|
1
|
Liu Z, Yu K, Chen K, Zhang Y, Dai K, Zhao L, Zhao P. USP18 deubiquitinates and stabilizes SOX9 to promote the stemness and malignant progression of glioblastoma. Cell Death Discov 2025; 11:237. [PMID: 40374599 DOI: 10.1038/s41420-025-02522-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 04/27/2025] [Accepted: 05/01/2025] [Indexed: 05/17/2025] Open
Abstract
Glioblastoma (GBM), the most common and aggressive primary brain tumour, is associated with poor prognosis, primarily due to its stem-like subpopulation, glioblastoma stem cells (GSCs). The deubiquitinase (DUB) family has attracted an increasing amount of attention due to its roles in GSC biology and tumour aggressiveness. In this study, we focused on ubiquitin-specific peptidase 18 (USP18), a member of the DUB family whose role in GBM is poorly understood. Through integrated bioinformatics analyses and experimental investigations using patient-derived samples, cell models, and animal models, we elucidated the role of USP18 in enhancing GSC stemness and promoting malignant behaviours. Our findings revealed that USP18 expression is significantly elevated in GBM and is correlated with a poor prognosis. Mechanistically, USP18 interacts with SRY-box transcription factor 9 (SOX9), stabilising its protein levels by cleaving K48-linked polyubiquitin chains. Additionally, we identified YY1 as a transcriptional regulator of USP18, increasing its expression in GBM cells. These findings reveal that USP18 is a potential therapeutic target and highlight the novel YY1/USP18/SOX9 signalling axis implicated in GBM progression.
Collapse
Affiliation(s)
- Zhiyuan Liu
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China
| | - Kuo Yu
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China
| | - Kaile Chen
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China
| | - Yi Zhang
- Department of Non-Communicable Disease Prevention, Nanjing Municipal Center for Disease Control and Prevention, Nanjing, 210000, China
| | - Kexiang Dai
- Department of Neurosugery, Emergency General Hospital, Beijing, 100028, China
| | - Liang Zhao
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, 210000, China
| | - Peng Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China.
| |
Collapse
|
|
2
|
Ji PX, Zhang P, Zhou HL, Yu H, Fu Y. MEX3A promotes cell proliferation by regulating the RORA/β-catenin pathway in hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:102084. [PMID: 40235874 PMCID: PMC11995337 DOI: 10.4251/wjgo.v17.i4.102084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 01/27/2025] [Accepted: 02/14/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND MEX3A is a member of the human homologous gene MEX-3 family. It has been shown to promote cell proliferation and migration in various cancers, indicating its potential clinical significance. However, the role of MEX3A in hepatocellular carcinoma (HCC) remains largely unexplored, with limited reports available in the literature. AIM To investigate expression and clinical significance of MEX3A in HCC and explore its potential role in tumor progression. METHODS We analyzed MEX3A mRNA expression in HCC and adjacent tissues using data from The Cancer Genome Atlas (TCGA). The correlation between MEX3A expression and overall survival (OS) was evaluated. Immunohistochemistry was performed on HCC surgical specimens to validate MEX3A expression and its association with clinical parameters, including hepatitis B virus (HBV) positivity, tumor differentiation and tumor size. Additionally, MEX3A knockdown HCC cell lines were constructed to explore the biological functions of MEX3A. Cell proliferation was assessed using cell counting kit-8 and clone formation assays, while cell cycle progression was analyzed by flow cytometry. The effects of MEX3A on the Wnt/β-catenin signaling pathway were examined by western blotting and immunofluorescence. Cell migration was evaluated using scratch and Transwell assays. Finally, the role of the transcription factor RORA in mediating MEX3A effects was explored by silencing RORA and analyzing its impact on cell proliferation and protein expression. RESULTS TCGA data analysis revealed that MEX3A mRNA expression was significantly higher in HCC tissues compared to adjacent tissues. Higher MEX3A expression was associated with poorer OS. These findings were validated in HCC surgical specimens. Immunohistochemistry confirmed elevated MEX3A expression in HCC tissues and showed positive correlations with Ki-67 and vimentin levels. MEX3A expression was closely related to HBV positivity, tumor differentiation and tumor size. Mechanistic studies demonstrated that MEX3A knockdown inhibited cell proliferation and cell cycle progression, as shown by reduced expression of β-catenin, c-Myc and cyclin D1. Additionally, MEX3A knockdown inhibited the nuclear entry of β-catenin, thereby suppressing the activation of downstream oncogenic pathways. MEX3A depletion significantly reduced the migratory ability of HCC cells, likely through downregulation of the epithelial-mesenchymal transition pathway. Transcription factor analysis identified RORA as a potential mediator of MEX3A effects. Silencing RORA antagonized the effects of MEX3A on cell proliferation and the expression of β-catenin, c-Myc and cyclin D1. CONCLUSION MEX3A promotes cell proliferation in HCC by regulating the RORA/β-catenin pathway. Our findings suggest that MEX3A could serve as a prognostic marker and therapeutic target for HCC.
Collapse
Affiliation(s)
- Peng-Xiang Ji
- Hand Surgery Laboratory, Suzhou Ruihua Orthopedic Hospital, Suzhou Medical College of Soochow University, Suzhou 215104, Jiangsu Province, China
| | - Ping Zhang
- Hand Surgery Laboratory, Suzhou Ruihua Orthopedic Hospital, Suzhou Medical College of Soochow University, Suzhou 215104, Jiangsu Province, China
| | - Hui-Ling Zhou
- Department of Pathology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, Jiangsu Province, China
| | - Hong Yu
- Department of Pathology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, Jiangsu Province, China
| | - Yi Fu
- Department of Human Anatomy, Histology and Embryology, Suzhou Medical College of Soochow University, Suzhou 215123, Jiangsu Province, China
| |
Collapse
|
|
3
|
Lien HE, Hjelmeland ME, Berg HF, Gold RM, Woie K, Akslen LA, Haldorsen IS, Krakstad C. Multiplex single-cell profiling of putative cancer stem cell markers ALDH1, SOX9, SOX2, CD44, CD133 and CD15 in endometrial cancer. Mol Oncol 2025. [PMID: 39888143 DOI: 10.1002/1878-0261.13815] [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: 12/11/2024] [Revised: 08/26/2024] [Accepted: 12/22/2024] [Indexed: 02/01/2025] Open
Abstract
The presence of cancer stem cells is linked to aggressive disease and higher risk of recurrence, and multiple markers have been proposed to detect cancer stem cells. However, a detailed evaluation of the expression patterns and the prognostic value of markers relevant for endometrial cancer is lacking. As organoid models are suggested to be enriched in cancer stem cells, such models may prove valuable to define tissue-specific cancer stem cells. To address this, imaging mass cytometry and multiplex single-cell analyses were performed on an endometrial cancer patient series including both tumor biopsies and corresponding patient-derived organoids. An antibody panel focused on cancer stem cell markers was used to identify cancer stem cell phenotypes. Over 70% of epithelial cells in the tumor biopsies expressed at least one putative cancer stem cell marker. We identified distinct cancer cell phenotypes with heterogeneous expression within individual patients and between patient samples. Few differences in the distribution of cancer cell phenotypes were observed between tumor biopsies and corresponding organoids. Cells expressing aldehyde dehydrogenase 1 (ALDH1) were more prevalent in high-grade tumors, while expression of CD44 was more prevalent in grade 1 tumors. Spatial analysis revealed significantly less interaction between ALDH1- and CD44-expressing cells. Gene expression data was used to further investigate selected markers. CD44 gene expression was associated with a favorable prognosis and was further validated using immunohistochemistry. High expression of CD44 was significantly associated with better survival. The general high expression of proposed stem cell markers may indicate alternative roles for these in endometrial cancer.
Collapse
Affiliation(s)
- Hilde E Lien
- Department of Clinical Science, Centre for Cancer Biomarkers CCBIO, University of Bergen, Norway
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
| | - Marta E Hjelmeland
- Department of Clinical Science, Centre for Cancer Biomarkers CCBIO, University of Bergen, Norway
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
| | - Hege F Berg
- Department of Clinical Science, Centre for Cancer Biomarkers CCBIO, University of Bergen, Norway
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
| | - Rose M Gold
- Department of Clinical Science, Centre for Cancer Biomarkers CCBIO, University of Bergen, Norway
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
| | - Kathrine Woie
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
| | - Lars A Akslen
- Department of Clinical Medicine, Centre for Cancer Biomarkers CCBIO, University of Bergen, Norway
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Ingfrid S Haldorsen
- Department of Radiology, Mohn Medical Imaging and Visualization Centre, Haukeland University Hospital, Bergen, Norway
- Section for Radiology, Department of Clinical Medicine, University of Bergen, Norway
| | - Camilla Krakstad
- Department of Clinical Science, Centre for Cancer Biomarkers CCBIO, University of Bergen, Norway
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
| |
Collapse
|
|
4
|
Hibi D, Soma M, Suzuki Y, Takasu S, Ishii Y, Umemura T. Appearance of sex-determining region Y-box 9 (SOX9)- and glutathione S-transferase placental form (GST-P)-positive hepatocytes as possible carcinogenic events in the early stage of furan-induced hepatocarcinogenesis. J Appl Toxicol 2024; 44:1976-1985. [PMID: 39171654 DOI: 10.1002/jat.4691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/04/2024] [Accepted: 08/08/2024] [Indexed: 08/23/2024]
Abstract
Furan, the basic skeleton of various flavoring agents, induces cholangiocellular tumors with higher incidences in the caudate lobe and hepatocellular tumors without the lobe specificity in rats, but the mechanism is unclear. We investigated the lobe distribution of possible carcinogenic events. Furan caused proliferation/infiltration of oval and inflammatory cells prominently in the caudate lobe as early as 4 weeks and cholangiofibrosis in this lobe at 8 weeks. In vivo mutagenicity assays using DNA extracted from the caudate or left lateral lobe of male gpt delta rats, the reporter gene-transgenic rats, treated with 8 mg/kg furan for 4 or 8 weeks showed negative outcomes. The distribution of glutathione S-transferase placental form (GST-P)-positive or sex-determining region Y-box 9 (SOX9)-positive hepatocytes was examined. Significant increases in the number of GST-P-positive hepatocytes were observed in all lobes of furan-treated rats at 8 weeks. By contrast, SOX9-positive hepatocytes, liver injury-inducible progenitor cells, were also found in all lobes of treated rats, the incidences of which were by far the highest in the caudate lobe. In addition, some of these hepatocytes also co-expressed delta like 1 homolog (DLK1), a hepatoblast marker, particularly in areas with a predominant presence of inflammatory cells. Overall, furan induced liver injury, leading to the appearance of SOX9-positive hepatocytes, some of which were subjected to dedifferentiation in the inflammatory microenvironment of a cholangiocarcinoma-prone lobe. Thus, the appearance of SOX9-positive hepatocytes together with GST-P-positive hepatocytes could be initial events in furan-induced hepatocarcinogenesis via non-genotoxic mechanisms.
Collapse
Affiliation(s)
- Daisuke Hibi
- Division of Pathology, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan
| | - Meili Soma
- Division of Pathology, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan
- Graduate School of Animal Health Technology, Yamazaki University of Animal Health Technology, Tokyo, Japan
| | - Yuta Suzuki
- Division of Pathology, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan
| | - Shinji Takasu
- Division of Pathology, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan
| | - Yuji Ishii
- Division of Pathology, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan
| | - Takashi Umemura
- Division of Pathology, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan
- Graduate School of Animal Health Technology, Yamazaki University of Animal Health Technology, Tokyo, Japan
| |
Collapse
|
|
5
|
Che F, Wei Y, Xu Q, Li Q, Zhang T, Wang LY, Li M, Yuan F, Song B. Noninvasive identification of SOX9 status using radiomics signatures may help construct personalized treatment strategy in hepatocellular carcinoma. Abdom Radiol (NY) 2024; 49:3024-3035. [PMID: 38446180 DOI: 10.1007/s00261-024-04190-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/31/2023] [Accepted: 01/16/2024] [Indexed: 03/07/2024]
Abstract
OBJECTIVES To develop and validate a radiomics-based model for predicting SOX9-positive hepatocellular carcinoma (HCC) using preoperative contrast-enhanced computed tomography (CT) images. METHODS From January 2013 to April 2017, patients with histologically proven HCC who received systemic sorafenib treatment after curative resection were retrospectively enrolled. Radiomic features were extracted from portal venous phase CT images and selected to build a radiomics score using logistic regression analysis. The factors associated with SOX9 expression were selected and combined by univariate and multivariate analyses to establish clinico-liver imaging (CL) model and clinico-liver imaging-radiomics (CLR) model. Diagnostic performance was measured by area under curve (AUC). Overall survival (OS) and recurrence-free survival (RFS) rates were compared using Kaplan-Meier method. RESULTS A total of 108 patients (training cohort: n = 80; validation cohort: n = 28) were enrolled. Multivariate analyses revealed that the albumin-bilirubin grade and tumor size were significant independent factors for predicting SOX9-positive HCCs and were included in the CL model. The CLR model integrating the radiomics score with albumin-bilirubin grade and tumor size showed better discriminative performance than the CL model with AUCs of 0.912 and 0.790 in the training and validation cohorts. Survival curves for RFS and OS showed that SOX9 expression was closely related to the prognosis of HCC patients. RFS and OS rates were significantly lower in patients with SOX9-positive than SOX9-negative (51.02% vs. 75.00% at 1-year RFS rates; 76.92% vs. 94.94% at 2-year OS rates). CONCLUSION Radiomics signatures may serve as noninvasive predictors for SOX9 status evaluation in patients with HCC and may aid in constructing individualized treatment strategies.
Collapse
Affiliation(s)
- Feng Che
- Department of Radiology, West China Hospital, Sichuan University, No 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Yi Wei
- Department of Radiology, West China Hospital, Sichuan University, No 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Qing Xu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qian Li
- Department of Radiology, West China Hospital, Sichuan University, No 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Tong Zhang
- Department of Radiology, West China Hospital, Sichuan University, No 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Li-Ye Wang
- Department of Research and Development, Shanghai United Imaging Intelligence Co., Ltd., Shanghai, China
| | - Man Li
- Department of Research and Development, Shanghai United Imaging Intelligence Co., Ltd., Shanghai, China
| | - Fang Yuan
- Department of Radiology, West China Hospital, Sichuan University, No 37, Guoxue Alley, Chengdu, 610041, Sichuan, China.
| | - Bin Song
- Department of Radiology, West China Hospital, Sichuan University, No 37, Guoxue Alley, Chengdu, 610041, Sichuan, China.
