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Kim J, Mooren OL, Onken MD, Cooper JA. Septin and actin contributions to endothelial cell-cell junctions and monolayer integrity. Cytoskeleton (Hoboken) 2023; 80:228-241. [PMID: 36205643 PMCID: PMC10079785 DOI: 10.1002/cm.21732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/02/2022] [Accepted: 10/04/2022] [Indexed: 11/10/2022]
Abstract
Septins in endothelial cells (ECs) have important roles supporting the integrity of the endothelial monolayer. Cell-cell junctions in EC monolayers are highly dynamic, with continuous retractions and protrusions. Depletion of septins in ECs leads to disruption of cell-cell junctions, which are composed of VE-cadherin and other junctional proteins. In EC monolayers, septins are concentrated at the plasma membrane at sites of cell-cell contact, in curved- and scallop-shaped patterns. These membrane-associated septin accumulations are located in regions of positive membrane curvature, and those regions are often associated with and immediately adjacent to actin-rich protrusions with negative membrane curvature. EC septins associate directly with plasma membrane lipids, based on findings with site-specific mutations of septins in ECs, which is consistent with biochemical and cell biological studies in other systems. Loss of septins leads to disruption of the EC monolayer, and gaps form between cells. The number and breadth of cell-cell contacts and junctions decreases, and the number and frequency of retractions, ruffles, and protrusions at cell edges also decreases. In addition, loss of septins leads to decreased amounts of F-actin at the cortical membrane, along with increased amounts of F-actin in stress fibers of the cytoplasm. Endothelial monolayer disruption from loss of septins is also associated with decreased transendothelial electric resistance (TEER) and increased levels of transendothelial migration (TEM) by immune and cancer cells, owing to the gaps in the monolayer. A current working model is that assembly of septin filaments at regions of positive membrane curvature contributes to a mechanical footing or base for actin-based protrusive forces generated at adjoining regions of the membrane. Specific molecular interactions between the septin and actin components of the cytoskeleton may also be important contributors. Regulators of actin assembly may promote and support the assembly of septin filaments at the membrane, as part of a molecular feedback loop between the assembly of septin and actin filaments.
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Affiliation(s)
- Joanna Kim
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, Missouri, USA
| | - Olivia L Mooren
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, Missouri, USA
| | - Michael D Onken
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, Missouri, USA
| | - John A Cooper
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, Missouri, USA
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Zhang J, Ding Z, Chen L, Qin H. Hypermethylated WASF2: tumor suppressive role in head and neck squamous cell carcinoma. Transl Cancer Res 2023; 12:78-92. [PMID: 36760387 PMCID: PMC9906064 DOI: 10.21037/tcr-22-1133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 12/03/2022] [Indexed: 01/05/2023]
Abstract
Background WASF2 regulates actin reorganization during cell migration. WASF2 has been identified as a regulator of the development of gastric cancer, breast cancer, and pancreatic cancer. But its regulatory mechanisms remain unknown. Also, its function was absent in head and neck squamous cell carcinoma (HNSCC). Consequently, we examined the effect of DNA methylation on aberrant WASF2 expression in HNSCC. Methods TNMplot, TIMER, GSEA pathway analysis, and the Kaplan-Meier Plotter database were used to analyze the expression, function, and prognostic value of WASF2, as well as the correlation between WASF2 and infiltrating immune cells in HNSCC or pan-cancer analysis. WASF2 promoter methylation levels and the correlation between WASF2 expression and WASF2 promoter methylation in HNSCC were evaluated using the DNMIVD database. The effect of DNA methylation inhibitor on WASF2 expression was demonstrated in the GEO database. Finally, the TISIDB database determined the relationships between WASF2 methylation, immune cell infiltration, and immune inhibitors. Results WASF2 was significantly downregulated in HNSCC tissues where WASF2 promoter methylation was elevated. According to the GEO database, treatment with a DNA methylation inhibitor notably restored the mRNA expression of WASF2. WASF2 expression was also a favorable indicator of human papilloma virus (HPV)-positive HNSCC. Its level of promoter methylation had detrimental effects on patient survival. In addition, patients with elevated levels of WASF2 demonstrated active G2/M regulation, TGF-β signaling, Kras signaling, fatty acid metabolism, and p53 pathways. WASF2 was positively associated with tumor-killing immune cells, while WASF2 methylation was positively related to immunosuppressive cells and immune-inhibitors. Conclusions Hypermethylated WASF2 acted as a tumor suppressor of HNSCC by regulating tumor formation and immune imbalance.
