|
1
|
Saadh MJ, Ghnim ZS, Mahdi MS, Mandaliya V, Ballal S, Bareja L, Chaudhary K, Sharma R, Gupta S, Taher WM, Alwan M, Jawad MJ, Hamad AK. The emerging role of kinesin superfamily proteins in Wnt/β-catenin signaling: Implications for cancer. Pathol Res Pract 2025; 269:155904. [PMID: 40073645 DOI: 10.1016/j.prp.2025.155904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 02/27/2025] [Accepted: 03/06/2025] [Indexed: 03/14/2025]
Abstract
Cellular processes such as proliferation, differentiation, and tissue homeostasis are significantly influenced by the Wnt/β-catenin signaling pathway. Dysregulation of this pathway has been implicated in the development of various types of cancer. This study focuses on the emerging role of kinesin superfamily proteins (KIFs) in modulating cancer signaling. KIFs, a group of motor proteins, have attracted attention for their dual roles in intracellular transport: facilitating the cellular entry of Wnt ligands and contributing to the assembly of the β-catenin destruction complex. The study explores the interactions between KIFs and the Wnt/β-catenin pathway, identifying specific KIFs that interact with key components of the signaling cascade and examining their roles in cancer progression. Furthermore, it evaluates therapeutic strategies targeting KIFs to suppress aberrant Wnt activity in cancer and investigates how KIF-mediated transport spatially and temporally regulates Wnt signaling. The insights provided could guide future research into the role of KIFs in cancer biology and their involvement in oncogenic signaling pathways.
Collapse
Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan.
| | | | | | - Viralkumar Mandaliya
- Marwadi University Research Center, Department of Microbiology, Faculty of Science Marwadi University, Rajkot, Gujarat 360003, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Lakshay Bareja
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab 140401, India
| | - Kamlesh Chaudhary
- Department of Neurology, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Rsk Sharma
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh 531162, India
| | - Sofia Gupta
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab 140307, India
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | | | | | | |
Collapse
|
|
2
|
Jasim SA, Farhan SH, Ahmad I, Hjazi A, Kumar A, Jawad MA, Pramanik A, Altalbawy MAF, Alsaadi SB, Abosaoda MK. A cutting-edge investigation of the multifaceted role of SOX family genes in cancer pathogenesis through the modulation of various signaling pathways. Funct Integr Genomics 2025; 25:6. [PMID: 39753912 DOI: 10.1007/s10142-024-01517-6] [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: 09/03/2024] [Revised: 11/20/2024] [Accepted: 12/27/2024] [Indexed: 01/14/2025]
Abstract
This detailed study examines the complex role of the SOX family in various tumorigenic contexts, offering insights into how these transcription factors function in cancer. As the study progresses, it explores the specific contributions of each SOX family member. The significant roles of the SOX family in the oncogenic environment are well-recognized, highlighting a range of regulatory mechanisms that influence tumor progression. In brain, lung, and colorectal cancers, SOX types like SOX2, SOX3, and SOX4 promote the migration, proliferation, and angiogenesis of cancer cells. Conversely, in pancreatic, gastric, and breast cancers, SOX types, including SOX1, SOX9, and SOX17 inhibit various cancer cell activities such as proliferation and invasion. This thorough investigation enhances our understanding of the SOX family's complex role in cancer, establishing a foundation for future research and potential therapeutic strategies targeting these versatile transcription factors.
Collapse
Affiliation(s)
- Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al-maarif, Anbar, Iraq.
| | | | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | - Ashwani Kumar
- Department of Life Sciences, School of Sciences, Jain (Deemed-to-be) University, Bengaluru, Karnataka, 560069, India
- Department of Pharmacy, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | | | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand, India
| | - M A Farag Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | - Salim B Alsaadi
- Department of Pharmaceutics, Al-Hadi University College, Baghdad, 10011, Iraq
| | - Munther Kadhim Abosaoda
- College of Pharmacy, The Islamic University, Najaf, Iraq
- College of Pharmacy, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Pharmacy, The Islamic University of Babylon, Al Diwaniyah, Iraq
| |
Collapse
|
|
3
|
Kodama D, Takenaka M, Saigo C, Azuma M, Hanamatsu Y, Isobe M, Takeuchi T. SOX17 expression in ovarian clear cell carcinoma. J Ovarian Res 2024; 17:221. [PMID: 39529086 PMCID: PMC11552154 DOI: 10.1186/s13048-024-01549-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Recent studies have revealed that the Sry-related HMG box gene 17 (SOX17) plays an important role in ovarian carcinogenesis. Unlike other types of ovarian cancer, ovarian clear cell carcinoma (OCCC) has a distinct pathobiological phenotype, often harboring an AT-rich interaction domain 1 A (ARID1A) mutation. In the present study, to determine the SOX17 in OCCC cells, we immunohistochemically examined SOX17 expression in 47 whole-tissue specimens of OCCC. Although not statistically significant, SOX17-high immunoreactivity tended to be related to unfavorable patient outcomes. We also aimed to determine the relationship of SOX17 with ARID1A. Double immunofluorescence staining demonstrated that SOX17 immunoreactivity was not associated with ARID1A immunoreactivity. Immunoblotting revealed that SOX17 was abundantly expressed in cultured OVISE and RMG-V OCCC cells, but not in OVTOKO OCCC cells. Polyubiquitinated bands of SOX17 were observed in MG132 treated OVTOKO, but not in OVISE or RMG-V OCCC cells. Notably, si-RNA-mediated knockdown of a deubiquitinase enzyme, ubiquitin C-terminal hydrolase L1, increased polyubiquitination followed by proteasome degradation of SOX17 in OVISE. These findings indicate that SOX17 is not uniformly and heterogeneously expressed in OCCCs, independent of ARID1A deficiency. Impaired ubiquitin-mediated proteasome degradation may stabilize SOX17 in some OCCC cells.
Collapse
Affiliation(s)
- Daichi Kodama
- Department of Pathology and Translational Study, Gifu University School of Medicine, Gifu, Japan
| | - Motoki Takenaka
- Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu, Japan
| | - Chiemi Saigo
- Department of Pathology and Translational Study, Gifu University School of Medicine, Gifu, Japan
- The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
- Center for One Medicine Innovative Translational Research, Gifu University, COMIT, Gifu, Japan
| | - Masako Azuma
- Department of Pathology and Translational Study, Gifu University School of Medicine, Gifu, Japan
| | - Yuki Hanamatsu
- Department of Pathology and Translational Study, Gifu University School of Medicine, Gifu, Japan
- Center for One Medicine Innovative Translational Research, Gifu University, COMIT, Gifu, Japan
| | - Masanori Isobe
- Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu, Japan
| | - Tamotsu Takeuchi
- Department of Pathology and Translational Study, Gifu University School of Medicine, Gifu, Japan.
- Center for One Medicine Innovative Translational Research, Gifu University, COMIT, Gifu, Japan.
| |
Collapse
|
|
4
|
The Biomarker Like the Correlation between Vasculogenic Mimicry, Vascular Endothelial Cadherin, Sex-DeterminingRegion on Y-Box Transcription Factor 17, and Cyclin D1 in Oesophageal Squamous Cell Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:8915503. [PMID: 36072972 PMCID: PMC9444392 DOI: 10.1155/2022/8915503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 07/22/2022] [Indexed: 12/24/2022]
Abstract
Background This study aimed to explore the relationships between the sex-determining region on Y (SRY) box transcription factor 17 (SOX17), Cyclin D1, vascular endothelial cadherin (VE-cadherin), and vasculogenic mimicry (VM) in the occurrence and development of esophageal squamous cell carcinoma (ESCC). Methods The expressions of SOX17, Cyclin D1, and VE-cadherin, as well as VM, in tissues, were determined using immunohistochemistry. SOX17, Cyclin D1, and VE-cadherin mRNA in ESCC and their corresponding adjacent normal tissues were quantified using quantitative reverse transcription polymerase chain reaction analysis. Cell invasion, migration, and proliferation were determined after the silencing of VE-cadherin. SOX17, Cyclin D1, and VE-cadherin protein were quantified using Western blotting. Results The expression levels of SOX17, Cyclin D1, and VE-cadherin significantly correlated with the clinical characteristics of ESCC. After the VE-cadherin silencing, cell invasion, migration, and proliferation decreased, along with the Cyclin D1 levels, while the SOX17 levels increased. Conclusion SOX17, Cyclin D1, and VE-cadherin are involved in the development of ESCC.
Collapse
|
|
5
|
Sadeghi F, Kajbaf M, Shafiee F. BR2, a Buforin Derived Cancer Specific Cell Penetrating Peptide for Targeted Delivering of Toxic Agents: a Review Article. Int J Pept Res Ther 2022. [DOI: 10.1007/s10989-022-10384-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
6
|
Wu X, Liu H, Zhang M, Ma J, Qi S, Tan Q, Jiang Y, Hong Y, Yan L. miR-200a-3p promoted cell proliferation and metastasis by downregulating SOX17 in non-small cell lung cancer cells. J Biochem Mol Toxicol 2022; 36:e23037. [PMID: 35293083 DOI: 10.1002/jbt.23037] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 01/14/2022] [Accepted: 03/02/2022] [Indexed: 11/06/2022]
Abstract
Lung cancer has high mortality and incidence rates in which non-small cell lung cancer (NSCLC) is the primary type of lung cancer that accounts for about 80%-85% of total patients. It has been demonstrated that microRNAs (miRNAs) are critical in the incidence and progression of tumors, while the role and inner mechanism of miR-200a-3p, one type of essential miRNAs, in NSCLC have yet to be revealed. Herein, we investigated the in vitro and vivo pro-/antiproliferative influence of miR-200a-3p on NSCLC cells and utilized bioinformatic programs to further predict the SOX17 gene as miR-200a-3p's potential target. A double luciferase reporter gene experiment was performed to confirm that miR-200a-3p interacts with the SOX17 3'-UTR region specifically. On the basis of the results of Western blot and quantitative reverse-transcription polymerase chain reaction (qRT-PCR), miR-200a-3p impacted the posttranscriptional levels of SOX17 rather than influencing its mRNA expression. In the end, we found that overexpressed SOX17 can reverse miR-200a-3p's impact on NSCLC cell proliferation and metastasis. Therefore, this study demonstrated that miR-200a-3p influences NSCLC cell proliferation and metastasis by modulating the levels of SOX17.
Collapse
Affiliation(s)
- Xu Wu
- Provincial Key Laboratory of Biological Macro-molecules Research, Department of Biochemistry, School of Biomedicine, Wannan Medical College, Wuhu, China
| | - Haijun Liu
- Provincial Key Laboratory of Biological Macro-molecules Research, Department of Biochemistry, School of Biomedicine, Wannan Medical College, Wuhu, China
| | - Mingkang Zhang
- Provincial Key Laboratory of Biological Macro-molecules Research, Department of Biochemistry, School of Biomedicine, Wannan Medical College, Wuhu, China
| | - Jinzhu Ma
- Provincial Key Laboratory of Biological Macro-molecules Research, Department of Biochemistry, School of Biomedicine, Wannan Medical College, Wuhu, China
| | - Shimei Qi
- Provincial Key Laboratory of Biological Macro-molecules Research, Department of Biochemistry, School of Biomedicine, Wannan Medical College, Wuhu, China
| | - Qiuyu Tan
- Provincial Key Laboratory of Biological Macro-molecules Research, Department of Biochemistry, School of Biomedicine, Wannan Medical College, Wuhu, China
| | - Yuxin Jiang
- Department of Pathogen Biology and Immunology, Jiaxing University College of Medicine, Jiaxing, China
| | - Yeting Hong
- College of Laboratory Medicine, Hangzhou Medical College, Hangzhou, China
| | - Liang Yan
- Provincial Key Laboratory of Biological Macro-molecules Research, Department of Biochemistry, School of Biomedicine, Wannan Medical College, Wuhu, China
| |
Collapse
|
|
7
|
Wang XH, Zhang SF, Wu HY, Gao J, Wang XH, Gao TH. SOX17 inhibits proliferation and invasion of neuroblastoma through CXCL12/CXCR4 signaling axis. Cell Signal 2021; 87:110093. [PMID: 34302955 DOI: 10.1016/j.cellsig.2021.110093] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 07/14/2021] [Accepted: 07/19/2021] [Indexed: 11/30/2022]
Abstract
SOX17 has been shown to be involved in the transcriptional regulation of CXCR4, and CXCL12 functions by binding to its receptor CXCR4. Here, we explored the expression of SOX17 in neuroblastoma (NB), its mutual regulation with CXCL12, and its effects on cancer cell proliferation, migration and invasion. Five human NB cell lines and 15 pairs of NB and adjacent tissue specimens were used, to conduct RT-qPCR, immunohistochemistry, western blot, ELISA, CCK-8, colony formation, Edu, transwell, chromatin immunoprecipitation (ChIP), and dual-luciferase assays, to study the role of SOX17 in NB. SOX17 levels were reduced in both NB tissues and cell lines. SOX17 inhibited NB tumor growth, migration and invasion in vivo and suppressed NB cell proliferation, migration, and invasion in vitro. SOX17 knockdown or overexpression revealed a negative correlation between SOX17 and CXCL12/CXCR4 pathway activation. ChIP and dual-luciferase assays in NB cells demonstrated that SOX17 significantly inhibited CXCL12 gene and protein levels by binding to CXCL12 promoter regions. In vivo and in vitro experiments using the CXCR4 antagonist, AMD3100, demonstrated that cell proliferation, migration and invasion were significantly abrogated by AMD3100 in NB cells with SOX17 knocked down. Further, AMD3100 impaired growth of NB tumors with SOX17 knocked down in mice. Importantly, SOX17 bound to the CXCL12 promoter, which then activated downstream targets to regulate cell viability, proliferation, and migration. In conclusion, our data demonstrate that SOX17 expression is repressed in NB tissues and cells, and that SOX17 suppresses NB tumor formation and proliferation through inhibition of CXCL12/CXCR4 signaling.