- Department of Radiology, Sanya People's Hospital, Sanya, Hainan, China.
| |
Collapse
|
|
6
|
Guo DZ, Zhang X, Zhang SQ, Zhang SY, Zhang XY, Yan JY, Dong SY, Zhu K, Yang XR, Fan J, Zhou J, Huang A. Single-cell tumor heterogeneity landscape of hepatocellular carcinoma: unraveling the pro-metastatic subtype and its interaction loop with fibroblasts. Mol Cancer 2024; 23:157. [PMID: 39095854 PMCID: PMC11295380 DOI: 10.1186/s12943-024-02062-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 07/05/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Tumor heterogeneity presents a formidable challenge in understanding the mechanisms driving tumor progression and metastasis. The heterogeneity of hepatocellular carcinoma (HCC) in cellular level is not clear. METHODS Integration analysis of single-cell RNA sequencing data and spatial transcriptomics data was performed. Multiple methods were applied to investigate the subtype of HCC tumor cells. The functional characteristics, translation factors, clinical implications and microenvironment associations of different subtypes of tumor cells were analyzed. The interaction of subtype and fibroblasts were analyzed. RESULTS We established a heterogeneity landscape of HCC malignant cells by integrated 52 single-cell RNA sequencing data and 5 spatial transcriptomics data. We identified three subtypes in tumor cells, including ARG1+ metabolism subtype (Metab-subtype), TOP2A+ proliferation phenotype (Prol-phenotype), and S100A6+ pro-metastatic subtype (EMT-subtype). Enrichment analysis found that the three subtypes harbored different features, that is metabolism, proliferating, and epithelial-mesenchymal transition. Trajectory analysis revealed that both Metab-subtype and EMT-subtype originated from the Prol-phenotype. Translation factor analysis found that EMT-subtype showed exclusive activation of SMAD3 and TGF-β signaling pathway. HCC dominated by EMT-subtype cells harbored an unfavorable prognosis and a deserted microenvironment. We uncovered a positive loop between tumor cells and fibroblasts mediated by SPP1-CD44 and CCN2/TGF-β-TGFBR1 interaction pairs. Inhibiting CCN2 disrupted the loop, mitigated the transformation to EMT-subtype, and suppressed metastasis. CONCLUSION By establishing a heterogeneity landscape of malignant cells, we identified a three-subtype classification in HCC. Among them, S100A6+ tumor cells play a crucial role in metastasis. Targeting the feedback loop between tumor cells and fibroblasts is a promising anti-metastatic strategy.
Collapse
Affiliation(s)
- De-Zhen Guo
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xin Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Sen-Quan Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Shi-Yu Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiang-Yu Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jia-Yan Yan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - San-Yuan Dong
- Department of Radiology, Zhongshan Hospital, Shanghai Institute of Medical Imaging, Fudan University, Shanghai, 200032, China
| | - Kai Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xin-Rong Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China.
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
| | - Ao Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China.
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| |
Collapse
|
|
7
|
van Luyk ME, Krotenberg Garcia A, Lamprou M, Suijkerbuijk SJE. Cell competition in primary and metastatic colorectal cancer. Oncogenesis 2024; 13:28. [PMID: 39060237 PMCID: PMC11282291 DOI: 10.1038/s41389-024-00530-5] [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: 01/19/2024] [Revised: 07/05/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
Adult tissues set the scene for a continuous battle between cells, where a comparison of cellular fitness results in the elimination of weaker "loser" cells. This phenomenon, named cell competition, is beneficial for tissue integrity and homeostasis. In fact, cell competition plays a crucial role in tumor suppression, through elimination of early malignant cells, as part of Epithelial Defense Against Cancer. However, it is increasingly apparent that cell competition doubles as a tumor-promoting mechanism. The comparative nature of cell competition means that mutational background, proliferation rate and polarity all factor in to determine the outcome of these processes. In this review, we explore the intricate and context-dependent involvement of cell competition in homeostasis and regeneration, as well as during initiation and progression of primary and metastasized colorectal cancer. We provide a comprehensive overview of molecular and cellular mechanisms governing cell competition and its parallels with regeneration.
Collapse
Affiliation(s)
- Merel Elise van Luyk
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Ana Krotenberg Garcia
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Maria Lamprou
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Saskia Jacoba Elisabeth Suijkerbuijk
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
| |
Collapse
|
|
8
|
Panda M, Biswal S, Biswal BK. Evodiamine potentiates cisplatin-induced cell death and overcomes cisplatin resistance in non-small-cell lung cancer by targeting SOX9-β-catenin axis. Mol Biol Rep 2024; 51:523. [PMID: 38630183 DOI: 10.1007/s11033-024-09477-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 03/25/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND In recent decades, phytotherapy has remained as a key therapeutic option for the treatment of various cancers. Evodiamine, an excellent phytocompound from Evodia fructus, exerts anticancer activity in several cancers by modulating drug resistance. However, the role of evodiamine in cisplatin-resistant NSCLC cells is not clear till now. Therefore, we have used evodiamine as a chemosensitizer to overcome cisplatin resistance in NSCLC. METHODS Here, we looked into SOX9 expression and how it affects the cisplatin sensitivity of cisplatin-resistant NSCLC cells. MTT and clonogenic assays were performed to check the cell proliferation. AO/EtBr and DAPI staining, ROS measurement assay, transfection, Western blot analysis, RT-PCR, Scratch & invasion, and comet assay were done to check the role of evodiamine in cisplatin-resistant NSCLC cells. RESULTS SOX9 levels were observed to be higher in cisplatin-resistant A549 (A549CR) and NCI-H522 (NCI-H522CR) compared to parental A549 and NCI-H522. It was found that SOX9 promotes cisplatin resistance by regulating β-catenin. Depletion of SOX9 restores cisplatin sensitivity by decreasing cell proliferation and cell migration and inducing apoptosis in A549CR and NCI-H522CR. After evodiamine treatment, it was revealed that evodiamine increases cisplatin-induced cytotoxicity in A549CR and NCI-H522CR cells through increasing intracellular ROS generation. The combination of both drugs also significantly inhibited cell migration by inhibiting epithelial to mesenchymal transition (EMT). Mechanistic investigation revealed that evodiamine resensitizes cisplatin-resistant cells toward cisplatin by decreasing the expression of SOX9 and β-catenin. CONCLUSION The combination of evodiamine and cisplatin may be a novel strategy for combating cisplatin resistance in NSCLC.
Collapse
Affiliation(s)
- Munmun Panda
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology, Rourkela, Odisha,, 769008, India
| | - Stuti Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology, Rourkela, Odisha,, 769008, India
| | - Bijesh K Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology, Rourkela, Odisha,, 769008, India.
| |
Collapse
|
|
9
|
Thng DKH, Hooi L, Siew BE, Lee KY, Tan IJW, Lieske B, Lin NS, Kow AWC, Wang S, Rashid MBMA, Ang C, Koh JJM, Toh TB, Tan KK, Chow EKH. A functional personalised oncology approach against metastatic colorectal cancer in matched patient derived organoids. NPJ Precis Oncol 2024; 8:52. [PMID: 38413740 PMCID: PMC10899621 DOI: 10.1038/s41698-024-00543-8] [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: 11/16/2023] [Accepted: 02/08/2024] [Indexed: 02/29/2024] Open
Abstract
Globally, colorectal cancer (CRC) is the third most frequently occurring cancer. Progression on to an advanced metastatic malignancy (metCRC) is often indicative of poor prognosis, as the 5-year survival rates of patients decline rapidly. Despite the availability of many systemic therapies for the management of metCRC, the long-term efficacies of these regimens are often hindered by the emergence of treatment resistance due to intratumoral and intertumoral heterogeneity. Furthermore, not all systemic therapies have associated biomarkers that can accurately predict patient responses. Hence, a functional personalised oncology (FPO) approach can enable the identification of patient-specific combinatorial vulnerabilities and synergistic combinations as effective treatment strategies. To this end, we established a panel of CRC patient-derived organoids (PDOs) as clinically relevant biological systems, of which three pairs of matched metCRC PDOs were derived from the primary sites (ptCRC) and metastatic lesions (mCRC). Histological and genomic characterisation of these PDOs demonstrated the preservation of histopathological and genetic features found in the parental tumours. Subsequent application of the phenotypic-analytical drug combination interrogation platform, Quadratic Phenotypic Optimisation Platform, in these pairs of PDOs identified patient-specific drug sensitivity profiles to epigenetic-based combination therapies. Most notably, matched PDOs from one patient exhibited differential sensitivity patterns to the rationally designed drug combinations despite being genetically similar. These findings collectively highlight the limitations of current genomic-driven precision medicine in guiding treatment strategies for metCRC patients. Instead, it suggests that epigenomic profiling and application of FPO could complement the identification of novel combinatorial vulnerabilities to target synchronous ptCRC and mCRC.
Collapse
Affiliation(s)
- Dexter Kai Hao Thng
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Lissa Hooi
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Bei En Siew
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Kai-Yin Lee
- Division of Colorectal Surgery, Department of Surgery, National University Hospital, National University Health System, Singapore, Singapore
| | - Ian Jse-Wei Tan
- Division of Colorectal Surgery, Department of Surgery, National University Hospital, National University Health System, Singapore, Singapore
| | - Bettina Lieske
- Division of Colorectal Surgery, Department of Surgery, National University Hospital, National University Health System, Singapore, Singapore
| | - Norman Sihan Lin
- Division of Colorectal Surgery, Department of Surgery, National University Hospital, National University Health System, Singapore, Singapore
| | - Alfred Wei Chieh Kow
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, National University Hospital, National University Health System, Singapore, Singapore
| | - Shi Wang
- Department of Pathology, National University Hospital, National University Health System, Singapore, Singapore
| | | | - Chermaine Ang
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jasmin Jia Min Koh
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tan Boon Toh
- The N.1 Institute for Health, National University of Singapore, Singapore, Singapore
- The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ker-Kan Tan
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Division of Colorectal Surgery, Department of Surgery, National University Hospital, National University Health System, Singapore, Singapore.
| | - Edward Kai-Hua Chow
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- The N.1 Institute for Health, National University of Singapore, Singapore, Singapore.
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore.
| |
Collapse
|
|
10
|
Wang J, Wan X, Le Q. Cross-regulation between SOX9 and the canonical Wnt signalling pathway in stem cells. Front Mol Biosci 2023; 10:1250530. [PMID: 37664185 PMCID: PMC10469848 DOI: 10.3389/fmolb.2023.1250530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 08/09/2023] [Indexed: 09/05/2023] Open
Abstract
SOX9, a member of the SRY-related HMG-box transcription factors, has been reported to critically regulate fetal development and stem cell homeostasis. Wnt signalling is a highly conserved signalling pathway that controls stem cell fate decision and stemness maintenance throughout embryonic development and adult life. Many studies have shown that the interactions between SOX9 and the canonical Wnt signalling pathway are involved in many of the physiological and pathological processes of stem cells, including organ development, the proliferation, differentiation and stemness maintenance of stem cells, and tumorigenesis. In this review, we summarize the already-known molecular mechanism of cross-interactions between SOX9 and the canonical Wnt signalling pathway, outline its regulatory effects on the maintenance of homeostasis in different types of stem cells, and explore its potential in translational stem cell therapy.
Collapse
Affiliation(s)
- Jiajia Wang
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China
| | - Xichen Wan
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China
| | - Qihua Le
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China
- Research Center, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China
- Myopia Key Laboratory of Ministry of Health, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China
| |
Collapse
|
|
11
|
Yang X, Xu G, Liu X, Zhou G, Zhang B, Wang F, Wang L, Li B, Li L. Carbon nanomaterial-involved EMT and CSC in cancer. REVIEWS ON ENVIRONMENTAL HEALTH 2023; 38:1-13. [PMID: 34619029 DOI: 10.1515/reveh-2021-0082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/26/2021] [Indexed: 06/13/2023]
Abstract
Carbon nanomaterials (CNMs) are ubiquitous in our daily lives because of the outstanding physicochemical properties. CNMs play curial parts in industrial and medical fields, however, the risks of CNMs exposure to human health are still not fully understood. In view of, it is becoming extremely difficult to ignore the existence of the toxicity of CNMs. With the increasing exploitation of CNMs, it's necessary to evaluate the potential impact of these materials on human health. In recent years, more and more researches have shown that CNMs are contributed to the cancer formation and metastasis after long-term exposure through epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) which is associated with cancer progression and invasion. This review discusses CNMs properties and applications in industrial and medical fields, adverse effects on human health, especially the induction of tumor initiation and metastasis through EMT and CSCs procedure.
Collapse
Affiliation(s)
- Xiaotong Yang
- Tianjin Medical University General Hospital, Tianjin, China
| | - Gongquan Xu
- Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaolong Liu
- Tianjin Medical University General Hospital, Tianjin, China
| | - Guiming Zhou
- Tianjin Medical University General Hospital, Tianjin, China
| | - Bing Zhang
- Rushan Hospital of Traditional Chinese Medicine, Weihai, China
| | - Fan Wang
- Tianjin Medical University General Hospital, Tianjin, China
| | - Lingjuan Wang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Bin Li
- Tianjin Medical University General Hospital, Tianjin, China
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
| | - Liming Li
- Tianjin Medical University General Hospital, Tianjin, China
| |
Collapse
|
|
12
|
SOX9 Expression Is Superior to Other Stem Cell Markers K19 and EpCAM in Predicting Prognosis in Hepatocellular Carcinoma. Am J Surg Pathol 2023; 47:1-11. [PMID: 36322988 DOI: 10.1097/pas.0000000000001990] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Various stem cell markers (eg, epithelial cell adhesion molecule [EpCAM], cytokeratin 19 [K19]) have been reported as predictors of poor prognosis in hepatocellular carcinoma (HCC). However, the data remain limited, particularly in Western populations, and are often contradictory. In this study, the prognostic value of positive SOX9 immunohistochemistry was compared with that of more established markers EpCAM and K19 in a large cohort (n=216) of North American patients. The independent HCC cohort in The Cancer Gene Atlas (n=360) was utilized to validate our findings. Finally, molecular signatures associated with SOX9 -high HCC were determined. We found that the expression of SOX9, but not EpCAM or K19, was associated with worse overall survival and disease-free survival (DFS) and was an independent prognostic factor for DFS in our North American cohort, in which hepatitis C infection was the most common underlying etiology. High SOX9 mRNA level, but not increased expression of EpCAM mRNA or K19 mRNA, was also associated with worse DFS and was an independent prognostic factor for DFS in The Cancer Gene Atlas cohort. This group had underlying causes, including an increased incidence of hepatitis B, significantly different from our initial cohort. High SOX9 mRNA level is associated with molecular pathways important in HCC pathogenesis. Increased SOX9 expression is clinically and biologically relevant for HCC arising in patients with a variety of underlying etiologies. Immunohistochemistry for SOX9 is a reliable proxy for increased SOX9 mRNA and can be used to predict prognosis in HCC cases.
Collapse
|
|
13
|
Zhang K, Yu M, Liu H, Hui Z, Yang N, Bi X, Sun L, Lin R, Lü G. Upregulated TUBG1 expression is correlated with poor prognosis in hepatocellular carcinoma. PeerJ 2022; 10:e14415. [PMID: 36523478 PMCID: PMC9745943 DOI: 10.7717/peerj.14415] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 10/28/2022] [Indexed: 12/11/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) development is a complex pathological process. Tubulin gamma 1 (TUBG1) plays an oncogenic role in several human cancers; however, its functional role in HCC tumorigenesis remains unknown. Methods Herein we first evaluated the gene expression levels of TUBG1 in HCC using data from The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis databases. We then elucidated the association between TUBG1 gene expression levels and survival rates of patients with HCC. Cell cycle, proliferation, transwell migration, and matrigel invasion assays were used to study the effects of TUBG1 on the malignant phenotypes of HCC cells. Results Based on the data obtained from the aforementioned databases and our in vitro experiments, TUBG1 was found to be overexpressed in HCC and patients with high TUBG1 expression levels showed a remarkably poor overall survival rate. In addition, the expression of TUBG1 significantly promoted the malignant phenotypes of HCC cells in vitro. Gene ontology term enrichment analysis revealed that co-regulated genes were enriched in biological processes mainly involved in chromosome segregation, chromosomal region, and chromatin binding; moreover, Kyoto Encyclopedia of Genes and Genome pathway analysis showed that they were mainly involved in cell cycle, oocyte meiosis, platinum drug resistance, and the p53 signaling pathway. Conclusions We report that TUBG1 is an important oncogene in HCC. It promotes HCC progression and may serve as a potential prognostic biomarker for HCC. Future studies are warranted to unveil molecular biological mechanisms underlying TUBG1 carcinogenesis.
