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Sanghvi G, R R, Kashyap A, Sabarivani A, Ray S, Bhakuni PN. Identifying the function of kinesin superfamily proteins in gastric cancer: Implications for signal transduction, clinical significance, and potential therapeutic approaches. Clin Res Hepatol Gastroenterol 2025; 49:102571. [PMID: 40064398 DOI: 10.1016/j.clinre.2025.102571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 03/06/2025] [Accepted: 03/08/2025] [Indexed: 03/16/2025]
Abstract
Gastric cancer (GC), a leading cause of cancer-related mortality, poses a significant global health challenge. Given its complex etiology, understanding the molecular pathways driving GC progression is crucial for developing innovative therapeutic strategies. Among the diverse proteins involved in cellular transport and mitotic regulation, kinesin superfamily proteins (KIFs) have emerged as key players in tumor biology. These motor proteins mediate intracellular transport along microtubules and are essential for processes such as cell division, signaling, and organelle distribution. Evidence indicates that specific KIFs are dysregulated in GC, potentially driving cancer cell proliferation, metastasis, and chemoresistance. Moreover, aberrant KIF expression has been associated with poorer prognoses, highlighting their potential as biomarkers for early diagnosis and therapeutic intervention. This review explores the roles of KIFs in GC and assesses their implications for research and clinical applications. By elucidating the significance of KIFs in GC, this discussion aims to inspire novel insights in cancer biology and advance targeted therapeutic strategies.
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Affiliation(s)
- Gaurav Sanghvi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot, Gujarat 360003, India
| | - Roopashree R
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Aditya Kashyap
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab 140401, India
| | - A Sabarivani
- Department of Biomedical, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Subhashree Ray
- Department of Biochemistry, IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, Odisha 751003, India
| | - Pushpa Negi Bhakuni
- Department of Allied Science, Graphic Era Hill University, Bhimtal, Uttarakhand 248002, India; Graphic Era Deemed to be University, Dehradun, Uttarakhand, India.
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Rahimi-Farsi N, Bostanian F, Shahbazi T, Shamsinejad FS, Bolideei M, Mohseni P, Zangooie A, Boustani F, Shoorei H. Novel oncogenes and tumor suppressor genes in Hepatocellular Carcinoma: Carcinogenesis, progression, and therapeutic targets. Gene 2025; 941:149229. [PMID: 39800198 DOI: 10.1016/j.gene.2025.149229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 10/21/2024] [Accepted: 01/07/2025] [Indexed: 01/15/2025]
Abstract
Hepatocellular carcinoma (HCC) is the primary malignancy affecting the liver and the leading cause of mortality among individuals with cirrhosis. This complex disease is associated with various risk factors, including environmental, pathological, and genetic influences, which dysregulate gene expression crucial for the cell cycle and cellular/molecular pathways. The disruption of the balance between tumor suppressors and proto-oncogenes amplifies the pathogenic cascade. Given its predilection for diseased or cirrhotic livers and late-stage diagnosis, HCC prognosis is typically poor. Current therapies offer limited benefits, with conventional non-specific cytotoxic agents exhibiting suboptimal efficacy. However, molecularly targeted therapies have emerged as a promising avenue, leveraging the strategic inhibition of carcinogenic molecules to provide heightened specificity and potency compared to cytotoxic chemotherapy. Several clinical trials have demonstrated promising outcomes in advanced HCC with targeted pharmacotherapies. Many genes have been implicated in HCC pathogenesis, underscoring the need to elucidate their molecular functions and roles. This has profound implications for early HCC prognostication via biomarkers and for identifying therapeutic targets to impede neoplastic progression. Notably, evidence highlights the pivotal roles of oncogenes and tumor suppressors in HCC pathophysiology. This discourse examines the potential involvement of ABL1, Annexins, FAK, FOX, and KIF as candidate oncogenes, contrasted with SORBS2, HPCAL1, PCDH10, PLAC8, and CXXC5 as plausible tumor suppressors. Their signaling cascades and relevance to HCC prognosis and progression are delineated to identify targets for improving HCC diagnosis, prognostication, and therapy.
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Affiliation(s)
| | | | - Taha Shahbazi
- Neurosurgery Research Group (NRG), Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mansoor Bolideei
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Parvin Mohseni
- Department of Pathobiology, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Alireza Zangooie
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran; Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farnaz Boustani
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran; Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.
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Giron-Michel J, Padelli M, Oberlin E, Guenou H, Duclos-Vallée JC. State-of-the-Art Liver Cancer Organoids: Modeling Cancer Stem Cell Heterogeneity for Personalized Treatment. BioDrugs 2025; 39:237-260. [PMID: 39826071 PMCID: PMC11906529 DOI: 10.1007/s40259-024-00702-0] [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] [Accepted: 12/21/2024] [Indexed: 01/20/2025]
Abstract
Liver cancer poses a global health challenge with limited therapeutic options. Notably, the limited success of current therapies in patients with primary liver cancers (PLCs) may be attributed to the high heterogeneity of both hepatocellular carcinoma (HCCs) and intrahepatic cholangiocarcinoma (iCCAs). This heterogeneity evolves over time as tumor-initiating stem cells, or cancer stem cells (CSCs), undergo (epi)genetic alterations or encounter microenvironmental changes within the tumor microenvironment. These modifications enable CSCs to exhibit plasticity, differentiating into various resistant tumor cell types. Addressing this challenge requires urgent efforts to develop personalized treatments guided by biomarkers, with a specific focus on targeting CSCs. The lack of effective precision treatments for PLCs is partly due to the scarcity of ex vivo preclinical models that accurately capture the complexity of CSC-related tumors and can predict therapeutic responses. Fortunately, recent advancements in the establishment of patient-derived liver cancer cell lines and organoids have opened new avenues for precision medicine research. Notably, patient-derived organoid (PDO) cultures have demonstrated self-assembly and self-renewal capabilities, retaining essential characteristics of their respective in vivo tissues, including both inter- and intratumoral heterogeneities. The emergence of PDOs derived from PLCs serves as patient avatars, enabling preclinical investigations for patient stratification, screening of anticancer drugs, efficacy testing, and thereby advancing the field of precision medicine. This review offers a comprehensive summary of the advancements in constructing PLC-derived PDO models. Emphasis is placed on the role of CSCs, which not only contribute significantly to the establishment of PDO cultures but also faithfully capture tumor heterogeneity and the ensuing development of therapy resistance. The exploration of PDOs' benefits in personalized medicine research is undertaken, including a discussion of their limitations, particularly in terms of culture conditions, reproducibility, and scalability.
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Affiliation(s)
- Julien Giron-Michel
- INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France.
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France.
| | - Maël Padelli
- INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France
- Department of Biochemistry and Oncogenetics, Paul Brousse Hospital, AP-HP, Villejuif, France
| | - Estelle Oberlin
- INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France
| | - Hind Guenou
- INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France
| | - Jean-Charles Duclos-Vallée
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France
- INSERM UMR-S 1193, Paul Brousse Hospital, Villejuif, France
- Hepato-Biliary Department, Paul Brousse Hospital, APHP, Villejuif, France
- Fédération Hospitalo-Universitaire (FHU) Hepatinov, Villejuif, France
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Wu M, Wu B, Huang X, Wang Z, Zhu M, Zhu Y, Yu L, Liu J. Inhibition of the FEN1-PBX1 axis elicits cellular senescence in breast cancer via the increased intracellular reactive oxygen species levels. J Transl Med 2025; 23:248. [PMID: 40022092 PMCID: PMC11871692 DOI: 10.1186/s12967-025-06216-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 02/10/2025] [Indexed: 03/03/2025] Open
Abstract
BACKGROUND Cellular senescence is a state of irreversible cell growth arrest. As such, senescence induction is viewed as an efficacious countermeasure in cancer treatment. Flap endonuclease 1 (FEN1) has been reported to participate in tumor growth, metastasis and immunomodulation. However, the role of FEN1 in cellular senescence of breast cancer and its molecular mechanism remains unclear. METHODS In vitro assessments of breast cancer cell senescence and apoptosis were conducted using CCK-8 assay, cell cycle assay, senescence-associated β-galactosidase (SA-β-gal) staining, and cleaved caspase-3 staining. Western blot, dihydroethidium (DHE) staining, RNA-sequencing, quantitative real-time polymerase chain reaction (qRT-PCR), rescue experiments, and dual-luciferase reporter assay were performed to explore the potential target of FEN1. Co-Immunoprecipitation (Co-IP), Chromatin immunoprecipitation (ChIP)-qPCR assay, and immunostaining were used to evaluate the interaction between FEN1 and Pre-B-cell leukemia homeobox transcription factor 1 (PBX1). A xenograft mouse model was employed to validate the effect of FEN1 on breast cancer cell senescence and apoptosis. RESULTS Functional analysis demonstrated that FEN1 suppressed both senescence and apoptosis of breast cancer cells in vitro, while in vivo experiments demonstrated moderate therapeutic effects. Further studies indicated that FEN1 deficiency promoted the aforementioned effects by increasing intracellular reactive oxygen species (ROS) levels. RNA-sequencing and qRT-PCR assays revealed that FEN1 knockdown enhanced the expressions of several senescence-associated secretory phenotype (SASP) factors and resulted in decreased PBX1 level. The rescue experiments by PBX1 overexpression verified that PBX1 mediated the senescence and apoptosis of breast cancer cells induced by FEN1 inhibition. In detail, FEN1 downregulation inhibited the transcription activity of PBX1, which was partially restored by itself overexpression. Of note, FEN1 directly interacted with PBX1. Furthermore, immunostaining illustrated the colocalization of FEN1 and PBX1 in breast cancer cells and tissues. In our local breast cancer cohort, a positive correlation was identified between the expression levels of FEN1 and PBX1. CONCLUSIONS Knockdown of FEN1 facilitates breast cancer cell senescence through PBX1 down-regulation mediating increase in intracellular ROS levels. This study reveals FEN1 as a negative regulator of cellular senescence and provides support for pro-senescence cancer therapy. Given that FEN1 knockdown exhibited only moderate in vivo effects, these findings underscore the necessity of combining it with senolytic therapy to enhance therapeutic efficacy.
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Affiliation(s)
- Min Wu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China.
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China.
| | - Benmeng Wu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China
| | - Xiaoshan Huang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China
| | - Zirui Wang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China
| | - Miaolin Zhu
- Department of Pathology, Jiangsu Cancer Hospital, Nanjing, 210018, China
| | - Yaqin Zhu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China
| | - Lin Yu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China
| | - Jingjing Liu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China.
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China.
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Cheng B, Ma J, Tang N, Liu R, Peng P, Wang K. Non-canonical function of PHGDH promotes HCC metastasis by interacting with METTL3. Cell Oncol (Dordr) 2024; 47:2427-2438. [PMID: 39695045 DOI: 10.1007/s13402-024-01029-2] [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] [Accepted: 12/12/2024] [Indexed: 12/20/2024] Open
Abstract
PURPOSE Phosphoglycerate dehydrogenase (PHGDH), a pivotal enzyme in serine synthesis, plays a key role in the malignant progression of tumors through both its metabolic activity and moonlight functions. This study aims to elucidate the non-canonical function of PHGDH in promoting hepatocellular carcinoma (HCC) metastasis through its interaction with methyltransferase-like 3 (METTL3), potentially uncovering a novel therapeutic target. METHODS Western blot was used to study PHGDH expression changes under anoikis and cellular functional assays were employed to assess its role in HCC metastasis. PHGDH-METTL3 interactions were explored using GST pull-down, Co-immunoprecipitation and immunofluorescence assays. Protein stability and ubiquitination assays were performed to understand PHGDH's impact on METTL3. Flow cytometry, cellular assays and nude mice model were used to confirm PHGDH's effects on anoikis resistance and HCC metastasis in vitro and in vivo. RESULTS PHGDH is upregulated under anoikis conditions, thereby enhancing the metastatic potential of HCC cells. By interacting with METTL3, PHGDH prevents its ubiquitin-dependent degradation, resulting in higher METTL3 protein levels. This interaction upregulates epithelial-mesenchymal transition related genes, contributing to anoikis resistance and HCC metastasis. Nude mice model confirms that PHGDH's interaction with METTL3 is crucial for driving HCC metastasis. CONCLUSION Our research presents the first evidence that PHGDH promotes HCC metastasis by interacting with METTL3. The PHGDH-METTL3 axis may serve as a potential clinical therapeutic target, offering new insights into the multifaceted roles of PHGDH in HCC metastasis.
