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Qiu Y, Xu J, Liao W, Yang S, Wen Y, Farag MA, Zheng L, Zhao C. Ulvan derived from Ulva lactuca suppresses hepatocellular carcinoma cell proliferation through miR-542-3p-mediated downregulation of SLC35F6. Int J Biol Macromol 2025; 308:142252. [PMID: 40118430 DOI: 10.1016/j.ijbiomac.2025.142252] [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: 12/12/2024] [Revised: 03/13/2025] [Accepted: 03/16/2025] [Indexed: 03/23/2025]
Abstract
Hepatocellular carcinoma (HCC) therapy still presents significant challenges, with a critical need for novel molecular targets and effective natural compound-based therapies. Despite its known oncogenic potential in other cancers, the role of SLC35F6 in HCC has not been previously reported, leaving a gap in our understanding of its function and therapeutic relevance. Here, we demonstrate that SLC35F6 is overexpressed in HCC and is associated with poor prognosis. Ulva lactuca polysaccharide (ULP), a natural extract with known antitumor properties, exerts its effects by upregulating miR-542-3p, which in turn inhibits SLC35F6 expression and significantly increases TP53 protein levels. Furthermore, TP53 is positively regulated by miR-542-3p, and our results indicate that SLC35F6 is a target gene of miR-542-3p. Knockdown of SLC35F6 in H22 and HepG2 cells markedly reduced cell growth while elevating TP53 expression, supporting SLC35F6 as a key regulatory factor in the miR-542-3p/TP53 axis. While this study did not confirm direct mutual regulation between SLC35F6 and TP53, our findings provide evidence that targeting SLC35F6 can suppress HCC progression. Collectively, these results identify SLC35F6 as a potential therapeutic target for HCC and provide mechanistic insights into its regulation through the miR-542-3p/SLC35F6/TP53 axis.
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Affiliation(s)
- Yinghui Qiu
- College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; School of Materials Science and Engineering, Huaqiao University, Xiamen 361021, China
| | - Jingxiang Xu
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Wei Liao
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, Fujian Agriculture and Forestry University, Fuzhou 350002, China; State Key Laboratory of Food Science and Resources, China-Canada Joint Lab of Food Science and Technology, Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang 330047, China
| | - Shuxin Yang
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Yuxi Wen
- University of Vigo, Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Science, E32004 Ourense, Spain
| | - Mohamed A Farag
- Pharmacognosy Department, College of Pharmacy, Cairo University, Cairo, Egypt
| | - Lingjun Zheng
- School of Agriculture and Biology, Shanghai JiaoTong University, Shanghai 200240, China
| | - Chao Zhao
- College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
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2
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Yu J, Wang J, Liu X, Wang C, Wu L, Zhang Y. Bioinformatics analysis of ferroptosis-related biomarkers and potential drug predictions in doxorubicin-induced cardiotoxicity. Front Cardiovasc Med 2025; 12:1566782. [PMID: 40342975 PMCID: PMC12058674 DOI: 10.3389/fcvm.2025.1566782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Accepted: 04/09/2025] [Indexed: 05/11/2025] Open
Abstract
Background Doxorubicin-induced cardiotoxicity (DIC) significantly impacts the survival and prognosis of cancer patients. Ferroptosis is involved in the pathogenesis of DIC, but its specific mechanisms remain unclear. This study aims to explore key genes of ferroptosis in DIC and potential therapeutic drugs using various bioinformatics methods. Methods This study obtained the GSE106297 and GSE157282 datasets from the GEO database, conducted differential gene expression screening and GSEA enrichment analysis using R software. Subsequently obtained ferroptosis-related genes from FerrDb V2, Genecards, Geneontology, and GSEA databases, performed GO and KEGG enrichment analysis after intersecting them with the differentially expressed genes using a Venn diagram. Utilized LASSO regression, SVM-RFE, and RF algorithms to identify key genes, followed by validation using external datasets (GSE232331, GSE230638) and ROC curve plotting to determine the diagnostic value of key genes. Further validation of the expression levels of key genes were conducted through the establishment of a cell damage model. Constructed an mRNA-miRNA-lncRNA network diagram, and performed immune cell composition analysis using CIBERSORT. Finally, predicted potential drugs for key genes using the DSigDB database. Results We obtained 119 genes after intersecting 1380 Differentially Expressed Genes (DEGs) with Ferroptosis-Related Genes (FRGs). Three key genes (KLHDC3, NDRG1, SPHK1) were identified through further analysis using LASSO, SAM-RFE and RF. The ROC analysis demonstrated that KLHDC3 and NDRG1 have significant diagnostic value, and qRT-PCR verification results also showed statistical significance. We constructed miRNA-lncRNA networks by identifying target miRNAs for KLHDC3 (hsa-miR-24-3p, hsa-miR-486-3p, hsa-miR-214-3p) and NDRG1 (hsa-miR-4510, hsa-miR-182-5p, hsa-miR-96-5p). Immunoinfiltration analysis revealed the relationship between KLHDC3, NDRG1 and immune cells. Anisomycin emerges as a promising small molecule drug for treating DIC, exhibiting good relative binding with KLHDC3 and NDRG1. Conclusion KLHDC3 and NDRG1 serve as ferroptosis biomarkers implicated in DIC and demonstrate good diagnostic value. In addition, anisomycin may also be a potential drug for treating DIC.