Collapse
Affiliation(s)
- Kainan Zhang
- Xinjiang Medical University, Urumqi, Xinjiang, China,State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Mengsi Yu
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Hui Liu
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Zhao Hui
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Ning Yang
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiaojuan Bi
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Li Sun
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - RenYong Lin
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Guodong Lü
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China,College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, China
| |
Collapse
|
|
14
|
Wong TLM, Wong TL, Zhou L, Man K, Purcell J, Lee TK, Yun JP, Ma S. Protein Tyrosine Kinase 7 (PTK7) Promotes Metastasis in Hepatocellular Carcinoma via SOX9 Regulation and TGF-β Signaling. Cell Mol Gastroenterol Hepatol 2022; 15:13-37. [PMID: 36202326 PMCID: PMC9672488 DOI: 10.1016/j.jcmgh.2022.09.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS Metastasis is found in most advanced hepatocellular carcinoma (HCC) patients, and it drives tumor recurrence and systemic failure. There is no effective treatment owing to its complex biological features. Many of the molecular drivers of metastasis are crucial players in normal physiology but behave unconventionally during cancer progression. Targeting these molecular drivers for therapy and differentiating them from a physiological background require a detailed examination of the novel mechanisms involved in their activation during metastasis. METHODS Publicly available transcriptomic data such as that of TCGA-LIHC and Gene Expression Omnibus were utilized to identify novel targets upregulated in advanced and metastatic HCC. Validation of candidates was assisted by immunohistochemistry performed on tissue microarrays derived from more than 100 HCC patients. Expression of protein tyrosine kinase 7 (PTK7) was studied under the treatment of transforming growth factor-β1 and knockdown of SRY-Box Transcription Factor 9 (SOX9) to delineate upstream regulation, while CRISPR-mediated knockout and lentiviral overexpression of PTK7 in HCC cells were performed to study their functional and signaling consequences. Manipulated HCC cells were injected into mice models either by orthotopic or tail-vein injection to observe for any in vivo pro-metastatic effects. RESULTS PTK7 was discovered to be the kinase most significantly upregulated in advanced and metastatic HCC, at both transcriptomic and proteomic level. Bioinformatic analyses and functional assays performed in HCC cell lines revealed transforming growth factor-β signaling and SOX9 to be important activators of PTK7 expression. Functionally, enrichment of PTK7 expression could positively regulate metastatic potential of HCC cells in vitro and in lung metastasis models performed in immunodeficient mice. The up-regulation of PTK7 recruited the epithelial-mesenchymal transition components, zinc finger protein SNAI2 (SLUG) and zinc finger E-box-binding homeobox 1 (ZEB1). CONCLUSIONS Our study proposes PTK7 as a novel molecular driver in metastatic HCC, particularly in a transforming growth factor-β-activated microenvironment. The preferential expression of PTK7 resulted in a previously unobserved regulatory effect on the recruitment of epithelial-mesenchymal transition components, which established PTK7 as a potential determinant of specific epithelial-mesenchymal transition status. Therefore, our data support the continual development of PTK7-targeted agents as antimetastatic therapies.
Collapse
Affiliation(s)
- Tsz Lam Matthew Wong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Tin-Lok Wong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Lei Zhou
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Kwan Man
- Department of Surgery, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | | | - Terence K. Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
| | - Jing-Ping Yun
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Stephanie Ma
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong; The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
| |
Collapse
|
|
15
|
Deubiquitylase OTUD1 confers Erlotinib sensitivity in non-small cell lung cancer through inhibition of nuclear translocation of YAP1. Cell Death Dis 2022; 8:403. [PMID: 36182943 PMCID: PMC9526728 DOI: 10.1038/s41420-022-01119-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 06/30/2022] [Accepted: 07/05/2022] [Indexed: 12/24/2022]
Abstract
Evidence exists suggesting tumor-inhibiting properties of deubiquitylase OTUD1 in various malignancies. We herein investigated the anti-tumor effect and clarified the downstream mechanisms of OTUD1 in the chemoresistance of non-small cell lung cancer (NSCLC) cells. Expression of OTUD1 was examined in NSCLC (PC-9 cells) and erlotinib-resistant NSCLC (PC-9/ER) cell lines. OTUD1 was bioinformatically predicted to be weakly expressed in NSCLC tissue samples and verified in PC-9/ER cells. PC-9/ER cells were subsequently subjected to ectopic expression of OTUD1 alone or combined with SOX9 to dissect out the effect of OTUD1 on the proliferation, chemoresistance and apoptosis in vitro and in vivo. OTUD1 upregulation sensitized NSCLC cells to erlotinib both in vitro and in vivo. In the presence of OTUD1 overexpression, nuclear translocation of YAP1 was inhibited and its expression was inactivated. This effect of OTUD1 was associated with the decreased ubiquitination level of YAP1. SOX9/SPP1 inactivation was the consequence of inhibited nuclear translocation of YAP1. Overexpression of SOX9 reversed the inhibitory effect of OTUD1 on the resistance of NSCLC cells to erlotinib. In conclusion, our study reveals that OTUD1 potentially acts as a tumor suppressor and suppresses erlotinib resistance of NSCLC through the YAP1/SOX9/SPP1 axis, suggesting that OTUD1 may serve as a target for reducing chemoresistance for NSCLC.
Collapse
|
|
16
|
Ievlev V, Jensen-Cody CC, Lynch TJ, Pai AC, Park S, Shahin W, Wang K, Parekh KR, Engelhardt JF. Sox9 and Lef1 Regulate the Fate and Behavior of Airway Glandular Progenitors in Response to Injury. Stem Cells 2022; 40:778-790. [PMID: 35639980 PMCID: PMC9406614 DOI: 10.1093/stmcls/sxac038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 05/12/2022] [Indexed: 11/12/2022]
Abstract
Cartilaginous airways of larger mammals and the mouse trachea contain at least 3 well-established stem cell compartments, including basal cells of the surface airway epithelium (SAE) and ductal and myoepithelial cells of the submucosal glands (SMG). Here we demonstrate that glandular Sox9-expressing progenitors capable of SAE repair decline with age in mice. Notably, Sox9-lineage glandular progenitors produced basal and ciliated cells in the SAE, but failed to produce secretory cells. Lef1 was required for glandular Sox9 lineage contribution to SAE repair, and its deletion significantly reduced proliferation following injury. By contrast, in vivo deletion of Sox9 enhanced proliferation of progenitors in both the SAE and SMG shortly following injury, but these progenitors failed to proliferate in vitro in the absence of Sox9, similar to that previously shown for Lef1 deletion. In cystic fibrosis ferret airways, Sox9 expression inversely correlated with Ki67 proliferative marker expression in SMG and the SAE. Using in vitro and ex vivo models, we demonstrate that Sox9 is extinguished as glandular progenitors exit ducts and proliferate on the airway surface and that Sox9 is required for migration and proper differentiation of SMG, but not surface airway, progenitors. We propose a model whereby Wnt/Lef1 and Sox9 signals differentially regulate the proliferative and migratory behavior of glandular progenitors, respectively.
Collapse
Affiliation(s)
- Vitaly Ievlev
- Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA
| | | | - Thomas J Lynch
- Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA
| | - Albert C Pai
- Department of Cardiothoracic Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Soo Park
- Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA
| | - Weam Shahin
- Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA
| | - Kai Wang
- Department of Biostatistics, University of Iowa College of Public Health, Iowa City, IA, USA
| | - Kalpaj R Parekh
- Department of Cardiothoracic Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - John F Engelhardt
- Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA
| |
Collapse
|
|
17
|
Tu WL, Chih YC, Shih YT, Yu YR, You LR, Chen CM. Context-specific roles of diphthamide deficiency in hepatocellular carcinogenesis. J Pathol 2022; 258:149-163. [PMID: 35781884 DOI: 10.1002/path.5986] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 06/13/2022] [Accepted: 07/01/2022] [Indexed: 11/07/2022]
Abstract
Diphthamide biosynthesis protein 1 (DPH1) is biochemically involved in the first step of diphthamide biosynthesis, a post-translational modification of eukaryotic elongation factor 2 (EEF2). Earlier studies showed that DPH1, also known as ovarian cancer-associated gene 1 (OVCA1), is involved in ovarian carcinogenesis. However, the role of DPH1 in hepatocellular carcinoma (HCC) remains unclear. To investigate the impact of DPH1 in hepatocellular carcinogenesis, we have performed data mining from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. We found that reduced DPH1 levels were associated with advanced stages and poor survival of patients with HCC. Also, we generated hepatocyte-specific Dph1 deficient mice and showed that diphthamide deficient EEF2 resulted in a reduced translation elongation rate in the hepatocytes and let to mild liver damage with fatty accumulation. After N-diethylnitrosamine (DEN) -induced acute liver injury, p53-mediated pericentral hepatocyte death was increased, and compensatory proliferation was reduced in Dph1-deficient mice. Consistent with these effects, Dph1 deficiency decreased the incidence of DEN-induced pericentral-derived HCC and revealed a protective effect against p53 loss. In contrast, Dph1 deficiency combined with Trp53- or Trp53/Pten-deficient hepatocytes led to increased tumor loads associated with KRT19 (K19)-positive periportal-like cell expansion in mice. Further gene set enrichment analysis also revealed that HCC patients with lower levels of DPH1 and TP53 expression had enriched gene-sets related to the cell cycle and K19-upregulated HCC. Additionally, liver tumor organoids obtained from 6-month-old Pten/Trp53/Dph1-triple-mutant mice had a higher frequency of organoid re-initiation cells and higher proliferative index compared with those of the Pten/Trp53-double-mutant. Pten/Trp53/Dph1-triple-mutant liver tumor organoids showed expression of genes associated with stem/progenitor phenotypes, including Krt19 and Prominin-1 (Cd133) progenitor markers, combined with low hepatocyte-expressed fibrinogen genes. These findings indicate that diphthamide deficiency differentially regulates hepatocellular carcinogenesis, which inhibits pericentral hepatocytes-derived tumor and promotes periportal progenitors-associated liver tumors. This article is protected by copyright. All rights reserved.
Collapse
Affiliation(s)
- Wei-Ling Tu
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming, Chiao Tung University, Taipei, Taiwan
| | - Yu-Chan Chih
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming, Chiao Tung University, Taipei, Taiwan
| | - Ya-Tung Shih
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming, Chiao Tung University, Taipei, Taiwan
| | - Yi-Ru Yu
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming, Chiao Tung University, Taipei, Taiwan
| | - Li-Ru You
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chun-Ming Chen
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming, Chiao Tung University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| |
Collapse
|
|
18
|
Wang Z, Zhao Z, Xia Y, Cai Z, Wang C, Shen Y, Liu R, Qin H, Jia J, Yuan G. Potential biomarkers in the fibrosis progression of nonalcoholic steatohepatitis (NASH). J Endocrinol Invest 2022; 45:1379-1392. [PMID: 35226336 DOI: 10.1007/s40618-022-01773-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/17/2022] [Indexed: 12/13/2022]
Abstract
PURPOSE Fibrosis is the only histological feature reflecting the severity and prognosis of nonalcoholic steatohepatitis (NASH). We aim to explore novel genes associated with fibrosis progression in NASH. METHODS Two human RNA-seq datasets were downloaded from the public database. Weighted gene co-expression network analysis (WGCNA) was used to identify their co-expressed modules and further bioinformatics analysis was performed to identify hub genes within the modules. Finally, based on two single-cell RNA-seq datasets from mice and one microarray dataset from human, we further observed the expression of hub genes in different cell clusters and liver tissues. RESULTS 7 hub genes (SPP1, PROM1, SOX9, EPCAM, THY1, CD34 and MCAM) associated with fibrosis progression were identified. Single-cell RNA-seq analysis revealed that those hub genes were expressed by different cell clusters such as cholangiocytes, natural killer (NK) cells, and hepatic stellate cells (HSCs). We also found that SPP1 and CD34 serve as markers of different HSCs clusters, which are associated with inflammatory response and fibrogenesis, respectively. Further study suggested that SPP1, SOX9, MCAM and THY1 might be related to NASH-associated hepatocellular carcinoma (HCC). Receiver operating characteristic (ROC) analysis showed that the high expression of these genes could well predict the occurrence of HCC. At the same time, there were significant differences in metabolism-related pathway changes between different HCC subtypes, and SOX9 may be involved in these changes. CONCLUSIONS The present study identified novel genes associated with NASH fibrosis and explored their effects on fibrosis from a single-cell perspective that might provide new ideas for the early diagnosis, monitoring, evaluation, and prediction of fibrosis progression in NASH.
Collapse
Affiliation(s)
- Z Wang
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China
| | - Z Zhao
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China
| | - Y Xia
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China
| | - Z Cai
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China
| | - C Wang
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China
| | - Y Shen
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China
| | - R Liu
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China
| | - H Qin
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China
| | - J Jia
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China.
| | - G Yuan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China.
| |
Collapse
|
|
19
|
Kopantzev E, Kondratyeva L, Kopantseva M, Kashkin K, Gnatenko D, Grigorieva E, Alekseenko I, Safina D, Chernov I. SOX9 Protein in Pancreatic Cancer Regulates Multiple Cellular Networks in a Cell-Specific Manner. Biomedicines 2022; 10:biomedicines10071466. [PMID: 35884771 PMCID: PMC9312990 DOI: 10.3390/biomedicines10071466] [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: 05/26/2022] [Revised: 06/16/2022] [Accepted: 06/17/2022] [Indexed: 11/29/2022] Open
Abstract
SOX9 is upregulated in the majority of pancreatic ductal adenocarcinoma cases. It is hypothesized that the increased expression of SOX9 is necessary for the formation and maintenance of tumor phenotypes in pancreatic cancer cells. In our research, we studied six pancreatic cancer cell lines, which displayed varying levels of differentiation and a range of oncogenic mutations. We chose the method of downregulation of SOX9 expression via siRNA transfection as the main method for investigating the functional role of the SOX9 factor in pancreatic cancer cells. We discovered that the downregulation of SOX9 expression in the cell lines leads to cell-line-specific changes in the expression levels of epithelial and mesenchymal protein markers. Additionally, the downregulation of SOX9 expression had a specific effect on the expression of pancreatic developmental master genes. SOX9 downregulation had the greatest effect on the expression levels of the protein regulators of cell proliferation. In three of the four cell lines studied, the transfection of siSOX9 led to a significant decrease in proliferative activity and to the activation of proapoptotic caspases in transfected cells. The acquired results demonstrate that the SOX9 protein exerts its multiple functions as a pleiotropic regulator of differentiation and a potential promoter of tumor growth in a cell-specific manner in pancreatic cancer cells.