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Affiliation(s)
- Bin Cheng
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jing Ma
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ni Tang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Rui Liu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Pai Peng
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Kai Wang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
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Airola C, Pallozzi M, Cesari E, Cerrito L, Stella L, Sette C, Giuliante F, Gasbarrini A, Ponziani FR. Hepatocellular-Carcinoma-Derived Organoids: Innovation in Cancer Research. Cells 2024; 13:1726. [PMID: 39451244 PMCID: PMC11505656 DOI: 10.3390/cells13201726] [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: 09/04/2024] [Revised: 10/13/2024] [Accepted: 10/14/2024] [Indexed: 10/26/2024] Open
Abstract
Hepatocellular carcinomas (HCCs) are highly heterogeneous malignancies. They are characterized by a peculiar tumor microenvironment and dense vascularization. The importance of signaling between immune cells, endothelial cells, and tumor cells leads to the difficult recapitulation of a reliable in vitro HCC model using the conventional two-dimensional cell cultures. The advent of three-dimensional organoid tumor technology has revolutionized our understanding of the pathogenesis and progression of several malignancies by faithfully replicating the original cancer genomic, epigenomic, and microenvironmental landscape. Organoids more closely mimic the in vivo environment and cell interactions, replicating factors such as the spatial organization of cell surface receptors and gene expression, and will probably become an important tool in the choice of therapies and the evaluation of tumor response to treatments. This review aimed to describe the ongoing and potential applications of organoids as an in vitro model for the study of HCC development, its interaction with the host's immunity, the analysis of drug sensitivity tests, and the current limits in this field.
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Affiliation(s)
- Carlo Airola
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (L.S.); (A.G.)
| | - Maria Pallozzi
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (L.S.); (A.G.)
| | - Eleonora Cesari
- GSTeP Organoids Research Core Facility, Fondazione Policlinico A. Gemelli, 00168 Rome, Italy; (E.C.); (C.S.)
| | - Lucia Cerrito
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (L.S.); (A.G.)
| | - Leonardo Stella
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (L.S.); (A.G.)
| | - Claudio Sette
- GSTeP Organoids Research Core Facility, Fondazione Policlinico A. Gemelli, 00168 Rome, Italy; (E.C.); (C.S.)
- Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Felice Giuliante
- Department of Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy;
| | - Antonio Gasbarrini
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (L.S.); (A.G.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (L.S.); (A.G.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Huang Z, Zhang K, Jiang Y, Wang M, Li M, Guo Y, Gao R, Li N, Wang C, Chen J, Wang J, Liu N, Liu X, Liu S, Wei M, Yang C, Yang G. Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH. Acta Pharm Sin B 2024; 14:4001-4013. [PMID: 39309493 PMCID: PMC11413658 DOI: 10.1016/j.apsb.2024.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 05/06/2024] [Accepted: 05/20/2024] [Indexed: 09/25/2024] Open
Abstract
Cancer stem cells (CSCs) play a pivotal role in tumor initiation, proliferation, metastasis, drug resistance, and recurrence. Consequently, targeting CSCs has emerged as a promising avenue for cancer therapy. Recently, 3-phosphoglycerate dehydrogenase (PHGDH) has been identified as being intricately associated with the regulation of numerous cancer stem cells. Yet, reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited. In this study, the novel "molecular glue" LXH-3-71 was identified, and it robustly induced degradation of PHGDH, thereby modulating the stemness of colorectal cancer cells (CRCs) both in vitro and in vivo. Remarkably, LXH-3-71 was observed to form a dynamic chimera, between PHGDH and the DDB1-CRL E3 ligase. These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors. Additionally, compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase, facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.
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Affiliation(s)
- Ziqi Huang
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Kun Zhang
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Yurui Jiang
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Mengmeng Wang
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Mei Li
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Yuda Guo
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Ruolin Gao
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Ning Li
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Chenyang Wang
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Jia Chen
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Jiefu Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Ning Liu
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Xiang Liu
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Shuangwei Liu
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Mingming Wei
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Cheng Yang
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
| | - Guang Yang
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, China
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8
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Wang JM, Zhang FH, Liu ZX, Tang YJ, Li JF, Xie LP. Cancer on motors: How kinesins drive prostate cancer progression? Biochem Pharmacol 2024; 224:116229. [PMID: 38643904 DOI: 10.1016/j.bcp.2024.116229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 04/02/2024] [Accepted: 04/18/2024] [Indexed: 04/23/2024]
Abstract
Prostate cancer causes numerous male deaths annually. Although great progress has been made in the diagnosis and treatment of prostate cancer during the past several decades, much about this disease remains unknown, especially its pathobiology. The kinesin superfamily is a pivotal group of motor proteins, that contains a microtubule-based motor domain and features an adenosine triphosphatase activity and motility characteristics. Large-scale sequencing analyses based on clinical samples and animal models have shown that several members of the kinesin family are dysregulated in prostate cancer. Abnormal expression of kinesins could be linked to uncontrolled cell growth, inhibited apoptosis and increased metastasis ability. Additionally, kinesins may be implicated in chemotherapy resistance and escape immunologic cytotoxicity, which creates a barrier to cancer treatment. Here we cover the recent advances in understanding how kinesins may drive prostate cancer progression and how targeting their function may be a therapeutic strategy. A better understanding of kinesins in prostate cancer tumorigenesis may be pivotal for improving disease outcomes in prostate cancer patients.
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Affiliation(s)
- Jia-Ming Wang
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Feng-Hao Zhang
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Zi-Xiang Liu
- Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, People's Republic of China
| | - Yi-Jie Tang
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Jiang-Feng Li
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
| | - Li-Ping Xie
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
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Wang XY, Li HM, Xia R, Li X, Zhang X, Jin TZ, Zhang HS. KDM4B down-regulation facilitated breast cancer cell stemness via PHGDH upregulation in H3K36me3-dependent manner. Mol Cell Biochem 2024; 479:915-928. [PMID: 37249813 DOI: 10.1007/s11010-023-04777-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/21/2023] [Indexed: 05/31/2023]
Abstract
Despite recent advances have been made in clinical treatments of breast cancer, the general prognosis of patients remains poor. Therefore, it is imperative to develop a more effective therapeutic strategy. Lysine demethylase 4B (KDM4B) has been reported to participate in breast cancer development recently, but its exact biological role in breast cancer remains unclear. Here, we observed that KDM4B was down-regulated in human primary BRCA tissues and the low levels of KDM4B expression were correlated with poor survival. Gain- and loss-of-function experiments showed that KDM4B inhibited the proliferation and metastasis of breast cancer cells. Besides, knockdown of KDM4B promoted the epithelial-mesenchymal transition (EMT) and cell stemness in breast cancer cells. Mechanistically, KDM4B down-regulates PHGDH by decreasing the enrichment of H3K36me3 on the promoter region of PHGDH. Knockdown of PHGDH could significantly reversed proliferation, migration, EMT, and cell stemness induced by KDM4B silencing in breast cancer cells. Collectively, we propose a model for a KDM4B/PHGDH axis that provides novel insight into breast cancer development, which may serve as a potential factor for predicting prognosis and a therapeutic target for breast cancer.
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Affiliation(s)
- Xin-Yu Wang
- Faculty of Environment and Life, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing, 100124, China
| | - Hong-Ming Li
- Faculty of Environment and Life, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing, 100124, China
| | - Ran Xia
- Faculty of Environment and Life, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing, 100124, China
| | - Xiang Li
- Faculty of Environment and Life, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing, 100124, China
| | - Xing Zhang
- Faculty of Environment and Life, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing, 100124, China
| | - Tong-Zhao Jin
- Faculty of Environment and Life, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing, 100124, China
| | - Hong-Sheng Zhang
- Faculty of Environment and Life, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing, 100124, China.
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10
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Li L, Qin Y, Chen Y. The enzymes of serine synthesis pathway in cancer metastasis. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119697. [PMID: 38382845 DOI: 10.1016/j.bbamcr.2024.119697] [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: 11/03/2023] [Revised: 02/05/2024] [Accepted: 02/14/2024] [Indexed: 02/23/2024]
Abstract
Metastasis, the major cause of cancer mortality, requires cancer cells to reprogram their metabolism to adapt to and thrive in different environments, thereby leaving metastatic cells metabolic characteristics different from their parental cells. Mounting research has revealed that the de novo serine synthesis pathway (SSP), a glycolytic branching pathway that consumes glucose carbons for serine makeup and α-ketoglutarate generation and thus supports the proliferation, survival, and motility of cancer cells, is one such reprogrammed metabolic pathway. During different metastatic cascades, the SSP enzyme proteins or their enzymatic activity are both dynamically altered; manipulating their expression or catalytic activity could effectively prevent the progression of cancer metastasis; and the SSP enzymatic proteins could even conduce to metastasis via their nonenzymatic functions. In this article we overview the SSP dynamics during cancer metastasis and put the focuses on the regulatory role of the SSP in metastasis and the underlying mechanisms that mainly involve cellular anabolism/catabolism, redox balance, and epigenetics, aiming to provide a theoretical basis for the development of therapeutic strategies for targeting metastatic lesions.
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Affiliation(s)
- Lei Li
- Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Yuting Qin
- School of Pharmaceutical Sciences, University of South China, Hengyang, Hunan 421001, China
| | - Yuping Chen
- Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; School of Pharmaceutical Sciences, University of South China, Hengyang, Hunan 421001, China.
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11
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Zhao K, Li X, Feng Y, Wang J, Yao W. The role of kinesin family members in hepatobiliary carcinomas: from bench to bedside. Biomark Res 2024; 12:30. [PMID: 38433242 PMCID: PMC10910842 DOI: 10.1186/s40364-024-00559-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: 10/06/2023] [Accepted: 01/03/2024] [Indexed: 03/05/2024] Open
Abstract
As a major component of the digestive system malignancies, tumors originating from the hepatic and biliary ducts seriously endanger public health. The kinesins (KIFs) are molecular motors that enable the microtubule-dependent intracellular trafficking necessary for mitosis and meiosis. Normally, the stability of KIFs is essential to maintain cell proliferation and genetic homeostasis. However, aberrant KIFs activity may destroy this dynamic stability, leading to uncontrolled cell division and tumor initiation. In this work, we have made an integral summarization of the specific roles of KIFs in hepatocellular and biliary duct carcinogenesis, referring to aberrant signal transduction and the potential for prognostic evaluation. Additionally, current clinical applications of KIFs-targeted inhibitors have also been discussed, including their efficacy advantages, relationship with drug sensitivity or resistance, the feasibility of combination chemotherapy or other targeted agents, as well as the corresponding clinical trials. In conclusion, the abnormally activated KIFs participate in the regulation of tumor progression via a diverse range of mechanisms and are closely associated with tumor prognosis. Meanwhile, KIFs-aimed inhibitors also carry out a promising tumor-targeted therapeutic strategy that deserves to be further investigated in hepatobiliary carcinoma (HBC).
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Affiliation(s)
- Kai Zhao
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Xiangyu Li
- Department of Thoracic Surgery Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Yunxiang Feng
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Jianming Wang
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
- Affiliated Tianyou Hospital, Wuhan University of Science & Technology, 430064, Wuhan, China.
| | - Wei Yao
- Department of Oncology Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
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12
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Xiu Z, Yang Q, Xie F, Han F, He W, Liao W. Revolutionizing digestive system tumor organoids research: Exploring the potential of tumor organoids. J Tissue Eng 2024; 15:20417314241255470. [PMID: 38808253 PMCID: PMC11131411 DOI: 10.1177/20417314241255470] [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: 01/15/2024] [Accepted: 05/02/2024] [Indexed: 05/30/2024] Open
Abstract
Digestive system tumors are the leading cause of cancer-related deaths worldwide. Despite ongoing research, our understanding of their mechanisms and treatment remain inadequate. One promising tool for clinical applications is the use of gastrointestinal tract tumor organoids, which serve as an important in vitro model. Tumor organoids exhibit a genotype similar to the patient's tumor and effectively mimic various biological processes, including tissue renewal, stem cell, and ecological niche functions, and tissue response to drugs, mutations, or injury. As such, they are valuable for drug screening, developing novel drugs, assessing patient outcomes, and supporting immunotherapy. In addition, innovative materials and techniques can be used to optimize tumor organoid culture systems. Several applications of digestive system tumor organoids have been described and have shown promising results in related aspects. In this review, we discuss the current progress, limitations, and prospects of this model for digestive system tumors.