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Affiliation(s)
- Jian Yu
- Department of Cardio-Oncology, Tumor Hospital of Xinjiang Medical University, Urumqi, China
- Xinjiang Medical University, Urumqi, China
| | - Jiangtao Wang
- Department of Cardiothoracic Surgery, General Hospital of Xinjiang Military Command, Urumqi, China
| | - Xinya Liu
- Department of Cardio-Oncology, Tumor Hospital of Xinjiang Medical University, Urumqi, China
- Xinjiang Medical University, Urumqi, China
| | - Cancan Wang
- Xinjiang Medical University, Urumqi, China
- Pathology Department, Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Li Wu
- Department of Cardio-Oncology, Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Yuanming Zhang
- Department of Cardio-Oncology, Tumor Hospital of Xinjiang Medical University, Urumqi, China
- Xinjiang Medical University, Urumqi, China
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3
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Jin S, Zhao Q, Sun X, Su J, Wang P, Li P, Guo J, Zhang Y, Zong H, Gan X. L-741626 inhibits hepatocellular carcinoma progression by targeting Ref-1 to suppress MAPK/ERK signalling pathway activity. Biol Direct 2025; 20:54. [PMID: 40241114 PMCID: PMC12001403 DOI: 10.1186/s13062-025-00624-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 02/24/2025] [Indexed: 04/18/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a common and challenging malignancy of the digestive tract. Unfortunately, patients with advanced HCC frequently experience limited long-term benefits from current treatments, highlighting the critical need for innovative therapeutic agents. The discovery and development of new small-molecule compounds that target tumours have become crucial aspects of cancer research. In this study, we report on L-741626, a compound that has significant inhibitory effects on HCC. Both in vivo and in vitro experiments confirmed that L-741626 inhibited the growth of HCC by suppressing the MAPK/ERK signalling pathway. Molecular docking simulations and drug affinity responsive target stability assays further identified redox Factor 1 (Ref-1) as a target of L-741626. Ref-1 is overexpressed in HCC and is correlated with poor prognosis and high stage. Further studies demonstrated that Ref-1 interacts with CRAF, a crucial component of the MAPK/ERK signalling pathway. Knockdown of Ref-1 in HCC cells led to inhibition of the MAPK/ERK pathway. Sorafenib is a well-established targeted therapy for the treatment of HCC, with its primary antitumor mechanism being the inhibition of the MAPK/ERK signalling pathway. However, the presence of tumor stem cells is a key factor contributing to resistance to sorafenib. Our study demonstrates that L-741626 can suppress tumor stemness in HCC. The combination of L-741626 and sorafenib significantly enhances the sensitivity of HCC, resulting in increased tumoricidal effects. Our findings reveal a novel pharmacological effect of L-741626, which inhibits MAPK/ERK signalling activity in HCC by targeting Ref-1. Furthermore, L-741626 exhibits a synergistic effect when combined with sorafenib, suggesting a new potential approach for HCC treatment.
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Affiliation(s)
- Shuiling Jin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
| | - Qi Zhao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xiao Sun
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Jinsong Su
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Peiwen Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Peixian Li
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Jing Guo
- China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, 450008, Henan, China
| | - Yibing Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hong Zong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Xiaoli Gan
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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Liu ZZ, Ji FH, Piao Y. Non-coding RNAs participate in interactions between senescence and gastrointestinal cancers. Front Genet 2025; 15:1461404. [PMID: 39831201 PMCID: PMC11739115 DOI: 10.3389/fgene.2024.1461404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 12/04/2024] [Indexed: 01/22/2025] Open
Abstract
Relationships between cellular senescence and gastrointestinal cancers have gained prominence in recent years. The currently accepted theory suggests that cellular senescence and cancer occurrence exhibit "double-edged sword" effects. Cellular senescence is related to cancer via four "meta-hallmarks" i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis, along with two "antagonistic hallmarks" i.e., telomere attrition and stem cell exhaustion. These relationships are characterized by both agonistic and antagonistic elements, but the existence of an intricate dynamic balance remains unknown. Non-coding RNAs (ncRNAs) have vital roles in post-transcriptional regulation, but how they participate in agonistic and antagonistic relationships between cellular senescence and gastrointestinal cancers remains to be fully investigated. In this article, we systematically review how ncRNAs (including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circularRNAs (circRNAs)) participate in interactions between cellular senescence and gastrointestinal cancers. Our aim is to elucidate a triangular relationship between "ncRNAs-senescence-gastrointestinal cancers" which considered these three elements as an equal important standing. We are keen to identify prognostic or therapeutic targets for gastrointestinal cancers from, i.e., aging-related ncRNAs, or discover novel strategies to treat and manage in the elderly. We seek to clarify complex relationships where ncRNAs participate in "senescence-gastrointestinal cancers" interactions.
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Affiliation(s)
| | | | - Ying Piao
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, China
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Li S, Yang L, Ding X, Sun H, Dong X, Yang F, Wang M, Zhang H, Li Y, Li B, Liu C. USP32 facilitates non-small cell lung cancer progression via deubiquitinating BAG3 and activating RAF-MEK-ERK signaling pathway. Oncogenesis 2024; 13:27. [PMID: 39030175 PMCID: PMC11271578 DOI: 10.1038/s41389-024-00528-z] [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: 03/06/2024] [Revised: 07/03/2024] [Accepted: 07/04/2024] [Indexed: 07/21/2024] Open
Abstract
The regulatory significance of ubiquitin-specific peptidase 32 (USP32) in tumor is significant, nevertheless, the biological roles and regulatory mechanisms of USP32 in non-small cell lung cancer (NSCLC) remain unclear. According to our research, USP32 was strongly expressed in NSCLC cell lines and tissues and was linked to a bad prognosis for NSCLC patients. Interference with USP32 resulted in a significant inhibition of NSCLC cell proliferation, migration potential, and EMT development; on the other hand, USP32 overexpression had the opposite effect. To further elucidate the mechanism of action of USP32 in NSCLC, we screened H1299 cells for interacting proteins and found that USP32 interacts with BAG3 (Bcl2-associated athanogene 3) and deubiquitinates and stabilizes BAG3 in a deubiquitinating activity-dependent manner. Functionally, restoration of BAG3 expression abrogated the antitumor effects of USP32 silencing. Furthermore, USP32 increased the phosphorylation level of the RAF/MEK/ERK signaling pathway in NSCLC cells by stabilizing BAG3. In summary, these findings imply that USP32 is critical to the development of NSCLC and could offer a theoretical framework for the clinical diagnosis and management of NSCLC patients in the future.
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Affiliation(s)
- Shuang Li
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China
| | - Lina Yang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China
| | - Xiaoyan Ding
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China
- School of Basic Medicine, Institute of Stem Cell and Regenerative Medicine, Qingdao University, 266071, Qingdao, China
| | - Hongxiao Sun
- Heart Center, Women and Children's Hospital, Qingdao University, 6 Tongfu Road, 266034, Qingdao, China
| | - Xiaolei Dong
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China
| | - Fanghao Yang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China
| | - Mengjun Wang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China
| | - Huhu Zhang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China
| | - Ya Li
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China
| | - Bing Li
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China.
- Department of Dermatology, The Affiliated Haici Hospital of Qingdao University, 266000, Qingdao, China.
| | - Chunyan Liu
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China.