Collapse
Affiliation(s)
- Xiao-Hui Wang
- Department of Pediatric Surgery, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Zhengzhou 450003, Henan Province, PR China
| | - Shu-Feng Zhang
- Department of Pediatric Surgery, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Zhengzhou 450003, Henan Province, PR China.
| | - Hai-Ying Wu
- Obstetrical Department, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Zhengzhou 450003, Henan Province, PR China
| | - Jian Gao
- Department of Pediatric Surgery, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Zhengzhou 450003, Henan Province, PR China
| | - Xu-Hui Wang
- Department of Pediatric Surgery, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Zhengzhou 450003, Henan Province, PR China
| | - Tian-Hui Gao
- Medical Oncology, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Zhengzhou 450003, Henan Province, PR China
| |
Collapse
|
|
8
|
Hu F, Li M, Mo L, Xiao Y, Wang X, Xie B. SOX-17 is involved in invasion and apoptosis of colorectal cancer cells through regulating miR-302b-3p expression. Cell Biol Int 2021; 45:1296-1305. [PMID: 33739578 DOI: 10.1002/cbin.11594] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 01/21/2021] [Accepted: 02/07/2021] [Indexed: 01/16/2023]
Abstract
The prognosis of advanced colorectal cancer (CRC) is currently still very poor, which suggests that the biological mechanisms of CRC oncogenesis are not fully understood. This study was conducted to explore the regulatory effect of SOX-17 on the expression of microRNA (miR)-302b-3p, and the involvement of SOX-17 in the invasion and apoptosis of CRC cells. The expression of SOX-17 and miR-302a,b,c,d-3p in colorectal cancer and normal colon epithelial cell lines was measured by real-time polymerase chain reaction and/or western blot. The regulatory effects of SOX-17 on miR-302b-3p gene in HT29 and LoVo cells were tested using the ChiP assay. The biological activities of SOX-17 and miR-302b-3p were evaluated by invasion and apoptosis assay. Results showed that transfection of SOX-17 small interfering RNA (siSOX-17) significantly increased, whereas transfection of SOX-17 overexpression vector (oeSOX-17) significantly decreased, miR-302b expression in HT29 and LoVo cells. Cotransfection of oeSOX-17 and miR-302b-3p inhibitor (INmiR-302b) significantly blocked the effects of SOX-17 in HT29 and LoVo cells. ChIP experiments showed that SOX-17 bonded to the miR-302b-3p promoter in HT29 and LoVo cells. Transfection of oeSOX-17 and miR-302b-3p mimics (MImiR-302b) significantly decreased, whereas transfection of siSOX-17 and INmiR-302b significantly increased, the invasion of HT29 and LoVo cells. In contrast, transfection of oeSOX-17 and MImiR-302b significantly increased, while transfection of siSOX-17 and INmiR-302b significantly decreased, apoptosis in HT29 and LoVo cells. Cotransfection of oeSOX-17 and INmiR-302b significantly blocked the effects of oeSOX-17 on cell invasion and apoptosis in HT29 and LoVo cells. These results suggested that SOX-17 can bind to the promoter of miR-302b-3p gene to regulate its expression, while both SOX-17 and miR-302b regulate the invasion and apoptosis in colorectal cancer cells.
Collapse
Affiliation(s)
- Fan Hu
- Department One of Anorectal Surgery, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Mei Li
- Department One of Anorectal Surgery, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Li Mo
- Department One of Anorectal Surgery, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - You Xiao
- Department One of Anorectal Surgery, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Xiaoyan Wang
- Department One of Anorectal Surgery, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Biao Xie
- Department One of Anorectal Surgery, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| |
Collapse
|
|
9
|
Yu Z, Gopinath SC, Lakshmipriya T, Anbu P. Single-walled carbon nanotube-gold urchin nanohybrid for identifying gastric cancer on dimicroelectrodes junction. J Taiwan Inst Chem Eng 2021. [DOI: 10.1016/j.jtice.2021.04.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
|
|
10
|
Du Z, Li L, Sun W, Zhu P, Cheng S, Yang X, Luo C, Yu X, Wu X. Systematic Evaluation for the Influences of the SOX17/Notch Receptor Family Members on Reversing Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cells. Front Oncol 2021; 11:607291. [PMID: 33791203 PMCID: PMC8006330 DOI: 10.3389/fonc.2021.607291] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 01/05/2021] [Indexed: 12/14/2022] Open
Abstract
The treatment of castration-resistant prostate cancer (CRPC) remains challenging due to the failure of androgen deprivation therapy (ADT); hence the search for other molecular therapeutic targets besides androgen receptor signaling is ongoing. This study systematically investigated the expression of SOX17 and Notch receptors in CRPC tissues and cells in vitro, showing that consistent clinical CRPC, SOX17/Notch1, and Notch4 were responsible for enzalutamide resistance in CRPC cells. The γ secretase inhibitors, BMS-708163, GSI-IX, PF-3084014, and RO4929097 abrogated the enzalutamide resistance by inhibiting Notch1 or/and Notch4 in vitro, with GSI-IX and RO4929097 being more effective than BMS-708163 and PF-3084014 in reliving bone metastasis in vivo. In conclusion, the Notch1 and Notch4 inhibitors GSI-IX and RO4929097 are promising therapeutic agents for the treatment of CRPC.
Collapse
Affiliation(s)
- Zhongbo Du
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong, China.,Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Department of Urology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Luo Li
- Center for Immunology Research, Chongqing Medical University, Chongqing, China
| | - Wei Sun
- Department of Urology, Fuling Center Hospital of Chongqing, Chongqing, China
| | - Pingyu Zhu
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong, China.,Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Shulin Cheng
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong, China.,Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Xuesong Yang
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Chunli Luo
- Key Laboratory of Diagnostics Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Xiaodong Yu
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong, China.,Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Xiaohou Wu
- Department of Urology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
11
|
The role of SOX family transcription factors in gastric cancer. Int J Biol Macromol 2021; 180:608-624. [PMID: 33662423 DOI: 10.1016/j.ijbiomac.2021.02.202] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 02/26/2021] [Indexed: 02/08/2023]
Abstract
Gastric cancer (GC) is a leading cause of death worldwide. GC is the third-most common cause of cancer-related death after lung and colorectal cancer. It is also the fifth-most commonly diagnosed cancer. Accumulating evidence has revealed the role of signaling networks in GC progression. Identification of these molecular pathways can provide new insight into therapeutic approaches for GC. Several molecular factors involved in GC can play both onco-suppressor and oncogene roles. Sex-determining region Y (Sry)-box-containing (SOX) family members are transcription factors with a well-known role in cancer. SOX proteins can bind to DNA to regulate cellular pathways via a highly conserved domain known as high mobility group (HMG). In the present review, the roles of SOX proteins in the progression and/or inhibition of GC are discussed. The dual role of SOX proteins as tumor-promoting and tumor-suppressing factors is highlighted. SOX members can affect upstream mediators (microRNAs, long non-coding RNAs and NF-κB) and down-stream mediators (FAK, HIF-1α, CDX2 and PTEN) in GC. The possible role of anti-tumor compounds to target SOX pathway members in GC therapy is described. Moreover, SOX proteins may be used as diagnostic or prognostic biomarkers in GC.
Collapse
|
|
12
|
Wang C, Wang Y, Hong T, Ye J, Chu C, Zuo L, Zhang J, Cui X. Targeting a positive regulatory loop in the tumor-macrophage interaction impairs the progression of clear cell renal cell carcinoma. Cell Death Differ 2021; 28:932-951. [PMID: 33009518 PMCID: PMC7937678 DOI: 10.1038/s41418-020-00626-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 09/11/2020] [Accepted: 09/16/2020] [Indexed: 11/09/2022] Open
Abstract
Although the interaction between tumors and tumor-associated macrophages (TAMs) has been reported to facilitate the targeted drug resistance and progression of clear cell renal cell carcinoma (ccRCC), the related mechanisms remain unknown. Here, we report that SOX17 serves as a novel tumor suppressor in ccRCC and a positive regulatory loop, SOX17low/YAP/TEAD1/CCL5/CCR5/STAT3, facilitates the ccRCC-TAM interaction. SOX17 expression was commonly downregulated and negatively correlated with TAM infiltration in ccRCC specimens, and the integration of SOX17 and TAMs with the existing clinical indicators TNM stage or SSIGN score achieved better accuracy for predicting the prognosis of ccRCC patients. Mechanistically, SOX17 knockdown activated YAP signaling by promoting the transcription and nuclear distribution of YAP, which recruited TEAD1 to trigger CCL5 transcription. Then, CCL5 educated macrophages toward TAMs, which reciprocally enhanced ccRCC progression through CCL5/CCR5 and activated STAT3/SOX17low/YAP. However, SOX17 overexpression in ccRCC achieved the opposite effect. Thus, a positive regulatory loop, SOX17low/YAP/TEAD1/CCL5/CCR5/STAT3, was identified in the ccRCC-TAM interaction. Furthermore, targeting tumor-TAM interactions by blocking this positive regulatory network impaired the metastasis and targeted drug resistance of ccRCC in in vivo mouse models of lung metastasis and orthotopic ccRCC. These findings provide a new mechanism underlying the tumor-TAM interplay in ccRCC progression and present a potential target for inhibiting targeted drug resistance and metastasis in advanced ccRCC.
Collapse
Affiliation(s)
- Chao Wang
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), 219 Miaopu Road, Shanghai, 200135, China
- Department of Urology, the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, 29 Xinglong Road, Changzhou, 213000, Jiangsu, China
| | - Yuning Wang
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), 219 Miaopu Road, Shanghai, 200135, China
| | - Tianyu Hong
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), 219 Miaopu Road, Shanghai, 200135, China
| | - Jianqing Ye
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), 219 Miaopu Road, Shanghai, 200135, China
- Department of Urinary Surgery, The Third Affiliated Hospital of Second Military Medical University (Eastern Hepatobiliary Surgery Hospital), 700 North Moyu Road, Shanghai, 201805, China
| | - Chuanmin Chu
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), 219 Miaopu Road, Shanghai, 200135, China
- Department of Urinary Surgery, The Third Affiliated Hospital of Second Military Medical University (Eastern Hepatobiliary Surgery Hospital), 700 North Moyu Road, Shanghai, 201805, China
| | - Li Zuo
- Department of Urology, the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, 29 Xinglong Road, Changzhou, 213000, Jiangsu, China
| | - Jing Zhang
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), 219 Miaopu Road, Shanghai, 200135, China
| | - Xingang Cui
- Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), 219 Miaopu Road, Shanghai, 200135, China.
