could protect and alleviate osteoporosis complicated with arthritis.
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Affiliation(s)
- Wei Liu
- Department of Orthopedics, Yongchuan Hospital Affiliated to Chongqing Medical University, Chongqing, 402100, China
| | - Lili Huang
- Department of Infections, Yongchuan Hospital Affiliated to Chongqing Medical University, Chongqing, 402100, China
| | - Cuiying Zhang
- Department of Gynaecology and Obstetrics, Yongchuan Hospital Affiliated to Chongqing Medical University, Chongqing, 402100, China
| | - Zuozhong Liu
- Department of Orthopedics, Yongchuan Hospital Affiliated to Chongqing Medical University, Chongqing, 402100, China
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27
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Zhao B, Hui X, Wang J, Zeng H, Yan Y, Hu Q, Ge G, Lei T. Matrine suppresses lung cancer metastasis via targeting M2-like tumour-associated-macrophages polarization. Am J Cancer Res 2021; 11:4308-4328. [PMID: 34659889 PMCID: PMC8493404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 07/16/2021] [Indexed: 06/13/2023] Open
Abstract
Metastasis is the primary cause of death in lung cancer, one of the most prevalent and deadly neoplasms. The tumour-associated macrophages (TAMs) are crucial mediators to induce epithelial-mesenchymal transition (EMT) and promote lung metastasis via release of the cytokines. Matrine, a naturally occurring alkaloid, has been found with a variety of pharmacological effects, such as anti-cancer. In this study, an in vitro co-culture cell systems and a Lewis-bearing mouse model were employed to assay the potential effects of matrine on macrophages polarization, and its regulatory effects on EMT of Lewis lung cancer cells (LLCs). Our results clearly demonstrated that matrine inhibited M2-like RAW264.7 polarization, reducing the production of anti-inflammatory cytokines (IL-4, IL-10, and Arg-1), and M2 surface markers (CD206) were induced by LLCs via mTOR/PI3k/Akt signaling pathway, while it had no significant effect on M1 macrophages polarization. In vitro assays suggested that matrine partially blocked the metastasis of LLCs, and inhibited EMT induced by M2-like macrophages, which was evidenced by up-regulating the expression of E-cadherin and down-regulating the expression of N-cadherin, vimentin, and Snail. In vivo studies revealed that matrine decreased the ratio of CD206+/F4/80+, promoted the expression of CD4+ and CD8+ T cells, and inhibited the expression of Th2 in tumor and spleen tissues. Cell co-culture experiments revealed that Matrine promoted T-cell proliferation, which was impaired by tumour-derived CD11b+ myeloid cells. Collectively, our findings suggest that suppression of M2-like macrophages polarization of TAMs is a potential mechanism underlying the anti-metastasis effects of matrine in lung cancer.
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Affiliation(s)
- Bei Zhao
- Putuo Hospital, Shanghai University of Traditional Chinese MedicineShanghai 200062, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Xiaodan Hui
- Department of Wine, Food and Molecular Bioscience, Faculty of Life Science, Lincoln UniversityLincoln 7647, Christchurch, New Zealand
| | - Jie Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Hairong Zeng
- Putuo Hospital, Shanghai University of Traditional Chinese MedicineShanghai 200062, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Yu Yan
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Qing Hu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Guangbo Ge
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Tao Lei
- Putuo Hospital, Shanghai University of Traditional Chinese MedicineShanghai 200062, China
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28
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Fu Z, Wang L, Li S, Chen F, Au-Yeung KKW, Shi C. MicroRNA as an Important Target for Anticancer Drug Development. Front Pharmacol 2021; 12:736323. [PMID: 34512363 PMCID: PMC8425594 DOI: 10.3389/fphar.2021.736323] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer has become the second greatest cause of death worldwide. Although there are several different classes of anticancer drugs that are available in clinic, some tough issues like side-effects and low efficacy still need to dissolve. Therefore, there remains an urgent need to discover and develop more effective anticancer drugs. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that regulate gene expression by inhibiting mRNA translation or reducing the stability of mRNA. An abnormal miRNA expression profile was found to exist widely in cancer cell, which induces limitless replicative potential and evading apoptosis. MiRNAs function as oncogenes (oncomiRs) or tumor suppressors during tumor development and progression. It was shown that regulation of specific miRNA alterations using miRNA mimics or antagomirs can normalize the gene regulatory network and signaling pathways, and reverse the phenotypes in cancer cells. The miRNA hence provides an attractive target for anticancer drug development. In this review, we will summarize the latest publications on the role of miRNA in anticancer therapeutics and briefly describe the relationship between abnormal miRNAs and tumorigenesis. The potential of miRNA-based therapeutics for anticancer treatment has been critically discussed. And the current strategies in designing miRNA targeting therapeutics are described in detail. Finally, the current challenges and future perspectives of miRNA-based therapy are conferred.
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Affiliation(s)
- Zhiwen Fu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Liu Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Shijun Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Fen Chen
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | | | - Chen Shi
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
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Iksen, Pothongsrisit S, Pongrakhananon V. Targeting the PI3K/AKT/mTOR Signaling Pathway in Lung Cancer: An Update Regarding Potential Drugs and Natural Products. Molecules 2021; 26:4100. [PMID: 34279440 PMCID: PMC8271933 DOI: 10.3390/molecules26134100] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/02/2021] [Accepted: 07/02/2021] [Indexed: 12/12/2022] Open
Abstract
Lung cancer is one of the most common cancers and has a high mortality rate. Due to its high incidence, the clinical management of the disease remains a major challenge. Several reports have documented a relationship between the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway and lung cancer. The recognition of this pathway as a notable therapeutic target in lung cancer is mainly due to its central involvement in the initiation and progression of the disease. Interest in using natural and synthetic medications to target these signaling pathways has increased in recent years, with promising results in vitro, in vivo, and in clinical trials. In this review, we focus on the current understanding of PI3K/AKT/mTOR signaling in tumor development. In addition to the signaling pathway, we highlighted the therapeutic potential of recently developed PI3K/AKT/mTOR inhibitors based on preclinical and clinical trials.
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Affiliation(s)
- Iksen
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (I.); (S.P.)
- Department of Pharmacy, Sekolah Tinggi Ilmu Kesehatan Senior Medan, Medan 20131, Indonesia
| | - Sutthaorn Pothongsrisit
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (I.); (S.P.)
| | - Varisa Pongrakhananon
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (I.); (S.P.)
