|
1
|
Lan YZ, Wu Z, Chen WJ, Yu XN, Wu HT, Liu J. Sine oculis homeobox homolog family function in gastrointestinal cancer: Progression and comprehensive analysis. World J Clin Oncol 2025; 16:97163. [PMID: 39867730 PMCID: PMC11528897 DOI: 10.5306/wjco.v16.i1.97163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 09/20/2024] [Accepted: 10/20/2024] [Indexed: 10/30/2024] Open
Abstract
The sine oculis homeobox homolog (SIX) family, a group of transcription factors characterized by a conserved DNA-binding homology domain, plays a critical role in orchestrating embryonic development and organogenesis across various organisms, including humans. Comprising six distinct members, from SIX1 to SIX6, each member contributes uniquely to the development and differentiation of diverse tissues and organs, underscoring the versatility of the SIX family. Dysregulation or mutations in SIX genes have been implicated in a spectrum of developmental disorders, as well as in tumor initiation and progression, highlighting their pivotal role in maintaining normal developmental trajectories and cellular functions. Efforts to target the transcriptional complex of the SIX gene family have emerged as a promising strategy to inhibit tumor development. While the development of inhibitors targeting this gene family is still in its early stages, the significant potential of such interventions holds promise for future therapeutic advances. Therefore, this review aimed to comprehensively explore the advancements in understanding the SIX family within gastrointestinal cancers, focusing on its critical role in normal organ development and its implications in gastrointestinal cancers, including gastric, pancreatic, colorectal cancer, and hepatocellular carcinomas. In conclusion, this review deepened the understanding of the functional roles of the SIX family and explored the potential of utilizing this gene family for the diagnosis, prognosis, and treatment of gastrointestinal cancers.
Collapse
Affiliation(s)
- Yang-Zheng Lan
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xin-Ning Yu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| |
Collapse
|
|
2
|
Qin M, Ma L, Du W, Chen D, Luo G, Liu Z. Cytoplasmatic Localization of Six1 in Male Testis and Spermatogonial Stem Cells. Int J Stem Cells 2024; 17:298-308. [PMID: 38225887 PMCID: PMC11361848 DOI: 10.15283/ijsc23093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/27/2023] [Accepted: 10/11/2023] [Indexed: 01/17/2024] Open
Abstract
Sine oculis homeobox 1 (Six1) is an important factor for embryonic development and carcinoma malignancy. However, the localization of Six1 varies due to protein size and cell types in different organs. In this study, we focus on the expression and localization of Six1 in male reproductive organ via bioinformatics analysis and immunofluorescent detection. The potential interacted proteins with Six1 were also predicted by protein-protein interactions (PPIs) and Enrichr analysis. Bioinformatic data from The Cancer Genome Atlas and Genotype-Tissue Expression project databases showed that SIX1 was highly expressed in normal human testis, but low expressed in the testicular germ cell tumor sample. Human Protein Atlas examination verified that SIX1 level was higher in normal than that in cancer samples. The sub-localization of SIX1 in different reproductive tissues varies but specifically in the cytoplasm and membrane in testicular cells. In mouse cells, single cell RNA-sequencing data analysis indicated that Six1 expression level was higher in mouse spermatogonial stem cells (mSSCs) and differentiating spermatogonial than in other somatic cells. Immunofluorescence staining showed the cytoplasmic localization of Six1 in mouse testis and mSSCs. Further PPIs and Enrichr examination showed the potential interaction of Six1 with bone morphogenetic protein 4 (Bmp4) and catenin Beta-1 (CtnnB1) and stem cell signal pathways. Cytoplasmic localization of Six1 in male testis and mSSCs was probably associated with stem cell related proteins Bmp4 and CtnnB1 for stem cell development.