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Affiliation(s)
- Zhian Xiu
- Department of Medical Laboratory, Clinical Medical College, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
| | - Qian Yang
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fusheng Xie
- Department of Medical Laboratory, Clinical Medical College, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
| | - Feng Han
- Department of Medical Laboratory, Clinical Medical College, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
| | - Weiwei He
- Department of Medical Laboratory, Clinical Medical College, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
| | - Weifang Liao
- Department of Medical Laboratory, Clinical Medical College, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
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13
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Zhang S, Qin O, Xu H, Wu S, Huang W, Song H. A comprehensive analysis of the prognostic and immunotherapeutic characteristics of KIFC1 in pan-cancer and its role in the malignant phenotype of pancreatic cancer. Aging (Albany NY) 2023; 15:14845-14863. [PMID: 38112634 PMCID: PMC10781448 DOI: 10.18632/aging.205311] [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: 08/16/2023] [Accepted: 11/06/2023] [Indexed: 12/21/2023]
Abstract
BACKGROUND Kinesin family member C1 (KIFC1) is an essential member of the motor protein family, which is critically involved in various cellular events, such as mitosis, meiosis, and macromolecular transport, but also in carcinogenesis, malignant progression, and tumor recurrence. METHODS The analysis determined the relationship between KIFC1 expression, prognosis significance, immune characteristics landscape, and genetic alterations in pan-cancer with the data extracted from web-based platforms and databases, including but not limited to UCSC, NCBI, GEPIA2, HPA, cBioPortal, SangerBox, UALCAN, GEO and TCGA. Additionally, the expression of KIFC1 in pancreatic cancer tumor tissues and adjacent normal tissues was evaluated through immunohistochemistry. In vitro Edu, colony formation, wound healing, and Transwell assay were done to elucidate the biological functions of KIFC1 in pancreatic cancer cells. RESULTS The analysis revealed that KIFC1 is upregulated in most cancers, and its increased expression is significantly associated with reduced overall survival and disease-free survival in multiple cancer types. Additionally, strong correlations between KIFC1 expression and tumor immunotherapy were observed across various malignancies. Through univariate and multivariate Cox regression analyses using TCGA data, KIFC1 was identified as an independent predictor of prognosis in pancreatic cancer cases. Furthermore, cellular experiments demonstrated that knockdown of KIFC1 resulted in the suppression of cell proliferation, migration, and invasive ability. CONCLUSIONS Our study indicated that KIFC1 harbors the potential to be a prognostic and immunotherapeutic biomarker of tumors, and it can have an impact on the metastasis and the cell cycle of pancreatic cancer cells.
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Affiliation(s)
- Shihang Zhang
- Department of General Surgery, Dalang Hospital, Dongguan, Guangdong, PR China
| | - Ouyang Qin
- Department of General Surgery, Dalang Hospital, Dongguan, Guangdong, PR China
| | - Huanming Xu
- Department of General Surgery, Dalang Hospital, Dongguan, Guangdong, PR China
| | - Shu Wu
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Dongguan Hospital Southern Medical University (Dongguan People’s Hospital), Dongguan, Guangdong, PR China
| | - Wei Huang
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, PR China
| | - Hailiang Song
- Department of General Surgery, Dalang Hospital, Dongguan, Guangdong, PR China
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14
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Li Q, Sun M, Meng Y, Feng M, Wang M, Chang C, Dong H, Bu F, Xu C, Liu J, Ling Q, Qiao Y, Chen J. Kinesin family member 18B activates mTORC1 signaling via actin gamma 1 to promote the recurrence of human hepatocellular carcinoma. Oncogenesis 2023; 12:54. [PMID: 37957153 PMCID: PMC10643429 DOI: 10.1038/s41389-023-00499-7] [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: 02/20/2023] [Revised: 10/08/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is frequently reported to be hyperactivated in hepatocellular carcinoma (HCC) and contributes to HCC recurrence. However, the underlying regulatory mechanisms of mTORC1 signaling in HCC are not fully understood. In the present study, we found that the expression of kinesin family member 18B (KIF18B) was positively correlated with mTORC1 signaling in HCC, and the upregulation of KIF18B and p-mTOR was associated with a poor prognosis and HCC recurrence. Utilizing in vitro and in vivo assays, we showed that KIF18B promoted HCC cell proliferation and migration through activating mTORC1 signaling. Mechanistically, we identified Actin gamma 1 (γ-Actin) as a binding partner of KIF18B. KIF18B and γ-Actin synergistically modulated lysosome positioning, promoted mTORC1 translocation to lysosome membrane, and prohibited p70 S6K from entering lysosomes for degradation, which finally led to the enhancement of mTORC1 signaling transduction. Moreover, we found that KIF18B was a direct target of Forkhead box M1, which explains the potential mechanism of KIF18B overexpression in HCC. Our study highlights the potential of KIF18B as a therapeutic target for the treatment of HCC.
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Affiliation(s)
- Qian Li
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Mengqing Sun
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Yao Meng
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Mengqing Feng
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Menglan Wang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Cunjie Chang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Heng Dong
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Fangtian Bu
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Chao Xu
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Jing Liu
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Qi Ling
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, P. R. China.
| | - Yiting Qiao
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China.
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, P. R. China.
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, 250000, P. R. China.
| | - Jianxiang Chen
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China.
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China.
- Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Centre, Singapore, 169610, Singapore.
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15
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Shi T, Yuan Z, He Y, Zhang D, Chen S, Wang X, Yao L, Shao J, Wang X. Competition between p53 and YY1 determines PHGDH expression and malignancy in bladder cancer. Cell Oncol (Dordr) 2023; 46:1457-1472. [PMID: 37326803 DOI: 10.1007/s13402-023-00823-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/02/2023] [Indexed: 06/17/2023] Open
Abstract
PURPOSE Serine metabolism is frequently dysregulated in many types of cancers and the tumor suppressor p53 is recently emerging as a key regulator of serine metabolism. However, the detailed mechanism remains unknown. Here, we investigate the role and underlying mechanisms of how p53 regulates the serine synthesis pathway (SSP) in bladder cancer (BLCA). METHODS Two BLCA cell lines RT-4 (WT p53) and RT-112 (p53 R248Q) were manipulated by applying CRISPR/Cas9 to examine metabolic differences under WT and mutant p53 status. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and non-targeted metabolomics analysis were adopted to identify metabolomes changes between WT and p53 mutant BLCA cells. Bioinformatics analysis using the cancer genome atlas and Gene Expression Omnibus datasets and immunohistochemistry (IHC) staining was used to investigate PHGDH expression. Loss-of-function of PHGDH and subcutaneous xenograft model was adopted to investigate the function of PHGDH in mice BLCA. Chromatin immunoprecipitation (Ch-IP) assay was performed to analyze the relationships between YY1, p53, SIRT1 and PHGDH expression. RESULTS SSP is one of the most prominent dysregulated metabolic pathways by comparing the metabolomes changes between wild-type (WT) p53 and mutant p53 of BLCA cells. TP53 gene mutation shows a positive correlation with PHGDH expression in TCGA-BLCA database. PHGDH depletion disturbs the reactive oxygen species homeostasis and attenuates the xenograft growth in the mouse model. Further, we demonstrate WT p53 inhibits PHGDH expression by recruiting SIRT1 to the PHGDH promoter. Interestingly, the DNA binding motifs of YY1 and p53 in the PHGDH promoter are partially overlapped which causes competition between the two transcription factors. This competitive regulation of PHGDH is functionally linked to the xenograft growth in mice. CONCLUSION YY1 drives PHGDH expression in the context of mutant p53 and promotes bladder tumorigenesis, which preliminarily explains the relationship between high-frequency mutations of p53 and dysfunctional serine metabolism in bladder cancer.
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Affiliation(s)
- Tiezhu Shi
- Precise Genome Engineering Centre, School of Life Sciences, Guangzhou University, 510006, Guangzhou, China
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, 200080, Shanghai, China
| | - Zhihao Yuan
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, 200080, Shanghai, China
| | - Yanying He
- Precise Genome Engineering Centre, School of Life Sciences, Guangzhou University, 510006, Guangzhou, China
| | - Dongliang Zhang
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, 200080, Shanghai, China
| | - Siteng Chen
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, 200080, Shanghai, China
| | - Xiongjun Wang
- Precise Genome Engineering Centre, School of Life Sciences, Guangzhou University, 510006, Guangzhou, China
| | - Linli Yao
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, 200080, Shanghai, China.
| | - Jialiang Shao
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, 200080, Shanghai, China.
| | - Xiang Wang
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, 200080, Shanghai, China.
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16
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Shunxi W, Xiaoxue Y, Guanbin S, Li Y, Junyu J, Wanqian L. Serine Metabolic Reprogramming in Tumorigenesis, Tumor Immunity, and Clinical Treatment. Adv Nutr 2023; 14:1050-1066. [PMID: 37187454 PMCID: PMC10509429 DOI: 10.1016/j.advnut.2023.05.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 05/04/2023] [Accepted: 05/11/2023] [Indexed: 05/17/2023] Open
Abstract
Serine has been recently identified as an essential metabolite for oncogenesis, progression, and adaptive immunity. Influenced by many physiologic or tumor environmental factors, the metabolic pathways of serine synthesis, uptake, and usage are heterogeneously reprogrammed and frequently amplified in tumor or tumor-associated cells. The hyperactivation of serine metabolism promotes abnormal cellular nucleotide/protein/lipid synthesis, mitochondrial function, and epigenetic modifications, which drive malignant transformation, unlimited proliferation, metastasis, immunosuppression, and drug resistance of tumor cells. Dietary restriction of serine or phosphoglycerate dehydrogenase depletion mitigates tumor growth and extends the survival of tumor patients. Correspondingly, these findings triggered a boom in the development of novel therapeutic agents targeting serine metabolism. In this study, recent discoveries in the underlying mechanism and cellular function of serine metabolic reprogramming are summarized. The vital role of serine metabolism in oncogenesis, tumor stemness, tumor immunity, and therapeutic resistance is outlined. Finally, some potential tumor therapeutic concepts, strategies, and limitations of targeting the serine metabolic pathway are described in detail. Taken together, this review underscores the importance of serine metabolic reprogramming in tumorigenesis and progression and highlights new opportunities for dietary restriction or selective pharmacologic intervention.
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Affiliation(s)
- Wang Shunxi
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China
| | - Yuan Xiaoxue
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China
| | - Song Guanbin
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China
| | - Yang Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China
| | - Jin Junyu
- Department of Oncology, Chenjiaqiao Hospital, Shapingba, Chongqing, China.
| | - Liu Wanqian
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China.
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17
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Tabassum G, Singh P, Gurung R, Hakami MA, Alkhorayef N, Alsaiari AA, Alqahtani LS, Hasan MR, Rashid S, Kumar A, Dev K, Dohare R. Investigating the role of Kinesin family in lung adenocarcinoma via integrated bioinformatics approach. Sci Rep 2023; 13:9859. [PMID: 37330525 PMCID: PMC10276827 DOI: 10.1038/s41598-023-36842-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 06/11/2023] [Indexed: 06/19/2023] Open
Abstract
Lung cancer is the leading cause of mortality from cancer worldwide. Lung adenocarcinoma (LUAD) is a type of non-small cell lung cancer (NSCLC) with highest prevalence. Kinesins a class of motor proteins are shown to be involved in carcinogenesis. We conducted expression, stage plot and survival analyses on kinesin superfamily (KIF) and scrutinized the key prognostic kinesins. Genomic alterations of these kinesins were studied thereafter via cBioPortal. A protein-protein interaction network (PPIN) of selected kinesins and 50 closest altering genes was constructed followed by gene ontology (GO) term and pathway enrichment analyses. Multivariate survival analysis based on CpG methylation of selected kinesins was performed. Lastly, we conducted tumor immune infiltration analysis. Our results found KIF11/15/18B/20A/2C/4A/C1 to be significantly upregulated and correlated with poor survival in LUAD patients. These genes also showed to be highly associated with cell cycle. Out of our seven selected kinesins, KIFC1 showed the highest genomic alteration with highest number of CpG methylation. Also, CpG island (CGI) cg24827036 was discovered to be linked to LUAD prognosis. Therefore, we deduced that reducing the expression of KIFC1 could be a feasible treatment strategy and that it can be a wonderful individual prognostic biomarker. CGI cg24827036 can also be used as a therapy site in addition to being a great prognostic biomarker.
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Affiliation(s)
- Gulnaz Tabassum
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Prithvi Singh
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Rishabh Gurung
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Mohammed Ageeli Hakami
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Al- Quwayiyah, Shaqra University, Riyadh, 13343, Saudi Arabia
| | - Nada Alkhorayef
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Al- Quwayiyah, Shaqra University, Riyadh, 13343, Saudi Arabia
| | - Ahad Amer Alsaiari
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, 21944, Saudi Arabia
| | - Leena S Alqahtani
- Department of Biochemistry, College of Science, University of Jeddah, Jeddah, 23445, Saudi Arabia
| | - Mohammad Raghibul Hasan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Al- Quwayiyah, Shaqra University, Riyadh, 13343, Saudi Arabia
| | - Summya Rashid
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, 16278, Saudi Arabia
| | - Atul Kumar
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Kapil Dev
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi, 110025, India.
| | - Ravins Dohare
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India.