- Department of Urinary Surgery, The Third Affiliated Hospital of Second Military Medical University (Eastern Hepatobiliary Surgery Hospital), 700 North Moyu Road, Shanghai, 201805, China.
| |
Collapse
|
|
13
|
Anani M, Nobuhisa I, Taga T. Sry-related High Mobility Group Box 17 Functions as a Tumor Suppressor by Antagonizing the Wingless-related Integration Site Pathway. J Cancer Prev 2020; 25:204-212. [PMID: 33409253 PMCID: PMC7783240 DOI: 10.15430/jcp.2020.25.4.204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 12/01/2020] [Accepted: 12/05/2020] [Indexed: 11/16/2022] Open
Abstract
A transcription factor Sry-related high mobility group box (Sox) 17 is involved in developmental processes including spermatogenesis, cardiovascular system, endoderm formation, and so on. In this article, we firstly review the studies on the relation between the Sox17 expression and tumor malignancy. Although Sox17 positively promotes various tissue development, most of the cancers associated with Sox17 show decreased expression levels of Sox17, and an inverse correlation between Sox17 expression and malignancy is revealed. We briefly discuss the mechanism of such Sox17 down-regulation by focusing on DNA methylation of CpG sites located in the Sox17 gene promoter. Next, we overview the function of Sox17 in the fetal hematopoiesis, particularly in the dorsal aorta in midgestation mouse embryos. The Sox17 expression in hematopoietic stem cell (HSC)-containing intra-aortic hematopoietic cell cluster (IAHCs) is important for the cluster formation with the hematopoietic ability. The sustained expression of Sox17 in adult bone marrow HSCs and the cells in IAHCs of the dorsal aorta indicate abnormalities that are low lymphocyte chimerism and the aberrant proliferation of common myeloid progenitors in transplantation experiments. We then summarize the perspectives of Sox17 research in cancer control.
Collapse
Affiliation(s)
- Maha Anani
- Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Ikuo Nobuhisa
- Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tetsuya Taga
- Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| |
Collapse
|
|
14
|
Yang Y, Li W, Wei B, Wu K, Liu D, Zhu D, Zhang C, Wen F, Fan Y, Zhao S. MicroRNA let-7i Inhibits Histone Lysine Demethylase KDM5B to Halt Esophageal Cancer Progression. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 22:846-861. [PMID: 33230480 PMCID: PMC7658493 DOI: 10.1016/j.omtn.2020.09.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 09/11/2020] [Indexed: 11/25/2022]
Abstract
Recent studies have suggested that microRNA let-7i is a tumor suppressor in human cancers, including esophageal cancer, but its underlying mechanism is not yet fully understood. We investigated the role and mechanisms of let-7i in the progression of esophageal cancer. We first showed that let-7i was downregulated in esophageal cancer tissues and cells and then linked its low expression to cancer progression. Bioinformatic analysis predicted KDM5B as a target gene of let-7i, which was confirmed by a dual-luciferase reporter assay. Loss- and gain-of function approaches were adopted to examine the interactions of let-7i, KDM5B, SOX17, and GREB1 in vitro and in vivo. Overexpression of let-7i suppressed esophageal cancer cell proliferation and invasion and promoted apoptosis. Mechanistic investigation showed that let-7i targeted and inhibited KDM5B expression, whereas KDM5B enhanced H3K4me3 at the SOX17 promoter region. Overexpression of let-7i suppressed the expression of GREB1 in esophageal cancer cells by regulating the KDM5B/SOX17 axis in vivo and in vitro. Taken together, our findings reveal the tumor-suppressive properties of let-7i in esophageal cancer in association with an apparent KDM5B-dependent SOX17/GREB1 axis. This study offers a potential prognostic marker and therapeutic target for esophageal cancer.
Collapse
Affiliation(s)
- Yang Yang
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Wenhua Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Bochong Wei
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Kai Wu
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Donglei Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Dengyan Zhu
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Chunyang Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Fengbiao Wen
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Yuxia Fan
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| | - Song Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China
| |
Collapse
|
|
15
|
Tan DS, Holzner M, Weng M, Srivastava Y, Jauch R. SOX17 in cellular reprogramming and cancer. Semin Cancer Biol 2020; 67:65-73. [DOI: 10.1016/j.semcancer.2019.08.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 07/19/2019] [Accepted: 08/08/2019] [Indexed: 12/19/2022]
|
|
16
|
Olbromski M, Podhorska-Okołów M, Dzięgiel P. Role of SOX Protein Groups F and H in Lung Cancer Progression. Cancers (Basel) 2020; 12:cancers12113235. [PMID: 33152990 PMCID: PMC7692225 DOI: 10.3390/cancers12113235] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 10/24/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022] Open
Abstract
Simple Summary The expression of SOX proteins has been demonstrated in many tissues at various stages of embryogenesis, where they play the role of transcription factors. The SOX18 protein (along with SOX7 and SOX17) belongs to the SOXF group and is mainly involved in the development of the cardiovascular system, where its expression was found in the endothelium. SOX18 expression was also demonstrated in neoplastic lines of gastric, pancreatic and colon adenocarcinomas. The prognostic role of SOX30 expression has only been studied in lung adenocarcinomas, where a low expression of this factor in the stromal tumor was associated with a worse prognosis for patients. Because of the complexity of non-small-cell lung cancer (NSCLC) development, the role of the SOX proteins in this malignancy is still not fully understood. Many recently published papers show that SOX family protein members play a crucial role in the progression of NSCLC. Abstract The SOX family proteins are proved to play a crucial role in the development of the lymphatic ducts and the cardiovascular system. Moreover, an increased expression level of the SOX18 protein has been found in many malignances, such as melanoma, stomach, pancreatic breast and lung cancers. Another SOX family protein, the SOX30 transcription factor, is responsible for the development of male germ cells. Additionally, recent studies have shown its proapoptotic character in non-small cell lung cancer cells. Our preliminary studies showed a disparity in the amount of mRNA of the SOX18 gene relative to the amount of protein. This is why our attention has been focused on microRNA (miRNA) molecules, which could regulate the SOX18 gene transcript level. Recent data point to the fact that, in practically all types of cancer, hundreds of genes exhibit an abnormal methylation, covering around 5–10% of the thousands of CpG islands present in the promoter sequences, which in normal cells should not be methylated from the moment the embryo finishes its development. It has been demonstrated that in non-small-cell lung cancer (NSCLC) cases there is a large heterogeneity of the methylation process. The role of the SOX18 and SOX30 expression in non-small-cell lung cancers (NSCLCs) is not yet fully understood. However, if we take into account previous reports, these proteins may be important factors in the development and progression of these malignancies.
Collapse
Affiliation(s)
- Mateusz Olbromski
- Department of Histology and Embryology, Department of Human Morphology and Embryology, Medical University, 50-368 Wroclaw, Poland;
- Correspondence: ; Tel.: +48-717-841-354; Fax: +48-717-840-082
| | - Marzenna Podhorska-Okołów
- Department of Ultrastructural Research, Department of Human Morphology and Embryology, Medical University, 50-368 Wroclaw, Poland;
| | - Piotr Dzięgiel
- Department of Histology and Embryology, Department of Human Morphology and Embryology, Medical University, 50-368 Wroclaw, Poland;
- Department of Physiotherapy, University School of Physical Education, 51-612 Wroclaw, Poland
| |
Collapse
|
|
17
|
Yang L, Wu Y, He H, Hu F, Li M, Mo L, Xiao Y, Wang X, Xie B. Delivery of BR2‐SOX17 fusion protein can inhibit cell survival, proliferation, and invasion in gastric cancer cells through regulating Klotho gene expression. Cell Biol Int 2020; 44:2011-2020. [PMID: 32544287 DOI: 10.1002/cbin.11407] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 05/30/2020] [Accepted: 06/13/2020] [Indexed: 12/14/2022]
Affiliation(s)
- Lixia Yang
- Department of Cancer The First Affiliated Hospital of Changsha Medical School Changsha Hunan China
| | - Yue Wu
- Department of Cancer The First Affiliated Hospital of Changsha Medical School Changsha Hunan China
| | - Heli He
- Department of Cancer The First Affiliated Hospital of Changsha Medical School Changsha Hunan China
| | - Fan Hu
- Department One of Anorectal Surgery The Second Affiliated Hospital of Hunan University of Chinese Medicine Changsha Hunan China
| | - Mei Li
- Department One of Anorectal Surgery The Second Affiliated Hospital of Hunan University of Chinese Medicine Changsha Hunan China
| | - Li Mo
- Department One of Anorectal Surgery The Second Affiliated Hospital of Hunan University of Chinese Medicine Changsha Hunan China
| | - You Xiao
- Department One of Anorectal Surgery The Second Affiliated Hospital of Hunan University of Chinese Medicine Changsha Hunan China
| | - Xiaoyan Wang
- Department One of Anorectal Surgery The Second Affiliated Hospital of Hunan University of Chinese Medicine Changsha Hunan China
| | - Biao Xie
- Department of Cancer The First Affiliated Hospital of Changsha Medical School Changsha Hunan China
- Department One of Anorectal Surgery The Second Affiliated Hospital of Hunan University of Chinese Medicine Changsha Hunan China
| |
Collapse
|
|
18
|
Wang C, Li Q, He Y. MicroRNA‑21‑5p promotes epithelial to mesenchymal transition by targeting SRY‑box 17 in endometrial cancer. Oncol Rep 2020; 43:1897-1905. [PMID: 32236579 PMCID: PMC7160535 DOI: 10.3892/or.2020.7556] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Accepted: 07/24/2018] [Indexed: 12/12/2022] Open
Abstract
MicroRNA (miRNA/miR)‑21‑5p has been proposed as an oncogenic miRNA in human tumors; however, the exact role of miR‑21‑5p has not been fully determined in endometrial cancer. SRY‑box 17 (SOX17) is associated with endometrial cancer development and progression; however, the regulatory mechanisms underlying SOX17 expression in endometrial cancer remain unclear. In the present study, tumor samples were collected from 160 postmenopausal women with endometrial cancer. All tumor samples were examined for miR‑21‑5p expression by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The results demonstrated that miR‑21‑5p expression was associated with shorter overall survival. In addition, overexpression of miR‑21‑5p promoted epithelial to mesenchymal transition (EMT), whereas silencing miR‑21‑5p reversed EMT in endometrial cancer cell lines. Using RT‑qPCR and western blotting, it was revealed that overexpressing miR‑21‑5p significantly inhibited SOX17 protein expression in endometrial cancer cell lines. Furthermore, as determined by luciferase reporter assay, ectopic expression of miR‑21‑5p inhibited the activity of the SOX17 mRNA 3'‑untranslated region (3'UTR), whereas silencing miR‑21‑5p promoted the activity of the SOX17 mRNA 3'UTR in endometrial cancer cell lines. Overexpression of SOX17 promoted mesenchymal to epithelial transition, whereas silencing SOX17 induced EMT in endometrial cancer cell lines. In addition, tumor SOX17 expression was associated with better overall survival. Therefore, it may be concluded that miR‑21‑5p promotes EMT by targeting SOX17 in human endometrial cancer.
Collapse
Affiliation(s)
- Cuilan Wang
- Department of Gynecology and Obstetrics, Jinan Maternity and Child Health Care Hospital, Jinan, Shandong 250001, P.R. China
| | - Qing Li
- Department of Gynecology and Obstetrics, Jinan Maternity and Child Health Care Hospital, Jinan, Shandong 250001, P.R. China
| | - Yuan He
- Department of Gynecology and Obstetrics, Jinan Maternity and Child Health Care Hospital, Jinan, Shandong 250001, P.R. China
| |
Collapse
|
|
19
|
Sexton RE, Hallak MNA, Uddin MH, Diab M, Azmi AS. Gastric Cancer Heterogeneity and Clinical Outcomes. Technol Cancer Res Treat 2020; 19:1533033820935477. [PMID: 32799763 PMCID: PMC7432987 DOI: 10.1177/1533033820935477] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/16/2020] [Accepted: 05/22/2020] [Indexed: 12/21/2022] Open
Abstract
Gastric adenocarcinoma is a highly aggressive disease with poor overall survival. The aggressive nature of this disease is in part due to the high intra and inter tumoral heterogeneity and also due to the late diagnosis at presentation. Once progression occurs, treatment is more difficult due to the adaptation of tumors, which acquires resistance to commonly used chemotherapeutics. In this report, using publicly available data sets and pathway analysis, we highlight the vast heterogeneity of gastric cancer by investigating genes found to be significantly perturbed. We found several upregulated genes in the diffuse gastric cancer subtypes share similarity to gastric cancer as a whole which can be explained by the increase in this subtype of gastric cancer throughout the world. We report significant downregulation of genes that are underrepresented within the literature, such as ADH7, GCNT2, and LIF1, while other genes have not been explored within gastric cancer to the best of our knowledge such as METTL7A, MAL, CWD43, and SLC2A12. We identified gender to be another heterogeneous component of this disease and suggested targeted treatment strategies specific to this heterogeneity. In this study, we provide an in-depth exploration of the molecular landscape of gastric cancer in order to shed light onto novel areas of gastric cancer research and explore potential new therapeutic targets.