- Preclinical Toxicity and Efficacy Assessment of Medicines and Chemicals Research Cluster, Chulalongkorn University, Bangkok 10330, Thailand
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30
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Wang Z, Ao X, Shen Z, Ao L, Wu X, Pu C, Guo W, Xing W, He M, Yuan H, Yu J, Li L, Xu X. TNF-α augments CXCL10/CXCR3 axis activity to induce Epithelial-Mesenchymal Transition in colon cancer cell. Int J Biol Sci 2021; 17:2683-2702. [PMID: 34345201 PMCID: PMC8326125 DOI: 10.7150/ijbs.61350] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 06/13/2021] [Indexed: 12/18/2022] Open
Abstract
Chronic inflammation-induced metastases have long been regarded as one of the significant obstacles in treating cancer. Tumor necrosis factor-α (TNF-α), a main inflammation mediator within tumor microenvironment, affects tumor development by inducing multiple chemokines to establish a complex network. Recent reports have revealed that CXCL10/CXCR3 axis affects cancer cells invasiveness and metastases, and Epithelial-mesenchymal transition (EMT) is the main reason for frequent proliferation and distant organ metastases of colon cancer (CC) cells, However, it is unclear whether TNF-α- mediated chronic inflammation can synergically enhance EMT-mediated CC metastasis through promoting chemokine expression. According to this study, TNF-α activated the PI3K/Akt and p38 MAPK parallel signal transduction pathways, then stimulate downstream NF-κB pathway p65 into the nucleus to activate CXCL10 transcription. CXCL10 enhanced the metastases of CC-cells by triggering small GTPases such as RhoA and cdc42. Furthermore, overexpression of CXCL10 significantly enhanced tumorigenicity and mobility of CC cells in vivo. We further clarified that CXCL10 activated the PI3K/Akt pathway through CXCR3, resulting in suppression of GSK-3β phosphorylation and leading to upregulation of Snail expression, thereby regulating EMT in CC cells. These outcomes lay the foundation for finding new targets to inhibit CC metastases.
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Affiliation(s)
- Zhengcheng Wang
- Department of Human Anatomy and Histology and Embryology, School of Basic Medical Sciences, Qingdao University, Qingdao 266000, China
| | - Xiang Ao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Zhilin Shen
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Luoquan Ao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Xiaofeng Wu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Chengxiu Pu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wei Guo
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wei Xing
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Min He
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Hongfeng Yuan
- Department of Ophthalmology, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Jianhua Yu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Ling Li
- Department of Human Anatomy and Histology and Embryology, School of Basic Medical Sciences, Qingdao University, Qingdao 266000, China
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
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Yin Z, Yang Y, Guo T, Veeraraghavan VP, Wang X. Potential chemotherapeutic effect of betalain against human non-small cell lung cancer through PI3K/Akt/mTOR signaling pathway. ENVIRONMENTAL TOXICOLOGY 2021; 36:1011-1020. [PMID: 33522684 DOI: 10.1002/tox.23100] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 01/10/2021] [Indexed: 06/12/2023]
Abstract
This work focuses on evaluating the therapeutic ability of betalain and its causal mechanisms in NSCLC both in vivo and in vitro. The experimental results demonstrated that betalain was able to reduce the viability of A549 cells dose dependently with undetectable toxicity toward normal human cells. Betalain also augmented the apoptotic cells of A549 and cell cycle arrest which was evidenced via increased in level of p53/p21 and decreasing levels of cyclin-D1 complex. Moreover, betalain also reduced the levels of p-PI3K, p-Akt, and mammalian target of rapamycin significantly, justifying the pro-apoptotic effect on A549 cells. The in vivo anticancer activity of betalain was determined further in nude mice injected with A549 cells. Xenograft in vivo experiments confirmed betalain administration of ameliorates the expression of pro-inflammatory cytokines, tumor markers with reduced toxic effect. Accordingly, this combined study provides significant insight on betalain as a therapeutic agent.
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Affiliation(s)
- Zongxiu Yin
- Department of Respiratory and Critical Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan City, China
| | - Yanna Yang
- Department of Respiratory and Critical Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan City, China
| | - Tianfang Guo
- Department of Respiratory and Critical Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan City, China
| | - Vishnu Priya Veeraraghavan
- Department of Biochemistry, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamilnadu, India
| | - Xin Wang
- Department of Respiratory and Critical Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan City, China
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Cai Y, Wang B, Li B, Huang X, Guo H, Liu Y, Chen B, Zhao S, Wu S, Li W, Wang L, Jia K, Wang H, Chen P, Jiang M, Tang X, Qi H, Dai C, Ye J, He Y. Collection on reports of molecules linked to epithelial-mesenchymal transition in the process of treating metastasizing cancer: a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:946. [PMID: 34350261 PMCID: PMC8263858 DOI: 10.21037/atm-20-7002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 04/12/2021] [Indexed: 12/26/2022]
Abstract
Epithelial-mesenchymal transition (EMT) is a morphological process in which epithelial cells transform into mesenchymal cells via a specific procedure. EMT plays an important role in the cancer invasion-metastasis cascade and the current treatment of metastatic cancer, influences the migration, polarity, and adhesion of tumor cells, promotes their migration, invasiveness, anti-apoptotic ability. It contributes to the changes of the tumor microenvironment and suppresses the sensitivity of tumor cells to chemotherapy, causing cancer metastasis and worse, hindering the control and therapy of it. This paper reviews the mechanisms, detection, and treatments of cancer metastasis that have been identified and applied to date, summarizes the EMT-related biological molecules, providing a reference for EMT-targeted research and therapy. As EMT is significant in the progress of tumor metastasis, it is meaningful for the therapy and control of metastatic cancer to understand the mechanism of EMT at the molecular level. We summarized the mechanisms, detection and therapeutic implications of EMT, listed the research progress of molecules like genes, miRNAs, signaling pathways in EMT. We also discussed the prospects of EMT-targeted treatment in cancer metastasis interventions and the challenges the treatment and researches are facing. The summary is conducive to the treatment and further research of EMT and metastatic cancer.