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Huang J, Sun X, Diao G, Li R, Guo J, Han J. KIF15 knockdown inhibits the development of endometrial cancer by suppressing epithelial-mesenchymal transition and stemness through Wnt/β-catenin signaling. ENVIRONMENTAL TOXICOLOGY 2023. [PMID: 37186152 DOI: 10.1002/tox.23809] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/21/2023] [Accepted: 04/16/2023] [Indexed: 05/17/2023]
Abstract
Endometrial cancer (EC) is one of the most common cancers among women, while the incidence of EC is rising. Many studies have found that Kinesin family member 15 (KIF15) is highly expressed in a series of cancers, but the role of KIF15 in EC is unclear. We detected the expression level of KIF15 in a microarray of EC tissues by immunohistochemical staining (IHC), and analyzed the correlation between the expression level of KIF15 and the pathological characteristics of patients. After inhibit the expression of KIF15 in EC cells with lentivirus, cell proliferation and apoptosis were detected respectively by CCK8 assay, flow cytometry and tunnel assay. Transwell assay and wound healing assay were used to examine the migration ability and invasion ability of EC cells. Spheroid formation assay was used to evaluate cell self-renewal ability. In vivo tumor xenograft model was used for validation. The expressions of epithelial-mesenchymal transition, cancer stem cells, and Wnt/β-catenin signaling molecules were detected by Western blotting. The results showed that the expression of KIF15 in EC tissues was higher than that in normal endometrial tissues, while the expression level of KIF15 in EC was positively correlated with the pathological grade of the tumor. The down-regulation of KIF15 reduced the proliferation, colony formation, invasion, migration and self-renewal ability of EC cells, while promoted cell apoptosis. Knockdown of KIF15 inactivates the Wnt/β-catenin signaling of EC cells, inhibitors of Wnt signaling can counteract the enhanced self-renewal ability caused by KIF15 overexpression. Therefore, KIF15 may be a new potential target for diagnosis and treatment of EC.
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Affiliation(s)
- Jie Huang
- Department of Obstetrics and Gynecology, Daping Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Xinwei Sun
- Department of Obstetrics and Gynecology, Daping Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Ge Diao
- Department of Obstetrics and Gynecology, Daping Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Runbo Li
- Department of Obstetrics and Gynecology, Daping Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Jianxin Guo
- Department of Obstetrics and Gynecology, Daping Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Jian Han
- Department of Obstetrics and Gynecology, Daping Hospital, Army Medical University, Chongqing, People's Republic of China
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Xu H, Liu J, Zhang Y, Zhou Y, Zhang L, Kang J, Ning C, He Z, Song S. KIF23, under regulation by androgen receptor, contributes to nasopharyngeal carcinoma deterioration by activating the Wnt/β-catenin signaling pathway. Funct Integr Genomics 2023; 23:116. [PMID: 37010644 DOI: 10.1007/s10142-023-01044-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/22/2023] [Accepted: 03/27/2023] [Indexed: 04/04/2023]
Abstract
Our study aimed to explore the potential mechanisms of KIF23 regulating function in the progression of nasopharyngeal carcinoma and pinpoint novel therapeutic targets for the clinical treatment of nasopharyngeal carcinoma patients. Firstly, the mRNA and protein level of KIF23 in nasopharyngeal carcinoma was measured using quantitative real-time PCR and western blot. Then, the influence of KIF23 on tumor metastasis and growth in nasopharyngeal carcinoma was determined through the in vivo and in vitro experiments. Lastly, the regulatory mechanisms of KIF23 in nasopharyngeal carcinoma were illustrated in the chromatin immunoprecipitation assay. KIF23 was first found to be overexpressed in nasopharyngeal carcinoma samples, and its expression was associated with poor prognosis. Then, the nasopharyngeal carcinoma cell's proliferation, migration, and invasion potential could be improved by inducing KIF23 expression both in vivo and in vitro. Furthermore, androgen receptor (AR) was found to bind to the KIF23 promoter region directly and enhance KIF23 transcription. At last, KIF23 could accelerate nasopharyngeal carcinoma deterioration via activating the Wnt/β-catenin signaling pathway. AR/KIF23/Wnt/β-catenin pathway promotes nasopharyngeal carcinoma deterioration. Our findings could serve as a new therapeutic strategy for nasopharyngeal carcinoma in the clinical practice.
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Affiliation(s)
- Hongbo Xu
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
- Anhui Province Key Laboratory of Translational Cancer Research Affiliated to Bengbu Medical College, Bengbu, Anhui, China
| | - Jingjing Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Yajun Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Yan Zhou
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Lei Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Jia Kang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Can Ning
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Zelai He
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China.
- Anhui Province Key Laboratory of Translational Cancer Research Affiliated to Bengbu Medical College, Bengbu, Anhui, China.
| | - Shilong Song
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China.
- Anhui Province Key Laboratory of Translational Cancer Research Affiliated to Bengbu Medical College, Bengbu, Anhui, China.
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Lu S, Liu Y, Tian S, He Y, Dong W. KIFC3 regulates progression of hepatocellular carcinoma via EMT and the AKT/mTOR pathway. Exp Cell Res 2023; 426:113564. [PMID: 36948354 DOI: 10.1016/j.yexcr.2023.113564] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 03/17/2023] [Accepted: 03/18/2023] [Indexed: 03/24/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. Despite an overall downward trend in cancer mortality, HCC-related mortality continues to increase. KIFC3 is involved in cell division and cancers. However, the role of KIFC3 in HCC has yet to be elucidated. METHODS A total of 36 cases of HCC tissues, 4 HCC cell lines, and TCGA databases were searched to explore the expression of KIFC3 in HCC. Subsequently, Western blot analysis, immunofluorescence, bioinformatic analysis, molecular docking, and Co-IP were performed to investigate the molecular mechanisms of KIFC3 in HCC. RESULT We found that the expression of KIFC3 was upregulated in HCC, and high KIFC3 expression was related to poor overall survival. In addition, the knockdown of KIFC3 inhibited the proliferation, migration, and invasion of HCC cells in vitro, and impeded the growth of HCC in vivo, while overexpression of KIFC3 in HCC cells revealed the opposite effect. Mechanistically, KIFC3 promotes the progression of HCC through the PI3K/AKT/mTOR signalling. And KIFC3 had slight effect on the protein expression of p-PI3K, p-AKT and p-mTOR in TRIP13-ablated or LY294002-treated HCC cells. The KIFC3 knockdown could further enhance the inhibitory effect of LY294002. CONCLUSION Our data revealed that KIFC3 is upregulated in HCC and may serve as a novel biomarker for predicting survival in HCC patients. Targeting KIFC3 may serve as a novel therapeutic strategy for HCC patients.
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Affiliation(s)
- Shimin Lu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan 430060, Hubei Province, China
| | - Yinghui Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan 430060, Hubei Province, China
| | - Shan Tian
- Department of Infectious Disease, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang He
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan 430060, Hubei Province, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan 430060, Hubei Province, China.
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Wang Y, Li ZX, Wang JG, Li LH, Shen WL, Dang XW. Deubiquitinating enzyme Josephin-2 stabilizes PHGDH to promote a cancer stem cell phenotype in hepatocellular carcinoma. Genes Genomics 2023; 45:215-224. [PMID: 36583817 DOI: 10.1007/s13258-022-01356-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 12/16/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND Deubiquitinating enzymes (DUBs) have been shown to be possible targets for hepatocellular carcinoma (HCC) treatment. OBJECTIVE This study was designed to reveal the effect and underlying mechanism of Josephin-2, a relatively newly defined DUB, in HCC progression. METHODS SNU-387 and PLC/PRF/5 cells were used for in vitro functional assays. The levels of Josephin-2 and phosphoglycerate dehydrogenase (PHGDH) were determined using RT-qPCR and western blotting. Cell proliferation, migration and invasion were assessed by CCK-8, colony formation and Transwell. Spheroid-forming assay was performed to assess the cancer stem cell (CSC)-phenotype of HCC cells. A xenograft mice model was applied to verify the effect of Josephin-2 on HCC cell growth in vivo. RESULTS Herein, we showed that Josephin-2 expression was negatively correlated with HCC patient survival in data from the online database. Cell experiments indicated that knockdown of Josephin-2 attenuated HCC cell malignant biological behaviors. Besides, Josephin-2 silencing also decreased the spheroid-formation while inhibited the expression of CSC biomarkers (CD133, OCT4, SOX2 and EpCAM) in HCC cells. Mechanistically, Josephin-2 had a deubiquitinating activity towards the regulation of PHGDH protein, the rate-limiting enzyme in the first step of serine biosynthesis pathway. Depletion of Josephin-2 enhanced the ubiquitination degradation of PHGDH and ultimately inhibited the proliferation and CSC-phenotype of HCC in vitro and in vivo. CONCLUSION Our work uncovered the regulatory effects of Josephin-2 on PHGDH protein stability and profiled its contribution in HCC malignant progression, which might provide a potential therapeutic target for HCC.
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Affiliation(s)
- Ying Wang
- The First Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, Henan Province, China.,Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province, China
| | - Ze-Xin Li
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province, China
| | - Jian-Guo Wang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province, China
| | - Lu-Hao Li
- The First Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, Henan Province, China
| | - Wen-Long Shen
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province, China
| | - Xiao-Wei Dang
- The First Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, Henan Province, China.
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Zhang H, Li C, Liao S, Tu Y, Sun S, Yao F, Li Z, Wang Z. PSMD12 promotes the activation of the MEK-ERK pathway by upregulating KIF15 to promote the malignant progression of liver cancer. Cancer Biol Ther 2022; 23:1-11. [PMID: 36137220 PMCID: PMC9519003 DOI: 10.1080/15384047.2022.2125260] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The tumor recurrence and drug resistance of hepatocellular carcinoma (HCC) threatened patients a lot. The mechanism should be further explored. The information of expression status and survival were available in public databases. The Western blot and immunohistochemistry staining displayed the level of related proteins. CCK-8, colony-formation assays, transwell assay and wound healing assay were performed to illustrate the ability of tumor growth, invasion and migration. In vivo model was established to verify our cell experiments. In our study, we revealed that proteasome 26S subunit, non-ATPase 12 (PSMD12) was high expressed in HCC tissues and positive related to the survival. In vitro experiments suggested that PSMD12 knockdown attenuated tumor cell growth, invasion and migration. Moreover, PSMD12 interference blocked the activation of MEK-ERK pathway. The ERK inhibitor could alleviate the tumor-promoting effect in PSMD12-overexpression cells. In addition, kinesin family member 15 (KIF15) was also observed to be highly expressed in HCC and be harmful to the survival. The public database, the images of immunohistochemistry and the western blot illustrated that PSMD12 and KIF15 was positive correlated. KIF15 knockdown impaired tumor progression and tumor-promoting effect of PSMD12. The xenograft models supported the results of cell experiments. In conclusion, PSMD12 could activated MEK-ERK pathway via KIF15 upregulation, thereby promoting tumor progression.
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Affiliation(s)
- Hanpu Zhang
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China.,Department of Colorectal Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chenyuan Li
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
| | - Shichong Liao
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
| | - Yi Tu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
| | - Shengrong Sun
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
| | - Feng Yao
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
| | - Zhiyu Li
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
| | - Zhong Wang
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, P. R. China
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Ishaq Y, Ikram A, Alzahrani B, Khurshid S. The Role of miRNAs, circRNAs and Their Interactions in Development and Progression of Hepatocellular Carcinoma: An Insilico Approach. Genes (Basel) 2022; 14:genes14010013. [PMID: 36672755 PMCID: PMC9858589 DOI: 10.3390/genes14010013] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/06/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of malignant tumor. miRNAs are noncoding RNAs and their differential expression patterns are observed in HCC-induced by alcoholism, HBV and HCV infections. By acting as a competing endogenous RNA (ceRNA), circRNA regulates the miRNA function, indirectly controlling the gene expression and leading to HCC progression. In the present study, data mining was performed to screen out all miRNAs and circRNA involved in alcohol, HBV or HCV-induced HCC with statistically significant (≤0.05%) expression levels reported in various studies. Further, the interaction of miRNAs and circRNA was also investigated to explore their role in HCC due to various causative agents. Together, these study data provide a deeper understanding of the circRNA-miRNA regulatory mechanisms in HCC. These screened circRNA, miRNA and their interactions can be used as prognostic biomarkers or therapeutic targets for the treatment of HCC.