Collapse
Affiliation(s)
- Mingming Qin
- Reproductive Medical Center, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University (Foshan Women and Children Hospital), Foshan, China
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Linzi Ma
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenjing Du
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
- Reproductive Medicine Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, China
| | - Dingyao Chen
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Guoqun Luo
- Reproductive Medical Center, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University (Foshan Women and Children Hospital), Foshan, China
| | - Zhaoting Liu
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
3
|
Davis JC, Waltz SE. The MET Family of Receptor Tyrosine Kinases Promotes a Shift to Pro-Tumor Metabolism. Genes (Basel) 2024; 15:953. [PMID: 39062731 PMCID: PMC11275592 DOI: 10.3390/genes15070953] [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: 06/26/2024] [Revised: 07/16/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
The development and growth of cancer is fundamentally dependent on pro-tumor changes in metabolism. Cancer cells generally shift away from oxidative phosphorylation as the primary source of energy and rely more heavily on glycolysis. Receptor tyrosine kinases (RTKs) are a type of receptor that is implicated in this shift to pro-tumor metabolism. RTKs are important drivers of cancer growth and metastasis. One such family of RTKs is the MET family, which consists of MET and RON (MST1R). The overexpression of either MET or RON has been associated with worse cancer patient prognosis in a variety of tumor types. Both MET and RON signaling promote increased glycolysis by upregulating the expression of key glycolytic enzymes via increased MYC transcription factor activity. Additionally, both MET and RON signaling promote increased cholesterol biosynthesis downstream of glycolysis by upregulating the expression of SREBP2-induced cholesterol biosynthesis enzymes via CTTNB1. These changes in metabolism, driven by RTK activity, provide potential targets in limiting tumor growth and metastasis via pharmacological inhibition or modifications in diet. This review summarizes pro-tumor changes in metabolism driven by the MET family of RTKs. In doing so, we will offer our unique perspective on metabolic pathways that drive worse patient prognosis and provide suggestions for future study.
Collapse
Affiliation(s)
- James C. Davis
- Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Susan E. Waltz
- Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
- Research Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA
| |
Collapse
|
|
4
|
Yu S, Chen C, Chen M, Liang J, Jiang K, Lou B, Lu J, Zhu X, Zhou D. MAGOH promotes gastric cancer progression via hnRNPA1 expression inhibition-mediated RONΔ160/PI3K/AKT signaling pathway activation. J Exp Clin Cancer Res 2024; 43:32. [PMID: 38268030 PMCID: PMC10809607 DOI: 10.1186/s13046-024-02946-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 01/05/2024] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is associated with high mortality and heterogeneity and poses a great threat to humans. Gene therapies for the receptor tyrosine kinase RON and its spliceosomes are attracting increasing amounts of attention due to their unique characteristics. However, little is known about the mechanism involved in the formation of the RON mRNA alternative spliceosome RONΔ160. METHODS Fourteen human GC tissue samples and six normal gastric tissue samples were subjected to label-free relative quantitative proteomics analysis, and MAGOH was identified as a candidate protein for subsequent studies. The expression of MAGOH in clinical specimens was verified by quantitative real-time PCR and western blotting. We then determined the biological function of MAGOH in GC through in vitro and in vivo experiments. RNA pulldown, RNA sequencing and RNA immunoprecipitation (RIP) were subsequently conducted to uncover the underlying mechanism by which MAGOH regulated the formation of RONΔ160. RESULTS Proteomic analysis revealed that MAGOH, which is located at key nodes and participates in RNA processing and mRNA splicing, was upregulated in GC tissue and GC cell lines and was associated with poor prognosis. Functional analysis showed that MAGOH promoted the proliferation, migration and invasion of GC cells in vitro and in vivo. Mechanistically, MAGOH inhibited the expression of hnRNPA1 and reduced the binding of hnRNPA1 to RON mRNA, thereby promoting the formation of RONΔ160 to activate the PI3K/AKT signaling pathway and consequently facilitating GC progression. CONCLUSIONS Our study revealed that MAGOH could promote the formation of RONΔ160 and activate the PI3K/AKT signaling pathway through the inhibition of hnRNPA1 expression. We elucidate a novel mechanism and potential therapeutic targets for the growth and metastasis of GC based on the MAGOH-RONΔ160 axis, and these findings have important guiding significance and clinical value for the future development of effective therapeutic strategies for GC.
Collapse
Affiliation(s)
- Shanshan Yu
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Cheng Chen
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ming Chen
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinxiao Liang
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kecheng Jiang
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bin Lou
- Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Lu
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaohua Zhu
- Department of Oncology, Shaoxing People's Hospital, Shaoxing, China
| | - Donghui Zhou
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| |
Collapse
|
|
5
|
Sanjeev D, Dagamajalu S, Shaji V, George M, Subbannayya Y, Prasad TSK, Raju R, Devasahayam Arokia Balaya R. A network map of macrophage-stimulating protein (MSP) signaling. J Cell Commun Signal 2023; 17:1113-1120. [PMID: 37142846 PMCID: PMC10409925 DOI: 10.1007/s12079-023-00755-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 04/20/2023] [Indexed: 05/06/2023] Open
Abstract
Macrophage-stimulating protein (MSP), a serum-derived growth factor belonging to the plasminogen-related kringle domain family, is mainly produced by the liver and released into the blood. MSP is the only known ligand for RON ("Recepteur d'Origine Nantais", also known as MST1R), which is a member of the receptor tyrosine kinase (RTK) family. MSP is associated with many pathological conditions, including cancer, inflammation, and fibrosis. Activation of the MSP/RON system regulates main downstream signaling pathways, including phosphatidylinositol 3-kinase/ AKT serine/threonine kinase/ (PI3-K/AKT), mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase (JNK) & Focal adhesion kinase (FAK). These pathways are mainly involved in cell proliferation, survival, migration, invasion, angiogenesis & chemoresistance. In this work, we created a pathway resource of signaling events mediated by MSP/RON considering its contribution to diseases. We provide an integrated pathway reaction map of MSP/RON that is composed of 113 proteins and 26 reactions based on the curation of data from the published literature. The consolidated pathway map of MSP/RON mediated signaling events contains seven molecular associations, 44 enzyme catalysis, 24 activation/inhibition, six translocation events, 38 gene regulation events, and forty-two protein expression events. The MSP/RON signaling pathway map can be freely accessible through the WikiPathways Database URL: https://classic.wikipathways.org/index.php/Pathway:WP5353 .