Collapse
Affiliation(s)
- Eugene Kopantzev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (M.K.); (K.K.); (D.G.); (E.G.); (I.A.); (I.C.)
- Correspondence: (E.K.); (L.K.); Tel.: +7-(916)-066-8752 (E.K.); +7-(965)-315-7274 (L.K.); Fax: +7-(495)-330-6538 (L.K.)
| | - Liya Kondratyeva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (M.K.); (K.K.); (D.G.); (E.G.); (I.A.); (I.C.)
- Correspondence: (E.K.); (L.K.); Tel.: +7-(916)-066-8752 (E.K.); +7-(965)-315-7274 (L.K.); Fax: +7-(495)-330-6538 (L.K.)
| | - Marina Kopantseva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (M.K.); (K.K.); (D.G.); (E.G.); (I.A.); (I.C.)
| | - Kirill Kashkin
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (M.K.); (K.K.); (D.G.); (E.G.); (I.A.); (I.C.)
| | - Dmitry Gnatenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (M.K.); (K.K.); (D.G.); (E.G.); (I.A.); (I.C.)
| | - Elizaveta Grigorieva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (M.K.); (K.K.); (D.G.); (E.G.); (I.A.); (I.C.)
| | - Irina Alekseenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (M.K.); (K.K.); (D.G.); (E.G.); (I.A.); (I.C.)
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, Ploshchad’ Akademika Kurchatova, 123182 Moscow, Russia;
| | - Dina Safina
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, Ploshchad’ Akademika Kurchatova, 123182 Moscow, Russia;
| | - Igor Chernov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ulitsa Miklukho-Maklaya, 117997 Moscow, Russia; (M.K.); (K.K.); (D.G.); (E.G.); (I.A.); (I.C.)
| |
Collapse
|
|
20
|
Ren Z, Chen Y, Shi L, Shao F, Sun Y, Ge J, Zhang J, Zang Y. Sox9/CXCL5 axis facilitates tumour cell growth and invasion in hepatocellular carcinoma. FEBS J 2022; 289:3535-3549. [PMID: 35038357 DOI: 10.1111/febs.16357] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 12/20/2021] [Accepted: 01/13/2022] [Indexed: 12/11/2022]
Abstract
High rates of metastasis and postsurgical recurrence contribute to the higher mortality of hepatocellular carcinoma (HCC), partly due to cancer stem cell (CSC)-dependent tumorigenesis and metastasis. Sex-determining region Y-box 9 (Sox9) has been previously characterized as a candidate CSC marker of HCC. Here, we observed that the increase of Sox9 significantly promoted HCC cell growth and invasion in cell cultures, whereas knockdown of Sox9 showed the opposite effects, suggesting that Sox9 may regulate the proliferation and invasion of hepatoma cells in an autocrine manner. RNA sequencing, together with functional assays and clinical analyses, identified CXCL5 as a key mediator downstream of Sox9 in HCC cells. Mechanistic studies revealed that Sox9 induced CXCL5 expression by directly binding to a promoter region. Using gain- and loss-of-function approaches, we demonstrated that the intrinsic effective role of Sox9 in hepatoma cell growth and invasion depended on CXCL5, and that blockade of CXCL5/CXCR2 signalling abolished Sox9-triggered HCC cell proliferation and migration. Furthermore, the Sox9/CXCL5 axis activated PI3K-AKT and ERK1/2 signalling which are implicated in regulating HCC cell proliferation and invasion. Finally, the Sox9/CXCL5 axis contributed to the infiltration of neutrophils and macrophages in both tumour and peritumoral tissues from the orthotopic xenograft model. In summary, our data identify the Sox9/CXCL5 axis as an endogenous factor in controlling HCC cell growth and invasion, thereby raising the possibility of pharmacologic intervention with CXCL5/CXCR2 pathway inhibitors in therapy for HCC patients with higher Sox9 expression.
Collapse
Affiliation(s)
- Zhengrong Ren
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, China
| | - Yu Chen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, China
| | - Lei Shi
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, China
| | - Fang Shao
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, China
| | - Yanyan Sun
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, China
| | - Jia Ge
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, China
| | - Junfeng Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, China
| | - Yuhui Zang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, China
| |
Collapse
|
|
21
|
Luo W, Nagaria TS, Sun H, Ma J, Lombardo JL, Bassett R, Cao AC, Tan D. Expression and Potential Prognostic Value of SOX9, MCL-1 and SPOCK1 in Gastric Adenocarcinoma. Pathol Oncol Res 2022; 28:1610293. [PMID: 35221802 PMCID: PMC8863590 DOI: 10.3389/pore.2022.1610293] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 01/19/2022] [Indexed: 11/21/2022]
Abstract
Gastric cancer is a common malignancy and remains one of the leading causes of cancer-related deaths, though its incidence is in decline in most developed countries. One of the major challenges of treating gastric cancer is tumor heterogeneity, which portends a high degree of prognostic variance and the necessity for different treatment modalities. Tumor heterogeneity is at least in part due to divergent differentiation of tumor cells to clones harboring different molecular alterations. Here we studied the expression of emerging prognostic markers SOX9, MCL-1, and SPOCK1 (Testican-1) in a cohort of gastric cancer by immunohistochemistry and investigated how individual biomarkers and their combinations predict disease prognosis. We found frequent expression of SPOCK1 (in both nuclei and cytoplasm), MCL-1 and SOX9 in gastric cancer. In univariate analysis, nuclear SPOCK1 expression and pathologic TNM stage were negative prognostic markers in this cohort. In multivariate analysis, SOX9 expression stood out as a predictor of poor prognosis. Further subgroup analysis suggested prognostic value of SOX9 expression in poorly differentiated gastric adenocarcinoma. MCL-1 showed no prognostic role in this cohort.
Collapse
Affiliation(s)
- Wenyi Luo
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.,Department of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Teddy S Nagaria
- Department of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States.,Department of Pathology, McGill University, Montreal, QC, Canada
| | - Hongxia Sun
- Department of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States.,Department of Pathology and Laboratory Medicine, University of Texas McGovern Medical School at Houston, Houston, TX, United States
| | - Junsheng Ma
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jamie L Lombardo
- Department of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States.,Department of Pathology, Walter Reed National Military Medical Center, Bethesda, MD, United States
| | - Roland Bassett
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Austin C Cao
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Dongfeng Tan
- Department of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| |
Collapse
|
|
22
|
Advance of SOX Transcription Factors in Hepatocellular Carcinoma: From Role, Tumor Immune Relevance to Targeted Therapy. Cancers (Basel) 2022; 14:cancers14051165. [PMID: 35267473 PMCID: PMC8909699 DOI: 10.3390/cancers14051165] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/12/2022] [Accepted: 02/18/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the deadliest human health burdens worldwide. However, the molecular mechanism of HCC development is still not fully understood. Sex determining region Y-related high-mobility group box (SOX) transcription factors not only play pivotal roles in cell fate decisions during development but also participate in the initiation and progression of cancer. Given the significance of SOX factors in cancer and their ‘undruggable’ properties, we summarize the role and molecular mechanism of SOX family members in HCC and the regulatory effect of SOX factors in the tumor immune microenvironment (TIME) of various cancers. For the first time, we analyze the association between the levels of SOX factors and that of immune components in HCC, providing clues to the pivotal role of SOX factors in the TIME of HCC. We also discuss the opportunities and challenges of targeting SOX factors for cancer. Abstract Sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) factors belong to an evolutionarily conserved family of transcription factors that play essential roles in cell fate decisions involving numerous developmental processes. In recent years, the significance of SOX factors in the initiation and progression of cancers has been gradually revealed, and they act as potential therapeutic targets for cancer. However, the research involving SOX factors is still preliminary, given that their effects in some leading-edge fields such as tumor immune microenvironment (TIME) remain obscure. More importantly, as a class of ‘undruggable’ molecules, targeting SOX factors still face considerable challenges in achieving clinical translation. Here, we mainly focus on the roles and regulatory mechanisms of SOX family members in hepatocellular carcinoma (HCC), one of the fatal human health burdens worldwide. We then detail the role of SOX members in remodeling TIME and analyze the association between SOX members and immune components in HCC for the first time. In addition, we emphasize several alternative strategies involved in the translational advances of SOX members in cancer. Finally, we discuss the alternative strategies of targeting SOX family for cancer and propose the opportunities and challenges they face based on the current accumulated studies and our understanding.
Collapse
|
|
23
|
Carrasco-Garcia E, Lopez L, Moncho-Amor V, Carazo F, Aldaz P, Collado M, Bell D, Gaafar A, Karamitopoulou E, Tzankov A, Hidalgo M, Rubio Á, Serrano M, Lawrie CH, Lovell-Badge R, Matheu A. SOX9 Triggers Different Epithelial to Mesenchymal Transition States to Promote Pancreatic Cancer Progression. Cancers (Basel) 2022; 14:cancers14040916. [PMID: 35205666 PMCID: PMC8870732 DOI: 10.3390/cancers14040916] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Pancreatic cancers are lethal types of cancer. A majority of patients progress to an advanced and metastatic disease, which remains a major clinical problem. Therefore, it is crucial to identify critical regulators to help predict the disease progression and to develop more efficacious therapeutic approaches. In this work we found that an increased expression of the developmental factor SOX9 is associated with metastasis, a poor prognosis and resistance to therapy in pancreatic ductal adenocarcinoma patients and in cell cultures. We also found that this effect is at least in part due to the ability of SOX9 to regulate the activity of stem cell factors, such as BMI1, in addition to those involved in EMT and metastasis. Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers mainly due to spatial obstacles to complete resection, early metastasis and therapy resistance. The molecular events accompanying PDAC progression remain poorly understood. SOX9 is required for maintaining the pancreatic ductal identity and it is involved in the initiation of pancreatic cancer. In addition, SOX9 is a transcription factor linked to stem cell activity and is commonly overexpressed in solid cancers. It cooperates with Snail/Slug to induce epithelial-mesenchymal transition (EMT) during neural development and in diseases such as organ fibrosis or different types of cancer. Methods: We investigated the roles of SOX9 in pancreatic tumor cell plasticity, metastatic dissemination and chemoresistance using pancreatic cancer cell lines as well as mouse embryo fibroblasts. In addition, we characterized the clinical relevance of SOX9 in pancreatic cancer using human biopsies. Results: Gain- and loss-of-function of SOX9 in PDAC cells revealed that high levels of SOX9 increased migration and invasion, and promoted EMT and metastatic dissemination, whilst SOX9 silencing resulted in metastasis inhibition, along with a phenotypic reversion to epithelial features and loss of stemness potential. In both contexts, EMT factors were not altered. Moreover, high levels of SOX9 promoted resistance to gemcitabine. In contrast, overexpression of SOX9 was sufficient to promote metastatic potential in K-Ras transformed MEFs, triggering EMT associated with Snail/Slug activity. In clinical samples, SOX9 expression was analyzed in 198 PDAC cases by immunohistochemistry and in 53 patient derived xenografts (PDXs). SOX9 was overexpressed in primary adenocarcinomas and particularly in metastases. Notably, SOX9 expression correlated with high vimentin and low E-cadherin expression. Conclusions: Our results indicate that SOX9 facilitates PDAC progression and metastasis by triggering stemness and EMT.
Collapse
Affiliation(s)
- Estefania Carrasco-Garcia
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (L.L.); (V.M.-A.); (P.A.)
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), 28029 Madrid, Spain
- Correspondence: (E.C.-G.); (A.M.); Tel.: +34-943-006073 (E.C.-G. & A.M.); Fax: +34-943-006250 (E.C.-G. & A.M.)
| | - Lidia Lopez
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (L.L.); (V.M.-A.); (P.A.)
| | - Veronica Moncho-Amor
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (L.L.); (V.M.-A.); (P.A.)
- The Francis Crick Institute, London NW1 1AT, UK; (D.B.); (R.L.-B.)
| | - Fernando Carazo
- School of Engineering, University of Navarra, 20009 San Sebastian, Spain; (F.C.); (Á.R.)
| | - Paula Aldaz
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (L.L.); (V.M.-A.); (P.A.)
| | - Manuel Collado
- Health Research Institute of Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), 15706 Santiago de Compostela, Spain;
| | - Donald Bell
- The Francis Crick Institute, London NW1 1AT, UK; (D.B.); (R.L.-B.)
| | - Ayman Gaafar
- Department of Pathology, Cruces University Hospital, 48903 Barakaldo, Spain;
| | | | - Alexandar Tzankov
- Institute of Pathology, University Hospital Basel, 4056 Basel, Switzerland;
| | - Manuel Hidalgo
- Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain;
- New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY 10065, USA
| | - Ángel Rubio
- School of Engineering, University of Navarra, 20009 San Sebastian, Spain; (F.C.); (Á.R.)
| | - Manuel Serrano
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain;
- Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain
| | - Charles H. Lawrie
- Molecular Oncology Group, Biodonostia Institute, 20014 San Sebastian, Spain;
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
| | | | - Ander Matheu
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (L.L.); (V.M.-A.); (P.A.)
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), 28029 Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
- Correspondence: (E.C.-G.); (A.M.); Tel.: +34-943-006073 (E.C.-G. & A.M.); Fax: +34-943-006250 (E.C.-G. & A.M.)
| |
Collapse
|
|
24
|
Guo C, Zhou S, Yi W, Yang P, Li O, Liu J, Peng C. SOX9/MKLN1-AS Axis Induces Hepatocellular Carcinoma Proliferation and Epithelial-Mesenchymal Transition. Biochem Genet 2022; 60:1914-1933. [PMID: 35138470 DOI: 10.1007/s10528-022-10196-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 01/25/2022] [Indexed: 01/12/2023]
Abstract
SOX9, as a transcript factor, has been confirmed to boost proliferation and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC), but the underlying mechanism remains incompletely elucidated. A bioinformatics analysis web, Jaspar, manifested that SOX9 can transcriptionally regulate an lncRNA, MKLN1-AS. To determine the role of MKLN1-AS in HCC, this study measured MKLN1-AS expression in HCC and the paracancerous tissues and conducted a series of assays, including MTT, colony formation, and transwell assays, in vitro. EMT of HCC was evaluated by E-cadherin and vimentin protein levels. The regulatory effect of SOX9 on MKLN1-AS was determined using dual luciferase reporter and ChIP assays. Both MKLN1-AS and SOX9 were up-regulated in HCC tissues compared to paracancerous tissues. SOX9 promoted cell viability, proliferation, invasion, and EMT of HCCs, but these promoting effects of SOX9 were attenuated after the knockdown of MKLN1-AS. Overexpression of SOX9 increased MKLN1-AS in HCCs, whereas silencing SOX9 decreased MKLN1-AS expression. According to dual luciferase reporter and ChIP assays, SOX9 can bind to the promoter of MKLN1-AS gene to stimulate the expression. MKLN1-AS is transcriptionally regulated by SOX9 and mediates the effects of SOX9 on the proliferation and EMT of HCCs.