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Affiliation(s)
- Jianyun Zhang
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Zhuang Ding
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Long Chen
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Haiyan Qin
- Department of Dental Implantology and Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
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Kang GJ, Park JH, Kim HJ, Kim EJ, Kim B, Byun HJ, Yu L, Nguyen TM, Nguyen TH, Kim KS, Huy HP, Rahman M, Kim YH, Jang JY, Park MK, Lee H, Choi CI, Lee K, Han HK, Cho J, Rho SB, Lee CH. PRR16/Largen Induces Epithelial-Mesenchymal Transition through the Interaction with ABI2 Leading to the Activation of ABL1 Kinase. Biomol Ther (Seoul) 2022; 30:340-347. [PMID: 35719027 PMCID: PMC9252882 DOI: 10.4062/biomolther.2022.066] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 05/28/2022] [Accepted: 06/01/2022] [Indexed: 11/28/2022] Open
Abstract
Advanced or metastatic breast cancer affects multiple organs and is a leading cause of cancer-related death. Cancer metastasis is associated with epithelial-mesenchymal metastasis (EMT). However, the specific signals that induce and regulate EMT in carcinoma cells remain unclear. PRR16/Largen is a cell size regulator that is independent of mTOR and Hippo signalling pathways. However, little is known about the role PRR16 plays in the EMT process. We found that the expression of PRR16 was increased in mesenchymal breast cancer cell lines. PRR16 overexpression induced EMT in MCF7 breast cancer cells and enhances migration and invasion. To determine how PRR16 induces EMT, the binding proteins for PRR16 were screened, revealing that PRR16 binds to Abl interactor 2 (ABI2). We then investigated whether ABI2 is involved in EMT. Gene silencing of ABI2 induces EMT, leading to enhanced migration and invasion. ABI2 is a gene that codes for a protein that interacts with ABL proto-oncogene 1 (ABL1) kinase. Therefore, we investigated whether the change in ABI2 expression affected the activation of ABL1 kinase. The knockdown of ABI2 and PRR16 overexpression increased the phosphorylation of Y412 in ABL1 kinase. Our results suggest that PRR16 may be involved in EMT by binding to ABI2 and interfering with its inhibition of ABL1 kinase. This indicates that ABL1 kinase inhibitors may be potential therapeutic agents for the treatment of PRR16-related breast cancer.
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Affiliation(s)
- Gyeoung Jin Kang
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Jung Ho Park
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Hyun Ji Kim
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Eun Ji Kim
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Boram Kim
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Hyun Jung Byun
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Lu Yu
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Tuan Minh Nguyen
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Thi Ha Nguyen
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Kyung Sung Kim
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Hiệu Phùng Huy
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Mostafizur Rahman
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Ye Hyeon Kim
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Ji Yun Jang
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea.,National Cancer Center, Goyang 10408, Republic of Korea
| | - Mi Kyung Park
- National Cancer Center, Goyang 10408, Republic of Korea
| | - Ho Lee
- National Cancer Center, Goyang 10408, Republic of Korea
| | - Chang Ick Choi
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Kyeong Lee
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Hyo Kyung Han
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Jungsook Cho
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Seung Bae Rho
- National Cancer Center, Goyang 10408, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
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The Role of WAVE2 Signaling in Cancer. Biomedicines 2021; 9:biomedicines9091217. [PMID: 34572403 PMCID: PMC8464821 DOI: 10.3390/biomedicines9091217] [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: 08/06/2021] [Revised: 09/09/2021] [Accepted: 09/10/2021] [Indexed: 11/18/2022] Open
Abstract
The Wiskott–Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE)—WAVE1, WAVE2 and WAVE3 regulate rapid reorganization of cortical actin filaments and have been shown to form a key link between small GTPases and the actin cytoskeleton. Upon receiving upstream signals from Rho-family GTPases, the WASP and WAVE family proteins play a significant role in polymerization of actin cytoskeleton through activation of actin-related protein 2/3 complex (Arp2/3). The Arp2/3 complex, once activated, forms actin-based membrane protrusions essential for cell migration and cancer cell invasion. Thus, by activation of Arp2/3 complex, the WAVE and WASP family proteins, as part of the WAVE regulatory complex (WRC), have been shown to play a critical role in cancer cell invasion and metastasis, drawing significant research interest over recent years. Several studies have highlighted the potential for targeting the genes encoding either part of or a complete protein from the WASP/WAVE family as therapeutic strategies for preventing the invasion and metastasis of cancer cells. WAVE2 is well documented to be associated with the pathogenesis of several human cancers, including lung, liver, pancreatic, prostate, colorectal and breast cancer, as well as other hematologic malignancies. This review focuses mainly on the role of WAVE2 in the development, invasion and metastasis of different types of cancer. This review also summarizes the molecular mechanisms that regulate the activity of WAVE2, as well as those oncogenic pathways that are regulated by WAVE2 to promote the cancer phenotype. Finally, we discuss potential therapeutic strategies that target WAVE2 or the WAVE regulatory complex, aimed at preventing or inhibiting cancer invasion and metastasis.