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Li HB, Wang D, Zhang Y, Shen D, Che YQ. Long noncoding RNA XIST: a novel independent prognostic biomarker for patients with ABC-DLBCL receiving R-CHOP treatment. Carcinogenesis 2024; 45:500-509. [PMID: 38426786 DOI: 10.1093/carcin/bgae017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 02/01/2024] [Accepted: 02/27/2024] [Indexed: 03/02/2024] Open
Abstract
Approximately one-third of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cases were unresponsive to standard first-line therapy; thus, identifying biomarkers to evaluate therapeutic efficacy and assessing the emergence of drug resistance is crucial. Through early-stage screening, long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) was found to be correlated with the R-CHOP treatment response. This study aimed to clarify the characteristics of XIST in ABC-DLBCL. The expression level of XIST in 161 patients with ABC-DLBCL receiving R-CHOP therapy was examined via RNA in situ hybridization, and the association between XIST expression and clinicopathological features, treatment response and prognosis was analyzed in the study cohort and validated in the Gene Expression Omnibus cohort. Cell biological experiments and bioinformatics analyses were conducted to reveal aberrant signaling. The proportion of complete response in patients with high XIST expression was lower than that in patients with low XIST expression (53.8% versus 77.1%) (P = 0.002). High XIST expression was remarkably associated with the characteristics of tumor progression and was an independent prognostic element for overall survival (P = 0.039) and progression-free survival (P = 0.027) in ABC-DLBCL. XIST was proven to be involved in m6A-related methylation and ATF6-associated autophagy. XIST knockdown repressed ABC-DLBCL cellular proliferation by regulating Raf/MEK/ERK signaling. High XIST expression was associated with ABC-DLBCL tumorigenesis and development and contributed to R-CHOP treatment resistance. XIST may be a promising signal to predict ABC-DLBCL prognosis.
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MESH Headings
- Humans
- RNA, Long Noncoding/genetics
- Male
- Vincristine/therapeutic use
- Female
- Cyclophosphamide/therapeutic use
- Prognosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Middle Aged
- Prednisone/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Rituximab/therapeutic use
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Large B-Cell, Diffuse/mortality
- Doxorubicin/therapeutic use
- Gene Expression Regulation, Neoplastic
- Aged
- Adult
- Cell Proliferation
- Drug Resistance, Neoplasm/genetics
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Affiliation(s)
- Han-Bing Li
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Di Wang
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Yue Zhang
- Department of Clinical Laboratory, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Di Shen
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Yi-Qun Che
- Center for Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
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Scardaci R, Berlinska E, Scaparone P, Vietti Michelina S, Garbo E, Novello S, Santamaria D, Ambrogio C. Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node. Mol Oncol 2024; 18:1355-1377. [PMID: 38362705 PMCID: PMC11161739 DOI: 10.1002/1878-0261.13605] [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: 07/24/2023] [Revised: 11/30/2023] [Accepted: 01/30/2024] [Indexed: 02/17/2024] Open
Abstract
Mutations in the RAS-RAF-MEK-ERK pathway are frequent alterations in cancer and RASopathies, and while RAS oncogene activation alone affects 19% of all patients and accounts for approximately 3.4 million new cases every year, less frequent alterations in the cascade's downstream effectors are also involved in cancer etiology. RAS proteins initiate the signaling cascade by promoting the dimerization of RAF kinases, which can act as oncoproteins as well: BRAFV600E is the most common oncogenic driver, mutated in the 8% of all malignancies. Research in this field led to the development of drugs that target the BRAFV600-like mutations (Class I), which are now utilized in clinics, but cause paradoxical activation of the pathway and resistance development. Furthermore, they are ineffective against non-BRAFV600E malignancies that dimerize and could be either RTK/RAS independent or dependent (Class II and III, respectively), which are still lacking an effective treatment. This review discusses the recent advances in anti-RAF therapies, including paradox breakers, dimer-inhibitors, immunotherapies, and other novel approaches, critically evaluating their efficacy in overcoming the therapeutic limitations, and their putative role in blocking the RAS pathway.
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Affiliation(s)
- Rossella Scardaci
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology CenterUniversity of TorinoItaly
| | - Ewa Berlinska
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology CenterUniversity of TorinoItaly
| | - Pietro Scaparone
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology CenterUniversity of TorinoItaly
| | - Sandra Vietti Michelina
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology CenterUniversity of TorinoItaly
| | - Edoardo Garbo
- Department of OncologyUniversity of Torino, San Luigi HospitalOrbassanoItaly
| | - Silvia Novello
- Department of OncologyUniversity of Torino, San Luigi HospitalOrbassanoItaly
| | - David Santamaria
- Centro de Investigación del CáncerCSIC‐Universidad de SalamancaSpain
| | - Chiara Ambrogio
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology CenterUniversity of TorinoItaly
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8
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Younis MA, Harashima H. Understanding Gene Involvement in Hepatocellular Carcinoma: Implications for Gene Therapy and Personalized Medicine. Pharmgenomics Pers Med 2024; 17:193-213. [PMID: 38737776 PMCID: PMC11088404 DOI: 10.2147/pgpm.s431346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 04/09/2024] [Indexed: 05/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the dominant type of liver cancers and is one of the deadliest health threats globally. The conventional therapeutic options for HCC are hampered by low efficiency and intolerable side effects. Gene therapy, however, now offers hope for the treatment of many disorders previously considered incurable, and gene therapy is beginning to address many of the shortcomings of conventional therapies. Herein, we summarize the involvement of genes in the pathogenesis and prognosis of HCC, with a special focus on dysregulated signaling pathways, genes involved in immune evasion, and non-coding RNAs as novel two-edged players, which collectively offer potential targets for the gene therapy of HCC. Herein, the opportunities and challenges of HCC gene therapy are discussed. These include innovative therapies such as genome editing and cell therapies. Moreover, advanced gene delivery technologies that recruit nanomedicines for use in gene therapy for HCC are highlighted. Finally, suggestions are offered for improved clinical translation and future directions in this area of endeavor.
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Affiliation(s)
- Mahmoud A Younis
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
- Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt
| | - Hideyoshi Harashima
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
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9
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Kumari S, Manoj A, Rungta S, Kumar M, Prasad G, Kumar D, Mahdi AA, Ahmad MK. Discovery and Validation of Novel microRNA Panel for Non-Invasive Prediction of Prostate Cancer. Cureus 2024; 16:e58207. [PMID: 38741808 PMCID: PMC11090259 DOI: 10.7759/cureus.58207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Early diagnosis remains a challenge for prostate cancer (PCa) due to molecular heterogeneity. The purpose of our study was to explore the diagnostic potential of microRNA (miRNA) in both tissue and serum that may aid in the precise and early clinical diagnosis of PCa. MATERIALS AND METHODS The miRNA expression pattern analysis was carried out in 250 subjects (discovery and validation cohort). The Discovery Cohort included the control (n = 30) and PCa (n = 35) subjects, while the Validation Cohort included the healthy control (n = 60), benign prostate hyperplasia (BPH) (n = 55), PCa (n = 50), and castration-resistant PCa (CRPC) (n = 20) patients. The expression analysis of tissue (Discovery Cohort) and serum (Validation Cohort) was carried out by quantitative polymerase chain reaction (qPCR). The diagnostic biomarker potential was evaluated using receiver operating characteristics (ROC). Bioinformatic tools were used to explore and analyze miRNA target genes. RESULTS MiRNA 4510 and miRNA 183 were significantly (p<0.001) upregulated and miRNA 329 was significantly (p<0.0001) downregulated in both PCa tissue and serum. ROC curve analysis showed excellent non-invasive biomarker potential of miRNA 4510 in both PCa (area under the curve (AUC) 0.984; p<0.001) and CRPC (AUC 0.944; p<0.001). The panel of serum miRNAs (miRNA 183 and miRNA 4510) designed for PCa had significant and greater AUC with both 100% sensitivity and specificity. Computational analysis shows that the maximum number of target genes are transcription factors that regulate oncogenes and tumor suppressors. CONCLUSION Based on ROC curve analysis, miRNAs 4510, 329, and 711 were identified as potential non-invasive diagnostic biomarkers in the early detection of PCa. Our findings imply that a panel of miRNAs 183 and 4510 has high specificity for distinguishing PCa from healthy controls and providing therapeutic targets for better and earlier PCa therapy.