Collapse
Affiliation(s)
- Rachel E. Sexton
- Department of Oncology, Wayne State University School of
Medicine, Detroit, MI, USA
| | | | - Md. Hafiz Uddin
- Department of Oncology, Wayne State University School of
Medicine, Detroit, MI, USA
| | - Maria Diab
- Department of Oncology, Wayne State University School of
Medicine, Detroit, MI, USA
| | - Asfar S. Azmi
- Department of Oncology, Wayne State University School of
Medicine, Detroit, MI, USA
| |
Collapse
|
|
20
|
High Detection Rate for Non-Muscle-Invasive Bladder Cancer Using an Approved DNA Methylation Signature Test. Clin Genitourin Cancer 2019; 18:210-221. [PMID: 32139301 DOI: 10.1016/j.clgc.2019.10.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/25/2019] [Accepted: 10/06/2019] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Cystoscopy and transurethral resection are the current reference standard tests to diagnose and histologically confirm non-muscle-invasive bladder cancer (NMIBC). In other tumor entities (ie, colon carcinoma, cervical cancer), DNA methylation markers have been approved as diagnostic tests with high diagnostic power. In our case-control study, we used an approved molecular cervical cancer diagnostics test that includes 6 DNA methylation markers (GynTect) for the detection of bladder cancer. PATIENTS AND METHODS We included samples from 40 patients with bladder cancer and 34 control subjects. In a pilot study, we analyzed DNA methylation in 38 tumor tissues and 4 healthy ureters using methylation-specific polymerase chain reaction. Subsequently, we determined the sensitivity and specificity of the GynTect for the detection of bladder cancer in urine sediments from 40 patients with bladder cancer and 30 control subjects with benign prostatic hyperplasia or urolithiasis. RESULTS The markers showed very different methylation rates in the NMIBC tissues, ranging from 2.6% to 78.9%. No methylation of any of the markers was detectable in the healthy ureters. Using the urine sediments from the patients with cancer and control subjects, we found surprisingly high sensitivity and specificity for the GynTect assay (60% and 96.7%, respectively). The application of different algorithms for evaluation of the markers included in GynTect resulted in a sensitivity of ≤ 90% and specificity of ≤ 100%. CONCLUSION The GynTect assay, originally designed for cervical cancer diagnostics, showed unexpectedly high diagnostic accuracy for bladder cancer detection. The inclusion of additional methylation markers might allow for the development of a suitable diagnostic marker set based on the GynTect test for NMIBC diagnostics.
Collapse
|
|
21
|
Srivastava Y, Tan DS, Malik V, Weng M, Javed A, Cojocaru V, Wu G, Veerapandian V, Cheung LWT, Jauch R. Cancer-associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17. FEBS J 2019; 287:122-144. [PMID: 31569299 DOI: 10.1111/febs.15076] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 07/26/2019] [Accepted: 09/29/2019] [Indexed: 12/21/2022]
Abstract
The functional consequences of cancer-associated missense mutations are unclear for the majority of proteins. We have previously demonstrated that the activity of SOX and Pit-Oct-Unc (POU) family factors during pluripotency reprogramming can be switched and enhanced with rationally placed point mutations. Here, we interrogated cancer mutation databases and identified recurrently mutated positions at critical structural interfaces of the DNA-binding domains of paralogous SOX and POU family transcription factors. Using the conversion of mouse embryonic fibroblasts to induced pluripotent stem cells as functional readout, we identified several gain-of-function mutations that enhance pluripotency reprogramming by SOX2 and OCT4. Wild-type SOX17 cannot support reprogramming but the recurrent missense mutation SOX17-V118M is capable of inducing pluripotency. Furthermore, SOX17-V118M promotes oncogenic transformation, enhances thermostability and elevates cellular protein levels of SOX17. We conclude that the mutational profile of SOX and POU family factors in cancer can guide the design of high-performance reprogramming factors. Furthermore, we propose cellular reprogramming as a suitable assay to study the functional impact of cancer-associated mutations.
Collapse
Affiliation(s)
- Yogesh Srivastava
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangzhou Medical University, China.,Genome Regulation Laboratory, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Daisylyn Senna Tan
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Vikas Malik
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangzhou Medical University, China.,Genome Regulation Laboratory, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Mingxi Weng
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Asif Javed
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Vlad Cojocaru
- Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Guangming Wu
- Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Veeramohan Veerapandian
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangzhou Medical University, China.,Genome Regulation Laboratory, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,University of Chinese Academy of Sciences, Beijing, China.,Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Lydia W T Cheung
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ralf Jauch
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangzhou Medical University, China.,Genome Regulation Laboratory, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| |
Collapse
|
|
22
|
Liao YM, Song Y, Li YK, Du JH, Zhou Y. SOX17, β-catenin and CyclinD1 expression in the endometrioid adenocarcinoma and influence of 5-AZA on expression. Cancer Gene Ther 2019; 27:256-263. [PMID: 31543512 DOI: 10.1038/s41417-019-0135-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 07/12/2019] [Accepted: 07/20/2019] [Indexed: 12/25/2022]
Abstract
The present study discusses the expression and effect of the SOX17 gene in endometrioid adenocarcinoma. MTT assay is performed to determine the growth inhibition ratio of the DNA methyltransferase inhibitor 5-AZA for endometrial carcinoma cells, and the real-time fluorescence quantification PCR (qRT-PCR) was used to detect the mRNA expression of SOX17, β-catenin, and CyclinD1 in endometrial carcinoma tissues before and after using 5-AZA to treat the endometrial carcinoma cell line. There were 30 cases on endometrioid adenocarcinoma tissues and 10 cases on normal endometrial tissues. The results revealed that the expression of SOX17 in endometrioid adenocarcinoma tissues was downregulated (P < 0.05), the expression of β-catenin and CyclinD1 was upregulated (P < 0.05), and the expression of SOX17, CyclinD1, and β-catenin was negatively correlated (r = -0.353, P > 0.05; R = -0.463, P < 0.05). The higher the histological grade and FIGO staging were, the lower the expression level of SOX17 was (P < 0.05). After HEC1A cells were treated by 5-AZA, the cell growth inhibition was most obvious (IC50 = 12.033) at 72 h, as determined by MTT assay. After cell treatment by 5-AZA, the genetic expression of SOX17 significantly increased, when compared with that before treatment (P < 0.05), while the genetic expression of β-catenin and CyclinD1 significantly declined (P < 0.05). These results indicate that the expression level of SOX17 in endometrioid adenocarcinoma declined, and the upregulated expression level of SOX17 in cells inhibited the growth of tumor cells.
Collapse
Affiliation(s)
- Yu-Mei Liao
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Yang Song
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuan-Kun Li
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jie-Hua Du
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ying Zhou
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| |
Collapse
|
|
23
|
The role of SOX family members in solid tumours and metastasis. Semin Cancer Biol 2019; 67:122-153. [PMID: 30914279 DOI: 10.1016/j.semcancer.2019.03.004] [Citation(s) in RCA: 265] [Impact Index Per Article: 44.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 03/07/2019] [Accepted: 03/21/2019] [Indexed: 02/07/2023]
Abstract
Cancer is a heavy burden for humans across the world with high morbidity and mortality. Transcription factors including sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) proteins are thought to be involved in the regulation of specific biological processes. The deregulation of gene expression programs can lead to cancer development. Here, we review the role of the SOX family in breast cancer, prostate cancer, renal cell carcinoma, thyroid cancer, brain tumours, gastrointestinal and lung tumours as well as the entailing therapeutic implications. The SOX family consists of more than 20 members that mediate DNA binding by the HMG domain and have regulatory functions in development, cell-fate decision, and differentiation. SOX2, SOX4, SOX5, SOX8, SOX9, and SOX18 are up-regulated in different cancer types and have been found to be associated with poor prognosis, while the up-regulation of SOX11 and SOX30 appears to be favourable for the outcome in other cancer types. SOX2, SOX4, SOX5 and other SOX members are involved in tumorigenesis, e.g. SOX2 is markedly up-regulated in chemotherapy resistant cells. The SoxF family (SOX7, SOX17, SOX18) plays an important role in angio- and lymphangiogenesis, with SOX18 seemingly being an attractive target for anti-angiogenic therapy and the treatment of metastatic disease in cancer. In summary, SOX transcription factors play an important role in cancer progression, including tumorigenesis, changes in the tumour microenvironment, and metastasis. Certain SOX proteins are potential molecular markers for cancer prognosis and putative potential therapeutic targets, but further investigations are required to understand their physiological functions.
Collapse
|
|
24
|
Uchuya-Castillo J, Aznar N, Frau C, Martinez P, Le Nevé C, Marisa L, Penalva LOF, Laurent-Puig P, Puisieux A, Scoazec JY, Samarut J, Ansieau S, Plateroti M. Increased expression of the thyroid hormone nuclear receptor TRα1 characterizes intestinal tumors with high Wnt activity. Oncotarget 2018; 9:30979-30996. [PMID: 30123421 PMCID: PMC6089551 DOI: 10.18632/oncotarget.25741] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 06/12/2018] [Indexed: 01/10/2023] Open
Abstract
Our previous work demonstrated a key function of the thyroid hormone nuclear receptor TRα1, a T3-modulated transcription factor, in controlling intestinal development and homeostasis via the Wnt and Notch pathways. Importantly, increased expression of TRα1 in the intestinal epithelium in a mutated Apc genetic background (vil-TRα1/Apc+/1638N mice) accelerated tumorigenesis and contributed to a more aggressive tumor phenotype compared to that of the Apc mutants alone. Therefore, the aim of this study was to determine the relevance of this synergistic effect in human colorectal cancers and to gain insights into the mechanisms involved. We analyzed cohorts of patients by in silico and experimental approaches and observed increased TRα1 expression and a significant correlation between TRα1 levels and Wnt activity. TRα1 loss-of-function and gain-of-function in Caco2 cell lines not only confirmed that TRα1 levels control Wnt activity but also demonstrated the role of TRα1 in regulating cell proliferation and migration. Finally, upon investigation of the molecular mechanisms responsible for the Wnt-TRα1 association, we described the repression by TRα1 of several Wnt inhibitors, including Frzb, Sox17 and Wif1. In conclusion, our results underline an important functional interplay between the thyroid hormone nuclear receptor TRα1 and the canonical Wnt pathway in intestinal cancer initiation and progression. More importantly, we show for the first time that the expression of TRα1 is induced in human colorectal cancers.
Collapse
Affiliation(s)
- Joel Uchuya-Castillo
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la recherche, Lyon 69000, France
| | - Nicolas Aznar
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la recherche, Lyon 69000, France
| | - Carla Frau
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la recherche, Lyon 69000, France
| | - Pierre Martinez
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la recherche, Lyon 69000, France
| | - Clementine Le Nevé
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la recherche, Lyon 69000, France
| | - Laetitia Marisa
- Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris 75000, France
| | - Luiz O F Penalva
- Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, TX 78229, USA
| | | | - Alain Puisieux
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la recherche, Lyon 69000, France
| | | | - Jacques Samarut
- Institute de Génomique Fonctionnelle de Lyon, ENS de Lyon, Lyon 69342, France
| | - Stephane Ansieau
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la recherche, Lyon 69000, France
| | - Michelina Plateroti
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la recherche, Lyon 69000, France
| |
Collapse
|
|
25
|
SOX17 restrains proliferation and tumor formation by down-regulating activity of the Wnt/β-catenin signaling pathway via trans-suppressing β-catenin in cervical cancer. Cell Death Dis 2018; 9:741. [PMID: 29970906 PMCID: PMC6030085 DOI: 10.1038/s41419-018-0782-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 05/28/2018] [Accepted: 05/29/2018] [Indexed: 01/17/2023]
Abstract
The SRY-box containing gene 17 (SOX17) is considered as a regulator in stemness maintenance and a suppressor in some malignant tumors. However, the biological function and molecular mechanism of SOX17 in the process of initiation and progression of cervical cancer remain obscure. In this study, immunohistochemistry showed that the expression of SOX17 was high in the normal cervix, moderate in the high-grade squamous intraepithelial lesion, and low in the cervical cancer. SOX17 inhibited the proliferation and viability of cervical cancer cells in vitro as well as tumor formation in vivo. Additionally, SOX17 induced the cell cycle arrest at the transition from the G0/G1 phase to the S phase. The TOP/ FOP-Flash reporter assay and Western blotting showed SOX17 inhibited the activity of the Wnt/β-catenin signaling pathway in cervical cancer. Further, firefly luciferase reporter assay and quantitative chromatin immunoprecipitation (qChIP) assays confirmed that SOX17 trans-suppressed the expression of β-catenin by directly binding to the specific region of the β-catenin promoter. Together, our data demonstrated that SOX17 restrained the proliferation and tumor formation by down-regulating the activity of the Wnt/β-catenin signaling pathway via trans-suppression of β-catenin in cervical cancer.