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Luttman JH, Colemon A, Mayro B, Pendergast AM. Role of the ABL tyrosine kinases in the epithelial-mesenchymal transition and the metastatic cascade. Cell Commun Signal 2021; 19:59. [PMID: 34022881 PMCID: PMC8140471 DOI: 10.1186/s12964-021-00739-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/16/2021] [Indexed: 12/20/2022] Open
Abstract
The ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease. Video abstract.
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Affiliation(s)
- Jillian Hattaway Luttman
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, 308 Research Drive, C-233A LSRC Bldg., P.O. Box 3813, Durham, NC 27710 USA
| | - Ashley Colemon
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, 308 Research Drive, C-233A LSRC Bldg., P.O. Box 3813, Durham, NC 27710 USA
| | - Benjamin Mayro
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, 308 Research Drive, C-233A LSRC Bldg., P.O. Box 3813, Durham, NC 27710 USA
| | - Ann Marie Pendergast
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, 308 Research Drive, C-233A LSRC Bldg., P.O. Box 3813, Durham, NC 27710 USA
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6
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Li K, Peng YF, Guo JZ, Li M, Zhang Y, Chen JY, Lin TR, Yu X, Yu WD. Abelson interactor 1 splice isoform-L plays an anti-oncogenic role in colorectal carcinoma through interactions with WAVE2 and full-length Abelson interactor 1. World J Gastroenterol 2021; 27:1595-1615. [PMID: 33958846 PMCID: PMC8058658 DOI: 10.3748/wjg.v27.i15.1595] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/17/2021] [Accepted: 03/13/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Expression of the full-length isoform of Abelson interactor 1 (ABI1), ABI1-p65, is increased in colorectal carcinoma (CRC) and is thought to be involved in one or more steps leading to tumor progression or metastasis. The ABI1 splice isoform-L (ABI1-SiL) has conserved WAVE2-binding and SH3 domains, lacks the homeo-domain homologous region, and is missing the majority of PxxP- and Pro-rich domains found in full-length ABI1-p65. Thus, ABI1-SiL domain structure suggests that the protein may regulate CRC cell morphology, adhesion, migration, and metastasis via interactions with the WAVE2 complex pathway. AIM To investigate the potential role and underlying mechanisms associated with ABI1-SiL-mediated regulation of CRC. METHODS ABI1-SiL mRNA expression in CC tissue and cell lines was measured using both qualitative reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time quantitative RT-PCR. A stably ABI1-SiL overexpressing SW480 cell model was constructed using Lipofectamine 2000, and cells selected with G418. Image J software, CCK8, and transwell assays were used to investigate SW480 cell surface area, proliferation, migration, and invasion. Immunoprecipitation, Western blot, and co-localization assays were performed to explore intermolecular interactions between ABI1-SiL, WAVE2, and ABI1-p65 proteins. RESULTS ABI1-SiL was expressed in normal colon tissue and was significantly decreased in CRC cell lines and tissues. Overexpression of ABI1-SiL in SW480 cells significantly increased the cell surface area and inhibited the adhesive and migration properties of the cells, but did not alter their invasive capacity. Similar to ABI1-p65, ABI1-SiL still binds WAVE2, and the ABI1-p65 isoform in SW480 cells. Furthermore, co-localization assays confirmed these intermolecular interactions. CONCLUSION These results support a model in which ABI1-SiL plays an anti-oncogenic role by competitively binding to WAVE2 and directly interacting with phosphorylated and non-phosphorylated ABI1-p65, functioning as a dominant-negative form of ABI1-p65.