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Affiliation(s)
- Shweta Kumari
- Biochemistry, King George's Medical University, Lucknow, IND
| | - Anveshika Manoj
- Biochemistry, King George's Medical University, Lucknow, IND
| | - Sumit Rungta
- Gastroenterology, King George's Medical University, Lucknow, IND
| | - Manoj Kumar
- Urology, King George's Medical University, Lucknow, IND
| | - Gautam Prasad
- Biochemistry, King George's Medical University, Lucknow, IND
| | - Durgesh Kumar
- Biochemistry, King George's Medical University, Lucknow, IND
| | - Abbas A Mahdi
- Biochemistry, King George's Medical University, Lucknow, IND
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10
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Wang P, Laster K, Jia X, Dong Z, Liu K. Targeting CRAF kinase in anti-cancer therapy: progress and opportunities. Mol Cancer 2023; 22:208. [PMID: 38111008 PMCID: PMC10726672 DOI: 10.1186/s12943-023-01903-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/16/2023] [Indexed: 12/20/2023] Open
Abstract
The RAS/mitogen-activated protein kinase (MAPK) signaling cascade is commonly dysregulated in human malignancies by processes driven by RAS or RAF oncogenes. Among the members of the RAF kinase family, CRAF plays an important role in the RAS-MAPK signaling pathway, as well as in the progression of cancer. Recent research has provided evidence implicating the role of CRAF in the physiological regulation and the resistance to BRAF inhibitors through MAPK-dependent and MAPK-independent mechanisms. Nevertheless, the effectiveness of solely targeting CRAF kinase activity remains controversial. Moreover, the kinase-independent function of CRAF may be essential for lung cancers with KRAS mutations. It is imperative to develop strategies to enhance efficacy and minimize toxicity in tumors driven by RAS or RAF oncogenes. The review investigates CRAF alterations observed in cancers and unravels the distinct roles of CRAF in cancers propelled by diverse oncogenes. This review also seeks to summarize CRAF-interacting proteins and delineate CRAF's regulation across various cancer hallmarks. Additionally, we discuss recent advances in pan-RAF inhibitors and their combination with other therapeutic approaches to improve treatment outcomes and minimize adverse effects in patients with RAF/RAS-mutant tumors. By providing a comprehensive understanding of the multifaceted role of CRAF in cancers and highlighting the latest developments in RAF inhibitor therapies, we endeavor to identify synergistic targets and elucidate resistance pathways, setting the stage for more robust and safer combination strategies for cancer treatment.
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Affiliation(s)
- Penglei Wang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Kyle Laster
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Xuechao Jia
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.
- Department of Pathophysiology, School of Basic Medical Sciences, China-US (Henan) Hormel Cancer Institute, AMS, College of Medicine, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China.
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.
- Department of Pathophysiology, School of Basic Medical Sciences, China-US (Henan) Hormel Cancer Institute, AMS, College of Medicine, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China.
- Basic Medicine Sciences Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450000, Henan, China.
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China.
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Majed SO, Mustafa SA. The profiles of miR-4510 expression level in breast cancer. Sci Rep 2023; 13:2262. [PMID: 36755123 PMCID: PMC9908886 DOI: 10.1038/s41598-022-25292-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 11/28/2022] [Indexed: 02/10/2023] Open
Abstract
MicroRNA that is abnormally produced in breast cells can disrupt biological processes, which can lead to cancer. This study aims to screen differentially expressed genes (DEGs) and ncRNAs (DEncRNAs) in the formalin-fixed paraffin-embedded (FFPE) tissues of breast cancer (BC) as compared with the normal adjacent tissues (NAT), and identify miR-4510 as a novel biomarker of BC. This study looked at differentially expressed genes (DEGs) using MACE-Seq and differentially expressed ncRNAs (DEncRNAs) using the small RNA-Seq. Real-time qPCR was used to determine the level of expression of miR-4510. In this study, MACE-Seq results showed that 26,795 genes, with a p-value < 0.05, were differentially expressed in BC paraffin tissues as compared with NAT. Small RNA-Seq results revealed that 1326 ncRNAs, with a p-value < 0.05, were differentially expressed. We confirmed that miR-4510 was significantly down-expressed (p-value = 0.001) by qRT-PCR in the paraffin tissue of 120 BC patients. Based on eleven computational prediction programs, TP53, TP53INP1, MMP11, and COL1A1 for the miR-4510 were identified as miR-4510 targets. The MACE-seq result showed that the gene of TP53 (p-value = 0.001) and TP53INP1 (p-value = 0.02) was significantly down-regulated, but the gene of MMP11 (p-value = 0.004) and COL1A1 (p-value = 0.0001) was significantly over-expressed in 20 paired specimens of the BC and NAT. We discovered that a single SNP inside the miR-4510 binding site occurred only in BC, in which Guanine (G) changed into Adenine (A). Two SNPs outside the miR-4510 binding site occurred, and Guanine (G) in both BC and NAT was changed into Thymine (T), as compared to the reference sequence (RefSeq). Overall, our results suggested that miR-4510 functions as a tumor suppressor in the BC. Mir-4510 may act as a tumor suppressor, however additional experimental data is needed to corroborate these assumptions and can be exploited as a biomarker for BC.
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Affiliation(s)
- Sevan Omer Majed
- Biology Department, College of Education, Salahaddin University-Erbil, Erbil, Iraq
| | - Suhad Asad Mustafa
- General Directorate of Scientific Research Center, Salahaddin University-Erbil, Erbil, Iraq.