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Affiliation(s)
- Yasmeen Ishaq
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
| | - Aqsa Ikram
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
- Correspondence:
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, Jouf University, Sakaka 42421, Saudi Arabia
| | - Sana Khurshid
- Department of Molecular Biology, Virtual University of Pakistan, 1-Davis Road, Lahore 54000, Pakistan
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Li Z, Yang HY, Zhang XL, Zhang X, Huang YZ, Dai XY, Shi L, Zhou GR, Wei JF, Ding Q. Kinesin family member 23, regulated by FOXM1, promotes triple negative breast cancer progression via activating Wnt/β-catenin pathway. J Exp Clin Cancer Res 2022; 41:168. [PMID: 35524313 PMCID: PMC9077852 DOI: 10.1186/s13046-022-02373-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Background Triple negative breast cancer (TNBC) is highly malignant and has a worse prognosis, compared with other subtypes of breast cancer due to the absence of therapeutic targets. KIF23 plays a crucial role in the tumorigenesis and cancer progression. However, the role of KIF23 in development of TNBC and the underlying mechanism remain unknown. The study aimed to elucidate the biological function and regulatory mechanism of KIF23 in TNBC. Methods Quantitative real-time PCR and Western blot were used to determine the KIF23 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of KIF23 on tumor growth and metastasis in TNBC. Chromatin immunoprecipitation assay was conducted to illustrate the potential regulatory mechanisms of KIF23 in TNBC. Results We found that KIF23 was significantly up-regulated and associated with poor prognosis in TNBC. KIF23 could promote TNBC proliferation, migration and invasion in vitro and in vivo. KIF23 could activate Wnt/β-catenin pathway and promote EMT progression in TNBC. In addition, FOXM1, upregulated by WDR5 via H3K4me3 modification, directly bound to the promoter of KIF23 gene to promote its transcription and accelerated TNBC progression via Wnt/β-catenin pathway. Both of small inhibitor of FOXM1 and WDR5 could inhibit TNBC progression. Conclusions Our findings elucidate WDR5/FOXM1/KIF23/Wnt/β-catenin axis is associated with TNBC progression and may provide a novel and promising therapeutic target for TNBC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02373-7.
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Identification of Prognostic Markers and Potential Therapeutic Targets in Gastric Adenocarcinoma by Machine Learning Based on mRNAsi Index. JOURNAL OF ONCOLOGY 2022; 2022:8926127. [PMID: 36213825 PMCID: PMC9546691 DOI: 10.1155/2022/8926127] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/11/2022] [Accepted: 09/14/2022] [Indexed: 11/23/2022]
Abstract
Background Cancer stem cells (CSCs), characterized by self-renewal and therapeutic resistance, play important roles in stomach adenocarcinoma (STAD). However, the molecular mechanism of STAD stem cells is still unclear. In this study, our purpose is to explore the expression of stem cell-related genes in STAD. Methods The stemness index based on mRNA expression (mRNAsi) was used to analyze STAD cases in The Cancer Genome Atlas (TCGA). Firstly, mRNAsi was used and analyzed by differential expression, survival analysis, clinical stage, and gender in STAD. Then, weighted gene coexpression network analysis (WGCNA) was used to discover the fascinating modules and key genes. Enrichment analysis was carried out to annotate the functions and pathways of key genes. The gene expression comprehensive database (GEO) in STAD was used to verify the expression levels of key genes in all cancers. Protein-protein interaction networks is used to determine the relationships between key genes. Results The mRNAsi was obviously upregulated in tumor cases. With the increase of tumor stage and T stage, the mRNAsi score decreased, and the overall survival rate of high score group patients was better. According to the degree of association with mRNAsi, different modules and key genes were screened out. A total of 6,740 differential genes were found, of which 1,147 genes were downregulated and 5,593 genes were upregulated. 19 key genes (BUB1, BUB1B, KIF14, NCAPH, RACGAP, KIF15, CENPF, TPX2, RAD54L, KIF18B, KIF4A, TTK, SGO2, PLK4, ARHGAP11A, XRCC2, Clorf112, NCAPG, and ORC6) were screened due to significant upregulation in STAD. And they had been proven that enriched from the cell cycle Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, relating to cell proliferation Gene Ontology (GO) terms, as well. Among them, 9 genes have been extensively associated to OS, and 3 genes had been associated to receive chemotherapy resistance. PPI protein network suggests that there is a sturdy correlation between these key genes. Conclusion A total of 19 key genes were found to play an essential position in retaining the traits of STAD stem cells. These genes can be used to evaluate the prognosis of STAD patients or become specific therapeutic targets.
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Zhang X, Sun M, Jiao Y, Lin B, Yang Q. PHGDH Inhibitor CBR-5884 Inhibits Epithelial Ovarian Cancer Progression via ROS/Wnt/ β-Catenin Pathway and Plays a Synergistic Role with PARP Inhibitor Olaparib. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9029544. [PMID: 36105480 PMCID: PMC9467758 DOI: 10.1155/2022/9029544] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 08/09/2022] [Accepted: 08/16/2022] [Indexed: 11/18/2022]
Abstract
PHGDH attaches importance to serine biosynthesis in cancer cells and maintaining mitochondrial redox homeostasis. However, the role of PHGDH inhibitor CBR-5884 in cell ROS level and its downstream pathways has not been explored in epithelial ovarian cancer. Thus, we investigated the function and possible mechanism of PHGDH inhibitor CBR-5884 on epithelial ovarian cancer in vitro and in vivo. A2780, OVCAR3, and ES-2 were treated with CBR-5884 at different concentrations or different time points. Results showed that CBR-5884 inhibited epithelial ovarian cancer cell proliferation, migration, and invasion and increases cell ROS level. Meanwhile, CBR-5884 exerts antitumor effect through activating ROS/Wnt/β-catenin pathway. Besides, CBR-5884 exerts antitumor effect in vivo. What's more, we explored the effect of CBR-5884 with or without PARP inhibitor Olaparib, which showed that the two together had a larger effect. In conclusion, PHGDH inhibitor CBR-5884 inhibits epithelial ovarian cancer proliferation, migration, and invasion through activating ROS/Wnt/β-catenin pathway and plays a synergistic role with PARP inhibitor olaparib, which provided a theoretical basis for PHGDH inhibitor CBR-5884 in clinical treatment.
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Affiliation(s)
- Xiaocui Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Meige Sun
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Yisheng Jiao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Bei Lin
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Qing Yang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
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Yin Y, Xu ZY, Liu YJ, Huang W, Zhang Q, Li JP, Zou X. Identification and Validation in a Novel Classification of Helicase Patterns for the Prediction of Tumor Proliferation and Prognosis. J Hepatocell Carcinoma 2022; 9:885-900. [PMID: 36061235 PMCID: PMC9432388 DOI: 10.2147/jhc.s378175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/10/2022] [Indexed: 11/23/2022] Open
Abstract
Background Helicases have been classified as a class of enzymes that determine the stability of the cellular genome. There is growing evidence that helicases can help tumor cells resist drug killing by repairing Deoxyribose Nucleic Acid (DNA) or stabilizing transcription, which may contribute to the understanding of drug resistance. Currently, identifying cancer biomarkers among helicases and stratifying patients according to helicase activity will be able to guide treatment well. Methods We clustered 371 hepatocellular carcinoma (HCC) patients from The Cancer Genome Atlas (TCGA) by consensus clustering based on helicase expression profiles to identify potential molecular subtypes. The Multiscale Embedded Gene Co-Expression Network Analysis (MEGENA) algorithm was used to find core differential gene modules between different molecular subtypes, and single-cell analysis was utlized to explore the potential function of hub gene. Immunohistochemical (IHC) staining was used to verify the diagnostic value of DDX56 and its ability to reflect the proliferation efficiency of cancer cells. Results We identified two subtypes associated with helicase. High helicase subtype was associated with poor clinical outcome, massive M0 macrophage infiltration, and highly active cell proliferation features. In addition, we identified a new biomarker, DDX56, which has not been reported in HCC, was highly expressed in HCC tissues, associated with poor prognosis, and was also shown to be associated with high cell proliferative activity. Conclusion In conclusion, based on helicase expression profiles, we have developed a new classification system for HCC, which is a proliferation-related system, and has clinical significance in evaluating prognosis and treating HCC patients, including immunotherapy and chemotherapy. In addition, we identified a new biomarker, DDX 56, which is overexpressed in HCC tissues, predicts a poor prognosis and is a validated index of tumor cell proliferation.
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Affiliation(s)
- Yi Yin
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China
| | - Zi-Yuan Xu
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China
| | - Yuan-jie Liu
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China
| | - Wei Huang
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China
| | - Qian Zhang
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China
| | - Jie-pin Li
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China
- Department of Oncology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, People’s Republic of China
| | - Xi Zou
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, Jiangsu, 210029, People’s Republic of China
- Correspondence: Xi Zou; Jie-pin Li, Email ;
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Tumor-Promoting ATAD2 and Its Preclinical Challenges. Biomolecules 2022; 12:biom12081040. [PMID: 36008934 PMCID: PMC9405547 DOI: 10.3390/biom12081040] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 02/06/2023] Open
Abstract
ATAD2 has received extensive attention in recent years as one prospective oncogene with tumor-promoting features in many malignancies. ATAD2 is a highly conserved bromodomain family protein that exerts its biological functions by mainly AAA ATPase and bromodomain. ATAD2 acts as an epigenetic decoder and transcription factor or co-activator, which is engaged in cellular activities, such as transcriptional regulation, DNA replication, and protein modification. ATAD2 has been reported to be highly expressed in a variety of human malignancies, including gastrointestinal malignancies, reproductive malignancies, urological malignancies, lung cancer, and other types of malignancies. ATAD2 is involved in the activation of multiple oncogenic signaling pathways and is closely associated with tumorigenesis, progression, chemoresistance, and poor prognosis, but the oncogenic mechanisms vary in different cancer types. Moreover, the direct targeting of ATAD2’s bromodomain may be a very challenging task. In this review, we summarized the role of ATAD2 in various types of malignancies and pointed out the pharmacological direction.
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Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
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Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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Zheng S, Tang D, Wang X, Liu C, Zuo N, Yan R, Wu C, Ma J, Wang C, Xu H, He Y, Liu D, Liu S. Kif15 Is Required in the Development of Auditory System Using Zebrafish as a Model. Front Mol Neurosci 2022; 15:844568. [PMID: 35370541 PMCID: PMC8971910 DOI: 10.3389/fnmol.2022.844568] [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: 12/28/2021] [Accepted: 02/21/2022] [Indexed: 11/30/2022] Open
Abstract
Kif15, a kinesin family member, is powerful in the formation of bipolar spindles. There is emerging evidence indicating that Kif15 plays vital roles in influencing the growth of axons and interference with the progression of the tumor. However, the function of Kif15 in the auditory organs remains unknown. The Western blotting test was used to examine the effect of Kif15 downregulation by specific morpholino targeting Kif15 (Kif15-MO). The development of the inner ear and posterior lateral line (PLL) system in zebrafish was under continuous observation from spawns to 96 h postfertilization (hpf) to investigate the potential role of Kif15 in the auditory and vestibular system. We uncovered that Kif15 inhibition induced otic organ deformities in zebrafish, including malformed semicircular canals, abnormal number and location of otoliths, and reduced number of hair cells (HCs) both in utricle and saccule. Furthermore, a remarkable reduction in the number of PLL neuromasts was also explored in Kif15-MO morphants compared to the normal larvae. We also detected notably reduced activity in locomotion after Kif15 was knocked down. Additionally, we performed rescue experiments with co-injection of Kif15 mRNA and found that the Kif15 splicing MO-induced deformities in otic vesicle and PLL of zebrafish were successfully rescued, and the severely reduced locomotor activity caused by Kif15-MO was partially rescued compared to the control-MO (Con-MO) embryos. Our findings uncover that Kif15 is essential in the early development of auditory and vestibular organs using zebrafish as models.