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Affiliation(s)
- Kun Li
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing 100044, China
- Department of Gastroenterology, Peking University People’s Hospital, Peking University, Beijing 100044, China
| | - Yi-Fan Peng
- Gastrointestinal Cancer Center, Unit III, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Jing-Zhu Guo
- Department of Pediatrics, Peking University People’s Hospital, Beijing 100044, China
| | - Mei Li
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing 100044, China
| | - Yu Zhang
- Department of Gastroenterology, Peking University People’s Hospital, Peking University, Beijing 100044, China
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing 100044, China
| | - Jing-Yi Chen
- Department of Gastroenterology, Peking University People’s Hospital, Peking University, Beijing 100044, China
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing 100044, China
| | - Ting-Ru Lin
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing 100044, China
- Department of Gastroenterology, Peking University People’s Hospital, Peking University, Beijing 100044, China
| | - Xin Yu
- Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing 100044, China
| | - Wei-Dong Yu
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing 100044, China
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Biber G, Ben-Shmuel A, Sabag B, Barda-Saad M. Actin regulators in cancer progression and metastases: From structure and function to cytoskeletal dynamics. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 356:131-196. [PMID: 33066873 DOI: 10.1016/bs.ircmb.2020.05.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The cytoskeleton is a central factor contributing to various hallmarks of cancer. In recent years, there has been increasing evidence demonstrating the involvement of actin regulatory proteins in malignancy, and their dysregulation was shown to predict poor clinical prognosis. Although enhanced cytoskeletal activity is often associated with cancer progression, the expression of several inducers of actin polymerization is remarkably reduced in certain malignancies, and it is not completely clear how these changes promote tumorigenesis and metastases. The complexities involved in cytoskeletal induction of cancer progression therefore pose considerable difficulties for therapeutic intervention; it is not always clear which cytoskeletal regulator should be targeted in order to impede cancer progression, and whether this targeting may inadvertently enhance alternative invasive pathways which can aggravate tumor growth. The entire constellation of cytoskeletal machineries in eukaryotic cells are numerous and complex; the system is comprised of and regulated by hundreds of proteins, which could not be covered in a single review. Therefore, we will focus here on the actin cytoskeleton, which encompasses the biological machinery behind most of the key cellular functions altered in cancer, with specific emphasis on actin nucleating factors and nucleation-promoting factors. Finally, we discuss current therapeutic strategies for cancer which aim to target the cytoskeleton.
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Affiliation(s)
- G Biber
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
| | - A Ben-Shmuel
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
| | - B Sabag
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
| | - M Barda-Saad
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
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8
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He C, Plattner R, Rangnekar V, Zhou B, Liu C, Stewart RL, Huang B, Wang C, Tucker TC. Potential protein markers for breast cancer recurrence: a retrospective cohort study. Cancer Causes Control 2018; 30:41-51. [PMID: 30488343 DOI: 10.1007/s10552-018-1099-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 11/21/2018] [Indexed: 11/28/2022]
Abstract
BACKGROUND We evaluated five key proteins involved in various cancer-related pathways and assessed their relation to breast cancer recurrence. METHODS We used the Kentucky Cancer Registry to retrospectively identify primary invasive breast cancer cases (n = 475) that were diagnosed and treated at University of Kentucky Medical Center between 2000 and 2007. Breast cancer recurrence was observed in 62 cases during the 5-year follow-up after diagnosis. Protein expression or activity level was analyzed from surgery tissue using immuno-histochemical assays. RESULTS Compared to ER+/PR+/HER2- patients without recurrence, those with recurrence had higher TWIST expression (p = 0.049) but lower ABL1/ABL2 activity (p = 0.003) in primary tumors. We also found that triple-negative breast cancer patients with recurrence had higher SNAI1 expression compared to those without recurrence (p = 0.03). After adjusting for potential confounders, the higher ABL1/ABL2 activity in primary tumors was associated with a decreased risk of recurrence (OR 0.72, 95% CI 0.85-0.90) among ER+/PR+/HER2- patients. In addition, among patients with recurrence we observed that the activity level of ABL1/ABL2 was significantly increased in recurrent tumors compared to the matched primary tumors regardless of the subtype (p = 0.013). CONCLUSIONS These findings provide evidence that the expression/activity level of various proteins may be differentially associated with risk of recurrence of breast tumor subtypes.