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12
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Zhang L, Xie J, Sun G, Ji R, Li X, Zhang X, Wang J. Identification of differentially expressed genes and signaling pathways in Gaoyou duck ovary at different physiological stages. Front Vet Sci 2023; 10:1190998. [PMID: 37206435 PMCID: PMC10189055 DOI: 10.3389/fvets.2023.1190998] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 04/03/2023] [Indexed: 05/21/2023] Open
Abstract
Introduction Gaoyou duck is famous in China and abroad for its good production of double-yolk eggs. However, there has been no systematic research on the egg-laying characteristics of the Gaoyou duck, which limits the development and utilization of breed resource. Methods To identify the essential genes related to ovarian development, the transcriptome profiles of the ovaries of Gaoyou ducks at different physiological stages were analyzed. The transcriptome profiles of the ovaries of Gaoyou ducks at 150 d (before laying), 240 d (egg laying) and 500 d (nesting) were constructed, and the differentially expressed genes (DEGs) underwent GO (gene ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses. Results The 6 randomly selected DEGs were verified by real-time fluorescent quantitative PCR that their relative expression was consistent with the transcriptional expression profile. Furthermore, KEGG analysis found that 8 candidate signaling pathways were essential for ovarian development, including the MAPK signaling pathway, Progesterone-mediated oocyte maturation, Cell adhesion molecules (CAMs), NOD-like receptor signaling pathway, ECM-receptor interaction, Focal adhesion, TGF-beta signaling path-way and Phagosome. Finally, 5 key DEGs were identified to participate in ovarian development, including TGIF1, TGFBR2, RAF1, PTK2 and FGF10. Discussion Our findings reveal the mechanisms under-lying the molecular regulation of related genes in Gaoyou duck ovarian development.
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13
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Deng Y, Feng Y, Lv Z, He J, Chen X, Wang C, Yuan M, Xu T, Gao W, Chen D, Zhu H, Hou D. Machine learning models identify ferroptosis-related genes as potential diagnostic biomarkers for Alzheimer’s disease. Front Aging Neurosci 2022; 14:994130. [PMID: 36262887 PMCID: PMC9575464 DOI: 10.3389/fnagi.2022.994130] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/12/2022] [Indexed: 11/13/2022] Open
Abstract
Alzheimer’s disease (AD) is a complex, and multifactorial neurodegenerative disease. Previous studies have revealed that oxidative stress, synaptic toxicity, autophagy, and neuroinflammation play crucial roles in the progress of AD, however, its pathogenesis is still unclear. Recent researches have indicated that ferroptosis, an iron-dependent programmed cell death, might be involved in the pathogenesis of AD. Therefore, we aim to screen correlative ferroptosis-related genes (FRGs) in the progress of AD to clarify insights into the diagnostic value. Interestingly, we identified eight FRGs were significantly differentially expressed in AD patients. 10,044 differentially expressed genes (DEGs) were finally identified by differential expression analysis. The following step was investigating the function of DEGs using gene set enrichment analysis (GSEA). Weight gene correlation analysis was performed to explore ten modules and 104 hub genes. Subsequently, based on machine learning algorithms, we constructed diagnostic classifiers to select characteristic genes. Through the multivariable logistic regression analysis, five features (RAF1, NFKBIA, MOV10L1, IQGAP1, FOXO1) were then validated, which composed a diagnostic model of AD. Thus, our findings not only developed genetic diagnostics strategy, but set a direction for further study of the disease pathogenesis and therapy targets.
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Affiliation(s)
- Yanyao Deng
- Department of Rehabilitation, The First Hospital of Changsha, Changsha, China
| | - Yanjin Feng
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhicheng Lv
- Department of Neurosurgery, The First People’s Hospital of Chenzhou, Chenzhou, China
| | - Jinli He
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xun Chen
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Chen Wang
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Mingyang Yuan
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ting Xu
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Wenzhe Gao
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Dongjie Chen
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Hongwei Zhu
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Deren Hou
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Deren Hou,
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14
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Takuma K, Fujihara S, Fujita K, Iwama H, Nakahara M, Oura K, Tadokoro T, Mimura S, Tani J, Shi T, Morishita A, Kobara H, Himoto T, Masaki T. Antitumor Effect of Regorafenib on MicroRNA Expression in Hepatocellular Carcinoma Cell Lines. Int J Mol Sci 2022; 23:ijms23031667. [PMID: 35163589 PMCID: PMC8835935 DOI: 10.3390/ijms23031667] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/25/2022] [Accepted: 01/27/2022] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is one of the leading causes of cancer-related deaths worldwide. Regorafenib, a multi-kinase inhibitor, is used as a second-line treatment for advanced HCC. Here, we aimed to investigate the mechanism of the antitumor effect of regorafenib on HCC and evaluate altered microRNA (miRNA) expression. Cell proliferation was examined in six HCC cell lines (HuH-7, HepG2, HLF, PLC/PRF/5, Hep3B, and Li-7) using the Cell Counting Kit-8 assay. Xenografted mouse models were used to assess the effects of regorafenib in vivo. Cell cycle analysis, western blotting analysis, and miRNA expression analysis were performed to identify the antitumor inhibitory potential of regorafenib on HCC cells. Regorafenib suppressed proliferation in HuH-7 cell and induced G0/G1 cell cycle arrest and cyclin D1 downregulation in regorafenib-sensitive cells. During miRNA analysis, miRNA molecules associated with the antitumor effect of regorafenib were found. Regorafenib suppresses cell proliferation and tumor growth in HCC by decreasing cyclin D1 via alterations in intracellular and exosomal miRNAs in HCC.
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Affiliation(s)
- Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
| | - Shintaro Fujihara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan;
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
| | - Tingting Shi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
| | - Takashi Himoto
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan; (K.T.); (S.F.); (K.F.); (M.N.); (K.O.); (T.T.); (S.M.); (J.T.); (T.S.); (A.M.); (H.K.); (T.H.)