Collapse
Affiliation(s)
- Chao Guo
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Hunan Normal University, Hunan Provincial People's Hospital, No.61 Jiefang West Road, Changsha City, 410005, Hunan Province, China
| | - Shuhuang Zhou
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Hunan Normal University, Hunan Provincial People's Hospital, No.61 Jiefang West Road, Changsha City, 410005, Hunan Province, China
| | - Weimin Yi
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Hunan Normal University, Hunan Provincial People's Hospital, No.61 Jiefang West Road, Changsha City, 410005, Hunan Province, China
| | - Pingzhou Yang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Hunan Normal University, Hunan Provincial People's Hospital, No.61 Jiefang West Road, Changsha City, 410005, Hunan Province, China
| | - Ou Li
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Hunan Normal University, Hunan Provincial People's Hospital, No.61 Jiefang West Road, Changsha City, 410005, Hunan Province, China
| | - Jianming Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Hunan Normal University, Hunan Provincial People's Hospital, No.61 Jiefang West Road, Changsha City, 410005, Hunan Province, China
| | - Chuang Peng
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Hunan Normal University, Hunan Provincial People's Hospital, No.61 Jiefang West Road, Changsha City, 410005, Hunan Province, China.
| |
Collapse
|
|
25
|
Fu L, Fan J, Maity S, McFadden G, Shi Y, Kong W. PD-L1 interacts with Frizzled 6 to activate β-catenin and form a positive feedback loop to promote cancer stem cell expansion. Oncogene 2022; 41:1100-1113. [PMID: 35034965 DOI: 10.1038/s41388-021-02144-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/19/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023]
Abstract
Cancer stem cells (CSCs) drive tumor initiation, progression, metastasis, and drug resistance. We report here that programmed cell death ligand 1 (PD-L1) is constitutively expressed in cancer cells to maintain and expand CSC through a novel mechanism in addition to promoting cancer cell immune evasion. We discovered that PD-L1 interacts with receptor Frizzled 6 to activate β-catenin signaling and increase β-catenin-targeted gene expression, such as a putative stem cell marker leucine-rich-repeat-containing G-protein-coupled receptor 5. Blockage of PD-L1 function, using a specific small hairpin RNA or a specific antibody, inhibits disease progression by reducing the CSC population in both colorectal and breast tumors. Moreover, β-catenin conversely regulates PD-L1 expression through a β-catenin complex binding site in the PD-L1 promoter. Our discoveries reveal that besides assistant tumor cell immune escaping, PD-L1 and β-catenin signaling form a positive feedback loop to promote cancer progression through CSC maintenance and expansion.
Collapse
Affiliation(s)
- Lingchen Fu
- Biodesign Center for Immunotherapy, Vaccines and Virotherapy, Arizona State University, Tempe, AZ, USA
| | - Jia Fan
- Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, LA, USA
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Sudipa Maity
- Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, LA, USA
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Grant McFadden
- Biodesign Center for Immunotherapy, Vaccines and Virotherapy, Arizona State University, Tempe, AZ, USA
- School of Life Sciences, Arizona State University, Tempe, AZ, USA
| | - Yixin Shi
- Biodesign Center for Immunotherapy, Vaccines and Virotherapy, Arizona State University, Tempe, AZ, USA.
- School of Life Sciences, Arizona State University, Tempe, AZ, USA.
| | - Wei Kong
- Biodesign Center for Immunotherapy, Vaccines and Virotherapy, Arizona State University, Tempe, AZ, USA.
| |
Collapse
|
|
26
|
Khashkhashi Moghadam S, Bakhshinejad B, Khalafizadeh A, Mahmud Hussen B, Babashah S. Non-coding RNA-associated competitive endogenous RNA regulatory networks: Novel diagnostic and therapeutic opportunities for hepatocellular carcinoma. J Cell Mol Med 2021; 26:287-305. [PMID: 34907642 PMCID: PMC8743668 DOI: 10.1111/jcmm.17126] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/09/2021] [Accepted: 12/03/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC), as the most prevalent liver malignancy, is annually diagnosed in more than half a million people worldwide. HCC is strongly associated with hepatitis B and C viral infections as well as alcohol abuse. Obesity and nonalcoholic fatty liver disease (NAFLD) also significantly enhance the risk of liver cancer. Despite recent improvements in therapeutic approaches, patients diagnosed in advanced stages show poor prognosis. Accumulating evidence provides support for the regulatory role of non-coding RNAs (ncRNAs) in cancer. There are a variety of reports indicating the regulatory role of microRNAs (miRNAs) in different stages of HCC. Long non-coding RNAs (LncRNAs) exert their effects by sponging miRNAs and controlling the expression of miRNA-targeted genes. Circular RNAs (circRNAs) perform their biological functions by acting as transcriptional regulators, miRNA sponges and protein templates. Diverse studies have illustrated that dysregulation of competing endogenous RNA networks (ceRNETs) is remarkably correlated with HCC-causing diseases such as chronic viral infections, nonalcoholic steatohepatitis and liver fibrosis/cirrhosis. The aim of the current article was to provide an overview of the role and molecular mechanisms underlying the function of ceRNETs that modulate the characteristics of HCC such as uncontrolled cell proliferation, resistance to cell death, metabolic reprogramming, immune escape, angiogenesis and metastasis. The current knowledge highlights the potential of these regulatory RNA molecules as novel diagnostic biomarkers and therapeutic targets in HCC.
Collapse
Affiliation(s)
| | - Babak Bakhshinejad
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Khalafizadeh
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq.,Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan Region, Iraq
| | - Sadegh Babashah
- Research and Development Center of Biotechnology, Tarbiat Modares University, Tehran, Iran.,Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| |
Collapse
|
|
27
|
Oncogenic role of SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2 positive diffuse large B-cell lymphomas. Blood 2021; 139:73-86. [PMID: 34624089 PMCID: PMC8740888 DOI: 10.1182/blood.2021012327] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 09/29/2021] [Indexed: 11/21/2022] Open
Abstract
SOX9 plays an oncogenic role in germinal center B-cell type, IGH-BCL2+ DLBCL, by promoting cell proliferation and inhibiting apoptosis. SOX9 drives lymphomagenesis through upregulation of DHCR24, the key final enzyme in the cholesterol biosynthesis pathway. Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, SOX9 was overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCLs) that harbor IGH-BCL2 translocations. SOX9 positivity in DLBCL correlated with an advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest, and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole-transcriptome analysis and chromatin immunoprecipitation–sequencing assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In models of DLBCL cell line xenografts, SOX9 knockdown resulted in a lower DHCR24 level, reduced cholesterol content, and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell lines with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrated that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCLs.
Collapse
|
|
28
|
Zhang K, Liu H, Yu M, Zhao H, Yang N, Bi X, Sun L, Lin R, Lü G. Upregulated LINC01667 Expression Is Correlated With Poor Prognosis in Hepatocellular Carcinoma. Front Oncol 2021; 11:650173. [PMID: 34458133 PMCID: PMC8397520 DOI: 10.3389/fonc.2021.650173] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 07/12/2021] [Indexed: 12/25/2022] Open
Abstract
The development of hepatocellular carcinoma (HCC) is a complex pathological process. Long intergenic non–protein-coding RNA 1667 (LINC01667, also known as MGC38584) plays an oncogenic role in several human cancers; however, its functional role in HCC tumorigenesis remains unknown. Here, we first evaluated the gene expression levels of LINC01667 in HCC using data from The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis (GEPIA) databases. We then elucidated the association between LINC01667 gene expression levels and the survival rates of patients with HCC. We detected the effect of LINC01667 on the malignant phenotypes (cell proliferation, migration, invasion and apoptosis etc.) and the MAPK and PI3K/AKT/mTOR signaling pathways of HepG2, SMMC-7721 and HUH7 cells. We also analyzed the sensitivity of HepG2, SMMC-7721 and HUH7 with different expression levels of LINC01667 to anti-HCC drugs in vitro. Based on data from the aforementioned databases and our experiments in vitro, we found that LINC01667 was overexpressed in HCC, and that patients with high LINC01667 levels had a remarkably poor overall survival rate. In addition, inhibition of LINC01667 expression suppressed the proliferation, migration and invasion of HepG2 and SMMC-7721 cells and promoted their apoptosis in vitro. In contrast, overexpression of LINC01667 promoted the proliferation, migration and invasion of HUH7 cells and suppressed their apoptosis in vitro. ChIRP-seq (chromatin isolation by RNA purification) showed that LINC01667 bound to MEG3, and downregulated the expression of MEG3. In addition, western blotting showed that LINC01667 could activate the NF-κB pathway to promote cancer progression. In conclusion, we report that LINC01667 is an important oncogene in HCC and may be used as a potential diagnostic and prognostic biomarker of HCC.
Collapse
Affiliation(s)
- Kainan Zhang
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Graduate Academy, Xinjiang Medical University, Urumqi, China
| | - Hui Liu
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Mengsi Yu
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hui Zhao
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Ning Yang
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xiaojuan Bi
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Li Sun
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Renyong Lin
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Guodong Lü
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,College of Pharmacy, Xinjiang Medical University, Urumqi, China
| |
Collapse
|
|
29
|
Chen J, Debebe A, Zeng N, Kopp J, He L, Sander M, Stiles BL. Transformation of SOX9 + cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma. Sci Rep 2021; 11:11823. [PMID: 34083580 PMCID: PMC8175600 DOI: 10.1038/s41598-021-90958-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 05/19/2021] [Indexed: 01/07/2023] Open
Abstract
SOX9 (Sex-determining region Y Box 9) is a well-characterized transcription factor that is a marker for progenitor cells in various tissues. In the liver, cells delineated by SOX9 are responsible for regenerating liver parenchyma when cell proliferation is impaired following chronic injury. However, whether these SOX9+ cells play a role in liver carcinogenesis has not been fully understood, although high SOX9 expression has been linked to poor survival outcome in liver cancer patients. To address this question, we developed a liver cancer mouse model (PtenloxP/loxP; Sox9-CreERT+; R26RYFP) where tumor suppressor Pten (phosphatase and tensin homolog deleted on chromosome ten) is deleted in SOX9+ cells following tamoxifen injection. In this paper, we employ lineage-tracing to demonstrate the tumorigenicity potential of the Pten-, SOX9+ cells. We show that these cells are capable of giving rise to mixed-lineage tumors that manifest features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA). Our results suggest that PTEN loss induces the transformation of SOX9+ cells. We further show that to activate these transformed SOX9+ cells, the presence of liver injury is crucial. Liver injury, induced by hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or high-fat diet (HFD), substantially increases tumor incidence and accelerates liver carcinogenesis from SOX9+ cells in Pten null mice but not in control mice. We further examine the mechanisms underlying tumor formation in this model to show that concurrent with the induction of niche signal (i.e., Wnt signaling), liver injury significantly stimulates the expansion of tumor-initiating cells (TICs). Together, these data show that (1) SOX9+ cells have the potential to become TICs following the primary transformation (i.e. Pten deletion) and that (2) liver injury is necessary for promoting the activation and proliferation of transformed SOX9+ cells, resulting in the genesis of mixed-lineage liver tumors.
Collapse
Affiliation(s)
- Jingyu Chen
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Anketse Debebe
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Ni Zeng
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Janel Kopp
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
| | - Lina He
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Maike Sander
- Department of Pediatrics and Cellar and Molecular Medicine, UCSD, La Jolla, CA, 92093, USA
| | - Bangyan L Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA.
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
| |
Collapse
|
|
30
|
Interplay between SOX9 transcription factor and microRNAs in cancer. Int J Biol Macromol 2021; 183:681-694. [PMID: 33957202 DOI: 10.1016/j.ijbiomac.2021.04.185] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/29/2021] [Accepted: 04/29/2021] [Indexed: 02/07/2023]
Abstract
SOX transcription factors are critical regulators of development, homeostasis and disease progression and their dysregulation is a common finding in various cancers. SOX9 belongs to SOXE family located on chromosome 17. MicroRNAs (miRNAs) possess the capacity of regulating different transcription factors in cancer cells by binding to 3'-UTR. Since miRNAs can affect differentiation, migration, proliferation and other physiological mechanisms, disturbances in their expression have been associated with cancer development. In this review, we evaluate the relationship between miRNAs and SOX9 in different cancers to reveal how this interaction can affect proliferation, metastasis and therapy response of cancer cells. The tumor-suppressor miRNAs can decrease the expression of SOX9 by binding to the 3'-UTR of mRNAs. Furthermore, the expression of downstream targets of SOX9, such as c-Myc, Wnt, PI3K/Akt can be affected by miRNAs. It is noteworthy that other non-coding RNAs including lncRNAs and circRNAs regulate miRNA/SOX9 expression to promote/inhibit cancer progression and malignancy. The pre-clinical findings can be applied as biomarkers for diagnosis and prognosis of cancer patients.
Collapse
|
|
31
|
Li SS, Chen DM, Chen LB, Wei H, Wang JL, Xiao J, Huang YH, Lian YF. GTSE1 promotes SNAIL1 degradation by facilitating its nuclear export in hepatocellular carcin oma cells. Mol Med Rep 2021; 23:454. [PMID: 33880590 PMCID: PMC8072310 DOI: 10.3892/mmr.2021.12093] [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: 08/18/2020] [Accepted: 02/02/2021] [Indexed: 12/24/2022] Open
Abstract
Snail family transcriptional repressor 1 (SNAIL1) is a master inducer of the epithelial-to-mesenchymal transition (EMT) process, contributing to tumor metastasis and recurrence. Our previous study reported that G2 and S phase-expressed-1 (GTSE1) served a role in regulating SNAIL1 expression in hepatocellular carcinoma (HCC). However, the underlying mechanism remains unknown. Therefore, the present study aimed to reveal the regulatory mechanism of GTSE1 on SNAIL1 expression using in vitro assays performed in HCC cell models. It was demonstrated that endogenous SNAIL1 expression was downregulated and upregulated by GTSE1 overexpression or small interfering RNA-mediated knockdown, respectively. Via cycloheximide chase experiments, it was identified that GTSE1 overexpression increased the protein turnover of SNAIL1, while knockdown of GTSE1 reduced its degradation rate. Furthermore, it was demonstrated that GTSE1 overexpression induced the cytoplasmic expression of SNAIL1 using immunofluorescence and subcellular fractionation methods. The nuclear export inhibitor leptomycin B was able to decrease the cytoplasmic retention of SNAIL1 caused by GTSE1 overexpression. In addition, TGF-βI treatment increased both the mRNA and protein expression levels of GTSE1, and decreased the protein expression level of SNAIL1 without affecting its mRNA transcription in Huh7 cells. It was also found that TGF-β signaling could upregulate the transcription of GTSE1 expression by transactivating the Smad binding elements in the GTSE1 promoter. Moreover, the TGF-βI-induced decrease in SNAIL1 protein expression was GTSE1-dependent in Huh7 cells. In conclusion, the current study provides a novel mechanism via which GTSE1 affects the stability of SNAIL1 by regulating its subcellular localization in HCC cells.