Collapse
|
|
26
|
Alonso-Martin S, Auradé F, Mademtzoglou D, Rochat A, Zammit PS, Relaix F. SOXF factors regulate murine satellite cell self-renewal and function through inhibition of β-catenin activity. eLife 2018; 7:26039. [PMID: 29882512 PMCID: PMC6021169 DOI: 10.7554/elife.26039] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 06/07/2018] [Indexed: 12/17/2022] Open
Abstract
Muscle satellite cells are the primary source of stem cells for postnatal skeletal muscle growth and regeneration. Understanding genetic control of satellite cell formation, maintenance, and acquisition of their stem cell properties is on-going, and we have identified SOXF (SOX7, SOX17, SOX18) transcriptional factors as being induced during satellite cell specification. We demonstrate that SOXF factors regulate satellite cell quiescence, self-renewal and differentiation. Moreover, ablation of Sox17 in the muscle lineage impairs postnatal muscle growth and regeneration. We further determine that activities of SOX7, SOX17 and SOX18 overlap during muscle regeneration, with SOXF transcriptional activity requisite. Finally, we show that SOXF factors also control satellite cell expansion and renewal by directly inhibiting the output of β-catenin activity, including inhibition of Ccnd1 and Axin2. Together, our findings identify a key regulatory function of SoxF genes in muscle stem cells via direct transcriptional control and interaction with canonical Wnt/β-catenin signaling.
Collapse
Affiliation(s)
- Sonia Alonso-Martin
- Institut Mondor de Recherche Biomédicale, INSERM U955-E10, Créteil, France.,Université Paris Est, Faculté de Medecine, Créteil, France.,Ecole Nationale Veterinaire d'Alfort, Maison Alfort, France
| | - Frédéric Auradé
- Sorbonne Université, INSERM U974, Center for Research in Myology, Paris, France
| | - Despoina Mademtzoglou
- Institut Mondor de Recherche Biomédicale, INSERM U955-E10, Créteil, France.,Université Paris Est, Faculté de Medecine, Créteil, France.,Ecole Nationale Veterinaire d'Alfort, Maison Alfort, France
| | - Anne Rochat
- Sorbonne Université, INSERM U974, Center for Research in Myology, Paris, France
| | - Peter S Zammit
- Randall Centre for Cell and Molecular Biophysics, King's College London, London, United Kingdom
| | - Frédéric Relaix
- Institut Mondor de Recherche Biomédicale, INSERM U955-E10, Créteil, France.,Université Paris Est, Faculté de Medecine, Créteil, France.,Ecole Nationale Veterinaire d'Alfort, Maison Alfort, France.,Etablissement Français du Sang, Creteil, France.,APHP, Hopitaux UniversitairesHenri Mondor, Centre de Référence des Maladies Neuromusculaires GNMH, Créteil, France
| |
Collapse
|
|
27
|
Zhang Y, Bao W, Wang K, Lu W, Wang H, Tong H, Wan X. SOX17 is a tumor suppressor in endometrial cancer. Oncotarget 2018; 7:76036-76046. [PMID: 27738313 PMCID: PMC5342796 DOI: 10.18632/oncotarget.12582] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Accepted: 09/26/2016] [Indexed: 01/04/2023] Open
Abstract
β-catenin is a key regulatory factor for the Wnt signaling pathway. SOX17 is an important β-catenin inhibitor, while MAML3 is a co-activator of β-catenin-mediated transcription. Out of 120 endometrial cancer (EC) patients, we found that those with tumors expressing higher SOX17 (n=68) had longer recurrence-free survival (P=0.024), while higher MAML3 expression (n=76) was associated with shorter recurrence-free survival (P=0.022). Immunohistochemical and immunoprecipitation analyses revealed that SOX17 and MAML3 co-localized in EC cell nuclei, and the MAML3 C-terminal region was necessary for SOX17 binding. SOX17 regulated MAML3 transcription via binding to the MAML3 promoter, decreasing Wnt pathway protein expression and suppressing EC cell growth and colony formation in vitro. In nude mice, SOX17 over-expression inhibited tumor growth, and co-inhibition or co-overexpression of SOX17 and MAML3 rescued this response. Our results suggest that decreasing SOX17 levels may promote EC development and progression, and that by downregulating MAML3 expression and Wnt signaling, SOX17 acts as a tumor suppressor that may improve outcome in patients with EC.
Collapse
Affiliation(s)
- Yongli Zhang
- Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wei Bao
- Department of Obstetrics and Gynecology, International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai Wang
- Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wen Lu
- Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Huihui Wang
- Department of Obstetrics and Gynecology, International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huan Tong
- Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoping Wan
- Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| |
Collapse
|
|
28
|
Zhu D, Yang D, Li X, Feng F. Heterogeneous expression and biological function of SOX18 in osteosaroma. J Cell Biochem 2018; 119:4184-4192. [DOI: 10.1002/jcb.26635] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 12/19/2017] [Indexed: 11/07/2022]
Affiliation(s)
- Danjie Zhu
- Department of OrthopedicsZhejiang Provincial People's HospitalPeople's Hospital of Hangzhou Medical CollegeHangzhouChina
| | - Di Yang
- Department of OrthopedicsZhejiang Provincial People's HospitalPeople's Hospital of Hangzhou Medical CollegeHangzhouChina
| | - Xiaolin Li
- Department of OrthopedicsZhejiang Provincial People's HospitalPeople's Hospital of Hangzhou Medical CollegeHangzhouChina
| | - Fabo Feng
- Department of OrthopedicsZhejiang Provincial People's HospitalPeople's Hospital of Hangzhou Medical CollegeHangzhouChina
| |
Collapse
|
|
29
|
Lima CR, Gomes CC, Santos MF. Role of microRNAs in endocrine cancer metastasis. Mol Cell Endocrinol 2017; 456:62-75. [PMID: 28322989 DOI: 10.1016/j.mce.2017.03.015] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 03/12/2017] [Accepted: 03/13/2017] [Indexed: 12/20/2022]
Abstract
The deregulation of transcription and processing of microRNAs (miRNAs), as well as their function, has been involved in the pathogenesis of several human diseases, including cancer. Despite advances in therapeutic approaches, cancer still represents one of the major health problems worldwide. Cancer metastasis is an aggravating factor in tumor progression, related to increased treatment complexity and a worse prognosis. After more than one decade of extensive studies of miRNAs, the fundamental role of these molecules in cancer progression and metastasis is beginning to be elucidated. Recent evidences have demonstrated a significant role of miRNAs on the metastatic cascade, acting either as pro-metastatic or anti-metastatic. They are involved in distinct steps of metastasis including epithelial-to-mesenchymal transition, migration/invasion, anoikis survival, and distant organ colonization. Studies on the roles of miRNAs in cancer have focused mainly on two fronts: the establishment of a miRNA signature for different tumors, which may aid in early diagnosis using these miRNAs as markers, and functional studies of specific miRNAs, determining their targets, function and regulation. Functional miRNA studies on endocrine cancers are still scarce and represent an important area of research, since some tumors, although not frequent, present a high mortality rate. Among the endocrine tumors, thyroid cancer is the most common and best studied. Several miRNAs show lowered expression in endocrine cancers (i.e. miR-200s, miR-126, miR-7, miR-29a, miR-30a, miR-137, miR-206, miR-101, miR-613, miR-539, miR-205, miR-9, miR-195), while others are commonly overexpressed (i.e. miR-21, miR-183, miR-31, miR-let7b, miR-584, miR-146b, miR-221, miR-222, miR-25, miR-595). Additionally, some miRNAs were found in serum exosomes (miR-151, miR-145, miR-31), potentially serving as diagnostic tools. In this review, we summarize studies concerning the discovery and functions of miRNAs and their regulatory roles in endocrine cancer metastasis, which may contribute for the finding of novel therapeutic targets. The review focus on miRNAs with at least some identified targets, with established functions and, if possible, upstream regulation.
Collapse
Affiliation(s)
- Cilene Rebouças Lima
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, Avenida Professor Lineu Prestes 1524, Prédio I, CEP 05508-000, São Paulo, SP, Brazil.
| | - Cibele Crastequini Gomes
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, Avenida Professor Lineu Prestes 1524, Prédio I, CEP 05508-000, São Paulo, SP, Brazil.
| | - Marinilce Fagundes Santos
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, Avenida Professor Lineu Prestes 1524, Prédio I, CEP 05508-000, São Paulo, SP, Brazil.
| |
Collapse
|
|
30
|
Different expression of sox17 gene during gametogenesis between scallop Chlamys farreri and vertebrates. Gene Expr Patterns 2017. [DOI: 10.1016/j.gep.2017.06.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
|
|
31
|
SOX15 regulates proliferation and migration of endometrial cancer cells. Biosci Rep 2017; 37:BSR20171045. [PMID: 28821564 PMCID: PMC5643738 DOI: 10.1042/bsr20171045] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 08/15/2017] [Accepted: 08/16/2017] [Indexed: 12/28/2022] Open
Abstract
The study aimed to investigate the effects of Sry-like high mobility group box 15 (SOX15) on proliferation and migration of endometrial cancer (EC) cells. Immunohistochemistry (IHC) was applied to determine the expression of SOX15 in EC tissues and adjacent tissues. We used cell transfection method to construct the HEC-1-A and Ishikawa cell lines with stable overexpression and low expression SOX15. Reverse-transcription quantitative real-time PCR (RT-qPCR) and Western blot were performed to examine expression of SOX15 mRNA and SOX15 protein, respectively. By conducting a series of cell proliferation assay and migration assay, we analyzed the influence of SOX15 overexpression or low expression on EC cell proliferation and migration. The expression of SOX15 mRNA and protein in EC tissues was significantly lower than that in adjacent tissues. After lentivirus-transfecting SOX15, the expression level of SOX15 mRNA and protein was significantly increased in cells of SOX15 group, and decreased in sh-SOX15 group. Overexpression of SOX15 could suppress cell proliferation, while down-regulation of SOX15 increased cell proliferation. Flow cytometry results indicated that overexpression of SOX15 induced the ratio of cell-cycle arrest in G1 stage. In addition, Transwell migration assay results showed that SOX15 overexpression significantly inhibited cell migration, and also down-regulation of SOX15 promoted the migration. As a whole, SOX15 could regulate the proliferation and migration of EC cells and up- regulation of SOX15 could be valuable for EC treatment.
Collapse
|
|
32
|
Julian LM, McDonald AC, Stanford WL. Direct reprogramming with SOX factors: masters of cell fate. Curr Opin Genet Dev 2017; 46:24-36. [PMID: 28662445 DOI: 10.1016/j.gde.2017.06.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 04/25/2017] [Accepted: 06/09/2017] [Indexed: 12/13/2022]
Abstract
Over the last decade significant advances have been made toward reprogramming the fate of somatic cells, typically by overexpression of cell lineage-determinant transcription factors. As key regulators of cell fate, the SOX family of transcription factors has emerged as potent drivers of direct somatic cell reprogramming into multiple lineages, in some cases as the sole overexpressed factor. The vast capacity of SOX factors, especially those of the SOXB1, E and F subclasses, to reprogram cell fate is enlightening our understanding of organismal development, cancer and disease, and offers tremendous potential for regenerative medicine and cell-based therapies. Understanding the molecular mechanisms through which SOX factors reprogram cell fate is essential to optimize the development of novel somatic cell transdifferentiation strategies.
Collapse
Affiliation(s)
- Lisa M Julian
- Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1L8L6, Canada
| | - Angela Ch McDonald
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, Ontario M5G0A4, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, Ontario M5S3G9, Canada
| | - William L Stanford
- Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1L8L6, Canada; Department of Cellular and Molecular Medicine, Faulty of Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, Ontario K1H8M5, Canada; Department of Biochemistry, Microbiology and Immunology, Faulty of Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, Ontario K1H8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Rd, Ottawa, Ontario K1H8M5, Canada.
| |
Collapse
|
|
33
|
Leopardo NP, Vitullo AD. Early embryonic development and spatiotemporal localization of mammalian primordial germ cell-associated proteins in the basal rodent Lagostomus maximus. Sci Rep 2017; 7:594. [PMID: 28377629 PMCID: PMC5429608 DOI: 10.1038/s41598-017-00723-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 03/09/2017] [Indexed: 11/22/2022] Open
Abstract
The gene network controlling primordial germ cell (PGC) specification in eutherian mammals has been exhaustively investigated in mice. The egg-cylinder morphology of the mouse embryo is the key event enabling inductive signals from the extra-embryonic ectoderm (ExE) to specify epiblast cells as PGCs early on. We investigated the embryonic development and the spatiotemporal localization of PGC-associated proteins in the basal Hystricognathi rodent Lagostomus maximus. L. maximus develops through a flat-disc epiblast far apart from the ExE. In the primitive streak stage, OCT4-positive cells are detected in the posterior pole of the embryo disc in the mesoderm of the proximal epiblast. In the neural plate stage, a reduced 8 to 12 OCT4-positive cell population transiently expresses FRAGILIS, STELLA and SOX17 in the posterior streak. Soon after translocation to the hindgut, pluripotent OCT4 cells start expressing VASA, and then, STELLA and FRAGILIS are turned on during migration toward the genital ridge. L. maximus shows a spatiotemporal pattern of PGC-associated markers divergent from the early PGC restriction model seen in mice. This pattern conforms to alternative models that are based on a pluripotent population in the embryonic axis, where PGCs are specified later during development.