- Correspondence: ; Tel.: +81-87-891-2156
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15
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Identification of miR-4510 as a metastasis suppressor of gastric cancer through regulation of tumor microenvironment via targeting GPC3. Clin Exp Metastasis 2022; 39:363-374. [PMID: 35050429 PMCID: PMC8971168 DOI: 10.1007/s10585-021-10143-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 12/27/2021] [Indexed: 11/08/2022]
Abstract
The genes miR-4510 and glypican-3 (GPC3) have reported to be closely associated with tumors, with miR-4510 inversely correlated with GPC3 mRNA and protein in hepatocellular carcinoma samples. Glypican-3-expressing gastric cancer (GPC3-GC), characterized as gastric cancer (GC) expressing GPC3, accounts for 11% of the GC cases. However, the expression and mechanism of action of miR-4510 in GPC3-GC have not been clearly defined. We found that miR-4510 expression in GC tissues was significantly lower than that in the adjacent tissues (p < 0.001). miRNA-4510 expression in GPC3-GC was significantly lower than that in GPC3‐negative GC tissue (p < 0.001). Our study confirmed that miR-4510 is inversely correlated with GPC3 in gastric cancer samples and that GPC3 is a direct target gene of miR-4510. The proportion of M2 macrophages in GC with low expression of miR-4510 was significantly increased, while the proliferation of CD8+ T cells was limited. miR-4510 may change the immunosuppressive signals in the tumor microenvironment by downregulating GPC3 and inhibiting gastric cancer cell metastasis. Oxaliplatin treatment may become a specific therapeutic drug for patients with miR-4510 inhibition and GPC3-GC.
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16
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Zheng W, Shen GL, Xu KY, Yin QQ, Hui TC, Zhou ZW, Xu CA, Wang SH, Wu WH, Shi LF, Pan HY. Lnc524369 promotes hepatocellular carcinoma progression and predicts poor survival by activating YWHAZ-RAF1 signaling. World J Gastrointest Oncol 2022; 14:253-264. [PMID: 35116115 PMCID: PMC8790426 DOI: 10.4251/wjgo.v14.i1.253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/28/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver cancer is one of the most highly malignant cancers, characterized by easy metastasis and chemoradiotherapy resistance. Emerging evidence indicates that long noncoding RNAs (LncRNAs), including Lnc524369, are highly involved in the initiation, progression, radioresistance, and chemoresistance of hepatocellular carcinoma (HCC). However, the function of Lnc524369 remains unclear.
AIM To explore the function of Lnc524369 in HCC.
METHODS To investigate the effect of Lnc524369, tissue from 41 HCC patients were analyzed using CCK8, migration, and invasion assays. Lnc524369 and YWHAZ (also named 14-3-3ζ) mRNA were detected by qPCR, and YWHAZ and RAF1 proteins were detected by western blot in liver cancer cell lines and human HCC tissues. The Cancer Cell Line Encyclopedia (CCLE) databases, STRING database, Human Protein Atlas database, and the TCGA database were used for bioinformatic analysis.
RESULTS Lnc524369 was significantly upregulated in the nucleus of liver cancer cells and human HCC tissues. Overexpression of Lnc524369 was associated with the proliferation, migration, and invasion of liver cancer cells. YWHAZ and RAF1 proteins and YWHAZ mRNA were overexpressed in liver cancer, which could be attenuated by overexpression of Lnc524369. Lnc524369 and its downstream target YWHAZ and RAF1 proteins were negatively associated with overall survival time.
CONCLUSION Lnc524369 might be a promising target of HCC as it can enhance liver cancer progression and decrease the overall survival time of HCC by activating the YWHAZ/RAF1 pathway.
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Affiliation(s)
- Wei Zheng
- Department of Clinical Medicine, Medical College of Soochow University, Suzhou 215006, Jiangsu Province, China
- Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Guo-Liang Shen
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Ke-Yang Xu
- School of Chinese Medicine, Hongkong Baptist university, Hong Kong 999777, China
| | - Qiao-Qiao Yin
- Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Tian-Chen Hui
- Department of Graduate School, Bengbu Medical College, Bengbu 233030, Anhui Province, China
| | - Zhe-Wen Zhou
- Department of Graduate School, Bengbu Medical College, Bengbu 233030, Anhui Province, China
| | - Cheng-An Xu
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Shou-Hao Wang
- Medical Department of Qingdao University, Qingdao University, Qingdao 266071, Shandong, China
| | - Wen-Hao Wu
- Medical Department of Qingdao University, Qingdao University, Qingdao 266071, Shandong, China
| | - Ling-Fei Shi
- Diagnosis and Treatment Center of Osteoporosis, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hang Zhou 310014, Zhejiang Province, China
| | - Hong-Ying Pan
- Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
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17
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Lai X, Schmitz U, Vera J. The Role of MicroRNAs in Cancer Biology and Therapy from a Systems Biology Perspective. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1385:1-22. [DOI: 10.1007/978-3-031-08356-3_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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18
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Khoubai FZ, Grosset CF. DUSP9, a Dual-Specificity Phosphatase with a Key Role in Cell Biology and Human Diseases. Int J Mol Sci 2021; 22:ijms222111538. [PMID: 34768967 PMCID: PMC8583968 DOI: 10.3390/ijms222111538] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 12/14/2022] Open
Abstract
Mitogen-activated protein kinases (MAPKs) are essential for proper cell functioning as they regulate many molecular effectors. Careful regulation of MAPKs is therefore required to avoid MAPK pathway dysfunctions and pathologies. The mammalian genome encodes about 200 phosphatases, many of which dephosphorylate the MAPKs and bring them back to an inactive state. In this review, we focus on the normal and pathological functions of dual-specificity phosphatase 9 (DUSP9)/MAP kinase phosphatases-4 (MKP-4). This cytoplasmic phosphatase, which belongs to the threonine/tyrosine dual-specific phosphatase family and was first described in 1997, is known to dephosphorylate ERK1/2, p38, JNK and ASK1, and thereby to control various MAPK pathway cascades. As a consequence, DUSP9 plays a major role in human pathologies and more specifically in cardiac dysfunction, liver metabolic syndromes, diabetes, obesity and cancer including drug response and cell stemness. Here, we recapitulate the mechanism of action of DUSP9 in the cell, its levels of regulation and its roles in the most frequent human diseases, and discuss its potential as a therapeutic target.
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Fujii Y, Ono A, Hayes CN, Aikata H, Yamauchi M, Uchikawa S, Kodama K, Teraoka Y, Fujino H, Nakahara T, Murakami E, Miki D, Okamoto W, Kawaoka T, Tsuge M, Imamura M, Chayama K. Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:215. [PMID: 34174931 PMCID: PMC8235843 DOI: 10.1186/s13046-021-02016-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/11/2021] [Indexed: 12/20/2022]
Abstract
Background There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). Method We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. Results In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAFmean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAFmean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. Conclusion Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02016-3.