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Affiliation(s)
- Yiyi Cai
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Boyuan Wang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Bingying Li
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Xintong Huang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Haoyue Guo
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Yu Liu
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Bin Chen
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Sha Zhao
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Shengyu Wu
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Wei Li
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Lei Wang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Keyi Jia
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Hao Wang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Peixin Chen
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Minlin Jiang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Xuzhen Tang
- Oncology and Immunology BU, Research Service Division, WuXi Apptec, Shanghai, China
| | - Hui Qi
- Oncology and Immunology BU, Research Service Division, WuXi Apptec, Shanghai, China
| | - Chunlei Dai
- Oncology and Immunology BU, Research Service Division, WuXi Apptec, Shanghai, China
| | - Junyan Ye
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Yayi He
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
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Ye H, Pan J, Gong E, Cai X, Xu C, Li Y, Zheng H, Cao Z. Inhibitory Effect of Immunologically Activated Mesenchymal Stem Cells on Lung Cancer Cell Growth and Metastasis. Cancer Biother Radiopharm 2021. [PMID: 33769841 DOI: 10.1089/cbr.2020.3855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Background: Mesenchymal stem cells (MSCs) could inhibit the proliferation of lung cancer cells. The authors' study aimed to investigate the effects of immunologically activated human umbilical cord (HUC)-MSCs on A549 lung cancer cells. Materials and Methods: HUC-MSCs were separated from the umbilical cord using the adherence method. Surface markers of HUC-MSCs were detected by flow cytometry for MSC identification. Imiquimod (TLR7 agonist) was incubated with HUC-MSCs for immune activation, and the expression of MSC-specific markers and immune inflammatory molecules was measured by quantitative real-time polymerase chain reaction. HUC A549 cells were cocultured with HUC-MSCs treated with imiquimod, siTLR7 (small interfering RNA for TLR7) or TLR7 overexpression, and then cell viability, proliferation, migration, and invasion, and the expression of phosphatidylinositol-3-kinase (PI3K)/Akt and NF-κB was investigated using MTT assay, clone formation assay, transwell assay, and western blot, respectively. Results: HUC-MSCs were identified as positive for CD73, CD105, CD44, CD29, and CD90. Expression of MSC markers was inhibited, while those of immune inflammatory molecules expression except IL-6 (interleukin-6) was enhanced after MSCs were immunologically activated by imiquimod. After being cocultured with HUC-MSCs treated with imiquimod or overexpressed TLR7, cell viability, proliferation, and metastasis, and the phosphorylation of P65 and AKT in A549 cells were decreased, but apoptosis was increased, while siTLR7 showed the opposite effect HUC. Conclusions: Immunologically activated HUC-MSCs inhibited the growth and metastasis, yet, promoted the apoptosis of A549 lung cancer cells via regulating the PI3K/Akt and NF-κB pathways.
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Affiliation(s)
- Hong Ye
- Department of Medical Examination Center, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Jiongwei Pan
- Department of Respiratory, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Enhui Gong
- Department of Respiratory, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Xiaoping Cai
- Department of Respiratory, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Cunlai Xu
- Department of Respiratory, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Yuling Li
- Department of Respiratory, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Hao Zheng
- Department of Respiratory, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Zhuo Cao
- Department of Respiration, The Sixth Affiliated Hospital of Wenzhou Medical University, People's Hospital of Longquan, Lishui, China
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Abolfathi H, Sheikhpour M, Shahraeini SS, Khatami S, Nojoumi SA. Studies in lung cancer cytokine proteomics: a review. Expert Rev Proteomics 2021; 18:49-64. [PMID: 33612047 DOI: 10.1080/14789450.2021.1892491] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Proteins are molecules that have role in the progression of the diseases. Proteomics is a tool that can play an effective role in identifying diagnostic and therapeutic biomarkers for lung cancer. Cytokines are proteins that play a decisive role in activating body's immune system in lung cancer. They can increase the growth of the tumor (oncogenic cytokines) or limit tumor growth (anti-tumor cytokines) by regulating related signaling pathways such as proliferation, growth, metastasis, and apoptosis. AREAS COVERED In the present study, a total of 223 papers including 196 research papers and 27 review papers, extracted from PubMed and Scopus and published from 1997 to present, are reviewed. The most important involved-cytokines in lung cancer including TNF-α, IFN- γ, TGF-β, VEGF and interleukins such as IL-6, IL-17, IL-8, IL-10, IL-22, IL-1β and IL-18 are introduced. Also, the pathological and biological role of such cytokines in cancer signaling pathways is explained. EXPERT OPINION In lung cancer, the cytokine expression changes under the physiological conditions of the immune system, and inflammatory cytokines are associated with the progression of lung cancer. Therefore, the cytokine expression profile can be used in the diagnosis, prognosis, prediction of therapeutic responses, and survival of patients with lung cancer.
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Affiliation(s)
- Hanie Abolfathi
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.,Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
| | - Mojgan Sheikhpour
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.,Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Sadegh Shahraeini
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.,Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Shohreh Khatami
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Ali Nojoumi
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.,Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Uncovering the Anti-Lung-Cancer Mechanisms of the Herbal Drug FDY2004 by Network Pharmacology. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6644018. [PMID: 33628308 PMCID: PMC7886515 DOI: 10.1155/2021/6644018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/21/2021] [Accepted: 01/28/2021] [Indexed: 12/24/2022]
Abstract
With growing evidence on the therapeutic efficacy and safety of herbal drugs, there has been a substantial increase in their application in the lung cancer treatment. Meanwhile, their action mechanisms at the system level have not been comprehensively uncovered. To this end, we employed a network pharmacology methodology to elucidate the systematic action mechanisms of FDY2004, an anticancer herbal drug composed of Moutan Radicis Cortex, Persicae Semen, and Rhei Radix et Rhizoma, in lung cancer treatment. By evaluating the pharmacokinetic properties of the chemical compounds present in FDY2004 using herbal medicine-associated databases, we identified its 29 active chemical components interacting with 141 lung cancer-associated therapeutic targets in humans. The functional enrichment analysis of the lung cancer-related targets of FDY2004 revealed the enriched Gene Ontology terms, involving the regulation of cell proliferation and growth, cell survival and death, and oxidative stress responses. Moreover, we identified key FDY2004-targeted oncogenic and tumor-suppressive pathways associated with lung cancer, including the phosphatidylinositol 3-kinase-Akt, mitogen-activated protein kinase, tumor necrosis factor, Ras, focal adhesion, and hypoxia-inducible factor-1 signaling pathways. Overall, our study provides novel evidence and basis for research on the comprehensive anticancer mechanisms of herbal medicines in lung cancer treatment.
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Sanookpan K, Nonpanya N, Sritularak B, Chanvorachote P. Ovalitenone Inhibits the Migration of Lung Cancer Cells via the Suppression of AKT/mTOR and Epithelial-to-Mesenchymal Transition. Molecules 2021; 26:molecules26030638. [PMID: 33530617 PMCID: PMC7866203 DOI: 10.3390/molecules26030638] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/22/2021] [Accepted: 01/24/2021] [Indexed: 12/09/2022] Open
Abstract
Cancer metastasis is the major cause of about 90% of cancer deaths. As epithelial-to-mesenchymal transition (EMT) is known for potentiating metastasis, this study aimed to elucidate the effect of ovalitenone on the suppression of EMT and metastasis-related behaviors, including cell movement and growth under detached conditions, and cancer stem cells (CSCs), of lung cancer cells. Methods: Cell viability and cell proliferation were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazo-liumbromide (MTT) and colony formation assays. Cell migration and invasion were analyzed using a wound-healing assay and Boyden chamber assay, respectively. Anchorage-independent cell growth was determined. Cell protrusions (filopodia) were detected by phalloidin-rhodamine staining. Cancer stem cell phenotypes were assessed by spheroid formation. The proteins involved in cell migration and EMT were evaluated by Western blot analysis and immunofluorescence staining. Results: Ovalitenone was used at concentrations of 0–200 μM. While it caused no cytotoxic effects on lung cancer H460 and A549 cells, ovalitenone significantly suppressed anchorage-independent growth, CSC-like phenotypes, colony formation, and the ability of the cancer to migrate and invade cells. The anti-migration activity was confirmed by the reduction of filopodia in the cells treated with ovalitenone. Interestingly, we found that ovalitenone could significantly decrease the levels of N-cadherin, snail, and slug, while it increased E-cadherin, indicating EMT suppression. Additionally, the regulatory signaling of focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (AKT), the mammalian target of rapamycin (mTOR), and cell division cycle 42 (Cdc42) was suppressed by ovalitenone. Conclusions: The results suggest that ovalitenone suppresses EMT via suppression of the AKT/mTOR signaling pathway. In addition, ovalitenone exhibited potential for the suppression of CSC phenotypes. These data reveal the anti-metastasis potential of the compound and support the development of ovalitenone treatment for lung cancer therapy.