Collapse
Affiliation(s)
- Noelia P Leopardo
- Departamento de Ciencias Biomédicas y Biotecnológicas, Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico -CEBBAD-, Universidad Maimónides, Hidalgo 775, C1405BCK, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, Buenos Aires, Argentina
| | - Alfredo D Vitullo
- Departamento de Ciencias Biomédicas y Biotecnológicas, Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico -CEBBAD-, Universidad Maimónides, Hidalgo 775, C1405BCK, Buenos Aires, Argentina. .,Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, Buenos Aires, Argentina.
| |
Collapse
|
|
34
|
Moradi A, Ghasemi F, Anvari K, Hassanian SM, Simab SA, Ebrahimi S, Hesari A, Forghanifard MM, Boroushaki MT, ShahidSales S, Avan A. The cross-regulation between SOX15 and Wnt signaling pathway. J Cell Physiol 2017; 232:3221-3225. [DOI: 10.1002/jcp.25802] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 01/13/2017] [Indexed: 11/11/2022]
Affiliation(s)
- Ali Moradi
- Department of Biology, Damghan Branch; Islamic Azad University; Damghan Iran
| | - Faezeh Ghasemi
- Molecular Medicine Group, Department of Modern Sciences and Technologies, School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
- Department of Biotechnology; Faculty of Medicine; Arak University of Medical Sciences; Arak Iran
| | - Kazem Anvari
- Cancer Research Center, School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
- Department of Medical Biochemistry, School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Saeideh Ahmadi Simab
- Cancer Research Center, School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Safieh Ebrahimi
- Department of Medical Biochemistry, School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Amirreza Hesari
- Department of Biology, Damghan Branch; Islamic Azad University; Damghan Iran
- Molecular Medicine Group, Department of Modern Sciences and Technologies, School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | | | - Mohammad Taher Boroushaki
- Department of Pharmacology and Pharmacological Research Center of Medicinal Plants; Faculty of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Soodabeh ShahidSales
- Cancer Research Center, School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Amir Avan
- Metabolic syndrome Research center, School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| |
Collapse
|
|
35
|
Mei Z, Zhou L, Zhu Y, Jie K, Fan D, Chen J, Liu X, Jiang L, Jia Q, Li W. Interleukin-22 promotes papillary thyroid cancer cell migration and invasion through microRNA-595/Sox17 axis. Tumour Biol 2016; 37:11753-11762. [PMID: 27022736 DOI: 10.1007/s13277-016-5030-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 03/18/2016] [Indexed: 12/18/2022] Open
Abstract
Interleukin-22 (IL-22) is an inflammatory cytokine mainly produced by activated Th17 and Th22 cells. The data presented here demonstrate that IL-22 induced the migration and invasion of papillary thyroid cancer (PTC) cells. MicroRNA expression analysis and functional studies indicated that IL-22-mediated migration and invasion is positively regulated by miR-595. Further mechanistic studies revealed that sex-determining region Y-box 17 (Sox17) is directly targeted by miR-595. We then demonstrated that IL-22 regulated migration and invasion of PTC cells via inhibiting Sox17 expression. Interestingly, in PTC cell lines and PTC tissues, expression of IL-22 and miR-595 was upregulated and Sox17 downregulated compared with normal thyroid, and their expression levels were closely correlated. Taken together, this present study suggests that IL-22 stimulation enhances the migration and invasion of PTC cells by regulating miR-595 and its target Sox17.
Collapse
Affiliation(s)
- Zhidan Mei
- The department of Head and Neck surgery, Hubei Cancer Hospital, Wuhan, Hubei, 430079, China
| | - Li Zhou
- Animal Biosafety Level III Laboratory at the Center for Animal Experiment, State Key Laboratory of Virology, Wuhan University, Wuhan, 430071, China
| | - Youhua Zhu
- The department of Head and Neck surgery, Hubei Cancer Hospital, Wuhan, Hubei, 430079, China
| | - Kejia Jie
- The department of Head and Neck surgery, Hubei Cancer Hospital, Wuhan, Hubei, 430079, China
| | - Daqing Fan
- The department of Head and Neck surgery, Hubei Cancer Hospital, Wuhan, Hubei, 430079, China
| | - Jian Chen
- The department of Head and Neck surgery, Hubei Cancer Hospital, Wuhan, Hubei, 430079, China
| | - Xiguo Liu
- The department of Head and Neck surgery, Hubei Cancer Hospital, Wuhan, Hubei, 430079, China
| | - Liang Jiang
- The department of Head and Neck surgery, Hubei Cancer Hospital, Wuhan, Hubei, 430079, China
| | - Qike Jia
- The department of Head and Neck surgery, Hubei Cancer Hospital, Wuhan, Hubei, 430079, China
| | - Wei Li
- The department of Head and Neck surgery, Hubei Cancer Hospital, Wuhan, Hubei, 430079, China.
| |
Collapse
|
|
36
|
Cheng H, Wang S, Feng R. STIM1 plays an important role in TGF-β-induced suppression of breast cancer cell proliferation. Oncotarget 2016; 7:16866-78. [PMID: 26919241 PMCID: PMC4941356 DOI: 10.18632/oncotarget.7619] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 02/11/2016] [Indexed: 01/08/2023] Open
Abstract
Store-operated calcium entry (SOCE) signaling is involved in cancer progression. Stromal interaction molecule 1 (STIM1) triggers store-operated calcium channels to induce SOCE. Transforming growth factor-β (TGF-β) influences a wide range of cellular behaviors, including cell proliferation. However, little is known about the relationship between calcium signaling and TGF-β signaling in cancer cell proliferation. Here, we found that TGF-β induced cell cycle arrest at the G0/G1 phase and suppressed cell proliferation in MDA-MB-231 and MCF-7 breast cancer cells. These effects were impaired by extracellular Ca2+ chelator EGTA or SOCE specific inhibitor SKF96365 in MDA-MB-231 cells. Treating MDA-MB-231 cells with TGF-β for 24 and 48 h markedly decreased STIM1 expression and thapsigargin-induced SOCE. A transcriptional inhibitor of STIM1, Wilm's tumor suppressor 1 (WT1), was upregulated in TGF-β-treated MDA-MB-231 cells, and knockdown of WT1 expression partially restored the TGF-β-induced downregulation of STIM1. Stably overexpressing STIM1 in MDA-MB-231 cells restored the TGF-β-induced effects. The p21 mRNA level increased in SKF96365- or TGF-β-treated MDA-MB-231 cells, whereas that for cyclin E1 decreased. Our findings demonstrate for the first time that STIM1 and SOCE are involved in the TGF-β-induced suppression of cell proliferation. Furthermore, our studies also provide a new approach to inhibit breast cancer cell proliferation with small molecules targeting STIM1 and SOCE.
Collapse
Affiliation(s)
- Huanyi Cheng
- State Key Laboratory of Membrane Biology, Department of Biochemistry and Molecular Biology, College of Life Sciences, Peking University, Beijing 100871, China
| | - Shiqiang Wang
- State Key Laboratory of Membrane Biology, Department of Biochemistry and Molecular Biology, College of Life Sciences, Peking University, Beijing 100871, China
| | - Renqing Feng
- State Key Laboratory of Membrane Biology, Department of Biochemistry and Molecular Biology, College of Life Sciences, Peking University, Beijing 100871, China
| |
Collapse
|
|
37
|
The SOX17/miR-371-5p/SOX2 axis inhibits EMT, stem cell properties and metastasis in colorectal cancer. Oncotarget 2016; 6:9099-112. [PMID: 25868860 PMCID: PMC4496205 DOI: 10.18632/oncotarget.3603] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 02/10/2015] [Indexed: 12/31/2022] Open
Abstract
Cancer stem cells (CSCs) and EMT-type cells, which share molecular characteristics with CSCs, have been believed to play critical roles in tumor metastasis. Although much progress has been garnered in elucidating the molecular pathways that trigger EMT, stemness and metastasis, a number of key mechanistic gaps remain elusive. In the study, miR-371-5p was obviously down-regulated in primary CRC tissues compared with matched adjacent normal mucosa and correlated significantly with differentiation, tumor size, lymphatic and liver metastases. MiR-371-5p could attenuate proliferation, invasion in vitro and metastasis in vivo in CRC cells. It also suppressed EMT by regulating Wnt/β-catenin signaling and strongly decreased the CRC stemness phenotypes. Moreover, demethylation of SOX17 induced miR-371-5p expression and consequently suppressed its direct target SOX2 in CRC cells. MiR-371-5p was necessary for SOX17 mediated cancer-related traits and SOX2 was a functional target of miR-371-5p. A positive relationship between SOX17 and miR-371-5p expression and a negative one between miR-371-5p and SOX2 expression were observed in CRC cell lines and tissues. In conclusion, we identified miR-371-5p as an important “oncosuppressor” in CRC progression and elucidated a novel mechanism of the SOX17/miR-371-5p/SOX2 axis in the regulation of EMT, stemness and metastasis, which may be a potential therapeutic target.
Collapse
|
|
38
|
Wang G, Wei Z, Jia H, Zhao W, Yang G, Zhao H. Knockdown of SOX18 inhibits the proliferation, migration and invasion of hepatocellular carcinoma cells. Oncol Rep 2015; 34:1121-8. [PMID: 26151573 PMCID: PMC4530902 DOI: 10.3892/or.2015.4112] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 06/15/2015] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. Recent studies have demonstrated that SOX18 is highly expressed in various types of cancer. In the present study, we found that SOX18 mRNA was overexpressed in HCC compared with non-tumorous tissues. We aimed to explore the effects of SOX18 siRNA on the proliferation, invasion and migration of two HCC cell lines, MHCC97H and HepG2, which overexpress SOX18. We found that SOX18 siRNA significantly inhibited the proliferation and induced cell cycle arrest at the G0/G1 phase. Results of the Transwell assay showed that the migration and invasion of the HCC cells were markedly impaired in the SOX18-knockdown cells. Gene set enrichment analysis (GSEA) showed that KEGG focal adhesion and chemokine signaling pathways were correlated with SOX18 expression. Furthermore, the mRNA and protein levels of RhoA, PDGFB, IGF1R, CCL2, CCL3 and CCL5 were decreased in the SOX18-knockdown cells. Importantly, we demonstrated that upregulation of SOX18 was associated with a poor outcome in HCC patients. These results indicate that SOX18 may serve as a prognostic factor and a promising therapeutic strategy for HCC.
Collapse
Affiliation(s)
- Guiming Wang
- Department of Surgery, The First Hospital of Shanxi Medical University, Taiyuan 030001, P.R. China
| | - Zhigang Wei
- Department of Surgery, The First Hospital of Shanxi Medical University, Taiyuan 030001, P.R. China
| | - Hongyan Jia
- Department of Surgery, The First Hospital of Shanxi Medical University, Taiyuan 030001, P.R. China
| | - Wenbo Zhao
- Department of Surgery, The First Hospital of Shanxi Medical University, Taiyuan 030001, P.R. China
| | - Gaochao Yang
- Department of Surgery, The First Hospital of Shanxi Medical University, Taiyuan 030001, P.R. China
| | - Haoliang Zhao
- Department of Surgery, Shanxi Dayi Hospital, Taiyuan 030032, P.R. China
| |
Collapse
|
|
39
|
Chiurillo MA. Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review. World J Exp Med 2015; 5:84-102. [PMID: 25992323 PMCID: PMC4436943 DOI: 10.5493/wjem.v5.i2.84] [Citation(s) in RCA: 244] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Revised: 12/05/2014] [Accepted: 03/20/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer remains one of the most common cancers worldwide and one of the leading cause for cancer-related deaths. Gastric adenocarcinoma is a multifactorial disease that is genetically, cytologically and architecturally more heterogeneous than other gastrointestinal carcinomas. The aberrant activation of the Wnt/β-catenin signaling pathway is involved in the development and progression of a significant proportion of gastric cancer cases. This review focuses on the participation of the Wnt/β-catenin pathway in gastric cancer by offering an analysis of the relevant literature published in this field. Indeed, it is discussed the role of key factors in Wnt/β-catenin signaling and their downstream effectors regulating processes involved in tumor initiation, tumor growth, metastasis and resistance to therapy. Available data indicate that constitutive Wnt signalling resulting from Helicobacter pylori infection and inactivation of Wnt inhibitors (mainly by inactivating mutations and promoter hypermethylation) play an important role in gastric cancer. Moreover, a number of recent studies confirmed CTNNB1 and APC as driver genes in gastric cancer. The identification of specific membrane, intracellular, and extracellular components of the Wnt pathway has revealed potential targets for gastric cancer therapy. High-throughput “omics” approaches will help in the search for Wnt pathway antagonist in the near future.