Collapse
Affiliation(s)
- Shan-Shan Li
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Dong-Mei Chen
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Lu-Biao Chen
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Huan Wei
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Jia-Liang Wang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Jian Xiao
- Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Yue-Hua Huang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Yi-Fan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| |
Collapse
|
|
32
|
Chen M, Lu C, Lu H, Zhang J, Qin D, Liu S, Li X, Zhang L. Farnesoid X receptor via Notch1 directs asymmetric cell division of Sox9 + cells to prevent the development of liver cancer in a mouse model. Stem Cell Res Ther 2021; 12:232. [PMID: 33845903 PMCID: PMC8042944 DOI: 10.1186/s13287-021-02298-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 03/18/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Asymmetrical cell division (ACD) maintains the proper number of stem cells to ensure self-renewal. The rate of symmetric division increases as more cancer stem cells (CSCs) become malignant; however, the signaling pathway network involved in CSC division remains elusive. FXR (Farnesoid X receptor), a ligand-activated transcription factor, has several anti-tumor effects and has been shown to target CSCs. Here, we aimed at evaluating the role of FXR in the regulation of the cell division of CSCs. METHODS The FXR target gene and downstream molecular mechanisms were confirmed by qRT-PCR, Western blot, luciferase reporter assay, EMAS, Chip, and IF analyses. Pulse-chase BrdU labeling and paired-cell experiments were used to detect the cell division of liver CSCs. Gain- and loss-of-function experiments in Huh7 cells and mouse models were performed to support findings and elucidate the function and underlying mechanisms of FXR-Notch1 in liver CSC division. RESULTS We demonstrated that activation of Notch1 was significantly elevated in the livers of hepatocellular carcinoma (HCC) in Farnesoid X receptor-knockout (FXR-KO) mice and that FXR expression negatively correlated with Notch1 level during chronic liver injury. Activation of FXR induced the asymmetric divisions of Sox9+ liver CSCs and ameliorated liver injury. Mechanistically, FXR directs Sox9+ liver CSCs from symmetry to asymmetry via inhibition of Notch1 expression and activity. Deletion of FXR signaling or over-expression of Notch1 greatly increased Notch1 expression and activity along with ACD reduction. FXR inhibited Notch1 expression by directly binding to its promoter FXRE. FXR also positively regulated Numb expression, contributing to a feedback circuit, which decreased Notch1 activity and directed ACD. CONCLUSION Our findings suggest that FXR represses Notch1 expression and directs ACD of Sox9+ cells to prevent the development of liver cancer.
Collapse
Affiliation(s)
- Mi Chen
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Chenxia Lu
- The Clinical Medical College of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Hanwen Lu
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Junyi Zhang
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Dan Qin
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Shenghui Liu
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Xiaodong Li
- Hubei Provincial Hospital of TCM, Hubei Provincial Academy of TCM, Wuhan, 430061, China
| | - Lisheng Zhang
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China.
| |
Collapse
|
|
33
|
Shirian FI, Ghorbani M, Khamseh ME, Imani M, Panahi M, Alimohammadi A, Nourbakhsh M, Salimi V, Tavakoli-Yaraki M. Up-regulation of sex-determining region Y-box 9 (SOX9) in growth hormone-secreting pituitary adenomas. BMC Endocr Disord 2021; 21:50. [PMID: 33736633 PMCID: PMC7971953 DOI: 10.1186/s12902-021-00720-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pituitary adenomas are benign brain tumors that cause considerable morbidity and neurological symptoms. SOX9 as a regulatory transcriptional mediator affects normal and tumor cell growth with an undefined role in pituitary adenomas pathogenesis. Thus, in the present study, the expression pattern of SOX9 in GH-secreting pituitary tumors and normal pituitary tissues is investigated. METHODS The SOX9 gene expression level was evaluated in 60 pituitary tissues including different types of GH-secreting adenomas and normal pituitary tissues through Real-Time PCR. The protein level of SOX9 was assessed using immunohistochemistry. The correlations of SOX9 gene and protein expression level with the patient's clinical and pathological features were considered. RESULTS The SOX9 over-expression was detected in GH-secreting adenomas tumor tissues compared to normal pituitary tissues which were accompanied by overexpression of SOX9 protein in tumor tissues. The over-expression of SOX9 had a significant impact on GH-secreting adenomas tumor incidence with the odds ratio of 8.4 and the diagnostic value of SOX9 was considerable. The higher level of SOX9 expression was associated with invasive and macro tumors in GH-secreting pituitary adenoma patients. The positive correlation of SOX9 gene and protein level was observed and the tumor size and tumor invasive features were valuable in predicting SOX9 expression level in GH-producing pituitary tumors. CONCLUSION The study provided the first shreds of evidence regarding the expression pattern of SOX9 in the GH- secreting pituitary adenomas at both gene and protein levels which may emphasize the possible involvement of SOX9 as a mediator in pituitary adenoma tumor formation also open up new intrinsic molecular mechanism regarding pituitary adenoma pathogenesis.
Collapse
Affiliation(s)
- Farzad Izak Shirian
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ghorbani
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Mohammad E Khamseh
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Mehrnaz Imani
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Mahshid Panahi
- Firozgar Hospital, Pathology Department, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mitra Nourbakhsh
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Vahid Salimi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Tavakoli-Yaraki
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
34
|
Edelman HE, McClymont SA, Tucker TR, Pineda S, Beer RL, McCallion AS, Parsons MJ. SOX9 modulates cancer biomarker and cilia genes in pancreatic cancer. Hum Mol Genet 2021; 30:485-499. [PMID: 33693707 DOI: 10.1093/hmg/ddab064] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/02/2021] [Accepted: 02/24/2021] [Indexed: 12/21/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with high mortality. The cellular origins of PDAC are largely unknown; however, ductal cells, especially centroacinar cells (CACs), have several characteristics in common with PDAC, such as expression of SOX9 and components of the Notch-signaling pathway. Mutations in KRAS and alterations to Notch signaling are common in PDAC, and both these pathways regulate the transcription factor SOX9. To identify genes regulated by SOX9, we performed siRNA knockdown of SOX9 followed by RNA-seq in PANC-1s, a human PDAC cell line. We report 93 differentially expressed (DE) genes, with convergence on alterations to Notch-signaling pathways and ciliogenesis. These results point to SOX9 and Notch activity being in a positive feedback loop and SOX9 regulating cilia production in PDAC. We additionally performed ChIP-seq in PANC-1s to identify direct targets of SOX9 binding and integrated these results with our DE gene list. Nine of the top 10 downregulated genes have evidence of direct SOX9 binding at their promoter regions. One of these targets was the cancer stem cell marker EpCAM. Using whole-mount in situ hybridization to detect epcam transcript in zebrafish larvae, we demonstrated that epcam is a CAC marker and that Sox9 regulation of epcam expression is conserved in zebrafish. Additionally, we generated an epcam null mutant and observed pronounced defects in ciliogenesis during development. Our results provide a link between SOX9, EpCAM and ciliary repression that can be exploited in improving our understanding of the cellular origins and mechanisms of PDAC.
Collapse
Affiliation(s)
- Hannah E Edelman
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Sarah A McClymont
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Tori R Tucker
- Department of Developmental and Cell Biology, University of California, Irvine, Natural Sciences II, CA 92697, USA
| | - Santiago Pineda
- Department of Developmental and Cell Biology, University of California, Irvine, Natural Sciences II, CA 92697, USA
| | - Rebecca L Beer
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Andrew S McCallion
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Michael J Parsons
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA.,Department of Developmental and Cell Biology, University of California, Irvine, Natural Sciences II, CA 92697, USA
| |
Collapse
|
|
35
|
Panda M, Tripathi SK, Biswal BK. SOX9: An emerging driving factor from cancer progression to drug resistance. Biochim Biophys Acta Rev Cancer 2021; 1875:188517. [PMID: 33524528 DOI: 10.1016/j.bbcan.2021.188517] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/20/2021] [Accepted: 01/25/2021] [Indexed: 02/06/2023]
Abstract
Dysregulation of transcription factors is one of the common problems in the pathogenesis of human cancer. Among them, SOX9 is one of the critical transcription factors involved in various diseases, including cancer. The expression of SOX9 is regulated by microRNAs (miRNAs), methylation, phosphorylation, and acetylation. Interestingly, SOX9 acts as a proto-oncogene or tumor suppressor gene, relying upon kinds of cancer. Recent studies have reported the critical role of SOX9 in the regulation of the tumor microenvironment (TME). Additionally, activation of SOX9 signaling or SOX9 regulated signaling pathways play a crucial role in cancer development and progression. Accumulating evidence also suggests that SOX9 acquires stem cell features to induce epithelial-mesenchymal transition (EMT). Moreover, SOX9 has been broadly studied in the field of cancer stem cell (CSC) and EMT in the last decades. However, the link between SOX9 and cancer drug resistance has only recently been discovered. Furthermore, its differential expression could be a potential biomarker for tumor prognosis and progression. This review outlined the various biological implications of SOX9 in cancer progression and cancer drug resistance and elucidated its signaling network, which could be a potential target for designing novel anticancer drugs.
Collapse
Affiliation(s)
- Munmun Panda
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India
| | - Surya Kant Tripathi
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India
| | - Bijesh K Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India.
| |
Collapse
|
|
36
|
Hao X, Li W. Chloroquine diphosphate suppresses liver cancer via inducing apoptosis in Wistar rats using interventional therapy. Oncol Lett 2021; 21:233. [PMID: 33613722 DOI: 10.3892/ol.2021.12494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 12/08/2020] [Indexed: 11/05/2022] Open
Abstract
Liver cancer ranks as the second leading cause of cancer-associated mortality worldwide. To date, neither current ablation therapy nor chemotherapy are considered ideal in improving the outcome of liver cancer. Therefore, more effective therapies for treating this devastating disease are urgently required. Interventional therapy has been used for numerous years in the treatment of different types of cancer, and is characterized by the direct delivery of anticancer drugs into the tumor. It has been reported that antimalarial chloroquine diphosphate (CQ) exerts effective anticancer activity against several types of cancer. However, its effect on liver cancer remains unclear. Therefore, in the present study, 2D monolayer cell culture and 3D spheroid in vitro models, and a rat model, were utilized to investigate the effect of CQ on liver cancer. CQ demonstrated an effective anticancer effect on HepG2 cells and 3D liver spheroids. Furthermore, the drug significantly inhibited cell growth and viability in the 2D and 3D in vitro models. The CQ-based intervention treatment effectively attenuated tumor size and weight, increased food intake and consumption of drinking water, and improved body weight and survival rate of rats in the in vivo model. In addition, treatment with CQ potently increased the expression levels of the apoptosis-related genes. Taken together, the findings of the present study may provide a novel insight into the development of safe and effective treatments for liver cancer.
Collapse
Affiliation(s)
- Xiaoguang Hao
- Department of Radiology, The Fourth Hospital of Hebei Medicine University, Shijiazhuang, Hebei 050000, P.R. China
| | - Weijing Li
- Department of Anesthesiology, The Fourth Hospital of Hebei Medicine University, Shijiazhuang, Hebei 050000, P.R. China
| |
Collapse
|
|
37
|
Butti R, Kumar TVS, Nimma R, Banerjee P, Kundu IG, Kundu GC. Osteopontin Signaling in Shaping Tumor Microenvironment Conducive to Malignant Progression. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1329:419-441. [PMID: 34664250 DOI: 10.1007/978-3-030-73119-9_20] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Context-dependent reciprocal crosstalk between cancer and surrounding stromal cells in the tumor microenvironment is imperative for the regulation of various hallmarks of cancer. A myriad of growth factors, chemokines, and their receptors aids in the interaction between cancer cells and tumor microenvironmental components. Osteopontin is a chemokine-like protein, overexpressed in different types of cancers. Osteopontin plays a crucial role in orchestrating dialogue between cancer and stromal cells. Osteopontin, in tumor microenvironment, is produced in tumor as well as stromal cells. Tumor-derived osteopontin regulates proliferation, migration, activation, and differentiation of different types of stromal cells. Osteopontin secreted from tumor cells regulates the generation of cancer-associated fibroblasts from resident fibroblasts and mesenchymal stem cells. Osteopontin also shapes immunosuppressive tumor microenvironment by controlling regulatory T cells and tumor-associated macrophages. Moreover, secretion of osteopontin from tumor stroma has been highly documented. Stromal cell-derived osteopontin induces epithelial-to-mesenchymal transition, angiogenesis, metastasis, and cancer stem cell enrichment. Tumor- or stroma-derived osteopontin mainly functions through binding with cell surface receptors, integrins and CD44, and activates downstream signaling events like PI-3 kinase/Akt and MAPK pathways. Presumably, disrupting the communication between the tumor cells and surrounding microenvironment by targeting osteopontin-regulated signaling using specific antibodies, small-molecule inhibitors, and chemotherapeutic agents is a novel therapeutic strategy for clinical management of cancer.
Collapse
Affiliation(s)
- Ramesh Butti
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Totakura V S Kumar
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Ramakrishna Nimma
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Pinaki Banerjee
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Ipsita G Kundu
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Institute of Eminence, Hyderabad, India
| | - Gopal C Kundu
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, SP Pune University Campus, Pune, India. .,School of Biotechnology and Kalinga Institute of Medical Sciences (KIMS), KIIT Deemed to be University, Institute of Eminence, Bhubaneswar, India.
| |
Collapse
|
|
38
|
Zhou T, Wu L, Ma N, Tang F, Yu Z, Jiang Z, Li Y, Zong Z, Hu K. SOX9-activated FARSA-AS1 predetermines cell growth, stemness, and metastasis in colorectal cancer through upregulating FARSA and SOX9. Cell Death Dis 2020; 11:1071. [PMID: 33318478 PMCID: PMC7736271 DOI: 10.1038/s41419-020-03273-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 11/13/2020] [Accepted: 11/17/2020] [Indexed: 02/06/2023]
Abstract
SRY-box transcription factors (SOXs) are effective inducers for the formation of stem-like phenotypes. As a member of SOX family, SOX9 (SRY-box transcription factor 9) has been reported to be highly expressed and exert oncogenic functions in multiple human cancers. In this study, we hypothesized that SOX9 could regulate the function of cancer stem/initiating cells (CSCs) to further facilitate the progression of colorectal cancer (CRC). Then, stable transfection of shRNAs was used to silence indicated genes. Loss-of-function experiments were conducted to demonstrate the in vitro function of CRC cells. In vivo study was conducted to determine the changes in tumorigenesis and metastasis in vivo. Bioinformatics analyses and mechanistic experiments were employed to explore the downstream molecules. Presently, GEPIA data indicated that SOX9 was upregulated in 275 COAD (colon adenocarcinoma) samples relative to 349 normal tissues. Besides, we also proved the upregulation of SOX9 in CRC cell lines (HCT15, SW480, SW1116, and HT-29) compared to normal NCM-460 cells. Silencing of SOX9 suppressed cell growth, stemness, migration, and invasion. Mechanistically, SOX9 activated the transcription of lncRNA phenylalanyl-tRNA synthetase subunit alpha antisense RNA 1 (FARSA-AS1), while FARSA-AS1 elevated SOX9 in turn by absorbing miR-18b-5p and augmented FARSA via sequestering miR-28-5p. Furthermore, loss of FARSA-AS1 hindered malignant phenotypes in vitro and blocked tumor growth and metastasis in vivo. Notably, we testified that FARSA-AS1 aggravated the malignancy in CRC by enhancing SOX9 and FARSA. Our study unveiled a mechanism of SOX9-FARSA-AS1-SOX9/FARSA loop in CRC, which provides some clews of promising targets for CRC.