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Affiliation(s)
- Chunyan He
- Markey Cancer Center, University of Kentucky, 744 Rose Street, Combs 206, Lexington, KY, 40536, USA. .,Department of Internal Medicine, Division of Medical Oncology, College of Medicine, University of Kentucky, Lexington, KY, USA.
| | - Rina Plattner
- Markey Cancer Center, University of Kentucky, 744 Rose Street, Combs 206, Lexington, KY, 40536, USA.,Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY, USA.,Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, USA
| | - Vivek Rangnekar
- Markey Cancer Center, University of Kentucky, 744 Rose Street, Combs 206, Lexington, KY, 40536, USA.,Department of Radiation Medicine, College of Medicine, University of Kentucky, Lexington, KY, USA
| | - Binhua Zhou
- Markey Cancer Center, University of Kentucky, 744 Rose Street, Combs 206, Lexington, KY, 40536, USA.,Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, USA
| | - Chunming Liu
- Markey Cancer Center, University of Kentucky, 744 Rose Street, Combs 206, Lexington, KY, 40536, USA.,Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, USA
| | - Rachel L Stewart
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Kentucky, Lexington, KY, USA
| | - Bin Huang
- Markey Cancer Center, University of Kentucky, 744 Rose Street, Combs 206, Lexington, KY, 40536, USA.,Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA
| | - Chi Wang
- Markey Cancer Center, University of Kentucky, 744 Rose Street, Combs 206, Lexington, KY, 40536, USA.,Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA
| | - Thomas C Tucker
- Markey Cancer Center, University of Kentucky, 744 Rose Street, Combs 206, Lexington, KY, 40536, USA. .,Department of Epidemiology, College of Public Health, University of Kentucky, Lexington, KY, USA. .,Markey Cancer Center, University of Kentucky, 2365 Harrodsburg Road, Suite A230, Lexington, KY, 40504, USA.
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Tripathi R, Liu Z, Plattner R. EnABLing Tumor Growth and Progression: Recent progress in unraveling the functions of ABL kinases in solid tumor cells. CURRENT PHARMACOLOGY REPORTS 2018; 4:367-379. [PMID: 30746323 PMCID: PMC6368175 DOI: 10.1007/s40495-018-0149-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
PURPOSE OF REVIEW The goal of this review is to summarize our current knowledge regarding how ABL family kinases are activated in solid tumors and impact on solid tumor development/progression, with a focus on recent advances in the field. RECENT FINDINGS Although ABL kinases are known drivers of human leukemia, emerging data also implicates the kinases in a large number of solid tumor types where they promote diverse processes such as proliferation, survival, cytoskeletal reorganization, cellular polarity, EMT (epithelial-mesenchymal-transition), metabolic reprogramming, migration, invasion and metastasis via unique signaling pathways. ABL1 and ABL2 appear to have overlapping but also unique roles in driving these processes. In some tumor types, the kinases may act to integrate pro- and anti-proliferative and -invasive signals, and also may serve as a switch during EMT/MET (mesenchymal-epithelial) transitions. CONCLUSIONS Most data indicate that targeting ABL kinases may be effective for reducing tumor growth and preventing metastasis; however, ABL kinases also may have a tumor suppressive role in some tumor types and in some cellular contexts. Understanding the functions of ABL kinases in solid tumors is critical for developing successful clinical trials aimed at targeting ABL kinases for the treatment of solid tumors.