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Affiliation(s)
- Kittipong Sanookpan
- Cell-Based Drug and Health Product Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (K.S.); (N.N.)
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nongyao Nonpanya
- Cell-Based Drug and Health Product Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (K.S.); (N.N.)
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Boonchoo Sritularak
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Pithi Chanvorachote
- Cell-Based Drug and Health Product Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (K.S.); (N.N.)
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Correspondence: ; Tel.: +662-218-8344
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Comparison of Chemical Composition and Biological Activities of Eight Selaginella Species. Pharmaceuticals (Basel) 2020; 14:ph14010016. [PMID: 33375355 PMCID: PMC7823444 DOI: 10.3390/ph14010016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 12/19/2022] Open
Abstract
Selaginella P. Beauv. is a group of vascular plants in the family Selaginellaceae Willk., found worldwide and numbering more than 700 species, with some used as foods and medicines. The aim of this paper was to compare methanolic (MeOH) and dichloromethane (DCM) extracts of eight Selaginella species on the basis of their composition and biological activities. Six of these Selaginella species are underinvestigated. Using ultra-high performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) analysis, we identified a total of 193 compounds among the tested Selaginella species, with flavonoids predominating. MeOH extracts recovered more constituents that were detected, including selaginellins, the occurrence of which is only typical for this plant genus. Of all the tested species, Selaginella
apoda contained the highest number of identified selaginellins. The majority of the compounds were identified in S. apoda, the fewest compounds in Selaginella
cupressina. All the tested species demonstrated antioxidant activity using oxygen radical absorption capacity (ORAC) assay, which showed that MeOH extracts had higher antioxidant capacity, with the half maximal effective concentration (EC50) ranging from 12 ± 1 (Selaginella
myosuroides) to 124 ± 2 (Selaginella
cupressina) mg/L. The antioxidant capacity was presumed to be correlated with the content of flavonoids, (neo)lignans, and selaginellins. Inhibition of acetylcholinesterase (AChE) was mostly discerned in DCM extracts and was only exhibited in S. myosuroides, S. cupressina, Selaginella
biformis, and S. apoda extracts with the half maximal inhibitory concentration (IC50) in the range of 19 ± 3 to 62 ± 1 mg/L. Substantial cytotoxicity against cancer cell lines was demonstrated by the MeOH extract of S. apoda, where the ratio of the IC50 HEK (human embryonic kidney) to IC50 HepG2 (hepatocellular carcinoma) was 7.9 ± 0.2. MeOH extracts inhibited the production of nitrate oxide and cytokines in a dose-dependent manner. Notably, S. biformis halved the production of NO, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 at the following concentrations: 105 ± 9, 11 ± 1, and 10 ± 1 mg/L, respectively. Our data confirmed that extracts from Selaginella species exhibited cytotoxicity against cancer cell lines and AChE inhibition. The activity observed in S. apoda was the most promising and is worth further exploration.
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Kiełbasiński K, Peszek W, Grabarek BO, Boroń D, Wierzbik-Strońska M, Oplawski M. Effect of Salinomycin on Expression Pattern of Genes Associated with Apoptosis in Endometrial Cancer Cell Line. Curr Pharm Biotechnol 2020; 21:1269-1277. [PMID: 32400328 PMCID: PMC7604770 DOI: 10.2174/1389201021666200513074022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/08/2020] [Accepted: 03/25/2020] [Indexed: 12/15/2022]
Abstract
Background Salinomycin is part of a group of ionophore antibiotics characterized by an activity towards tumor cells. To this day, the mechanism through which salinomycin induces their apoptosis is not fully known yet. The goal of this study was to assess the expression pattern of genes and the proteins coded by them connected with the process of programmed cell death in an endometrial cancer cell Ishikawa culture exposed to salinomycin and compared to the control. Materials and Methods Analysis of the effect of salinomycin on Ishikawa endometrial cancer cells (ECACC 99040201) included a cytotoxicity MTT test (with a concentration range of 0.1-100 µM), assessment of the induction of apoptosis and necrosis by salinomycin at a concentration of 1 µM as well the assessment of the expression of the genes chosen in the microarray experiment (microarray HG-U 133A_2) and the proteins coded by them connected with apoptosis (RTqPCR, ELISA assay). The statistical significance level for all analyses carried out as part of this study was p<0.05. Results It was observed that salinomycin causes the death of about 50% of cells treated by it (50.74±0.80% of all cells) at a concentration of 1µM. The decrease in the number of living cells was determined directly after treatment of the cells with the drug (time 0). The average percent of late apoptotic cells was 1.65±0.24% and 0.57±0.01% for necrotic cells throughout the entire observation period. Discussion Microarray analysis indicated the following number of mRNA differentiating the culture depending on the time of incubation with the drug: H_12 vs C = 114 mRNA, H_8 vs C = 84 mRNA, H_48 vs. C = 27 mRNA, whereas 5 mRNAs were expressed differently at all times. During the whole incubation period of the cells with the drug, the following dependence of the expression profile of the analyzed transcripts was observed: Bax>p53>FASL>BIRC5>BCL2L. Conclusion The analysis carried out indicated that salinomycin, at a concentration of 1 µM, stopped the proliferation of 50% of endometrial cancer cells, mainly by inducing the apoptotic process of the cells. The molecular exponent of the induction of programmed cell death was an observed increase in the transcriptional activity of pro-apoptotic genes: Bax;p53;FASL and a decrease in the expression of anti-apoptotic genes: BCL2L2; BIRC5.