Collapse
Affiliation(s)
- Diya Sanjeev
- Centre for Integrative OmicsData Science (CIODS), Yenepoya (Deemed to be University), Derlakatte, Mangalore, Karnataka 575018 India
| | - Shobha Dagamajalu
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka 575018 India
| | - Vineetha Shaji
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka 575018 India
| | - Mejo George
- Centre for Integrative OmicsData Science (CIODS), Yenepoya (Deemed to be University), Derlakatte, Mangalore, Karnataka 575018 India
| | - Yashwanth Subbannayya
- School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH UK
| | - T. S. Keshava Prasad
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka 575018 India
| | - Rajesh Raju
- Centre for Integrative OmicsData Science (CIODS), Yenepoya (Deemed to be University), Derlakatte, Mangalore, Karnataka 575018 India
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka 575018 India
| | - Rex Devasahayam Arokia Balaya
- Centre for Integrative OmicsData Science (CIODS), Yenepoya (Deemed to be University), Derlakatte, Mangalore, Karnataka 575018 India
| |
Collapse
|
|
6
|
Hunt BG, Fox LH, Davis JC, Jones A, Lu Z, Waltz SE. An Introduction and Overview of RON Receptor Tyrosine Kinase Signaling. Genes (Basel) 2023; 14:517. [PMID: 36833444 PMCID: PMC9956929 DOI: 10.3390/genes14020517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/07/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
RON is a receptor tyrosine kinase (RTK) of the MET receptor family that is canonically involved in mediating growth and inflammatory signaling. RON is expressed at low levels in a variety of tissues, but its overexpression and activation have been associated with malignancies in multiple tissue types and worse patient outcomes. RON and its ligand HGFL demonstrate cross-talk with other growth receptors and, consequentially, positions RON at the intersection of numerous tumorigenic signaling programs. For this reason, RON is an attractive therapeutic target in cancer research. A better understanding of homeostatic and oncogenic RON activity serves to enhance clinical insights in treating RON-expressing cancers.
Collapse
Affiliation(s)
- Brian G. Hunt
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA
| | - Levi H. Fox
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA
| | - James C. Davis
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA
| | - Angelle Jones
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA
| | - Zhixin Lu
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA
| | - Susan E. Waltz
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA
- Research Service, Cincinnati Veterans Affairs Hospital Medical Center, Cincinnati, OH 45220, USA
| |
Collapse
|
|
7
|
Zhu S, Li W, Zhang H, Yan Y, Mei Q, Wu K. Retinal determination gene networks: from biological functions to therapeutic strategies. Biomark Res 2023; 11:18. [PMID: 36750914 PMCID: PMC9906957 DOI: 10.1186/s40364-023-00459-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 01/28/2023] [Indexed: 02/09/2023] Open
Abstract
The retinal determinant gene network (RDGN), originally discovered as a critical determinator in Drosophila eye specification, has become an important regulatory network in tumorigenesis and progression, as well as organogenesis. This network is not only associated with malignant biological behaviors of tumors, such as proliferation, and invasion, but also regulates the development of multiple mammalian organs. Three members of this conservative network have been extensively investigated, including DACH, SIX, and EYA. Dysregulated RDGN signaling is associated with the initiation and progression of tumors. In recent years, it has been found that the members of this network can be used as prognostic markers for cancer patients. Moreover, they are considered to be potential therapeutic targets for cancer. Here, we summarize the research progress of RDGN members from biological functions to signaling transduction, especially emphasizing their effects on tumors. Additionally, we discuss the roles of RDGN members in the development of organs and tissue as well as their correlations with the pathogenesis of chronic kidney disease and coronary heart disease. By summarizing the roles of RDGN members in human diseases, we hope to promote future investigations into RDGN and provide potential therapeutic strategies for patients.