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Affiliation(s)
- Rakshamani Tripathi
- Department of Pharmacology and Nutritional Sciences, University of Kentucky School of Medicine, Lexington, Kentucky 40536
| | - Zulong Liu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky School of Medicine, Lexington, Kentucky 40536
| | - Rina Plattner
- Department of Pharmacology and Nutritional Sciences, University of Kentucky School of Medicine, Lexington, Kentucky 40536
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10
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Sun LN, Xing C, Zhi Z, Liu Y, Chen LY, Shen T, Zhou Q, Liu YH, Gan WJ, Wang JR, Xu Y, Li JM. Dicer suppresses cytoskeleton remodeling and tumorigenesis of colorectal epithelium by miR-324-5p mediated suppression of HMGXB3 and WASF-2. Oncotarget 2017; 8:55776-55789. [PMID: 28915552 PMCID: PMC5593523 DOI: 10.18632/oncotarget.18218] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 05/12/2017] [Indexed: 12/27/2022] Open
Abstract
Emerging evidence indicates that microRNAs, a class of small and well-conserved noncoding RNAs, participate in many physiological and pathological processes. RNase III endonuclease DICER is one of the key enzymes for microRNA biogenesis. Here, we found that DICER was downregulated in tumor samples of colorectal cancer (CRC) patients at both mRNA and protein levels. Importantly, intestinal epithelial cell (IEC)-specific deletion of Dicer mice got more tumors after azoxymethane and dextran sulfate sodium (DSS) administration. Interestingly, IEC-specific deletion of Dicer led to severe chronic inflammation and epithelium layer remodeling in mice with or without DSS administration. Microarray analysis of 3 paired Dicer deletion CRC cell lines showed that miR-324-5p was one of the most significantly decreased miRNAs. In the intestinal epithelium of IEC-specific deletion of Dicer mice, miR-324-5p was also found to be markedly reduced. Mechanistically, miR-324-5p directly bound to the 3′untranslated regions (3′UTRs) of HMG-box containing 3 (HMGXB3) and WAS protein family member 2 (WASF-2), two key proteins participated in cell motility and cytoskeleton remodeling, to suppress their expressions. Intraperitoneal injection of miR-324-5p AgomiR (an agonist of miR-324-5p) curtailed chronic inflammation and cytoskeleton remodeling of colorectal epithelium and restored intestinal barrier function in IEC-specific deletion of Dicer mice induced by DSS. Therefore, our study reveals a key role of a DICER/miR-324-5p/HMGXB3/WASF-2 axis in tumorigenesis of CRC by regulation of cytoskeleton remodeling and maintaining integrity of intestinal barriers.
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Affiliation(s)
- Li Na Sun
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, People's Republic of China
| | - Cheng Xing
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, People's Republic of China
| | - Zheng Zhi
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, People's Republic of China
| | - Yao Liu
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, People's Republic of China
| | - Liang-Yan Chen
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, People's Republic of China
| | - Tong Shen
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, People's Republic of China
| | - Qun Zhou
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, People's Republic of China
| | - Yu Hong Liu
- Department of Pathology, Baoan Hospital, Southern Medical University, Shenzhen, People's Republic of China
| | - Wen Juan Gan
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, People's Republic of China
| | - Jing-Ru Wang
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, People's Republic of China
| | - Yong Xu
- Department of Pathophysiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Jian Ming Li
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, People's Republic of China
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11
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Burgos-Ojeda D, Wu R, McLean K, Chen YC, Talpaz M, Yoon E, Cho KR, Buckanovich RJ. CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis. Mol Cancer Ther 2015; 14:1717-27. [PMID: 25969154 DOI: 10.1158/1535-7163.mct-14-0607] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 05/04/2015] [Indexed: 01/05/2023]
Abstract
Ovarian cancer is known to be composed of distinct populations of cancer cells, some of which demonstrate increased capacity for cancer initiation and/or metastasis. The study of human cancer cell populations is difficult due to long requirements for tumor growth, interpatient variability, and the need for tumor growth in immune-deficient mice. We therefore characterized the cancer initiation capacity of distinct cancer cell populations in a transgenic murine model of ovarian cancer. In this model, conditional deletion of Apc, Pten, and Trp53 in the ovarian surface epithelium (OSE) results in the generation of high-grade metastatic ovarian carcinomas. Cell lines derived from these murine tumors express numerous putative stem cell markers, including CD24, CD44, CD90, CD117, CD133, and ALDH. We show that CD24(+) and CD133(+) cells have increased tumor sphere-forming capacity. CD133(+) cells demonstrated a trend for increased tumor initiation while CD24(+) cells versus CD24(-) cells had significantly greater tumor initiation and tumor growth capacity. No preferential tumor-initiating or growth capacity was observed for CD44(+), CD90(+), CD117(+), or ALDH(+) versus their negative counterparts. We have found that CD24(+) cells, compared with CD24(-) cells, have increased phosphorylation of STAT3 and increased expression of STAT3 target Nanog and c-myc. JAK2 inhibition of STAT3 phosphorylation preferentially induced cytotoxicity in CD24(+) cells. In vivo JAK2 inhibitor therapy dramatically reduced tumor metastases, and prolonged overall survival. These findings indicate that CD24(+) cells play a role in tumor migration and metastasis and support JAK2 as a therapeutic target in ovarian cancer.