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Affiliation(s)
- Yasutoshi Fujii
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Kenichiro Kodama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Wataru Okamoto
- Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Masataka Tsuge
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Kazuaki Chayama
- Collaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. .,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan. .,RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
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20
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Moon H, Ro SW. MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:3026. [PMID: 34204242 PMCID: PMC8234271 DOI: 10.3390/cancers13123026] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. Recently, the MAPK/ERK signaling pathway in HCC has gained renewed attention from basic and clinical researchers. The MAPK/ERK signaling pathway is activated in more than 50% of human HCC cases; however, activating mutations in RAS and RAF genes are rarely found in HCC, which are major genetic events leading to the activation of the MAPK/ERK signaling pathway in other cancers. This suggests that there is an alternative mechanism behind the activation of the signaling pathway in HCC. Here, we will review recent advances in understanding the cellular and molecular mechanisms involved in the activation of the MAPK/ERK signaling pathway and discuss potential therapeutic strategies targeting the signaling pathway in the context of HCC.
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Affiliation(s)
| | - Simon Weonsang Ro
- Department of Genetics and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Korea;
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21
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He W, Huang X, Berges BK, Wang Y, An N, Su R, Lu Y. Artesunate Regulates Neurite Outgrowth Inhibitor Protein B Receptor to Overcome Resistance to Sorafenib in Hepatocellular Carcinoma Cells. Front Pharmacol 2021; 12:615889. [PMID: 33716742 PMCID: PMC7946852 DOI: 10.3389/fphar.2021.615889] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 01/19/2021] [Indexed: 12/24/2022] Open
Abstract
The multireceptor tyrosine kinase inhibitor sorafenib is a Food and Drug Administration-approved first-line drug for the treatment of advanced liver cancer that can reportedly extend overall survival in patients with advanced hepatocellular carcinoma (HCC). Primary and acquired resistance to sorafenib are gradually increasing however, leading to failure of HCC treatment with sorafenib. It is therefore crucial to study the potential mechanism of sorafenib resistance. The results of the current study indicate that neurite outgrowth inhibitor protein B receptor (NgBR) is overexpressed in cultured sorafenib-resistant cells, and that its expression is negatively correlated with the sensitivity of liver cancer cells to sorafenib. Artesunate can inhibit the expression of NgBR, and it may block sorafenib resistance. Herein we report that sorafenib treatment in combination with artesunate overcomes HCC resistance to sorafenib alone in a cell culture model.
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Affiliation(s)
- Wubin He
- Key laboratory of surgery of Liaoning Province of The First Affiliated Hospital of Jinzhou Medical University, Liaoning, China
| | - Xiaoxu Huang
- Key Laboratory of Molecular Cell Biology and New Drug Development of Jinzhou Medical University, Liaoning, Jinzhou, China
| | - Bradford K Berges
- Department of Microbiology and Molecular Biology of Brigham Young University, Provo, UT, United States
| | - Yue Wang
- Department of Pathlogy of The First Affiliated Hospital of Jinzhou Medical University, Liaoning, China
| | - Ni An
- Key Laboratory of Molecular Cell Biology and New Drug Development of Jinzhou Medical University, Liaoning, Jinzhou, China
| | - Rongjian Su
- Key Laboratory of Molecular Cell Biology and New Drug Development of Jinzhou Medical University, Liaoning, Jinzhou, China
| | - Yanyan Lu
- Department of Orthopedic Spine Surgery of The First Affiliated Hospital of Jinzhou Medical University, Liaoning, China
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22
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Moldogazieva NT, Mokhosoev IM, Zavadskiy SP, Terentiev AA. Proteomic Profiling and Artificial Intelligence for Hepatocellular Carcinoma Translational Medicine. Biomedicines 2021; 9:biomedicines9020159. [PMID: 33562077 PMCID: PMC7914649 DOI: 10.3390/biomedicines9020159] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/27/2021] [Accepted: 02/02/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver with high morbidity and mortality rates worldwide. Since 1963, when alpha-fetoprotein (AFP) was discovered as a first HCC serum biomarker, several other protein biomarkers have been identified and introduced into clinical practice. However, insufficient specificity and sensitivity of these biomarkers dictate the necessity of novel biomarker discovery. Remarkable advancements in integrated multiomics technologies for the identification of gene expression and protein or metabolite distribution patterns can facilitate rising to this challenge. Current multiomics technologies lead to the accumulation of a huge amount of data, which requires clustering and finding correlations between various datasets and developing predictive models for data filtering, pre-processing, and reducing dimensionality. Artificial intelligence (AI) technologies have an enormous potential to overcome accelerated data growth, complexity, and heterogeneity within and across data sources. Our review focuses on the recent progress in integrative proteomic profiling strategies and their usage in combination with machine learning and deep learning technologies for the discovery of novel biomarker candidates for HCC early diagnosis and prognosis. We discuss conventional and promising proteomic biomarkers of HCC such as AFP, lens culinaris agglutinin (LCA)-reactive L3 glycoform of AFP (AFP-L3), des-gamma-carboxyprothrombin (DCP), osteopontin (OPN), glypican-3 (GPC3), dickkopf-1 (DKK1), midkine (MDK), and squamous cell carcinoma antigen (SCCA) and highlight their functional significance including the involvement in cell signaling such as Wnt/β-catenin, PI3K/Akt, integrin αvβ3/NF-κB/HIF-1α, JAK/STAT3 and MAPK/ERK-mediated pathways dysregulated in HCC. We show that currently available computational platforms for big data analysis and AI technologies can both enhance proteomic profiling and improve imaging techniques to enhance the translational application of proteomics data into precision medicine.
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Affiliation(s)
- Nurbubu T. Moldogazieva
- Laboratory of Bioinformatics, Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
- Correspondence: or
| | - Innokenty M. Mokhosoev
- Department of Biochemistry and Molecular Biology, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (I.M.M.); (A.A.T.)
| | - Sergey P. Zavadskiy
- Department of Pharmacology, A.P. Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
| | - Alexander A. Terentiev
- Department of Biochemistry and Molecular Biology, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (I.M.M.); (A.A.T.)