Collapse
Affiliation(s)
- Shuangli Zhu
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Wanling Li
- grid.412793.a0000 0004 1799 5032Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China ,grid.470966.aCancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032 China
| | - Hao Zhang
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Yuheng Yan
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Qi Mei
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
| | - Kongming Wu
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China. .,Cancer Center, Tongji hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| |
Collapse
|
|
8
|
Cazes A, Childers BG, Esparza E, Lowy AM. The MST1R/RON Tyrosine Kinase in Cancer: Oncogenic Functions and Therapeutic Strategies. Cancers (Basel) 2022; 14:cancers14082037. [PMID: 35454943 PMCID: PMC9027306 DOI: 10.3390/cancers14082037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/10/2022] [Accepted: 04/13/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary MST1R/RON receptor tyrosine kinase is a highly conserved transmembrane protein present on epithelial cells, macrophages, and recently identified in a T-cell subset. RON activation attenuates inflammation in healthy tissue. Interestingly, it is overexpressed in several epithelial neoplasms with increasing levels of expression associated with worse outcomes. Though the mechanisms involved are still under investigation, RON is involved in carcinogenesis via immune modulation of the immune tumor microenvironment, activation of numerous oncogenic pathways, and is protective under cellular stress. Alternatively, inhibition of RON abrogates tumor progression in both animal and human tissue models. Given this, RON is a targetable protein of great interest for cancer treatment. Here, we review RON’s function in tissue inflammation and cancer progression, and review cancer clinical trials to date that have used agents targeting RON signaling. Abstract The MST1R/RON receptor tyrosine kinase is a homologue of the more well-known MET receptor. Like MET, RON orchestrates cell signaling pathways that promote oncogenesis and enable cancer cell survival; however, it has a more unique role in the regulation of inflammation. RON was originally described as a transmembrane receptor expressed on tissue resident macrophages and various epithelial cells. RON is overexpressed in a variety of cancers and its activation modifies multiple signaling pathways with resultant changes in epithelial and immune cells which together modulate oncogenic phenotypes. While several RON isoforms have been identified with differences in structure, activation, and pathway regulation, increased RON expression and/or activation is consistently associated with worse outcomes. Tyrosine kinase inhibitors targeting RON have been developed, making RON an actionable therapeutic target.
Collapse
|
|
9
|
Li Y, Tian M, Liu W, Wang D, Zhou Z, Pei Q, Huang Y, Tan F, Güngör C. Follistatin-Like 3 Enhances Invasion and Metastasis via β-Catenin-Mediated EMT and Aerobic Glycolysis in Colorectal Cancer. Front Cell Dev Biol 2021; 9:660159. [PMID: 34395416 PMCID: PMC8355564 DOI: 10.3389/fcell.2021.660159] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 07/12/2021] [Indexed: 12/14/2022] Open
Abstract
Previous studies reported that Follistatin-like 3 (FSTL3) is abundantly expressed in several solid tumors and participate in the regulation of cell metabolism. However, the clinico-pathological significance, biological role and molecular mechanism of FSTL3 in colorectal cancer (CRC) is still unclear. Here we report that the expression level of FSTL3 in colon cancer specimens was significantly higher, compared to normal tissue and interestingly, the expression of FSTL3 was related to lymph node metastasis, tumor stage, tumor size, and intravascular emboli (IVE). As an upstream molecular event, we found that transcriptional regulation of FSTL3 was highly dependent on YAP1 de-phosphorylation events and that increased FSTL3 expression readily activated the β-Catenin pathway, which is a well-known signaling hub that promotes EMT processes and aerobic glycolysis in cancer cells. We found that elevated FSTL3 expression strongly promotes migration, invasion and metastatic formation of CRC cells by directly activating β-Catenin -mediated EMT and aerobic glycolysis. In the xenograft mouse model, FSTL3 expression was linked to increased metastatic formation of CRC cells. Together, the activation of YAP1 induces FSTL3 expression. FSTL3-mediated β-Catenin pathway activation promotes EMT and aerobic glycolysis and therefore affecting the invasive and metastatic capacity of CRC cells. The abundant FSTL3 expression is a poor prognostic factor and pharmacological targeting of YAP1 can counteract FSTL3 expression, suggesting a promising therapeutic target for anti-metastatic strategies in patients suffering from CRC.
Collapse
Affiliation(s)
- Yuqiang Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mengxiang Tian
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Wenxue Liu
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China
| | - Dan Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhongyi Zhou
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Qian Pei
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yan Huang
- Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, China.,Department of Neurosurgery, Second Affiliated Hospital of Hunan Normal University, Changsha, China.,Hunan Provincial Key Laboratory of Neurorestoration, Changsha, China
| | - Fengbo Tan
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Cenap Güngör
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| |
Collapse
|