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Affiliation(s)
- Daniela Burgos-Ojeda
- Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, Michigan. Department of Internal Medicine Division Hematology-Oncology, University of Michigan, Ann Arbor, Michigan
| | - Rong Wu
- Department of Pathology, Division of Gynecological Pathology, University of Michigan, Ann Arbor, Michigan
| | - Karen McLean
- Department of Obstetrics-Gynecology, Division of Gynecologic Oncology, University of Michigan, Ann Arbor, Michigan
| | - Yu-Chih Chen
- Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, Michigan
| | - Moshe Talpaz
- Department of Internal Medicine Division Hematology-Oncology, University of Michigan, Ann Arbor, Michigan
| | - Euisik Yoon
- Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, Michigan. Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Kathleen R Cho
- Department of Pathology, Division of Gynecological Pathology, University of Michigan, Ann Arbor, Michigan
| | - Ronald J Buckanovich
- Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, Michigan. Department of Internal Medicine Division Hematology-Oncology, University of Michigan, Ann Arbor, Michigan. Department of Obstetrics-Gynecology, Division of Gynecologic Oncology, University of Michigan, Ann Arbor, Michigan.
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12
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Teng NY, Liu YS, Wu HH, Liu YA, Ho JH, Lee OKS. Promotion of mesenchymal-to-epithelial transition by Rac1 inhibition with small molecules accelerates hepatic differentiation of mesenchymal stromal cells. Tissue Eng Part A 2015; 21:1444-54. [PMID: 25625545 DOI: 10.1089/ten.tea.2014.0320] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
In vitro differentiation of stem cells into specific cell lineages provides a stable cell supply for cell therapy and tissue engineering. Therefore, understanding the mechanisms underlying such differentiation processes is critical for generating committed lineage-specific cell progenies effectively. We previously developed a two-step protocol to differentiate mesenchymal stromal cells (MSCs) into hepatocyte-like cells. Since hepatic differentiation involves mesenchymal-epithelial transition (MET), we hypothesize that promoting MET could further accelerate the differentiation process. Ras-related C3 botulinum toxin substrate 1 (Rac1) is involved in actin polymerization and its role in MET was investigated in the study. Our results showed that inhibition of Rac1 activation by Rac1-specific inhibitor, NSC23766, led to cells favoring epithelial morphology and being more packed during hepatic differentiation. In addition, Rac1 inhibition accelerated the upregulation of hepatic marker genes accompanied by more mature hepatic functions. Taken together, promotion of MET by inhibiting Rac1 accelerates the hepatic differentiation of MSCs. Our findings open a new prospect of directing the commitment of MSCs by manipulating cell morphology and cytoskeleton arrangement through small molecules. The results provide further insight into scaffold design for rapid production of MSC-differentiated hepatocytes.