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Affiliation(s)
- Shimei Zheng
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Dongmei Tang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
- NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China
| | - Xin Wang
- Nantong Laboratory of Development and Diseases, School of Life Sciences, Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and MOE, Nantong University, Nantong, China
| | - Chang Liu
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
- NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China
| | - Na Zuo
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Renchun Yan
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Cheng Wu
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Jun Ma
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Chuanxi Wang
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Hongfei Xu
- Department of Forensic Medicine, Soochow University, Suzhou, China
| | - Yingzi He
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
- NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China
- *Correspondence: Yingzi He,
| | - Dong Liu
- Nantong Laboratory of Development and Diseases, School of Life Sciences, Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and MOE, Nantong University, Nantong, China
- Dong Liu, ,
| | - Shaofeng Liu
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, China
- Shaofeng Liu,
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Mi J, Ma S, Chen W, Kang M, Xu M, Liu C, Li B, Wu F, Liu F, Zhang Y, Wang R, Jiang L. Integrative Pan-Cancer Analysis of KIF15 Reveals Its Diagnosis and Prognosis Value in Nasopharyngeal Carcinoma. Front Oncol 2022; 12:772816. [PMID: 35359374 PMCID: PMC8963360 DOI: 10.3389/fonc.2022.772816] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 02/18/2022] [Indexed: 12/19/2022] Open
Abstract
BackgroundKIF15 plays a vital role in many biological processes and has been reported to influence the occurrence and development of certain human cancers. However, there are few systematic evaluations on the role of KIF15 in human cancers, and the role of KIF15 in the diagnosis and prognosis of nasopharyngeal carcinoma (NPC) also remains unexplored. Therefore, this study aimed to conduct a pan-cancer analysis of KIF15 and evaluate its diagnostic and prognostic potential in NPC.MethodsThe expression pattern, prognostic value, molecular function, tumor mutation burden, microsatellite instability, and immune cell infiltration of KIF15 were examined based on public databases. Next, the diagnostic value of KIF15 in NPC was analyzed using the Gene Expression Omnibus (GEO) database and immunohistochemistry (IHC). Kaplan–Meier curves, Cox regression analyses, and nomograms were used to evaluate the effects of KIF15 expression on NPC prognosis. Finally, the effect of KIF15 on NPC was explored by in vitro experiments.ResultsThe expression of KIF15 was significantly upregulated in 20 out of 33 cancer types compared to adjacent normal tissue. Kyoto Encyclopedia of Genes and Genomes enrichment (KEGG) analysis showed that KIF15 could participate in several cancer-related pathways. The increased expression level of KIF15 was correlated with worse clinical outcomes in many types of human cancers. Additionally, KIF15 expression was related to cancer infiltration of immune cells, tumor mutation burden, and microsatellite instability. In the analysis of NPC, KIF15 was significantly upregulated based on the GEO database and immunohistochemistry. A high expression of KIF15 was negatively associated with the prognosis of patients with NPC. A nomogram model integrating clinical characteristics and KIF15 expression was established, and it showed good predictive ability with an area under the curve value of 0.73. KIF15 knockdown significantly inhibited NPC cell proliferation and migration.ConclusionsOur findings revealed the important and functional role of KIF15 as an oncogene in pan-cancer. Moreover, high expression of KIF15 was found in NPC tissues, and was correlated with poor prognosis in NPC. KIF15 may serve as a potential therapeutic target in NPC treatment.
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Affiliation(s)
- Jinglin Mi
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shanshan Ma
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Wei Chen
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Oncology, Yunfu People’s Hospital, Yunfu, China
| | - Min Kang
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Meng Xu
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Chang Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Bo Li
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Fang Wu
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Fengju Liu
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yong Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Rensheng Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
- *Correspondence: Li Jiang, ; Rensheng Wang,
| | - Li Jiang
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- *Correspondence: Li Jiang, ; Rensheng Wang,
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Li D, Yu T, Han J, Xu X, Wu J, Song W, Liu G, Zhu H, Zeng Z. Prognostic Value and Immunological Role of KIFC1 in Hepatocellular Carcinoma. Front Mol Biosci 2022; 8:799651. [PMID: 35111813 PMCID: PMC8802309 DOI: 10.3389/fmolb.2021.799651] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/06/2021] [Indexed: 12/16/2022] Open
Abstract
As one of the members of the kinesin family, the role and potential mechanism of kinesin family member C1 (KIFC1) in the development of liver hepatocellular carcinoma (LIHC), especially in the immune infiltration, have not been fully elucidated. In this study, multiple databases and immunohistochemistry were employed to analyze the role and molecular mechanism including the immune infiltration of KIFC1 in LIHC. Generally, KIFC1 mRNA expression was overexpressed in LIHC tissues than normal tissues, and its protein was also highly expressed in the LIHC. KIFC1 mRNA expression was correlated with tumor grade and TNM staging, which was negatively correlated with overall survival and disease-free survival. Moreover, univariable and multivariate Cox analysis revealed that upregulated KIFC1 mRNA is an independent prognostic factor for LIHC. The KIFC1 promoter methylation level was negatively associated with KIFC1 mRNA expression and advanced stages and grade in LIHC. The different methylation sites of KIFC1 had a different effect on the prognosis of LIHC. Specifically, the KIFC1 mRNA expression level showed intense correlation with tumor immunity, such as tumor-infiltrating immune cells and immune scores as well as multiple immune-related genes. Moreover, KIFC1 co-expressed with some immune checkpoints and related to the responses to immune checkpoint blockade (ICB) and chemotherapies. Significant GO analysis showed that genes correlated with KIFC1 served as catalytic activity, acting on DNA, tubulin binding, histone binding, ATPase activity, and protein serine/threonine kinase activity. KEGG pathway analysis showed that these genes related to KIFC1 are mainly enriched in signal pathways such as cell cycle, spliceosome, pyrimidine metabolism, and RNA transport. Conclusively, KIFC1 was upregulated and displayed a prognostic value in LIHC. Moreover, KIFC1 may be involved in the LIHC progression partially through immune evasion and serve as a predictor of ICB therapies and chemotherapies.
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Affiliation(s)
- Dan Li
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Tao Yu
- Department of Oncology, Integrated Traditional Chinese and Western Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingjing Han
- Department of Infection Control, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xu Xu
- Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jie Wu
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Song
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Gang Liu
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hua Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Hua Zhu, ; Zhi Zeng,
| | - Zhi Zeng
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Hua Zhu, ; Zhi Zeng,
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Malla RR, Marni R, Chakraborty A. ROS-mediated pathways: potential role in hepatocellular carcinoma biology and therapy. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA, VOLUME 2 2022:321-335. [DOI: 10.1016/b978-0-323-98807-0.00004-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abstract
Hepatocellular carcinoma (HCC) is a very deadly disease. HCC initiation and progression involve multiple genetic events, including the activation of proto-oncogenes and disruption of the function of specific tumor suppressor genes. Activation of oncogenes stimulates cell growth and survival, while loss-of-function mutations of tumor suppressor genes result in unrestrained cell growth. In this review, we summarize the new findings that identified novel proto-oncogenes and tumor suppressors in HCC over the past five years. These findings may inspire the development of novel therapeutic strategies to improve the outcome of HCC patients.
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Gao L, Zhao R, Liu J, Zhang W, Sun F, Yin Q, Wang X, Wang M, Feng T, Qin Y, Cai W, Li Q, Dong H, Chen X, Xiong X, Liu H, Hu J, Chen W, Han B. KIF15 Promotes Progression of Castration Resistant Prostate Cancer by Activating EGFR Signaling Pathway. Front Oncol 2021; 11:679173. [PMID: 34804913 PMCID: PMC8599584 DOI: 10.3389/fonc.2021.679173] [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: 03/11/2021] [Accepted: 10/18/2021] [Indexed: 11/29/2022] Open
Abstract
Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and its underlying mechanisms are still not fully understood. The epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling. EGFR signaling plays an important role in the transition from androgen dependence to castration-resistant state in prostate cancer (PCa). Kinesin family member 15 (KIF15) has been suggested to be overexpressed in multiple malignancies. Here, we demonstrate that KIF15 expression is elevated in CRPC. We show that KIF15 contributes to CRPC progression by enhancing the EGFR signaling pathway, which includes complex network intermediates such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. In CRPC tumors, increased expression of KIF15 is positively correlated with EGFR protein level. KIF15 binds to EGFR, and prevents EGFR proteins from degradation in a Cdc42-dependent manner. These findings highlight the key role of KIF15 in the development of CRPC and rationalize KIF15 as a potential therapeutic target.
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Affiliation(s)
- Lin Gao
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ru Zhao
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Junmei Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wenbo Zhang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Feifei Sun
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qianshuo Yin
- School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Xin Wang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Meng Wang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tingting Feng
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yiming Qin
- College of Chemical Engineering and Materials Science, Shandong Normal University, Jinan, China
| | - Wenjie Cai
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qianni Li
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Hanchen Dong
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xueqing Chen
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xueting Xiong
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Hui Liu
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jing Hu
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Weiwen Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bo Han
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Liu S, Zhang Y, Cui S, Song D, Li B, Chen Q, Yao G, Gong B. NAP1L1 interacts with hepatoma-derived growth factor to recruit c-Jun inducing breast cancer growth. Cancer Cell Int 2021; 21:605. [PMID: 34774047 PMCID: PMC8590370 DOI: 10.1186/s12935-021-02301-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 10/26/2021] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Breast cancer is a common cancer among women in the world. However, its pathogenesis is still to be determined. The role and molecular mechanism of Nucleosome Assembly Protein 1 Like 1 (NAP1L1) in breast cancer have not been reported. Elucidation of molecular mechanism might provide a novel therapeutic target for breast cancer treatment. METHODS A bioinformatics analysis was conducted to determine the differential expression of NAP1L1 in breast cancer and find the potential biomarker that interacts with NAP1L1 and hepatoma-derived growth factor (HDGF). The expression of NAP1L1 in tissues was detected by using immunohistochemistry. Breast cancer cells were transfected with the corresponding lentiviral particles and siRNA. The efficiency of transfection was measured by RT-qPCR and western blotting. Then, MTT, Edu, plate clone formation, and subcutaneous tumorigenesis in nude mice were used to detect the cell proliferation in breast cancer. Furthermore, coimmunoprecipitation (Co-IP) assay and confocal microscopy were performed to explore the detailed molecular mechanism of NAP1L1 in breast cancer. RESULTS In this study, NAP1L1 protein was upregulated based on the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Consistent with the prediction, immunohistochemistry staining showed that NAP1L1 protein expression was significantly increased in breast cancer tissues. Its elevated expression was an unfavorable factor for breast cancer clinical progression and poor prognosis. Stably or transiently knocking down NAP1L1 reduced the cell growth in vivo and in vitro via repressing the cell cycle signal in breast cancer. Furthermore, the molecular basis of NAP1L1-induced cell cycle signal was further studied. NAP1L1 interacted with the HDGF, an oncogenic factor for tumors, and the latter subsequently recruited the key oncogenic transcription factor c-Jun, which finally induced the expression of cell cycle promoter Cyclin D1(CCND1) and thus the cell growth of breast cancer. CONCLUSIONS Our data demonstrated that NAP1L1 functions as a potential oncogene via interacting with HDGF to recruit c-Jun in breast cancer.
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Affiliation(s)
- Shu Liu
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China. .,Guizhou Medical University, Guiyang, Guizhou, China.
| | - Yewei Zhang
- Guizhou Medical University, Guiyang, Guizhou, China
| | - Shien Cui
- Breast Center, Department of General Surgery, Nanfang Hospital Southern Medical University, Guangzhou, China.,Breast Center, Department of General Surgery, Zhongshan City People's Hospital, Zhongshan, Guangzhou, China
| | - Dajiang Song
- Department of Oncology Plastic Surgery, Hunan Province Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Bo Li
- Guizhou Medical University, Guiyang, Guizhou, China
| | - Qian Chen
- Guizhou Medical University, Guiyang, Guizhou, China
| | - Guangyu Yao
- Breast Center, Department of General Surgery, Nanfang Hospital Southern Medical University, Guangzhou, China.
| | - Bin Gong
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
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Wang J, Wang D, Fei Z, Feng D, Zhang B, Gao P, Hu G, Li W, Huang X, Chen D, Ding X, Wu W. KIF15 knockdown suppresses gallbladder cancer development. Eur J Cell Biol 2021; 100:151182. [PMID: 34781077 DOI: 10.1016/j.ejcb.2021.151182] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 10/26/2021] [Accepted: 11/03/2021] [Indexed: 11/17/2022] Open
Abstract
Gallbladder cancer (GBC) is commonly regarded as one of the most lethal malignant tumor types with poor prognosis. Kinesin family member 15 (KIF15) is reported to be tightly related with progression of multiple cancer types which, however, has not been clarified in GBC so far. KIF15 was significantly up-regulated in clinical GBC tissues compared with that in para-carcinoma tissues and the expression level was also correlated with tumor malignancies. In addition to tissues, GBC cells also exhibited a high expression abundance of KIF15. After down-regulating KIF15 via lentiviral transfection, GBC cell proliferation and migration were both inhibited, while cell apoptosis was promoted markedly. Likewise, silencing KIF15 significantly interfered the growth of nude mouse xenografts. Our experiments in GBC cell lines also demonstrated that KIF15 overexpression accelerated cell proliferation but lessened cell apoptosis in both GBC-SD and SGC-996 cells. Further investigation of the mechanism occurring in GBC inhibition mediated by KIF15 knockdown revealed that KIF15 deficiency led to decreased activity of several signaling pathways (TNF, PI3K/AKT and MAPK), a reduction of CDK6 expression regulated by enhanced p21, and HSP60 absence. Following the treatment of shCtrl- and shKIF15-transfected cells with AKT activator, we found that anti-tumor effects resulting from KIF15 deficiency could be relieved by AKT activator in both experimental cells. Overall, for the first time, we demonstrated that KIF15 was overexpressed in GBC and displayed a close relationship between KIF15 levels and GBC clinical stages. Furthermore, low expression of KIF15 resulted in obvious anti-tumor effects.