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Affiliation(s)
- Kamil Kiełbasiński
- Department of Obsterics and Gynaecology in Ruda Slaska, Medical University of Silesia, Ruda Slaska, Poland
| | - Wojciech Peszek
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Kraków, Poland
| | - Beniamin O Grabarek
- Department of Clinical Trials, Maria Sklodowska-Curie National Research Institute of Oncology Krakow Branch, Kraków, Poland,Department of Histology, Cytophysiology and Embryology, Faculty of Medicine, University of Technology, Zabrze, Poland
| | - Dariusz Boroń
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Kraków, Poland,Department of Clinical Trials, Maria Sklodowska-Curie National Research Institute of Oncology Krakow Branch, Kraków, Poland,Department of Histology, Cytophysiology and Embryology, Faculty of Medicine, University of Technology, Zabrze, Poland
| | | | - Marcin Oplawski
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Kraków, Poland
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Zarneshan SN, Fakhri S, Farzaei MH, Khan H, Saso L. Astaxanthin targets PI3K/Akt signaling pathway toward potential therapeutic applications. Food Chem Toxicol 2020; 145:111714. [DOI: 10.1016/j.fct.2020.111714] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/21/2020] [Accepted: 08/26/2020] [Indexed: 02/08/2023]
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Pourhanifeh MH, Vosough M, Mahjoubin-Tehran M, Hashemipour M, Nejati M, Abbasi-Kolli M, Sahebkar A, Mirzaei H. Autophagy-related microRNAs: Possible regulatory roles and therapeutic potential in and gastrointestinal cancers. Pharmacol Res 2020; 161:105133. [DOI: 10.1016/j.phrs.2020.105133] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/23/2020] [Accepted: 08/07/2020] [Indexed: 02/08/2023]
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Poly-(Lactic-co-Glycolic) Acid Nanoparticles for Synergistic Delivery of Epirubicin and Paclitaxel to Human Lung Cancer Cells. Molecules 2020; 25:molecules25184243. [PMID: 32947799 PMCID: PMC7570462 DOI: 10.3390/molecules25184243] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 09/11/2020] [Accepted: 09/12/2020] [Indexed: 12/21/2022] Open
Abstract
Combination therapy using chemically distinct drugs has appeared as one of the promising strategies to improve anticancer treatment efficiency. In the present investigation, poly-(lactic-co-glycolic) acid (PLGA) nanoparticles electrostatically conjugated with polyethylenimine (PEI)-based co-delivery system for epirubicin and paclitaxel (PLGA-PEI-EPI-PTX NPs) has been developed. The PLGA-PEI-EPI-PTX NPs exhibited a monodispersed size distribution with an average size of 240.93 ± 12.70 nm as measured through DLS and 70.8-145 nm using AFM. The zeta potential of 41.95 ± 0.65 mV from -17.45 ± 2.15 mV further confirmed the colloidal stability and PEI modification on PLGA nanoparticles. Encapsulation and loading efficiency along with in vitro release of drug for nanoparticles were done spectrophotometrically. The FTIR analysis of PLGA-PEI-EPI-PTX NPs revealed the involvement of amide moiety between polymer PLGA and PEI. The effect of nanoparticles on the cell migration was also corroborated through wound healing assay. The MTT assay demonstrated that PLGA-PEI-EPI-PTX NPs exhibited considerable anticancer potential as compared to the naïve drugs. Further, p53 protein expression analysed through western blot showed enhanced expression. This study suggests that combination therapy using PLGA-PEI-EPI-PTX NPs represent a potential approach and could offer clinical benefits in the future for lung cancer patients.
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Liu J, Hu HB, Liu YM, Li FX, Zhang LP, Liao ZM. LncRNA HOTTIP promotes the proliferation and invasion of ovarian cancer cells by activating the MEK/ERK pathway. Mol Med Rep 2020; 22:3667-3676. [PMID: 33000231 PMCID: PMC7533522 DOI: 10.3892/mmr.2020.11452] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 06/22/2020] [Indexed: 12/27/2022] Open
Abstract
Recent studies have revealed that long non-coding RNAs (lncRNAs) serve important roles in carcinogenesis and that this type of gene may be used as biomarkers in cancer. A high level of lncRNA HOXA distal transcript antisense RNA (HOTTIP) is associated with unfavorable prognosis for patients with ovarian cancer (OC), but the mechanism of HOTTIP involved in OC development remains to be elucidated. The present study aimed to investigate the mechanism of HOTTIP in metastasis-associated OC cell behaviors. HOTTIP levels in ovarian cells were quantified by reverse transcription-quantitative PCR, cell proliferation was analyzed by colony formation assay, and apoptosis was assessed by flow cytometry. Cell migratory and invasive abilities were evaluated by wound healing and Transwell assays, respectively. The expression levels of mitogen-activated protein kinase kinase (MEK)/ERK pathway-associated proteins were detected by western blotting. The results demonstrated that knockdown of HOTTIP in OC cells significantly reduced the phosphorylation levels of MEK and ERK, inhibited the proliferation and invasion of OC cells and promoted their apoptosis. Furthermore, the effects of HOTTIP on cell migration and invasion were partly associated with the epithelial-mesenchymal transition (EMT) process. Proliferation, invasion and EMT of OC cells were enhanced following overexpression of HOTTIP; however, these effects were reversed by the MEK/ERK pathway inhibitor U0126. In conclusion, HOTTIP was demonstrated to promote the proliferation, migration and invasion of OC cells by activating the MEK/ERK pathway. Therefore, HOTTIP may serve as a potential therapeutic target for OC.
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Affiliation(s)
- Jian Liu
- Department of Gynaecology, Yuebei People's Hospital, Shaoguan, Guangdong 512026, P.R. China
| | - Hong-Bo Hu
- Department of Gynaecology, Yuebei People's Hospital, Shaoguan, Guangdong 512026, P.R. China
| | - Yan-Ming Liu
- Department of Clinical Laboratory, Yuebei People's Hospital, Shaoguan, Guangdong 512026, P.R. China
| | - Fan-Xiang Li
- Department of Gynaecology, Yuebei People's Hospital, Shaoguan, Guangdong 512026, P.R. China
| | - Liu-Ping Zhang
- Department of Gynaecology, Yuebei People's Hospital, Shaoguan, Guangdong 512026, P.R. China
| | - Zong-Min Liao
- Department of Gynaecology, Yuebei People's Hospital, Shaoguan, Guangdong 512026, P.R. China
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Govindammal M, Prasath M. Vibrational spectra, Hirshfeld surface analysis, molecular docking studies of (RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide by DFT approach. Heliyon 2020; 6:e04641. [PMID: 32904270 PMCID: PMC7452535 DOI: 10.1016/j.heliyon.2020.e04641] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/11/2020] [Accepted: 08/03/2020] [Indexed: 01/06/2023] Open
Abstract
The Cyclophosphamide (CYC) is used as an anti cancer agent. It is chemically known as (RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide. The vibrational assignments survey of the CYC was implemented by employing FT-IR and FT-Raman spectroscopic investigation and the results are compared with theoretical features. The optimized geometrical parameters, IR intensity and Raman Activity of the vibrational bands of CYC were determined from the B3LYP functional with 6-311++G (d, p) level of theory. In the current work, quantum chemical calculations were adopted to contemplate the vibrational assignments of CYC and the outcomes are compared with experimental findings. Molecular Electrostatic Potential (MEP) and HOMO-LUMO energies are very effective in the examination of charge transfer and distribution of the molecular structure. The molecular orbital contributions were evaluated by using the Total Density of States (TDOS). The analysis of Natural Bond Orbital (NBO), Mulliken population and Fukui function studies were done. Intermolecular interaction of the title compound was examined through Hirshfeld surface analysis. The evaluation of drug-likeness was accomplished in accordance with Lipinski's Rule of Five and molecular descriptors were utilized to predict the ADMET profiles of the CYC molecule. The recent research studies reports that the structural and bio-activity of the CYC was affirmed by the docking analysis of CYC with protein PI3K/AKT inhibitor, it acts as anti-lung cancer agent.