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Affiliation(s)
- Nan-Yuan Teng
- 1 Institute of Clinical Medicine, National Yang-Ming University , Taipei, Taiwan
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13
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Lin Q, Sun MZ, Guo C, Shi J, Chen X, Liu S. CRKL overexpression suppresses in vitro proliferation, invasion and migration of murine hepatocarcinoma Hca-P cells. Biomed Pharmacother 2014; 69:11-7. [PMID: 25661331 DOI: 10.1016/j.biopha.2014.10.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 10/18/2014] [Indexed: 12/17/2022] Open
Abstract
The signal adaptor CRK family protein play important roles in cancer cell progression, proliferation, migration and invasion. Previously, we showed that CRK was involved in lymphatic metastatic potential of murine hepatocarcinoma cells. In current work, as a member of CRK family, chicken tumour virus number 10 regulator of kinase-like protein (CRKL) was revealed to be associated with malignant behaviors of Hca-P, a murine HCC cell with lymph node metastatic (LNM) rate of ∼25%. CRKL overexpression in Hca-P by a constructed eukaryotic expression vector of pcDNA3.1/V5-HisB-CRKL significantly ameliorated its malignant biological properties. CCK-8 and soft agar colony formation assays indicated CRKL overexpression significantly inhibits the cell proliferation and colony formation abilities of Hca-P. Additionally, transwell assays indicated that the Hca-P cell migration and invasion capacities were apparently reduced following CRKL overexpression. As Hca-P is an ideal hepatocarcinoma cell model with low (initial) LNM potential, CRKL is shown to act as a potential suppressor and to provide new insight for both the malignant behaviors of hepatocarcinoma cells and lymphatic metastasis mechanism of hepatocarcinoma.
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Affiliation(s)
- Qiuyue Lin
- Department of Biochemistry, Dalian Medical University, 116044 Dalian, PR China; Department of Biotechnology, Dalian Medical University, 116044 Dalian, PR China
| | - Ming-Zhong Sun
- Department of Biotechnology, Dalian Medical University, 116044 Dalian, PR China
| | - Chunmei Guo
- Department of Biotechnology, Dalian Medical University, 116044 Dalian, PR China
| | - Ji Shi
- Department of Biochemistry, Dalian Medical University, 116044 Dalian, PR China
| | - Xin Chen
- Department of General Surgery of The Second Hospital, Dalian Medical University, 116021 Dalian, PR China
| | - Shuqing Liu
- Department of Biochemistry, Dalian Medical University, 116044 Dalian, PR China; Provincial Key Laboratory of Cell and Molecular Biology, Dalian Medical University, 116044 Dalian, PR China.
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14
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Mooren OL, Li J, Nawas J, Cooper JA. Endothelial cells use dynamic actin to facilitate lymphocyte transendothelial migration and maintain the monolayer barrier. Mol Biol Cell 2014; 25:4115-29. [PMID: 25355948 PMCID: PMC4263454 DOI: 10.1091/mbc.e14-05-0976] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Actin assembly downstream of WAVE2 in endothelial cells is necessary to engage transmigrating lymphocytes, promote the transcellular route of migration, and close junctional pores after the lymphocyte moves away. In addition, WAVE2 is necessary for endothelial monolayer integrity. The vascular endothelium is a highly dynamic structure, and the integrity of its barrier function is tightly regulated. Normally impenetrable to cells, the endothelium actively assists lymphocytes to exit the bloodstream during inflammation. The actin cytoskeleton of the endothelial cell (EC) is known to facilitate transmigration, but the cellular and molecular mechanisms are not well understood. Here we report that actin assembly in the EC, induced by Arp2/3 complex under control of WAVE2, is important for several steps in the process of transmigration. To begin transmigration, ECs deploy actin-based membrane protrusions that create a cup-shaped docking structure for the lymphocyte. We found that docking structure formation involves the localization and activation of Arp2/3 complex by WAVE2. The next step in transmigration is creation of a migratory pore, and we found that endothelial WAVE2 is needed for lymphocytes to follow a transcellular route through an EC. Later, ECs use actin-based protrusions to close the gap behind the lymphocyte, which we discovered is also driven by WAVE2. Finally, we found that ECs in resting endothelial monolayers use lamellipodial protrusions dependent on WAVE2 to form and maintain contacts and junctions between cells.
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Affiliation(s)
- Olivia L Mooren
- Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110
| | - Jinmei Li
- Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110
| | - Julie Nawas
- Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110
| | - John A Cooper
- Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110
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