Collapse
|
|
40
|
Decreased expression of SOX17 is associated with tumor progression and poor prognosis in breast cancer. Tumour Biol 2015; 36:8025-34. [PMID: 25971583 DOI: 10.1007/s13277-015-3547-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 05/07/2015] [Indexed: 10/23/2022] Open
Abstract
The SOX17 (SRY-related HMG-box) transcription factor is involved in a variety of biological processes and is related to the tumorigenesis and progression of multiple tumors. However, the clinical application of SOX17 for breast cancer prognosis is currently limited. The aim of this study was to investigate the clinicopathologic and prognostic significance of SOX17 expression in human breast cancer. qPCR and western blot assays were performed to measure the expression of SOX17 in breast cancer cell lines and 30 matched pairs of breast cancer and corresponding noncancerous tissues. A SOX17 overexpression cell model was used to examine changes in cell growth in vitro. Immunohistochemical analyses were performed to retrospectively examine the prognostic impact of SOX17 expression in 187 additional breast cancer patients. Our results showed that SOX17 expression was decreased at both the messenger RNA (mRNA) and protein levels in the breast cancer cell lines and tissues, and that SOX17 overexpression could strongly suppress cell growth in vitro. Furthermore, the lack of SOX17 protein expression was strongly correlated with higher tumor grade (P = 0.002), lymph node metastasis (P < 0.001), and tumor node metastasis (TNM) stage (P = 0.001) and had poorer disease-free survival (DFS) and overall survival (OS) compared to normal SOX17 expression (P = 0.002 and 0.001, respectively). Univariate and multivariate analyses indicated that lower SOX17 expression was an independent prognostic factor for DFS (P = 0.007; HR = 2.854; 95 % CI 1.326-6.147) and OS (P = 0.005; HR = 5.035; 95 % CI 1.648-15.385) for breast cancer. Our findings indicate that SOX17 expression is a useful prognostic biomarker for breast cancer.
Collapse
|
|
41
|
Kremer PHC, Koeleman BPC, Pawlikowska L, Weinsheimer S, Bendjilali N, Sidney S, Zaroff JG, Rinkel GJE, van den Berg LH, Ruigrok YM, de Kort GAP, Veldink JH, Kim H, Klijn CJM. Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain. J Neurol Neurosurg Psychiatry 2015; 86:524-9. [PMID: 25053769 PMCID: PMC4302044 DOI: 10.1136/jnnp-2013-307276] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Accepted: 07/01/2014] [Indexed: 01/08/2023]
Abstract
BACKGROUND In genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often have associated aneurysms, we investigated whether these loci are also associated with sporadic brain AVM. METHODS We included 506 patients (168 Dutch, 338 American) and 1548 controls, all Caucasians. Controls had been recruited as part of previous GWAS. Dutch patients were genotyped by KASPar assay and US patients by Affymetrix SNP 6.0 array. Associations in each cohort were tested by univariable logistic regression modelling, with subgroup analysis in 205 American cases with aneurysm data. Meta-analysis was performed by a Mantel-Haenszel fixed-effect method. RESULTS In the Dutch cohort none of the single nucleotide polymorphisms (SNPs) were associated with AVMs. In the American cohort, genotyped SNPs near SOX-17 (OR 0.74; 95% CI 0.56-0.98), RBBP8 (OR 0.76; 95% CI 0.62-0.94) and an imputed SNP near CDKN2B-AS1 (OR 0.79; 95% CI 0.64-0.98) were significantly associated with AVM. The association with SNPs near SOX-17 and CDKN2B-AS1 but not RBBP8 were strongest in patients with AVM with associated aneurysms. In the meta-analysis we found no significant associations between allele frequencies and AVM occurrence, but rs9298506, near SOX-17 approached statistical significance (OR 0.77; 95% CI 0.57-1.03, p=0.08). CONCLUSIONS Our meta-analysis of two Caucasian cohorts did not show an association between five aneurysm-associated loci and sporadic brain AVM. Possible involvement of SOX-17 and RBBP8, genes involved in cell cycle progression, deserves further investigation.
Collapse
Affiliation(s)
- P H C Kremer
- Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - B P C Koeleman
- Department of Biomedical Genetics and Complex Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - L Pawlikowska
- Department of Anesthesia, Center for Cerebrovascular Research, University of California-San Francisco, San Francisco, California, USA Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA
| | - S Weinsheimer
- Department of Anesthesia, Center for Cerebrovascular Research, University of California-San Francisco, San Francisco, California, USA
| | - N Bendjilali
- Department of Anesthesia, Center for Cerebrovascular Research, University of California-San Francisco, San Francisco, California, USA
| | - S Sidney
- Division of Research, Kaiser Permanente of Northern California, Oakland, California, USA
| | - J G Zaroff
- Division of Research, Kaiser Permanente of Northern California, Oakland, California, USA
| | - G J E Rinkel
- Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - L H van den Berg
- Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Y M Ruigrok
- Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - G A P de Kort
- Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - J H Veldink
- Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - H Kim
- Department of Anesthesia, Center for Cerebrovascular Research, University of California-San Francisco, San Francisco, California, USA Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA
| | - C J M Klijn
- Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| |
Collapse
|
|
42
|
Fu D, Ren C, Tan H, Wei J, Zhu Y, He C, Shao W, Zhang J. Sox17 promoter methylation in plasma DNA is associated with poor survival and can be used as a prognostic factor in breast cancer. Medicine (Baltimore) 2015; 94:e637. [PMID: 25789956 PMCID: PMC4602484 DOI: 10.1097/md.0000000000000637] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Aberrant DNA methylation that leads to the inactivation of tumor suppressor genes is known to play an important role in the development and progression of breast cancer. Methylation status of cancer-related genes is considered to be a promising biomarker for the early diagnosis and prognosis of tumors. This study investigated the methylation status of the Sox17 gene in breast cancer tissue and its corresponding plasma DNA to evaluate the association of methylation levels with clinicopathological parameters and prognosis.The methylation status of the Sox17 gene promoter was evaluated with methylation-specific polymerase chain reaction (MSP) in 155 paired breast cancer tissue and plasma samples and in 60 paired normal breast tissue and plasma samples. Association of Sox17 methylation status with clinicopathological parameters was analyzed by χ tests. Overall and disease-free survival (DFS) curves were calculated using Kaplan-Meier analysis, and the differences between curves were analyzed by log-rank tests.The frequency of Sox17 gene methylation was 72.9% (113/155) in breast cancer tissues and 58.1% (90/155) in plasma DNA. Sox17 gene methylation was not found in normal breast tissues or in their paired plasma DNA. There was a significant correlation of Sox17 methylation between corresponding tumor tissues and paired plasma DNA (r = 0.688, P < 0.001). Aberrant Sox17 methylation in cancer tissues and in plasma DNA was significantly associated with the tumor node metastasis stage (P = 0.035 and P = 0.001, respectively) and with lymph node metastasis (P < 0.001 and P = 0.001, respectively). Kaplan-Meier survival curves showed that aberrant Sox17 promoter methylation in cancer tissues and plasma DNA was associated with poor DFS (P < 0.005) and overall survival (OS) (P < 0.005). Multivariate analysis showed that Sox17 methylation in plasma DNA was an independent prognostic factor in breast cancer for both DFS (P = 0.020; hazard ratio [HR] = 2.142; 95% confidence interval [CI]: 1.128-4.067) and for OS (P = 0.001; HR = 4.737; 95% CI: 2.088-10.747).Sox17 gene promoter methylation may play an important role in breast cancer progression and could be used as a prognostic biomarker to identify patients at risk of developing metastasis or recurrence after mastectomy.
Collapse
Affiliation(s)
- Deyuan Fu
- From the Department of Thyroid and Breast Surgery (DF, HT, JW, YZ, CH, WS, JZ); and Clinical Medical Testing Laboratory (CR), Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, Yangzhou, China
| | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Dinccelik-Aslan M, Gumus-Akay G, Elhan AH, Unal E, Tukun A. Diagnostic and prognostic significance of glypican 5 and glypican 6 gene expression levels in gastric adenocarcinoma. Mol Clin Oncol 2015; 3:584-590. [PMID: 26137271 DOI: 10.3892/mco.2015.486] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 12/09/2014] [Indexed: 12/26/2022] Open
Abstract
Gastric Cancer is one of the most common malignancies worldwide and the second most common cause of cancer-related mortality. Previous studies revealed several genetic alterations specific to gastric cancer. In this study, we aimed to investigate the diagnostic and prognostic significance of the expression levels of the glypican 5 and glypican 6 genes (GPC5 and GPC6, respectively) in gastric cancer. For this purpose, GPC5 and GPC6 expression was quantitatively determined by quantitative polymerase chain reaction method in normal gastric mucosa and intestinal type gastric adenocarcinoma samples from 35 patients. The expression levels of GPC5 and GPC6 were compared between normal and tumor tissues. Additionally, the association of the expression levels in tumor tissues with several clinicopathological parameters was evaluated. Although GPC5 was not expressed in any of the samples, the expression of GPC6, which was detected in both groups, was found to be significantly higher in tumor tissues compared to that in normal samples (P=0.039). However, there was no statistically significant association between GPC6 expression and any of the clinicopathological parameters investigated (P>0.05). Our findings suggested that an increase in GPC6 expression levels may be implicated in gastric cancer development, but not in cancer progression.
Collapse
Affiliation(s)
| | - Guvem Gumus-Akay
- Brain Research Centre, Ankara University, Mamak, Ankara 06900, Turkey
| | - Atilla Halil Elhan
- Department of Biostatistics, Faculty of Medicine, Ankara University, Sihhiye, Ankara 06100, Turkey
| | - Ekrem Unal
- Department of Surgical Oncology, Research and Training Hospital, Faculty of Medicine, Ankara University, Cebeci, Ankara 06580, Turkey
| | - Ajlan Tukun
- Department of Medical Genetics, Faculty of Medicine, Ankara University, Sihhiye, Ankara 06100, Turkey
| |
Collapse
|
|
44
|
Lu J, Zhang G, Cheng Y, Tang Y, Dong Z, McElwee KJ, Li G. Reduced expression of SRY-box containing gene 17 correlates with an unfavorable melanoma patient survival. Oncol Rep 2014; 32:2571-9. [PMID: 25310020 DOI: 10.3892/or.2014.3534] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 07/31/2014] [Indexed: 11/06/2022] Open
Abstract
SRY-box containing gene 17 (Sox17), a transcription factor, is considered as an antagonist to canonical Wnt/β‑catenin signaling in several types of malignant tumors. As the influence of Sox17 in the pathogenesis of human melanoma is still unknown, the investigation of Sox17 expression in melanoma is warranted and its prognostic value is of great interest. In the present study, Sox17 expression was examined in 525 cases of melanocytic lesions (33 common acquired nevi, 59 dysplastic nevi, 291 primary melanomas and 142 metastatic melanomas) at different stages by tissue microarray. The correlation of Sox17 expression with melanoma progression and its prognostic value in melanoma patients were examined. We also analyzed the correlation between Sox17 and cyclin-dependent kinase inhibitor p27 expression in 374 melanoma samples. The results showed that Sox17 expression was significantly decreased in primary and metastatic melanoma compared to common acquired nevi and dysplastic nevi (P=2.4x10-17). Furthermore, Sox17 expression was inversely correlated with American Joint Committee on Cancer stage (P=4.6x10-15), thickness (P=0.00004) and ulceration (P=0.03). Notably, reduced Sox17 expression was correlated with a poorer overall and disease-specific 5- and 10-year survival of the patients. Multivariate Cox regression analyses indicated that Sox17 is an independent prognostic marker for melanoma patients. Moreover, we found a significant positive correlation between Sox17 and p27 expression in melanoma biopsies; their concomitant expression was closely correlated with the survival of melanoma patients. Taken together, decreased Sox17 expression is correlated with melanoma progression, an unfavorable survival of melanoma patients and is an independent molecular prognostic factor for melanoma.