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Affiliation(s)
- M. Govindammal
- Department of Physics, Periyar University PG Extension Centre, Dharmapuri, 636701, India
| | - M. Prasath
- Department of Physics, Periyar University PG Extension Centre, Dharmapuri, 636701, India
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Yin C, Lin X, Wang Y, Liu X, Xiao Y, Liu J, Snijders AM, Wei G, Mao JH, Zhang P. FAM83D promotes epithelial-mesenchymal transition, invasion and cisplatin resistance through regulating the AKT/mTOR pathway in non-small-cell lung cancer. Cell Oncol (Dordr) 2020; 43:395-407. [PMID: 32006253 DOI: 10.1007/s13402-020-00494-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2020] [Indexed: 12/14/2022] Open
Abstract
PURPOSE FAM83D has been proposed to act as an oncoprotein in several types of human cancer. Its role and mode of action in human non-small cell lung cancer (NSCLC) metastasis and its impact on chemotherapy are as yet, however, poorly understood. METHODS FAM83D expression was measured in NSCLC cells and normal lung epithelial cells, as well as in primary NSCLC tissues and corresponding adjacent non-cancerous tissues, using qRT-PCR, Western blotting and immunohistochemistry. FAM83D was stably overexpressed in BEAS2B cells or silenced in A549 and H1299 cells using retroviral or lentiviral vectors. The growth capacity of NSCLC cells was evaluated using MTT and colony formation assays. Epithelial-mesenchymal transition (EMT) was assessed using Western blotting and immunofluorescence. NSCLC cell invasive capacities were assessed using scratch wound healing and Boyden chamber assays. NSCLC cell viability in response to cisplatin treatment was assessed using MTT assays in vitro and a xenograft model in vivo. RESULTS We found that FAM83D expression levels were significantly elevated in NSCLC cells and tissues, and positively correlated with tumor progression and a poor prognosis. Exogenous FAM83D overexpression promoted, while FAM83D silencing inhibited NSCLC cell proliferation, EMT and invasion. FAM83D silencing also reduced cisplatin resistance. Concordantly, we found that NSCLC patients with a low FAM83D expression benefited most from chemotherapy. Mechanistically, we found that FAM83D activated the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Pharmacological treatment with either AKT or mTOR inhibitors reverted FAM83D-induced tumorigenic phenotypes. CONCLUSIONS Our results suggest a role of FAM83D in NSCLC development. In addition, our results indicate that NSCLC patients exhibiting FAM83D overexpression are likely to benefit from AKT and/or mTOR inhibitor treatment.
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Affiliation(s)
- Chunli Yin
- Key Laboratory Experimental, Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Basic Medical Sciences, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
- Shandong Medical College, Linyi, China
| | - Xiaoyan Lin
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, Shandong, China
| | - Yige Wang
- Key Laboratory Experimental, Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Basic Medical Sciences, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Xianqiang Liu
- Department of Breast and thyroid Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, 250013, Shandong, China
| | - Yi Xiao
- Key Laboratory Experimental, Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Basic Medical Sciences, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Jingchao Liu
- Department of Urology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Antoine M Snijders
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
| | - Guangwei Wei
- Key Laboratory Experimental, Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Basic Medical Sciences, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Jian-Hua Mao
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
| | - Pengju Zhang
- Key Laboratory Experimental, Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Basic Medical Sciences, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
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Wang S, Xu X, Hu Y, Lei T, Liu T. Sotetsuflavone Induces Autophagy in Non-Small Cell Lung Cancer Through Blocking PI3K/Akt/mTOR Signaling Pathway in Vivo and in Vitro. Front Pharmacol 2019; 10:1460. [PMID: 31920653 PMCID: PMC6915081 DOI: 10.3389/fphar.2019.01460] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 11/13/2019] [Indexed: 12/19/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is a globally scaled disease with a high incidence and high associated mortality rate. Autophagy is one of the important physiological activities that helps to control cell survival, influences the dynamics of cell death, and which plays a crucial role in the pathophysiology of NSCLC. Sotetsuflavone is a naturally derived and occurring flavonoid, and previous studies have demonstrated that sotetsuflavone possesses potential anti-cancer activities. However, whether or not sotetsuflavone induces autophagy, as well as has effects and influences cell death in NSCLC cells remains unclear. Thus, in our study, we examined and elucidated the roles and underlying mechanisms of sotetsuflavone upon the dynamics of autophagy in NSCLC in vivo and in vitro. The results indicated that sotetsuflavone was able to inhibit proliferation, migration, and invasion of NSCLC cells. Mechanistically, sotetsuflavone was able to induce apoptosis by increasing the levels of expression of cytochrome C, cleaved-caspase 3, cleaved-caspase 9, and Bax, and contrastingly decreased levels of expression of Bcl-2. In addition, we also found that decreased levels of expression of cyclin D1 and CDK4 caused arrest of the G0/G1 phases of the cell cycle. Furthermore, we also found that sotetsuflavone could induce autophagy which in turn can play a cytoprotective effect on apoptosis in NSCLC. Sotetsuflavone-induced autophagy appeared related to the blocking of the PI3K/Akt/mTOR pathway. Our in vivo study demonstrated that sotetsuflavone significantly inhibited the growth of xenograft model inoculated A549 tumor with high a degree of safety. Taken together, these findings suggest that sotetsuflavone induces autophagy in NSCLC cells through its effects upon blocking of the PI3K/Akt/mTOR signaling pathways. Our study may provide a theoretical basis for future clinical applications of sotetsuflavone and its use as a chemotherapeutic agent for treatment of NSCLC.