Collapse
Affiliation(s)
- Taicheng Zhou
- Department of Gastroenterological Surgery and Hernia Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, 510655, Guangzhou, Guangdong, China
| | - Lili Wu
- Department of Medical Ultrasonics, Third Affiliated Hospital of Sun Yat-sen University, Guangdong Key Laboratory of Liver Disease Research, 510630, Guangzhou, Guangdong, China
| | - Ning Ma
- Department of Gastroenterological Surgery and Hernia Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, 510655, Guangzhou, Guangdong, China
| | - Fuxin Tang
- Department of Gastroenterological Surgery and Hernia Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, 510655, Guangzhou, Guangdong, China
| | - Zhuomin Yu
- Department of Gastroenterological Surgery and Hernia Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, 510655, Guangzhou, Guangdong, China
| | - Zhipeng Jiang
- Department of Gastroenterological Surgery and Hernia Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, 510655, Guangzhou, Guangdong, China
| | - Yingru Li
- Department of Gastroenterological Surgery and Hernia Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, 510655, Guangzhou, Guangdong, China
| | - Zhen Zong
- Department of Gastroenterological Surgery, The Second Affiliated Hospital of Nanchang University, No.1 Mingde Road, 330006, Nanchang, Jiangxi, China.
| | - Kunpeng Hu
- Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, No.2693 Kaichuang Road, Huangpu, 510000, Guangzhou, Guangdong, China.
| |
Collapse
|
|
39
|
Zhou TH, Su JZ, Qin R, Chen X, Ju GD, Miao S. Prognostic and Predictive Value of a 15 Transcription Factors (TFs) Panel for Hepatocellular Carcinoma. Cancer Manag Res 2020; 12:12349-12361. [PMID: 33293862 PMCID: PMC7719121 DOI: 10.2147/cmar.s279194] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/31/2020] [Indexed: 01/26/2023] Open
Abstract
Purpose Hepatocellular carcinoma (HCC) is one of the most devastating diseases worldwide. Limited performance of clinicopathologic parameters as prognostic factors underscores more accurate and effective biomarkers for high-confidence prognosis that guide decision-making for optimal treatment of HCC. The aim of the present study was to establish a novel panel to improve prognosis prediction of HCC patients, with a particular interest in transcription factors (TFs). Materials and Methods A TF-related prognosis model of liver cancer with data from ICGC-LIRP-JI cohort successively were processed by univariate and multivariate Cox regression analysis. Then, for evaluating the prognostic prediction value of the model, receiver operating characteristic (ROC) curve and survival analysis were performed both with internal data from the International Cancer Genome Consortium (ICGC) and external data from The Cancer Genome Atlas (TCGA). Furthermore, we verified the expression of three genes in HCC cell lines by Western blot and qPCR and protein expression level by IHC in liver cancer patients’ sample. Finally, we constructed a TF clinical characteristics nomogram to furtherly predict liver cancer patient survival probability with TCGA cohort. Results By Cox regression analysis, a panel of 15 TFs (ZNF331, MYCN, AHRR, LEF1, ZNF780A, POU1F1, DLX5, ZNF775, PLSCR1, FOXK1, TAL2, ZNF558, SOX9, TCFL5, GSC) was identified to present with powerful predictive performance for overall survival of HCC patients based on internal ICGC cohort and external TCGA cohort. A nomogram that integrates these factors was established, allowing efficient prediction of survival probabilities and displaying higher clinical utility. Conclusion The 15-TF panel is an independent prognostic factor for HCC, and 15 TF-based nomogram might provide implication an effective approach for HCC patient management and treatment.
Collapse
Affiliation(s)
- Tian-Hao Zhou
- Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, People's Republic of China
| | - Jing-Zhi Su
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan, People's Republic of China
| | - Rui Qin
- Department of Pathology, Affiliated Hospital of Jining Medical University, Jining 272000, People's Republic of China
| | - Xi Chen
- Department of Internal Medicine, Qilu Hospital of Shandong University, Jinan 250000, People's Republic of China
| | - Gao-Da Ju
- Department of Oncology, Beijing Cancer Hospital, Peking University, Beijing 102206, People's Republic of China
| | - Sen Miao
- Department of Pathology, Affiliated Hospital of Jining Medical University, Jining 272000, People's Republic of China
| |
Collapse
|
|
40
|
Zhang Z, Wu W, Fang X, Lu M, Wu H, Gao C, Xia Z. Sox9 promotes renal tubular epithelial‑mesenchymal transition and extracellular matrix aggregation via the PI3K/AKT signaling pathway. Mol Med Rep 2020; 22:4017-4030. [PMID: 32901875 DOI: 10.3892/mmr.2020.11488] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 06/05/2020] [Indexed: 11/05/2022] Open
Abstract
Sox9 is important for multiple aspects of development, such as testis, pancreas and heart development. Previous studies have reported that Sox9 induced epithelial‑mesenchymal transition (EMT) and extracellular matrix (ECM) production in organ fibrosis and associated diseases, such as vascular calcification. However, to the best of our knowledge, the role and underlying mechanism of action of Sox9 in renal fibrogenesis remains unknown. The results of the present study revealed that Sox9 expression levels were upregulated in the tubular epithelial cells of a rat model of obstructive nephropathy. Furthermore, the overexpression of Sox9 in NRK‑52E cells was discovered to promote renal tubular EMT and ECM aggregation, and these fibrogenic actions were potentiated by TGF‑β1. Notably, RNA‑sequencing analysis indicated the possible regulatory role of the PI3K/AKT signaling pathway in Sox9‑mediated renal tubular EMT and ECM aggregation. It was further demonstrated that the expression levels of phosphorylated AKT were upregulated in NRK‑52E cells overexpressing Sox9, while the PI3K inhibitors, LY29002 and wortmannin, inhibited the renal tubular EMT and ECM aggregation induced by the overexpression of Sox9 in NEK‑52E cells. In conclusion, the findings of the present study suggested that Sox9 may serve a profibrotic role in the development of renal tubular EMT and ECM aggregation via the PI3K/AKT signaling pathway. Therefore, Sox9 may be considered as a promising target for treating renal fibrosis.
Collapse
Affiliation(s)
- Zhiqiang Zhang
- Department of Pediatrics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu 210002, P.R. China
| | - Wei Wu
- Department of Pediatrics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu 210002, P.R. China
| | - Xiang Fang
- Department of Pediatrics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu 210002, P.R. China
| | - Mei Lu
- Department of Pediatrics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu 210002, P.R. China
| | - Heyan Wu
- Department of Pediatrics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu 210002, P.R. China
| | - Chunlin Gao
- Department of Pediatrics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu 210002, P.R. China
| | - Zhengkun Xia
- Department of Pediatrics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu 210002, P.R. China
| |
Collapse
|
|
41
|
Harris SE, Poolman TM, Arvaniti A, Cox RD, Gathercole LL, Tomlinson JW. The American lifestyle-induced obesity syndrome diet in male and female rodents recapitulates the clinical and transcriptomic features of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2020; 319:G345-G360. [PMID: 32755310 PMCID: PMC7509261 DOI: 10.1152/ajpgi.00055.2020] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the progression to nonalcoholic steatohepatitis (NASH) and increased risk of hepatocellular carcinoma remain poorly understood. Additionally, there is increasing recognition of the extrahepatic manifestations associated with NAFLD and NASH. We demonstrate that intervention with the American lifestyle-induced obesity syndrome (ALIOS) diet in male and female mice recapitulates many of the clinical and transcriptomic features of human NAFLD and NASH. Male and female C57BL/6N mice were fed either normal chow (NC) or ALIOS from 11 to 52 wk and underwent comprehensive metabolic analysis throughout the duration of the study. From 26 wk, ALIOS-fed mice developed features of hepatic steatosis, inflammation, and fibrosis. ALIOS-fed mice also had an increased incidence of hepatic tumors at 52 wk compared with those fed NC. Hepatic transcriptomic analysis revealed alterations in multiple genes associated with inflammation and tissue repair in ALIOS-fed mice. Ingenuity Pathway Analysis confirmed dysregulation of metabolic pathways as well as those associated with liver disease and cancer. In parallel the development of a robust hepatic phenotype, ALIOS-fed mice displayed many of the extrahepatic manifestations of NAFLD, including hyperlipidemia, increased fat mass, sarcopenia, and insulin resistance. The ALIOS diet in mice recapitulates many of the clinical features of NAFLD and, therefore, represents a robust and reproducible model for investigating the pathogenesis of NAFLD and its progression.NEW & NOTEWORTHY Nonalcoholic fatty liver disease (NAFLD) affects 30% of the general population and can progress to nonalcoholic steatohepatitis (NASH) and potentially hepatocellular carcinoma. Preclinical models rely on mouse models that often display hepatic characteristics of NAFLD but rarely progress to NASH and seldom depict the multisystem effects of the disease. We have conducted comprehensive metabolic analysis of both male and female mice consuming a Western diet of trans fats and sugar, focusing on both their hepatic phenotype and extrahepatic manifestations.
Collapse
Affiliation(s)
- Shelley E. Harris
- 1Oxford Centre for Diabetes, Endocrinology and Metabolism, National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, University of Oxford, Oxford, United Kingdom
| | - Toryn M. Poolman
- 1Oxford Centre for Diabetes, Endocrinology and Metabolism, National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, University of Oxford, Oxford, United Kingdom
| | - Anastasia Arvaniti
- 1Oxford Centre for Diabetes, Endocrinology and Metabolism, National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, University of Oxford, Oxford, United Kingdom,2Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Roger D. Cox
- 3Mammalian Genetics Unit, Medical Research Council Harwell Institute, Oxford, United Kingdom
| | - Laura L. Gathercole
- 1Oxford Centre for Diabetes, Endocrinology and Metabolism, National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, University of Oxford, Oxford, United Kingdom,2Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Jeremy W. Tomlinson
- 1Oxford Centre for Diabetes, Endocrinology and Metabolism, National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
42
|
Verheijen N, Suttorp CM, van Rheden REM, Regan RF, Helmich MPAC, Kuijpers-Jagtman AM, Wagener FADTG. CXCL12-CXCR4 Interplay Facilitates Palatal Osteogenesis in Mice. Front Cell Dev Biol 2020; 8:771. [PMID: 32974338 PMCID: PMC7471603 DOI: 10.3389/fcell.2020.00771] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 07/22/2020] [Indexed: 12/19/2022] Open
Abstract
Cranial neural crest cells (CNCCs), identified by expression of transcription factor Sox9, migrate to the first branchial arch and undergo proliferation and differentiation to form the cartilage and bone structures of the orofacial region, including the palatal bone. Sox9 promotes osteogenic differentiation and stimulates CXCL12-CXCR4 chemokine-receptor signaling, which elevates alkaline phosphatase (ALP)-activity in osteoblasts to initiate bone mineralization. Disintegration of the midline epithelial seam (MES) is crucial for palatal fusion. Since we earlier demonstrated chemokine-receptor mediated signaling by the MES, we hypothesized that chemokine CXCL12 is expressed by the disintegrating MES to promote the formation of an osteogenic center by CXCR4-positive osteoblasts. Disturbed migration of CNCCs by excess oxidative and inflammatory stress is associated with increased risk of cleft lip and palate (CLP). The cytoprotective heme oxygenase (HO) enzymes are powerful guardians harnessing injurious oxidative and inflammatory stressors and enhances osteogenic ALP-activity. By contrast, abrogation of HO-1 or HO-2 expression promotes pregnancy pathologies. We postulate that Sox9, CXCR4, and HO-1 are expressed in the ALP-activity positive osteogenic regions within the CNCCs-derived palatal mesenchyme. To investigate these hypotheses, we studied expression of Sox9, CXCL12, CXCR4, and HO-1 in relation to palatal osteogenesis between E15 and E16 using (immuno)histochemical staining of coronal palatal sections in wild-type (wt) mice. In addition, the effects of abrogated HO-2 expression in HO-2 KO mice and inhibited HO-1 and HO-2 activity by administrating HO-enzyme activity inhibitor SnMP at E11 in wt mice were investigated at E15 or E16 following palatal fusion. Overexpression of Sox9, CXCL12, CXCR4, and HO-1 was detected in the ALP-activity positive osteogenic regions within the palatal mesenchyme. Overexpression of Sox9 and CXCL12 by the disintegrating MES was detected. Neither palatal fusion nor MES disintegration seemed affected by either HO-2 abrogation or inhibition of HO-activity. Sox9 progenitors seem important to maintain the CXCR4-positive osteoblast pool to drive osteogenesis. Sox9 expression may facilitate MES disintegration and palatal fusion by promoting epithelial-to-mesenchymal transformation (EMT). CXCL12 expression by the MES and the palatal mesenchyme may promote osteogenic differentiation to create osteogenic centers. This study provides novel evidence that CXCL12-CXCR4 interplay facilitates palatal osteogenesis and palatal fusion in mice.
Collapse
Affiliation(s)
- Nanne Verheijen
- Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Christiaan M Suttorp
- Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, Netherlands.,Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - René E M van Rheden
- Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Raymond F Regan
- Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Maria P A C Helmich
- Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Anne Marie Kuijpers-Jagtman
- Department of Orthodontics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.,Department of Orthodontics and Dentofacial Orthopedics, University of Bern, Bern, Switzerland.,Faculty of Dentistry, Universitas Indonesia, Jakarta, Indonesia
| | - Frank A D T G Wagener
- Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, Netherlands.,Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| |
Collapse
|
|
43
|
Niu ZS, Wang WH, Dong XN, Tian LML. Role of long noncoding RNA-mediated competing endogenous RNA regulatory network in hepatocellular carcinoma. World J Gastroenterol 2020; 26:4240-4260. [PMID: 32848331 PMCID: PMC7422540 DOI: 10.3748/wjg.v26.i29.4240] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/05/2020] [Accepted: 07/15/2020] [Indexed: 02/06/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are noncoding RNAs (ncRNAs) that occupy over 90% of the human genome, and their main function is to directly or indirectly regulate messenger RNA (mRNA) expression and participate in the tumorigenesis and progression of malignances. In particular, some lncRNAs can interact with miRNAs as competing endogenous RNAs (ceRNAs) to modulate mRNA expression. Accordingly, these RNA molecules are interrelated and coordinate to form a dynamic lncRNA-mediated ceRNA regulatory network. Mounting evidence has revealed that lncRNAs that act as ceRNAs are closely related to tumorigenesis. To date, numerous studies have established many different regulatory networks in hepatocellular carcinoma (HCC), and perturbations in these ceRNA interactions may result in the initiation and progression of HCC. Herein, we emphasize recent advances concerning the biological function of lncRNAs as ceRNAs in HCC, with the aim of elucidating the molecular mechanism underlying these HCC-related RNA molecules and providing novel insights into the diagnosis and treatment of HCC.