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Affiliation(s)
- Jun Wang
- Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China
| | - Dandan Wang
- Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China
| | - Zhewei Fei
- Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China
| | - Dongxu Feng
- Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China
| | - Bo Zhang
- Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China
| | - Pingfa Gao
- Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China
| | - Gangfeng Hu
- Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China
| | - Wenbing Li
- Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China
| | - Xia Huang
- Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China
| | - Dawei Chen
- Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China
| | - Xinde Ding
- Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China
| | - Wei Wu
- Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China.
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Qureshi Z, Ahmad M, Yang WX, Tan FQ. Kinesin 12 (KIF15) contributes to the development and tumorigenicity of prostate cancer. Biochem Biophys Res Commun 2021; 576:7-14. [PMID: 34474246 DOI: 10.1016/j.bbrc.2021.08.072] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 08/25/2021] [Indexed: 02/05/2023]
Abstract
In Asia, prostate cancer is becoming a growing concern, impacting both socially and economically, compared with what is seen in western countries. Hence, it is essential to know the mechanisms associated with the development and tumorigenesis of PCa for primary diagnosis, risk management, and development of therapy strategies against PCa. Kinesin family member 15 (KIF15), a kinesin family member, is a plus-end-directed kinesin that functions to form bipolar spindles. There is emerging evidence indicating that KIF15 plays a significant role in several malignancies, such as pancreatic cancer, hepatocellular carcinoma, lung adenocarcinoma, and breast cancer. Still, the function of KIF15 remains unclear in prostate cancer. Here, we study the functional importance of KIF15 in the tumorigenesis of PCa. The bioinformatic analysis from PCa patients revealed high KIF15 expression compared to normal prostate tissues. High expression hinting at a possible functional role of KIF15 in regulating cell proliferation of PCa, which was demonstrated by both in vitro and in vivo assays. Downregulation of KIF15 silenced the expression of CDK2, p-RB, and Cyclin D1 and likewise blocked the cells at the G1 stage of the cell cycle. In addition, KIF15 downregulation inhibited MEK-ERK signaling by significantly silencing p-ERK and p-MEK levels. In conclusion, this study confirmed the functional significance of KIF15 in the growth and development of prostate cancer and could be a novel therapeutic target for the treatment of PCa.
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Affiliation(s)
- Zeeshan Qureshi
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Mashaal Ahmad
- Department of Biochemistry and Cancer Institute of Second Affiliated Hospital, Key Laboratory of Cancer Prevention and Intervention of China National MOE, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Wan-Xi Yang
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Fu-Qing Tan
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
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Wei S, Dai M, Zhang C, Teng K, Wang F, Li H, Sun W, Feng Z, Kang T, Guan X, Xu R, Cai M, Xie D. KIF2C: a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma. Protein Cell 2021; 12:788-809. [PMID: 32748349 PMCID: PMC8464548 DOI: 10.1007/s13238-020-00766-y] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 06/28/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide. HCC is refractory to many standard cancer treatments and the prognosis is often poor, highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments. Kinesin family member 2C (KIF2C) is reported to be highly expressed in several human tumors. Nevertheless, the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated. In this study, we found that KIF2C expression was significantly upregulated in HCC, and that KIF2C up-regulation was associated with a poor prognosis. Utilizing both gain and loss of function assays, we showed that KIF2C promoted HCC cell proliferation, migration, invasion, and metastasis both in vitro and in vivo. Mechanistically, we identified TBC1D7 as a binding partner of KIF2C, and this interaction disrupts the formation of the TSC complex, resulting in the enhancement of mammalian target of rapamycin complex1 (mTORC1) signal transduction. Additionally, we found that KIF2C is a direct target of the Wnt/β-catenin pathway, and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORC1 signaling. Thus, the results of our study establish a link between Wnt/β-catenin and mTORC1 signaling, which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.
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Affiliation(s)
- Shi Wei
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Miaomiao Dai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Chi Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Kai Teng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250200, China
| | - Fengwei Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Hongbo Li
- Department of Musculoskeletal Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Weipeng Sun
- Department of Anorectal Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 510370, China
| | - Zihao Feng
- Department of Urology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Tiebang Kang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Xinyuan Guan
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Ruihua Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Muyan Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - Dan Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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Qiu L, Yang X, Wu J, Huang C, Miao Y, Fu Z. HIST2H2BF Potentiates the Propagation of Cancer Stem Cells via Notch Signaling to Promote Malignancy and Liver Metastasis in Colorectal Carcinoma. Front Oncol 2021; 11:677646. [PMID: 34476209 PMCID: PMC8406628 DOI: 10.3389/fonc.2021.677646] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 06/18/2021] [Indexed: 11/17/2022] Open
Abstract
Background Growing evidence demonstrates that the initiation and progression of colorectal carcinoma (CRC) is related to the presence of cancer stem cells (CSCs). However, the mechanism through which the stem cell features of CRC cells are maintained is poorly understood. In this study, we identified the oncogenic histone cluster 2 H2B family member F (HIST2H2BF) and aimed to investigate the function of upregulated HIST2H2BF expression in maintaining the stem cell features of CRC cells, which accelerate the progression of CRC. Methods HIST2H2BF expression was quantified using real-time polymerase chain reaction, immunohistochemistry, and western blotting. The correlation between CpG island methylation status and HIST2H2BF re-expression was assessed through bisulfite sequencing polymerase chain reaction, methylation-specific polymerase chain reaction, and 5-Aza-dC treatment. Functional assays were performed on CRC cells and mice to investigate the HIST2H2BF-induced stem cell-like and cancer properties of CRC. Using the Notch pathway inhibitor FLI-06, the regulatory effect of HIST2H2BF on downstream Notch signaling was confirmed. Results HIST2H2BF was highly expressed in CRC tissues and cell lines. The reactivation of HIST2H2BF in CRC stems at least in part from the hypomethylated CpG islands. CRC patients with high HIST2H2BF expression have poor survival outcomes. Functional studies have shown that HIST2H2BF promotes CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. Blockage of the Notch pathway reduced the stem cell-like and cancer properties. Conclusion Our study suggests that HIST2H2BF upregulation enhances the CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. These results identified a new perspective on the mechanism by which the stem cell features of CRC cells are maintained and highlighted the potential novel therapeutic targets for CRC.
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Affiliation(s)
- Lei Qiu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of General Surgery, The Second People's Hospital of Lianyungang, Lianyungang Tumor Hospital, Lianyungang Hospital Affiliated to Bengbu Medical University, Lianyungang, China
| | - Xiuwei Yang
- Department of General Surgery, The Second People's Hospital of Lianyungang, Lianyungang Tumor Hospital, Lianyungang Hospital Affiliated to Bengbu Medical University, Lianyungang, China
| | - Jingyu Wu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Changzhi Huang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yongchang Miao
- Department of General Surgery, The Second People's Hospital of Lianyungang, Lianyungang Tumor Hospital, Lianyungang Hospital Affiliated to Bengbu Medical University, Lianyungang, China
| | - Zan Fu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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A retrospective overview of PHGDH and its inhibitors for regulating cancer metabolism. Eur J Med Chem 2021; 217:113379. [PMID: 33756126 DOI: 10.1016/j.ejmech.2021.113379] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 11/20/2022]
Abstract
Emerging evidence suggests that cancer metabolism is closely associated to the serine biosynthesis pathway (SSP), in which glycolytic intermediate 3-phosphoglycerate is converted to serine through a three-step enzymatic transformation. As the rate-limiting enzyme in the first step of SSP, phosphoglycerate dehydrogenase (PHGDH) is overexpressed in various diseases, especially in cancer. Genetic knockdown or silencing of PHGDH exhibits obvious anti-tumor response both in vitro and in vivo, demonstrating that PHGDH is a promising drug target for cancer therapy. So far, several types of PHGDH inhibitors have been identified as a significant and newly emerging option for anticancer treatment. Herein, this comprehensive review summarizes the recent achievements of PHGDH, especially its critical role in cancer and the development of PHGDH inhibitors in drug discovery.
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Fan T, Xie Y, Ma W. Research progress on the protection and detoxification of phytochemicals against aflatoxin B 1-Induced liver toxicity. Toxicon 2021; 195:58-68. [PMID: 33716068 DOI: 10.1016/j.toxicon.2021.03.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 03/03/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023]
Abstract
Aflatoxin B1 (AFB1) is a potent hepatotoxic toxin, which can cause hepatitis, cirrhosis, and liver immunological damage. It has been involved in the etiology of human hepatocellular carcinoma. AFB1 can cause oxidative stress in the body's metabolism process, and then cause cytotoxicity, such as apoptosis and DNA damage. Scientific research has discovered that phytochemicals can induce the detoxification pathway of AFB1 through its biotransformation, thereby reducing the damage of AFB1 to the human body. In clinical treatment, certain phytochemicals have been effectively used in the treatment of liver injury due to the advantages of multiple targets, multiple pathways, low toxicity and side effects. Therefore, the article summarizes the toxic mechanism of AFB1-induced hepatoxicity, and the related research progress of phytochemicals for preventing and treating its cytotoxicity and genotoxicity. We also look forward to the existing problems and application prospects of phytochemicals in the pharmaceutical industry, in order to provide theoretical reference for the prevention and treatment of AFB1 poisoning in future research work.
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Affiliation(s)
- Tingting Fan
- College of Food Science and Engineering, Henan University of Technology, Zhengzhou, 450001, People's Republic of China; Henan Key Laboratory of Cereal and Oil Food Safety Inspection and Control, Zhengzhou, Henan, 450001, People's Republic of China
| | - Yanli Xie
- College of Food Science and Engineering, Henan University of Technology, Zhengzhou, 450001, People's Republic of China; Henan Key Laboratory of Cereal and Oil Food Safety Inspection and Control, Zhengzhou, Henan, 450001, People's Republic of China.
| | - Weibin Ma
- College of Food Science and Engineering, Henan University of Technology, Zhengzhou, 450001, People's Republic of China; Henan Key Laboratory of Cereal and Oil Food Safety Inspection and Control, Zhengzhou, Henan, 450001, People's Republic of China
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Chandrika M, Chua PJ, Muniasamy U, Huang RYJ, Thike AA, Ng CT, Tan PH, Yip GW, Bay BH. Prognostic significance of phosphoglycerate dehydrogenase in breast cancer. Breast Cancer Res Treat 2021; 186:655-665. [PMID: 33625616 DOI: 10.1007/s10549-021-06123-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 02/01/2021] [Indexed: 12/18/2022]
Abstract
PURPOSE Breast cancer is the most common type of cancer affecting women worldwide. Phosphoglycerate dehydrogenase (PHGDH) is an oxidoreductase in the serine biosynthesis pathway. Although it has been reported to affect growth of various tumors, its role in breast cancer is largely unknown. This study aimed to analyze the expression of PHGDH in breast cancer tissue samples and to determine if PHGDH regulates breast cancer cell proliferation. METHODS Tissue microarrays consisting of 305 cases of breast invasive ductal carcinoma were used for immunohistochemical evaluation of PHGDH expression. The role of PHGDH in breast cancer was investigated in vitro by knocking down its expression and determining the effect on cell proliferation and cell cycling, and in ovo by using a chorioallantoic membrane (CAM) assay. RESULTS Immunohistochemical examination showed that PHGDH is mainly localized in the cytoplasm of breast cancer cells and significantly associated with higher cancer grade, larger tumor size, increased PCNA expression, and lymph node positivity. Analysis of the GOBO dataset of 737 patients demonstrated that increased PHGDH expression was associated with poorer overall survival. Knockdown of PHGDH expression in breast cancer cells in vitro resulted in a decrease in cell proliferation, reduction in cells entering the S phase of the cell cycle, and downregulation of various cell cycle regulatory genes. The volume of breast tumor in an in ovo CAM assay was found to be smaller when PHGDH was silenced. CONCLUSION The findings suggest that PHGDH has a regulatory role in breast cancer cell proliferation and may be a potential prognostic marker and therapeutic target in breast cancer.
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Affiliation(s)
- Muthukrishnan Chandrika
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Pei Jou Chua
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Umamaheswari Muniasamy
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Ruby Yun Ju Huang
- School of Medicine, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
| | - Aye Aye Thike
- Division of Pathology, Singapore General Hospital, Singapore, 169856, Singapore
| | - Cheng Teng Ng
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Puay Hoon Tan
- Division of Pathology, Singapore General Hospital, Singapore, 169856, Singapore
| | - George W Yip
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore.
| | - Boon Huat Bay
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore.