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Affiliation(s)
- Shaohui Wang
- Key Laboratory of Ethnomedicine (Minzu University of China), Minority of Education, Beijing, China.,Medical College, Qingdao Binhai University, Qingdao, China.,School of Pharmacy, Minzu University of China, Beijing, China
| | - Xiaoling Xu
- Department of Medical Oncology, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Yanlan Hu
- Key Laboratory of Ethnomedicine (Minzu University of China), Minority of Education, Beijing, China.,School of Pharmacy, Minzu University of China, Beijing, China
| | - Tao Lei
- Department of Medical Oncology, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Tongxiang Liu
- Key Laboratory of Ethnomedicine (Minzu University of China), Minority of Education, Beijing, China.,School of Pharmacy, Minzu University of China, Beijing, China
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Yu H, Xu L, Liu Z, Guo B, Han Z, Xin H. Circ_MDM2_000139, Circ_ATF2_001418, Circ_CDC25C_002079, and Circ_BIRC6_001271 Are Involved in the Functions of XAV939 in Non-Small Cell Lung Cancer. Can Respir J 2019; 2019:9107806. [PMID: 31885751 PMCID: PMC6900950 DOI: 10.1155/2019/9107806] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 09/29/2019] [Accepted: 10/05/2019] [Indexed: 01/26/2023] Open
Abstract
Background The small molecule inhibitor XAV939 could inhibit the proliferation and promote the apoptosis of non-small cell lung cancer (NSCLC) cells. This study was conducted to identify the key circular RNAs (circRNAs) and microRNAs (miRNAs) in XAV939-treated NSCLC cells. Methods After grouping, the NCL-H1299 cells in the treatment group were treated by 10 μM XAV939 for 12 h. RNA-sequencing was performed, and then the differentially expressed circRNAs (DE-circRNAs) were analyzed by the edgeR package. Using the clusterprofiler package, enrichment analysis for the hosting genes of the DE-circRNAs was performed. Using Cytoscape software, the miRNA-circRNA regulatory network was built for the disease-associated miRNAs and the DE-circRNAs. The DE-circRNAs that could translate into proteins were predicted using circBank database and IRESfinder tool. Finally, the transcription factor (TF)-circRNA regulatory network was built by Cytoscape software. In addition, A549 and HCC-827 cell treatment with XAV939 were used to verify the relative expression levels of key DE-circRNAs. Results There were 106 DE-circRNAs (including 61 upregulated circRNAs and 45 downregulated circRNAs) between treatment and control groups. Enrichment analysis for the hosting genes of the DE-circRNAs showed that ATF2 was enriched in the TNF signaling pathway. Disease association analysis indicated that 8 circRNAs (including circ_MDM2_000139, circ_ATF2_001418, circ_CDC25C_002079, and circ_BIRC6_001271) were correlated with NSCLC. In the miRNA-circRNA regulatory network, let-7 family members⟶circ_MDM2_000139, miR-16-5p/miR-134-5p⟶circ_ATF2_001418, miR-133b⟶circ_BIRC6_001271, and miR-221-3p/miR-222-3p⟶circ_CDC25C_002079 regulatory pairs were involved. A total of 47 DE-circRNAs could translate into proteins. Additionally, circ_MDM2_000139 was targeted by the TF POLR2A. The verification test showed that the relative expression levels of circ_MDM2_000139, circ_CDC25C_002079, circ_ATF2_001418, and circ_DICER1_000834 in A549 and HCC-827 cell treatment with XAV939 were downregulated comparing with the control. Conclusions Let-7 family members and POLR2A targeting circ_MDM2_000139, miR-16-5p/miR-134-5p targeting circ_ATF2_001418, miR-133b targeting circ_BIRC6_001271, and miR-221-3p/miR-222-3p targeting circ_CDC25C_002079 might be related to the mechanism in the treatment of NSCLC by XAV939.
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Affiliation(s)
- Haixiang Yu
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, China
| | - Lei Xu
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, China
| | - Zhengjia Liu
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, China
| | - Bo Guo
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, China
| | - Zhifeng Han
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, China
| | - Hua Xin
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, China
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Li F, Dai L, Niu J. GPX2 silencing relieves epithelial-mesenchymal transition, invasion, and metastasis in pancreatic cancer by downregulating Wnt pathway. J Cell Physiol 2019; 235:7780-7790. [PMID: 31774184 DOI: 10.1002/jcp.29391] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 09/27/2019] [Indexed: 12/13/2022]
Abstract
Glutathione peroxidase 2 (GPX2) participates in many cancers including pancreatic cancer (PC), and overexpression of GPX2 promotes tumor growth. Herein, we identified the role of GPX2 in epithelial-mesenchymal transformation (EMT), invasion, and metastasis in PC. Bioinformatics prediction was applied to select PC-related genes. The regulatory function of GPX2 in PC was explored by treatment with short hairpin RNA against GPX2 or LiCl (activator of wingless-type MMTV integration site [Wnt] pathway) in PC cells. GPX2 level in PC tissues, the levels of GPX2, β-catenin, Vimentin, Snail, epithelial-cadherin (E-cadherin), matrix metalloproteinase 2 (MMP2), MMP9, and Wnt2 in cells were determined. Subsequently, cell proliferation, invasion, and metastasis were assayed. Bioinformatics analysis revealed that GPX2 was involved in PC development mediated by the Wnt pathway. GPX2 was highly expressed in PC tissues. GPX2 silencing downregulated levels of β-catenin, Vimentin, Snail, MMP2, MMP9, and Wnt2 but upregulated levels of E-cadherin. It was confirmed that GPX2 silencing suppressed PC cell proliferation, metastasis, and invasion. Furthermore, the trend of EMT and invasion and metastasis of PC induced by the LiCl-activated Wnt pathway was reversed when the GPX2 was silenced. GPX2 silencing could inhibit the Wnt pathway, subsequently suppress PC development.
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Affiliation(s)
- Fuzhou Li
- Department of Imaging, Linyi People's Hospital, Linyi, China
| | - Lan Dai
- Department of Gynaecology and Obstetrics, Chinese Medicine Hospital of Linyi City, Linyi, China
| | - Jixiang Niu
- Department of General Surgery, Linyi People's Hospital, Linyi, China
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Liu J, Song W, Li J, Li X, Zhao R, Gong T. LINK-A lncRNA is upregulated in metastatic non-small cell lung cancer and is associated with poor prognosis. Oncol Lett 2019; 18:3049-3057. [PMID: 31404323 PMCID: PMC6676721 DOI: 10.3892/ol.2019.10613] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 03/21/2019] [Indexed: 12/12/2022] Open
Abstract
Long intergenic non-coding RNA for kinase activation (LINK-A) has been characterized as an oncogenic long non-coding RNA (lncRNA) in triple-negative breast cancer. However, its involvement in non-small cell lung cancer (NSCLC) remains unknown. The aim of the present study was to investigate the involvement of LINK-A in NSCLC. Expression of LINK-A lncRNA in the plasma of patients with NSCLC collected on the day of admission and the day of discharge, and in the plasma of healthy controls, was detected by reverse transcription-quantitative PCR. Diagnostic values of plasma LINK-A for metastatic NSCLC were evaluated by receiver operating characteristic curve analysis. A LINK-A lncRNA expression vector was constructed and transfected into human NSCLC cell lines, and the effects on cell migration and invasion, and Akt activation were detected by Transwell and Matrigel assays, and western blotting, respectively. Plasma levels of LINK-A were found to be significantly higher in patients with different types of metastatic NSCLC than in patients with non-metastatic NSCLC and healthy controls. Plasma levels of LINK-A were lower in patients with metastatic NSCLC on the day of discharge than on the day of admission. Patients with high plasma LINK-A had a higher mortality rate and lower progression-free survival rate within 2 years of discharge. In conclusion, LINK-A is overexpressed in metastatic NSCLC, and may promote the migration and invasion of NSCLC by activating Akt signaling.