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23
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Zhang B, Li F, Zhu Z, Ding A, Luo J. CircRNA CDR1as/miR-1287/Raf1 Axis Modulates Hepatocellular Carcinoma Progression Through MEK/ERK Pathway. Cancer Manag Res 2020; 12:8951-8964. [PMID: 33061591 PMCID: PMC7522432 DOI: 10.2147/cmar.s252679] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 08/18/2020] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a common lethal malignant tumor worldwide. Circular RNAs (circRNAs) have been reported to affect the development of human cancers, including HCC. In this project, we aim to clarify the functional effect of circular CDR1as (circ_CDR1as) on HCC progression. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot is implemented to detect the expression of circ_CDR1as, microRNA (miR)-1287 and Raf-1 proto-oncogene, serine/threonine kinase (Raf1). Cell proliferation is assessed via colony formation and 3-(4, 5)-dimethylthiazole-2-y1)-2, 5-biphenyl tetrazolium bromide (MTT) assays. Cell migration and invasion are measured by Transwell assay. The target relationship between miR-1287 and circ_CDR1as or Raf1 is validated through dual-luciferase reporter assay. The levels of epithelia–mesenchymal transition (EMT) markers and the MEK/ERK signal pathway-related proteins are examined by Western blot. Model in nude mice is constructed to determine the role of circ_CDR1as in vivo. Results Expression of circ_CDR1as and Raf1 is elevated, while miR-1287 expression is decreased in HCC. Depletion of circ_CDR1as or Raf1 could inhibit proliferation and metastasis of HCC cells. Besides, circ_CDR1as regulates Raf1 expression by targeting miR-1287. MiR-1287 upregulation or Raf1 depletion could partially counterbalance circ_CDR1as depletion-mediated inhibitory effects on HCC cell behaviors. Moreover, circ_CDR1as depletion represses HCC progression through inactivating MEK/ERK pathway. In addition, circ_CDR1as depletion suppresses tumor growth in vivo via regulating miR-1287/Raf1 pathway. Conclusion Circ_CDR1as depletion inhibits HCC cell proliferation and metastasis by miR-1287/Raf1 and MEK/ERK pathways, highlighting a promising molecular target for HCC treatment.
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Affiliation(s)
- Bashan Zhang
- Department of Clinical Laboratory, Affiliated Dongguan People's Hospital, Southern Medical University of Dongguan, Dongguan City, Guangdong Province, People's Republic of China
| | - Fei Li
- Department of Clinical Laboratory, Affiliated Dongguan People's Hospital, Southern Medical University of Dongguan, Dongguan City, Guangdong Province, People's Republic of China
| | - Zinian Zhu
- Department of Clinical Laboratory, Affiliated Dongguan People's Hospital, Southern Medical University of Dongguan, Dongguan City, Guangdong Province, People's Republic of China
| | - Aijiao Ding
- Department of Clinical Laboratory, Affiliated Dongguan People's Hospital, Southern Medical University of Dongguan, Dongguan City, Guangdong Province, People's Republic of China
| | - Jintong Luo
- Department of Clinical Laboratory, Affiliated Dongguan People's Hospital, Southern Medical University of Dongguan, Dongguan City, Guangdong Province, People's Republic of China
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24
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Younis MA, Khalil IA, Harashima H. Gene Therapy for Hepatocellular Carcinoma: Highlighting the Journey from Theory to Clinical Applications. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.202000087] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Mahmoud A. Younis
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences Hokkaido University Kita‐12, Nishi‐6, Kita‐ku Sapporo 060‐0812 Japan
- Faculty of Pharmacy Assiut University Assiut 71526 Egypt
| | - Ikramy A. Khalil
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences Hokkaido University Kita‐12, Nishi‐6, Kita‐ku Sapporo 060‐0812 Japan
- Faculty of Pharmacy Assiut University Assiut 71526 Egypt
| | - Hideyoshi Harashima
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences Hokkaido University Kita‐12, Nishi‐6, Kita‐ku Sapporo 060‐0812 Japan
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25
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Liu L, Wang Q, Qiu Z, Kang Y, Liu J, Ning S, Yin Y, Pang D, Xu S. Noncoding RNAs: the shot callers in tumor immune escape. Signal Transduct Target Ther 2020; 5:102. [PMID: 32561709 PMCID: PMC7305134 DOI: 10.1038/s41392-020-0194-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 05/05/2020] [Accepted: 05/06/2020] [Indexed: 01/17/2023] Open
Abstract
Immunotherapy, designed to exploit the functions of the host immune system against tumors, has shown considerable potential against several malignancies. However, the utility of immunotherapy is heavily limited due to the low response rate and various side effects in the clinical setting. Immune escape of tumor cells may be a critical reason for such low response rates. Noncoding RNAs (ncRNAs) have been identified as key regulatory factors in tumors and the immune system. Consequently, ncRNAs show promise as targets to improve the efficacy of immunotherapy in tumors. However, the relationship between ncRNAs and tumor immune escape (TIE) has not yet been comprehensively summarized. In this review, we provide a detailed account of the current knowledge on ncRNAs associated with TIE and their potential roles in tumor growth and survival mechanisms. This review bridges the gap between ncRNAs and TIE and broadens our understanding of their relationship, providing new insights and strategies to improve immunotherapy response rates by specifically targeting the ncRNAs involved in TIE.
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Affiliation(s)
- Lei Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Qin Wang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Zhilin Qiu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yujuan Kang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Jiena Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Shipeng Ning
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yanling Yin
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Da Pang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China. .,Heilongjiang Academy of Medical Sciences, Harbin, 150086, China.
| | - Shouping Xu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
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Sasaki R, Kanda T, Fujisawa M, Matsumoto N, Masuzaki R, Ogawa M, Matsuoka S, Kuroda K, Moriyama M. Different Mechanisms of Action of Regorafenib and Lenvatinib on Toll-Like Receptor-Signaling Pathways in Human Hepatoma Cell Lines. Int J Mol Sci 2020; 21:ijms21093349. [PMID: 32397371 PMCID: PMC7246870 DOI: 10.3390/ijms21093349] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/26/2020] [Accepted: 05/08/2020] [Indexed: 02/07/2023] Open
Abstract
Multiple kinase inhibitors are available for patients with advanced hepatocellular carcinoma (HCC). It is largely unknown whether regorafenib or lenvatinib modulates innate immunity including Toll-like receptor (TLR)-signaling pathways in HCC. We performed real-time RT-PCR to investigate 84 TLR-associated gene expression levels and compared these gene expression levels in each hepatoma cells treated with or without regorafenib or lenvatinib. In response to regorafenib, nine and 10 genes were upregulated in Huh7 and HepG2 cells, respectively, and only C-X-C motif chemokine ligand 10 was upregulated in both cell lines. A total of 14 and 12 genes were downregulated in Huh7 and HepG2 cells, respectively, and two genes (Fos proto-oncogene, AP-1 transcription factor subunit, and ubiquitin conjugating enzyme E2 N) were downregulated in both cell lines. In response to lenvatinib, four and 16 genes were upregulated in Huh7 and HepG2 cells, respectively, and two genes (interleukin 1 alpha and TLR4) were upregulated in both cells. Six and one genes were downregulated in Huh7 and HepG2, respectively, and no genes were downregulated in both cell lines. In summary, regorafenib and lenvatinib affect TLR signaling pathways in human hepatoma cell lines. Modulation of TLR signaling pathway may improve the treatment of HCC patients with refractory disease.
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