Collapse
Affiliation(s)
- Jing Lu
- Department of Dermatology and Skin Science, Research Pavilion, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC V5Z 1L8, Canada
| | - Guohong Zhang
- Department of Dermatology and Skin Science, Research Pavilion, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC V5Z 1L8, Canada
| | - Yabin Cheng
- Department of Dermatology and Skin Science, Research Pavilion, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC V5Z 1L8, Canada
| | - Yun Tang
- Department of Dermatology and Skin Science, Research Pavilion, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC V5Z 1L8, Canada
| | - Ziming Dong
- Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Kevin J McElwee
- Department of Dermatology and Skin Science, Research Pavilion, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC V5Z 1L8, Canada
| | - Gang Li
- Department of Dermatology and Skin Science, Research Pavilion, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC V5Z 1L8, Canada
| |
Collapse
|
|
45
|
Yang T, Li XN, Li L, Wu QM, Gao PZ, Wang HL, Zhao W. Sox17 inhibits hepatocellular carcinoma progression by downregulation of KIF14 expression. Tumour Biol 2014; 35:11199-207. [PMID: 25106407 DOI: 10.1007/s13277-014-2398-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 07/23/2014] [Indexed: 01/17/2023] Open
Abstract
Sox17, an antagonist of canonical Wnt/β-catenin signaling, inhibits several malignant carcinogenesis and progression. However, little is known about Sox17 in hepatocellular carcinoma (HCC). Here, we found that Sox17 is downregulated in HCC tissue. Furthermore, Sox17 inhibits cell proliferation and migration in HCC. KIF14, a member of kinesin superfamily protein (KIFs), is an oncogene in a variety of malignant tumors including HCC. We demonstrated that Sox17 is negatively related to KIF14 expression in HCC tissue and Sox17 inhibits HCC cell proliferation and migration by transcriptional downregulation of KIF14 expression. Our results may provide a strategy for blocking HCC carcinogenesis and progression.
Collapse
Affiliation(s)
- Tao Yang
- Department of Hepatobiliary Surgery, The First Hospital of Shijiazhuang City, Shijiazhuang, China
| | | | | | | | | | | | | |
Collapse
|
|
46
|
Li J, Yin LL, Su KL, Zhang GF, Wang J. Concomitant depletion of PTEN and p27 and overexpression of cyclin D1 may predict a worse prognosis for patients with post-operative stage II and III colorectal cancer. Oncol Lett 2014; 8:1543-1550. [PMID: 25202365 PMCID: PMC4156215 DOI: 10.3892/ol.2014.2350] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 05/29/2014] [Indexed: 01/31/2023] Open
Abstract
Prognostic markers for colorectal cancer (CRC) have not yet been fully investigated. Phosphatase and tensin homolog (PTEN), p27 and Cyclin D1 play significant roles in tumorigenesis and cell cycle regulation, and therefore require evaluation for their prognostic value in this disease. The aim of the present study was to assess the prognostic value of the single and combined expression of PTEN, p27 and Cyclin D1 in CRC patients. Protein expression levels of PTEN, p27 and Cyclin D1 were examined by immunohistochemistry from 61 patients with CRC in either stage II or III. In the CRC tissues, the frequencies of PTEN(−), p27(−) and Cyclin D1(+) expression were 42.62% (26/61), 32.79% (20/61) and 45.90% (28/61), respectively. Depletion of PTEN and p27 was more common with respect to stage III, low grade and lymph node metastasis compared with stage II, moderate grade and no lymph node metastasis (P<0.05). Cyclin D1-positive expression was frequently detected in CRC of stage III, with lymph node metastasis and deeper invasion (P<0.05). The depletion of PTEN was significantly correlated with the loss of p27 (P<0.001) and with the increased expression of Cyclin D1 (P<0.001). PTEN(−) and/or p27(−) expression was significantly correlated with Cyclin D1(+) expression (P<0.05). Combined PTEN(−)/p27(−)/Cyclin D1(+) expression was correlated with a significant decrease in overall survival time (P<0.05). Combined p27(−) and Cyclin D1(+) expression indicated a worse overall survival time than other combined expression patterns. These findings indicate that the single expression of PTEN(−), p27(−) and Cyclin D1(+) and the combined detection of p27(−) and Cyclin D1(+) may be used as prognostic markers for overall survival time in CRC.
Collapse
Affiliation(s)
- Jing Li
- Department of Oncology, The Fourth People's Hospital of Jinan, Jinan, Shandong 250031, P.R. China
| | - Lin-Lin Yin
- Department of Oncology, The Fourth People's Hospital of Jinan, Jinan, Shandong 250031, P.R. China
| | - Ke-Li Su
- Department of Oncology, The Fourth People's Hospital of Jinan, Jinan, Shandong 250031, P.R. China
| | - Gang-Feng Zhang
- Department of Oncology, The Fourth People's Hospital of Jinan, Jinan, Shandong 250031, P.R. China
| | - Jing Wang
- Department of Oncology, The Fourth People's Hospital of Jinan, Jinan, Shandong 250031, P.R. China
| |
Collapse
|
|
47
|
Bai R, Shi Z, Zhang JW, Li D, Zhu YL, Zheng S. ST13, a proliferation regulator, inhibits growth and migration of colorectal cancer cell lines. J Zhejiang Univ Sci B 2013; 13:884-93. [PMID: 23125081 DOI: 10.1631/jzus.b1200037] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND OBJECTIVE ST13, is the gene encoding the HSP70 interacting protein (HIP). Previous research has shown that ST13 mRNA and protein levels are down-regulated in colorectal cancer (CRC) tissues compared with adjacent normal tissues. This study aims at the role of ST13 in the proliferation and migration of CRC cells. METHODS The transcript level of ST13 in different CRC cell lines was evaluated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). ST13-overexpressed and ST13-knockdown CRC cells were constructed respectively by lentiviral transduction, followed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, plate colony formation, cell-cycle analysis, and migration assays to evaluate the influence of ST13 on proliferation and migration in vitro. Moreover, a mouse xenograft study was performed to test in vivo tumorigenicity of ST13-knockdown CRC cells. RESULTS Lentivirus-mediated overexpression of ST13 in CRC cells inhibited cell proliferation, colony formation, and cell migration in vitro. In contrast, down-regulation of ST13 by lentiviral-based short hairpin RNA (shRNA) interference in CRC cells significantly increased cell proliferation and cloning efficiency in vitro. In addition, down-regulation of ST13 expression significantly increased the tumorigenicity of CRC cells in vivo. CONCLUSIONS ST13 gene is a proliferation regulator that inhibits tumor growth in CRC and may affect cell migration.
Collapse
Affiliation(s)
- Rui Bai
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou 310009, China
| | | | | | | | | | | |
Collapse
|
|
48
|
Chen HL, Chew LJ, Packer RJ, Gallo V. Modulation of the Wnt/beta-catenin pathway in human oligodendroglioma cells by Sox17 regulates proliferation and differentiation. Cancer Lett 2013; 335:361-71. [PMID: 23474492 DOI: 10.1016/j.canlet.2013.02.058] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Revised: 02/19/2013] [Accepted: 02/24/2013] [Indexed: 02/07/2023]
Abstract
Oligodendrogliomas originate from oligodendrocyte progenitor cells (OPCs), whose development is regulated by the Sonic hedgehog and Wnt/beta-catenin pathways. We investigated the contribution of these pathways in the proliferation and differentiation of human oligodendroglioma cells (HOG). Inhibition of Hedgehog signaling with cyclopamine decreased cell survival and increased phosphorylated beta-catenin without altering myelin protein levels. Conversely, treatment of HOG with the Wnt antagonist secreted frizzled related protein (SFRP1), led to increased myelin protein levels and reduced cell proliferation, suggesting cell cycle arrest and differentiation. Unlike normal primary human OPCs, beta-catenin in HOG cells is not associated with endogenous Sox17 protein despite high levels of both proteins. Retroviral overexpression of recombinant Sox17 increased HOG cell cycle exit and apoptosis, and raised myelin protein levels and the percentage of O4(+) cells, indicating increased differentiation. Recombinant Sox17 also increased beta-catenin-TCF4-Sox17 complex formation and decreased total cellular levels of beta-catenin. These changes were associated with increased SFRP1, and reduced expression of Wnt-1 and Frizzled-1, -3 and -7 RNA, indicating that Sox17 induced a Hedgehog target, and regulated Wnt signaling at multiple levels. Our studies indicate that Wnt signaling regulates HOG cell cycle arrest and differentiation, and that recombinant Sox17 mediates modulation of the Wnt pathway through changes in beta-catenin, SFRP1 and Wnt/Frizzled expression. Our results thus identify Sox17 as a potential molecular target to include in HOG therapeutic strategies.
Collapse
Affiliation(s)
- Hui-Ling Chen
- Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA
| | | | | | | |
Collapse
|
|
49
|
SOX15 is a candidate tumor suppressor in pancreatic cancer with a potential role in Wnt/β-catenin signaling. Oncogene 2013; 33:279-88. [PMID: 23318427 DOI: 10.1038/onc.2012.595] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Revised: 10/23/2012] [Accepted: 11/02/2012] [Indexed: 12/19/2022]
Abstract
Pancreatic cancer is among the top five deadliest cancers in developed countries. Better knowledge of the molecular mechanisms contributing to its tumorigenesis is imperative to improve patient prognosis. Identification of novel tumor suppressor genes (TSGs) in pancreatic cancer will reveal new mechanisms of pathway deregulation and will ultimately help improve our understanding of this aggressive disease. According to Knudson's two-hit model, TSGs are classically disrupted by two concerted genetic events. In this study, we combined DNA methylation profiling with copy number and mRNA expression profiling to identify novel TSGs in a set of 20 pancreatic cancer cell lines. These data sets were integrated for each of ∼12 000 genes in each cell line enabling the elucidation of those genes that undergo DNA hypermethylation, copy-number loss and mRNA downregulation simultaneously in multiple cell lines. Using this integrative genomics strategy, we identified SOX15 (sex determining region Y-box 15) as a candidate TSG in pancreatic cancer. Expression of SOX15 in pancreatic cancer cell lines with undetectable expression resulted in reduced viability of cancer cells both in vitro and in vivo demonstrating its tumor suppressive capability. We also found reduced expression, homozygous deletion and aberrant DNA methylation of SOX15 in clinical pancreatic tumor data sets. Furthermore, we deduced a novel role for SOX15 in suppressing the Wnt/β-catenin signaling pathway, which we hypothesize is a pathway through which SOX15 may exert its tumor suppressive effects in pancreatic cancer.
Collapse
|
|
50
|
Chiyomaru T, Yamamura S, Zaman MS, Majid S, Deng G, Shahryari V, Saini S, Hirata H, Ueno K, Chang I, Tanaka Y, Tabatabai ZL, Enokida H, Nakagawa M, Dahiya R. Genistein suppresses prostate cancer growth through inhibition of oncogenic microRNA-151. PLoS One 2012; 7:e43812. [PMID: 22928040 PMCID: PMC3426544 DOI: 10.1371/journal.pone.0043812] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Accepted: 07/26/2012] [Indexed: 01/12/2023] Open
Abstract
Genistein has been shown to suppress the growth of several cancers through modulation of various pathways. However, the effects of genistein on the regulation of oncogenic microRNA-151 (miR-151) have not been reported. In this study, we investigated whether genistein could alter the expression of oncogenic miR-151 and its target genes that are involved in the progression and metastasis of prostate cancer (PCa). Real-time RT-PCR showed that the expression of miR-151 was higher in PC3 and DU145 cells compared with RWPE-1 cells. Treatment of PC3 and DU145 cells with 25 µM genistein down-regulated the expression of miR-151 compared with vehicle control. Inhibition of miR-151 in PCa cells by genistein significantly inhibited cell migration and invasion. In-silico analysis showed that several genes (CASZ1, IL1RAPL1, SOX17, N4BP1 and ARHGDIA) suggested to have tumor suppressive functions were target genes of miR-151. Luciferase reporter assays indicated that miR-151 directly binds to specific sites on the 3′UTR of target genes. Quantitative real-time PCR analysis showed that the mRNA expression levels of the five target genes in PC3 and DU145 were markedly changed with miR-151 mimics and inhibitor. Kaplan-Meier curves and log-rank tests revealed that high expression levels of miR-151 had an adverse effect on survival rate. This study suggests that genistein mediated suppression of oncogenic miRNAs can be an important dietary therapeutic strategy for the treatment of PCa.
Collapse
Affiliation(s)
- Takeshi Chiyomaru
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
| | - Soichiro Yamamura
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
| | - Mohd Saif Zaman
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
| | - Shahana Majid
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
| | - Guoren Deng
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
| | - Varahram Shahryari
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
| | - Sharanjot Saini
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
| | - Hiroshi Hirata
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
| | - Koji Ueno
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
| | - Inik Chang
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
| | - Yuichiro Tanaka
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
| | - Z. Laura Tabatabai
- Department of Pathology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
| | - Hideki Enokida
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Masayuki Nakagawa
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Rajvir Dahiya
- Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
- * E-mail:
| |
Collapse
|