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Affiliation(s)
- Junqiang Liu
- Department of Thoracic Surgery, People's Liberation Army Navy General Hospital, Beijing 100048, P.R. China
| | - Weian Song
- Department of Thoracic Surgery, People's Liberation Army Navy General Hospital, Beijing 100048, P.R. China
| | - Jun Li
- Department of Thoracic Surgery, People's Liberation Army Navy General Hospital, Beijing 100048, P.R. China
| | - Xuechang Li
- Department of Thoracic Surgery, People's Liberation Army Navy General Hospital, Beijing 100048, P.R. China
| | - Rongrong Zhao
- Department of Thoracic Surgery, People's Liberation Army Navy General Hospital, Beijing 100048, P.R. China
| | - Taiqian Gong
- Department of Thoracic Surgery, People's Liberation Army Navy General Hospital, Beijing 100048, P.R. China
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Yuan Q, Wen M, Xu C, Chen A, Qiu YB, Cao JG, Zhang JS, Song ZW. 8-bromo-7-methoxychrysin targets NF-κB and FoxM1 to inhibit lung cancer stem cells induced by pro-inflammatory factors. J Cancer 2019; 10:5244-5255. [PMID: 31602275 PMCID: PMC6775618 DOI: 10.7150/jca.30143] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 07/16/2019] [Indexed: 01/07/2023] Open
Abstract
We have previously reported that 8-bromo-7-methoxychrysin (BrMC), a novel synthetic derivative of chrysin, was demonstrated anti-tumor activities against several human cancers, including lung cancer. Interaction between inflammation and cancer stem cell are recently increasingly recognized in tumorigenesis and progression. The purpose of this study was to investigate whether BrMC inhibits lung cancer stemness of H460 cells induced by inflammatory factors (TGF-β combined with TNF-α) and its potential mechanism. Our results showed that BrMC inhibited lung cancer stemness, as validated by enhanced self-renewal ability, higher in vitro tumorigenicity, and increased expression of CD133, CD44, Bmi1 and Oct4 in H460 cells administered TNF-α after prolonged induction by TGF-β, in a concentration-dependent manner. Both NF-κB inhibition by SN50 and FoxM1 suppression by thiostrepton (THI) prompted the inhibition of BrMC on lung CSCs. Conversely, overexpression of NF-κBp65 significantly antagonized the above effects of BrMC. Meanwhile, overexpression of FoxM1 also significantly compromised BrMC function on suppression of FoxM1 and NF-κBp65 as well as stemness of lung CSCs. Our results suggest that activation of NF-κB and FoxM1 by cytokines facilitate the acquisition CSCs phenotype, and compromise the chemical inhibition, which may represent an effective therapeutic target for treatment of human lung cancer. Moreover, BrMC may be a potential promising candidate for targeting NF-κB/ FoxM1 to prevent the tumorigenesis under inflammatory microenvironment.
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Affiliation(s)
- Qing Yuan
- Department of preclinical medicine, Medical College, Hunan Normal University, Changsha, 410013, China
| | - Min Wen
- Department of preclinical medicine, Medical College, Hunan Normal University, Changsha, 410013, China
| | - Chang Xu
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013, China,Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China
| | - A Chen
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013, China,Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China
| | - Ye-Bei Qiu
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013, China,Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China
| | - Jian-Guo Cao
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013, China,Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China
| | - Jian-Song Zhang
- Department of preclinical medicine, Medical College, Hunan Normal University, Changsha, 410013, China,✉ Corresponding authors: Zhen-Wei Song, Jian-Song Zhang
| | - Zhen-Wei Song
- Department of preclinical medicine, Medical College, Hunan Normal University, Changsha, 410013, China,Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013, China,Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China,✉ Corresponding authors: Zhen-Wei Song, Jian-Song Zhang
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Sang S, Zhang C, Shan J. Pyrroline-5-Carboxylate Reductase 1 Accelerates the Migration and Invasion of Nonsmall Cell Lung Cancer In Vitro. Cancer Biother Radiopharm 2019; 34:380-387. [PMID: 30916574 DOI: 10.1089/cbr.2019.2782] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Background: Pyrroline-5-carboxylate reductase 1 (PYCR1) is involved in tumor progression, for instance, breast cancer and prostate cancer. However, its role in tumor metastasis, especially in nonsmall cell lung cancer (NSCLC), is still elusive. Materials and Methods: The messenger RNA (mRNA) expression of PYCR1 between NSCLC and normal lung specimens was compared using Oncomine database. The endogenous PYCR1 expressions in NSCLC cell lines 95C and H1299 were knocked down by lentiviral-mediated delivery of short hairpin RNA (shRNA). Then the effects of PYCR1 on the migration and invasion of NSCLC cells were studied by wound healing assay and transwell assay. Results: PYCR1 mRNA expression was significantly higher in NSCLC specimens than that in normal lung tissues. Depletion of PYCR1 in NSCLC cell significantly repressed the cell migration and invasion. Moreover, depletion of PYCR1 influenced the expression of epithelial-mesenchymal transition molecules E-cadherin, Vimentin, N-cadherin, and Snail1. Conclusions: Our data suggested that PYCR1 plays a positive role in NSCLC metastasis in vitro and might be a promising target for treating NSCLC.
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Affiliation(s)
- Senhua Sang
- 1College of Life Science and Technology, Guangxi University, Nanning, China
- 2Shanghai Linger Biotechnology Co., Ltd., Shanghai, China
| | - Cuicui Zhang
- 1College of Life Science and Technology, Guangxi University, Nanning, China
| | - Jianwei Shan
- 1College of Life Science and Technology, Guangxi University, Nanning, China
- 3Crops Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou, China
- 4Guangdong Provincial Key Laboratory of Crop Genetic Improvement, Guangzhou, China
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