Collapse
Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Medical Department of Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Medical Department of Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xian-Ning Dong
- Department of Pathology, the Affiliated Hospital of Qingdao University, Qingdao 266061, Shandong Province, China
| | - Li-Mei-Li Tian
- BGI Gene Innovation Class, School of Basic Medicine, Medical Department of Qingdao University, Qingdao 266071, Shandong Province, China
| |
Collapse
|
|
44
|
Ma Y, Shepherd J, Zhao D, Bollu LR, Tahaney WM, Hill J, Zhang Y, Mazumdar A, Brown PH. SOX9 Is Essential for Triple-Negative Breast Cancer Cell Survival and Metastasis. Mol Cancer Res 2020; 18:1825-1838. [PMID: 32661114 DOI: 10.1158/1541-7786.mcr-19-0311] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 05/21/2020] [Accepted: 07/06/2020] [Indexed: 12/16/2022]
Abstract
Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and lacks effective targeted treatment strategies. Previously, we identified 33 transcription factors highly expressed in TNBC. Here, we focused on six sex determining region Y-related HMG-box (SOX) transcription factors (SOX4, 6, 8, 9, 10, and 11) highly expressed in TNBCs. Our siRNA screening assay demonstrated that SOX9 knockdown suppressed TNBC cell growth and invasion in vitro. Thus, we hypothesized that SOX9 is an important regulator of breast cancer survival and metastasis, and demonstrated that knockout of SOX9 reduced breast tumor growth and lung metastasis in vivo. In addition, we found that loss of SOX9 induced profound apoptosis, with only a slight impairment of G1 to S progression within the cell cycle, and that SOX9 directly regulates genes controlling apoptosis. On the basis of published CHIP-seq data, we demonstrated that SOX9 binds to the promoter of apoptosis-regulating genes (tnfrsf1b, fadd, tnfrsf10a, tnfrsf10b, and ripk1), and represses their expression. SOX9 knockdown upregulates these genes, consistent with the induction of apoptosis. Analysis of available CHIP-seq data showed that SOX9 binds to the promoters of several epithelial-mesenchymal transition (EMT)- and metastasis-regulating genes. Using CHIP assays, we demonstrated that SOX9 directly binds the promoters of genes involved in EMT (vim, cldn1, ctnnb1, and zeb1) and that SOX9 knockdown suppresses the expression of these genes. IMPLICATIONS: Our studies identified the SOX9 protein as a "master regulator" of breast cancer cell survival and metastasis, and provide preclinical rationale to develop SOX9 inhibitors for the treatment of women with metastatic triple-negative breast cancer.
Collapse
Affiliation(s)
- Yanxia Ma
- Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Jonathan Shepherd
- Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Dekuang Zhao
- Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Lakshmi Reddy Bollu
- Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - William M Tahaney
- Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Jamal Hill
- Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Yun Zhang
- Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Abhijit Mazumdar
- Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Powel H Brown
- Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. .,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.,Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| |
Collapse
|
|
45
|
Gu Y, Zheng X, Ji J. Liver cancer stem cells as a hierarchical society: yes or no? Acta Biochim Biophys Sin (Shanghai) 2020; 52:723-735. [PMID: 32490517 DOI: 10.1093/abbs/gmaa050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer stem cells (CSCs) are cells possessing abilities of self-renewal, differentiation, and tumorigenicity in NOD/SCID mice. Based on this definition, multiple cell surface markers (such as CD24, CD133, CD90, and EpCAM) as well as chemical methods are discovered to enrich liver CSCs in the recent decade. Accumulated studies have revealed molecular signatures and signaling pathways involved in regulating different liver CSCs. Among liver CSCs positive for different markers, some molecular features and regulatory pathways are commonly shared, while some are only unique in certain CSC populations. These studies imply that liver CSCs exhibit diverse heterogeneity, while a functional relationship also exists. The aim of this review is to revisit the society of liver CSCs and summarize the common or unique molecular features of known liver CSCs. We hope to call for attention of researchers on the relationship of the liver CSC subgroups and to provide clues on the hierarchical structure of the liver CSC society.
Collapse
Affiliation(s)
- Yuanzhuo Gu
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Xin Zheng
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Junfang Ji
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| |
Collapse
|
|
46
|
Hosseini A, Mirzaei A, Salimi V, Jamshidi K, Babaheidarian P, Fallah S, Rampisheh Z, Khademian N, Abdolvahabi Z, Bahrabadi M, Ibrahimi M, Hosami F, Tavakoli-Yaraki M. The local and circulating SOX9 as a potential biomarker for the diagnosis of primary bone cancer. J Bone Oncol 2020; 23:100300. [PMID: 32551218 PMCID: PMC7292907 DOI: 10.1016/j.jbo.2020.100300] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 05/14/2020] [Accepted: 05/15/2020] [Indexed: 01/02/2023] Open
Abstract
The SOX9 expression increased in tumor tissues and peripheral blood of malignant and benign bone tumors. The protein level of SOX9 is enhanced in malignant bone tumor tissues. SOX9 over-expression correlated with tumor severity, grade, invasion feature, poor response to therapy, and recurrence. Purpose The status of the local and circulating SOX9, a master regulator of the tumor fate, and its relevance to tumor types, severity, invasion feature, response to therapy, and chemotherapy treatment were surveyed in bone cancer in the current study. Methods The SOX9 expression level was evaluated in tissue and peripheral blood mononuclear cells from patients with different types of malignant and benign bone tumors also tumor margin tissues using Real-Time PCR. The protein level of SOX9 was assessed using immunohistochemistry and western blot analysis. Also, the correlations of the SOX9 expression level with the patient’s clinical and pathological features were considered. Results The remarkable overexpression of SOX9 was detected in bone tumors compared to tumor margin tissues (P < 0.0001). Malignant bone tumors revealed a higher expression of SOX9 compared to benign tumors (P < 0.0001) while osteosarcoma tumors showed higher expression levels compared to Ewing sarcoma, and chondrosarcoma. Overexpression of SOX9 was observed in high grade, metastatic, recurrent tumors also tumors with poor response to therapy. Besides, the patients under the chemotherapy treatment demonstrated higher levels of SOX9 compared to the rest of malignant tumors (P = 0.02). The simultaneous up-regulation of circulating SOX9 in the patients with bone cancer was observed compared to healthy individuals (P < 0.0001) accompanying with overexpression of SOX9 in malignant tumors compared to benign tumors (P < 0.0001). The circulating SOX9 expression was up-regulated in the patients with malignant bone tumors who receive chemotherapy treatment also patients with high grade, metastatic, recurrent tumors. The protein level of SOX9 was in line with our data on the SOX9 gene expression. Conclusion The simultaneous overexpression of local and circulating SOX9 in bone cancer besides its positive correlation with tumor severity, malignancy, size, and chemotherapy may deserve receiving more attention in bone cancer diagnosis and therapy.
Collapse
Key Words
- Benign bone tumors
- Bone cancer
- CPP, C - reactive protein test
- CSC marker
- CSC, cancer stem cell
- DAB, 3, 3′-diaminobenzidine
- ESR, erythrocyte sedimentation rate
- FBS, fasting blood sugar
- FOXO1, Forkhead Box O1
- FOXO3, Forkhead Box O3
- GCT, giant cell tumor
- HB, memoglobin
- LDL, low-density lipoprotein
- MSC, multipotent stem cells
- Malignant bone tumors
- OCT, optimal cutting temperature
- PBMC, peripheral blood mononuclear cell
- PBS, phosphate-buffered saline
- PMSF, phenylmethylsulfonyl fluoride
- PVDF, polyvinylidene difluoride
- RBC, red blood cell
- SEM, standard error mean
- SOX9
- SOX9, SRY-Box Transcription Factor 9
- WBC, white blood cells
Collapse
Affiliation(s)
- Ameinh Hosseini
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Mirzaei
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Vahid Salimi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Khodamorad Jamshidi
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Pegah Babaheidarian
- Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Soudabeh Fallah
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Rampisheh
- Preventive Medicine and Public Health Research Center, Department of Community Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Narges Khademian
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zohreh Abdolvahabi
- Department of Biochemistry and Genetics, Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mehrdad Bahrabadi
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mostafa Ibrahimi
- Department of Clinical Biochemistry, School of Medicine, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Hosami
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Tavakoli-Yaraki
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
47
|
SOX9 represses hepatitis B virus replication through binding to HBV EnhII/Cp and inhibiting the promoter activity. Antiviral Res 2020; 177:104761. [PMID: 32147495 DOI: 10.1016/j.antiviral.2020.104761] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 02/26/2020] [Accepted: 02/28/2020] [Indexed: 12/13/2022]
Abstract
Hepatitis B virus (HBV) infection affects 364 million people worldwide and causes a serious global public health problem. The SRY-related high mobility group-box 9 (SOX9) is a risk of developing cirrhosis in patients with chronic hepatitis B and a cancer stem cell marker. However, the role of SOX9 in HBV replication has not been reported. This study revealed a distinct mechanism underling the regulation of HBV replication mediated by SOX9. HBV induces SOX9 mRNA and protein expression in human hepatoma cells, including HepG2.2.15, HepG2, Huh7, and HepG2-NTCP cells. Further study demonstrated that HBV activates SOX9 expression at the transcriptional level through inducing SOX9 promoter activity and HBc could induce the activity of SOX9 promoter. Interestingly, SOX9 in turn represses HBV replication in human hepatoma cells. More importantly, SOX9 inhibits HBV infection in HepG2-NTCP cells and C57/BL6 mice. Detailed study revealed that SOX9 suppresses HBV replication through directly binding to HBV EnhII/Cp (HBV 1667-1672 nt) to inhibit EnhII/Cp activation. Results from deletion mutant analysis, ChIP assay, nuclear and cytoplasmic extraction analysis, and immunofluorescence demonstrated that SOX9 high mobility group (HMG) domain is required for SOX9 anti-HBV activity. Moreover, we demonstrated that SOX9 and hepatocyte nuclear factor 4 alpha (HNF4α) can bind to HBV EnhII/Cp (HBV 1667-1672 nt) individually and simultaneously to regulate the promoter activity. Collectively, the results revealed a distinct negative feedback mechanism underlying HBV replication and SOX9 expression, and identified SOX9 as a new host restriction factor in HBV replication and infection. IMPORTANCE: HBV infection is a global public health problem by causing serious liver diseases, but the mechanisms underlying HBV pathogenesis remain largely unknown. SOX9 is a risk of developing cirrhosis and a cancer stem cell marker, however, the role of SOX9 in HBV infection has not been reported. The authors revealed a distinct mechanism underling the regulation of HBV replication and SOX9 expression. On the one hand, HBV induces SOX9 expression in human hepatoma cells through activating SOX9 promoter. On the other hand, SOX9 in turn represses HBV replication in human hepatoma cells by binding to and inhibiting HBV EnhII/Cp through its HMG domain. More importantly, SOX9 inhibits HBV infection in HepG2-NTCP cells and C57/BL6 mice. Therefore, this study identifies SOX9 as a novel and potential therapeutic reagent for the prevention and treatment of HBV-associated diseases.
Collapse
|
|
48
|
Sang X, Wu F, Wu D, Lin S, Li J, Zhao N, Chen X, Xu A. Human Hepatic Cancer Stem Cells (HCSCs) Markers Correlated With Immune Infiltrates Reveal Prognostic Significance of Hepatocellular Carcinoma. Front Genet 2020; 11:112. [PMID: 32184801 PMCID: PMC7058667 DOI: 10.3389/fgene.2020.00112] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 01/30/2020] [Indexed: 12/21/2022] Open
Abstract
Background Several markers have been reported to be specific for hepatic cancer stem cells (HCSCs), which is usually thought to be highly associated with poor clinical outcomes. Tumor-infiltrating immune cells act as an important factor for oncogenesis. Little is known about the correlation of HCSC markers to prognosis and immune infiltrates. Methods Expression of HCSC markers was analyzed through Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA) and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), respectively. The prognostic effect of HCSC markers was evaluated using Kaplan-Meier plotter in association with different tumor stages, risk factors, and gender. The correlation of HCSC markers to tumor-infiltrating immune cells was tested by Tumor Immune Estimation Resource (TIMER). HCSC markers related gene sets were investigated by GEPIA, with their biological functions being analyzed by Cytoscape software. Results The expression level of 10 HCSC markers in HCC was higher than that in normal tissues in at least one database. Among them, high expression of CD24, SOX9, and SOX12 was positively correlated with poor prognosis (CD24: OS P = 0.0012, PFS P = 7.9E–05. SOX9: OS P = 0.012. SOX12: OS P = 0.0004, PFS P = 0.0013, respectively). However, the expression of CD13, CD34 and ALDH1A1 was associated with prolonged OS and PFS. SOX12 was significantly upregulated in poor prognosis of HCC patients with different conditions. Besides, total nine HCSC markers were identified to be positively associated with immune infiltration, including SOX12. Furthermore, Toll-like receptor signaling pathway was found to be one major pathway of these HCSC markers related gene networks. Conclusion Our results suggest that seven upregulated HCSC markers (CD90, EpCAM, CD133, CD24, SOX9, CK19, and SOX12) are related with poor prognosis and immune infiltration in HCC. In addition, we find that high SOX12 expression remarkably affect prognosis in male HCC patients but not in female. HCC patients under viral infection or alcohol intake with increased SOX12 expression had poorer prognosis. Therefore, HCSCs markers likely play an important role in tumor related immune infiltration and SOX12 might be a potential therapeutic target in patients with HCC.
Collapse
Affiliation(s)
- Xiaopu Sang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Fenfang Wu
- Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Di Wu
- Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Shan Lin
- Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Jingyi Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Nan Zhao
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoni Chen
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Anlong Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.,Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| |
Collapse
|
|
49
|
Ma XL, Hu B, Tang WG, Xie SH, Ren N, Guo L, Lu RQ. CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma. J Hematol Oncol 2020; 13:11. [PMID: 32024555 PMCID: PMC7003355 DOI: 10.1186/s13045-020-0845-z] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 01/16/2020] [Indexed: 12/11/2022] Open
Abstract
Background Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. Methods CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation. Results We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73– counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis. Conclusions Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.
Collapse
Affiliation(s)
- Xiao-Lu Ma
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Bo Hu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wei-Guo Tang
- Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201100, China
| | - Su-Hong Xie
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Ning Ren
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. .,Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201100, China.
| | - Lin Guo
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China.
| | - Ren-Quan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China.
| |
Collapse
|
|
50
|
Tsunedomi R, Yoshimura K, Suzuki N, Hazama S, Nagano H. Clinical implications of cancer stem cells in digestive cancers: acquisition of stemness and prognostic impact. Surg Today 2020; 50:1560-1577. [PMID: 32025858 DOI: 10.1007/s00595-020-01968-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 01/14/2020] [Indexed: 02/06/2023]
Abstract
Digestive system cancers are the most frequent cancers worldwide and often associated with poor prognosis because of their invasive and metastatic characteristics. Recent studies have found that the plasticity of cancer cells can impart cancer stem-like properties via the epithelial-mesenchymal transition (EMT). Cancer stem-like properties such as tumor initiation are integral to the formation of metastasis, which is the main cause of poor prognosis. Numerous markers of cancer stem cells (CSCs) have been identified in many types of cancer. Therefore, CSCs, via their stem cell-like functions, may play an important role in prognosis after surgery. While several reports have described prognostic analysis using CSC markers, few reviews have summarized CSCs and their association with prognosis. Herein, we review the prognostic potential of eight CSC markers, CD133, CD44, CD90, ALDH1A1, EPCAM, SOX2, SOX9, and LGR5, in digestive cancers including those of the pancreas, colon, liver, gastric, and esophagus.
Collapse
Affiliation(s)
- Ryouichi Tsunedomi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
| | - Kiyoshi Yoshimura
- Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan
| | - Nobuaki Suzuki
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Shoichi Hazama
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.,Faculty of Medicine, Department of Translational Research and Developmental Therapeutics against Cancer, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| |
Collapse
|