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Li Q, Ni Y, Zhang L, Jiang R, Xu J, Yang H, Hu Y, Qiu J, Pu L, Tang J, Wang X. HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation. Signal Transduct Target Ther 2021; 6:76. [PMID: 33619246 PMCID: PMC7900110 DOI: 10.1038/s41392-020-00453-8] [Citation(s) in RCA: 252] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 11/15/2020] [Accepted: 12/08/2020] [Indexed: 12/29/2022] Open
Abstract
N6-methyladenosine (m6A), and its reader protein YTHDF1, play a pivotal role in human tumorigenesis by affecting nearly every stage of RNA metabolism. Autophagy activation is one of the ways by which cancer cells survive hypoxia. However, the possible involvement of m6A modification of mRNA in hypoxia-induced autophagy was unexplored in human hepatocellular carcinoma (HCC). In this study, specific variations in YTHDF1 expression were detected in YTHDF1-overexpressing, -knockout, and -knockdown HCC cells, HCC organoids, and HCC patient-derived xenograft (PDX) murine models. YTHDF1 expression and hypoxia-induced autophagy were significantly correlated in vitro; significant overexpression of YTHDF1 in HCC tissues was associated with poor prognosis. Multivariate cox regression analysis identified YTHDF1 expression as an independent prognostic factor in patients with HCC. Multiple HCC models confirmed that YTHDF1 deficiency inhibited HCC autophagy, growth, and metastasis. Luciferase reporter assays and chromatin immunoprecipitation demonstrated that HIF-1α regulated YTHDF1 transcription by directly binding to its promoter region under hypoxia. The results of methylated RNA immunoprecipitation sequencing, proteomics, and polysome profiling indicated that YTHDF1 contributed to the translation of autophagy-related genes ATG2A and ATG14 by binding to m6A-modified ATG2A and ATG14 mRNA, thus facilitating autophagy and autophagy-related malignancy of HCC. Taken together, HIF-1α-induced YTHDF1 expression was associated with hypoxia-induced autophagy and autophagy-related HCC progression via promoting translation of autophagy-related genes ATG2A and ATG14 in a m6A-dependent manner. Our findings suggest that YTHDF1 is a potential prognostic biomarker and therapeutic target for patients with HCC.
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Affiliation(s)
- Qing Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.,School of Medicine, Southeast University, Nanjing, China
| | - Yong Ni
- Department of Hepatopancreatobiliary Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China
| | - Liren Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Runqiu Jiang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China.,Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Jing Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Hong Yang
- Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yuanchang Hu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Jiannan Qiu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Liyong Pu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
| | - Jinhai Tang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Xuehao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China. .,School of Medicine, Southeast University, Nanjing, China.
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Liu Z, Liu L, Lu T, Wang L, Li Z, Jiao D, Han X. Hypoxia Molecular Characterization in Hepatocellular Carcinoma Identifies One Risk Signature and Two Nomograms for Clinical Management. JOURNAL OF ONCOLOGY 2021; 2021:6664386. [PMID: 33552157 PMCID: PMC7846409 DOI: 10.1155/2021/6664386] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/06/2021] [Accepted: 01/09/2021] [Indexed: 12/24/2022]
Abstract
Hypoxia is a universal feature in the tumor microenvironment (TME). Nonetheless, the heterogeneous hypoxia patterns of TME have still not been elucidated in hepatocellular carcinoma (HCC). Using consensus clustering algorithm and public datasets, we identified heterogeneous hypoxia subtypes. We also revealed the specific biological and clinical characteristics via bioinformatic methods. The principal component analysis algorithm was employed to develop a hypoxia-associated risk score (HARS). We identified the two hypoxia subtypes: low hypoxia pattern (C1) and high hypoxia pattern (C2). C1 was less sensitive to immunotherapy compared to C2, consistent with the lack of immune cells and immune checkpoints (ICPs) in C1, whereas C2 was the opposite. C2 displayed worse prognosis and higher sensitivity to obatoclax relative to C1, while C1 was more sensitive to sorafenib. The two subtypes also demonstrated subtype-specific genomic variations including mutation, copy number alteration, and methylation. Moreover, we developed and validated a risk signature: HARS, which had excellent performance for predicting prognosis and immunotherapy. We revealed two hypoxia subtypes with distinct biological and clinical characteristics in HCC, which enhanced the understanding of hypoxia pattern. The risk signature was a promising biomarker for predicting prognosis and immunotherapy.
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Affiliation(s)
- Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Interventional Institute of Zhengzhou University, Zhengzhou 450052, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou 450052, China
| | - Long Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Taoyuan Lu
- Department of Cerebrovascular Disease, Zhengzhou University People's Hospital, Zhengzhou 450003, China
| | - Libo Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Zhaonan Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Interventional Institute of Zhengzhou University, Zhengzhou 450052, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou 450052, China
| | - Dechao Jiao
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Interventional Institute of Zhengzhou University, Zhengzhou 450052, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou 450052, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Interventional Institute of Zhengzhou University, Zhengzhou 450052, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou 450052, China
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Abstract
Liver cancer is the second most lethal malignancy worldwide. Cell lines and murine models are the most common tools for modeling human liver carcinogenesis. Most recently, organoids with a three-dimensional structure derived from primary tissues or cells have been applied to liver cancer research. Organoids can be generated from induced pluripotent stem cells, embryonic or adult, healthy or diseased tissues. In particular, liver organoids have been widely employed in mechanistic studies aimed at delineating the molecular pathways responsible for hepatocarcinogenesis. The introduction of clustered regularly interspaced palindromic repeats (CRISPR)-associated protein 9 (Cas9) and microengineered miniorganoid technologies into liver organoids for cancer study has significantly accelerated these investigations. Translational advances have been made by utilizing liver tumor organoids for anticancer drug screening, biobanking, omics profiling, and biomarker discovery. This review summarizes the latest advances and the remaining challenges in the use of organoid models for the study of liver cancer.
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Affiliation(s)
- Haichuan Wang
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, China,Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China,Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
| | - Diego F. Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
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Gao L, Zhang W, Zhang J, Liu J, Sun F, Liu H, Hu J, Wang X, Wang X, Su P, Chen S, Qu S, Shi B, Xiong X, Chen W, Dong X, Han B. KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer. Cancer Res 2020; 81:1026-1039. [PMID: 33277366 DOI: 10.1158/0008-5472.can-20-1965] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/10/2020] [Accepted: 11/30/2020] [Indexed: 11/16/2022]
Abstract
The new generation androgen receptor (AR) pathway inhibitor enzalutamide can prolong the survival of patients with metastatic prostate cancer. However, resistance to enzalutamide inevitably develops in these patients, and the underlying mechanisms of this resistance are not fully defined. Here we demonstrate that the kinesin family member 15 (KIF15) contributes to enzalutamide resistance by enhancing the AR signaling in prostate cancer cells. KIF15 directly bound the N-terminus of AR/AR-V7 and prevented AR/AR-V7 proteins from degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7. In turn, the transcriptionally active AR stimulated KIF15 expression. KIF15 inhibitors alone or in combination with enzalutamide significantly suppressed enzalutamide-resistant prostate cancer cell growth and xenograft progression. These findings highlight a key role of KIF15 in enabling prostate cancer cells to develop therapy resistance to enzalutamide and rationalize KIF15 as a potential therapeutic target. SIGNIFICANCE: These findings demonstrate how reciprocal activation between KIF15 and AR contributes to enzalutamide resistance in prostate cancer and highlights cotargeting KIF15 and AR as a therapeutic strategy for these tumors.
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Affiliation(s)
- Lin Gao
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Wenbo Zhang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jing Zhang
- Department of Pharmacy, Shandong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Junmei Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Feifei Sun
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Hui Liu
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jing Hu
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xin Wang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xueli Wang
- Department of Pathology, Binzhou City Central Hospital, Binzhou, China
| | - Peng Su
- Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Shouzhen Chen
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Sifeng Qu
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Benkang Shi
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xueting Xiong
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Weiwen Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xuesen Dong
- Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada. .,Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Bo Han
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. .,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
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Li J, Zhu Y. Recent Advances in Liver Cancer Stem Cells: Non-coding RNAs, Oncogenes and Oncoproteins. Front Cell Dev Biol 2020; 8:548335. [PMID: 33117795 PMCID: PMC7575754 DOI: 10.3389/fcell.2020.548335] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 09/14/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide, with high morbidity, relapse, metastasis and mortality rates. Although liver surgical resection, transplantation, chemotherapy, radiotherapy and some molecular targeted therapeutics may prolong the survival of HCC patients to a certain degree, the curative effect is still poor, primarily because of tumor recurrence and the drug resistance of HCC cells. Liver cancer stem cells (LCSCs), also known as liver tumor-initiating cells, represent one small subset of cancer cells that are responsible for disease recurrence, drug resistance and death. Therefore, understanding the regulatory mechanism of LCSCs in HCC is of vital importance. Thus, new studies that present gene regulation strategies to control LCSC differentiation and replication are under development. In this review, we provide an update on the latest advances in experimental studies on non-coding RNAs (ncRNAs), oncogenes and oncoproteins. All the articles addressed the crosstalk between different ncRNAs, oncogenes and oncoproteins, as well as their upstream and downstream products targeting LCSCs. In this review, we summarize three pathways, the Wnt/β-catenin signaling pathway, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, and interleukin 6/Janus kinase 2/signal transducer and activator of transcription 3 (IL6/JAK2/STAT3) signaling pathway, and their targeting gene, c-Myc. Furthermore, we conclude that octamer 4 (OCT4) and Nanog are two important functional genes that play a pivotal role in LCSC regulation and HCC prognosis.
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Affiliation(s)
- Juan Li
- Department of Radiotherapy Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ying Zhu
- Department of Infectious Disease, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Liver Disease Center of Integrated Traditional and Western Medicine, Institute of Integrative Medicine, Dalian Medical University, Dalian, China
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Chang S, Sun G, Zhang D, Li Q, Qian H. MiR-3622a-3p acts as a tumor suppressor in colorectal cancer by reducing stemness features and EMT through targeting spalt-like transcription factor 4. Cell Death Dis 2020; 11:592. [PMID: 32719361 PMCID: PMC7385142 DOI: 10.1038/s41419-020-02789-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 07/08/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023]
Abstract
MicroRNAs are a class of small non-coding RNAs which act as oncogenes or tumor suppressors through targeting specific mRNAs. Colorectal cancer (CRC) is one of the most common malignancies worldwide. MiR-3622a-3p is found to be decreased in colorectal cancer (CRC) by analyzing data from TCGA database and there are few reports about the role of miR-3622a-3p in cancers. Our research aimed to explore the effects of miR-3622a-3p on CRC. MiR-3622a-3p was found to be down-regulated in CRC tissues and cells by qRT-PCR. The effect of miR-3622a-3p on proliferation, apoptosis, cell cycle, migration and invasion of CRC cells were investigated by a serious of biological function assays and the results revealed that miR-3622a-3p could inhibit the malignant biological properties of CRC. We performed dual luciferase assay, RNA immunoprecipitation (RIP) assay and pull-down assay to confirm the interaction between miR-3622a-3p and spalt-like transcription factor 4 (SALL4). Western blot was carried out to determine the effects of miR-3622a-3p and SALL4 on stemness features and EMT. We found that miR-3622a-3p suppressed stemness features and EMT of CRC cells by SALL4 mRNA degradation. MiR-3622a-3p could inhibit CRC cell proliferation and metastasis in vivo with tumor xenograft model and in vivo metastasis model. The CRC organoid model was constructed with fresh CRC tissues and the growth of organoids was suppressed by miR-3622a-3p. Taken together, the results of our study indicate miR-3622a-3p exerts antioncogenic role in CRC by downregulation of SALL4. The research on miR-3622a-3p might provide a new insight into treatment of CRC.
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Affiliation(s)
- Shuchen Chang
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu province, China
| | - Guangli Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu province, China
| | - Dan Zhang
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu province, China
| | - Qing Li
- Medical College of Southeast University, Nanjing, 210009, Jiangsu province, China
| | - Haihua Qian
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu province, China.
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KIF15 Promotes Proliferation and Growth of Hepatocellular Carcinoma. Anal Cell Pathol (Amst) 2020; 2020:6403012. [PMID: 32318326 PMCID: PMC7157793 DOI: 10.1155/2020/6403012] [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: 09/23/2019] [Revised: 01/16/2020] [Accepted: 02/24/2020] [Indexed: 12/14/2022] Open
Abstract
Liver cancer is thought as the most common human malignancy worldwide, and hepatocellular carcinoma (HCC) accounts for nearly 90% liver cancer. Due to its poor early diagnosis and limited treatment, HCC has therefore become the most lethal malignant cancers in the world. Recently, molecular targeted therapies showed great promise in the treatment of HCC, and novel molecular therapeutic targets is urgently needed. KIF15 is a microtubule-dependent motor protein involved in multiple cell processes, such as cell division. Additionally, KIF15 has been reported to participate in the growth of various types of tumors; however, the relation between KIF15 and HCC is unclear. Herein, our study investigated the possible role of KIF15 on the progression of HCC and found that KIF15 has high expression in tumor samples from HCC patients. KIF15 could play a critical role in the regulation of cell proliferation of HCC, which was proved by in vitro and in vivo assays. In conclusion, this study confirmed that KIF15 could be a novel therapeutic target for the treatment of HCC.
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