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Deng M, Luo R, Wang H, Abuduwaili A, Jiang D, Zhang X, Xu L, Zhang X, Niu Z, Su J, Xu C, Hou Y. Loss of SWI/SNF complex expression (SMARCA4, SMARCA2, SMARCB1, ARID1A) is associated with dMMR in primary adenocarcinoma of jejunum and ileum: A clinicopathological and molecular analysis based on the Chinese population. Pathol Res Pract 2025; 269:155891. [PMID: 40101550 DOI: 10.1016/j.prp.2025.155891] [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: 08/29/2024] [Revised: 01/31/2025] [Accepted: 03/01/2025] [Indexed: 03/20/2025]
Abstract
OBJECTIVE The SWI/SNF complex is an important chromatin remodeling complex that has been reported in various tumors. To date, there have been no reports on the subunits of this complex in primary small bowel adenocarcinoma (PSBA). METHODS Hematoxylin & Eosin (H&E) staining slides were reviewed, and the expression of MMR protein, BRM (SMARCA2), BRG1 (SMARCA4), INI1 (SMARCB1), and ARID1A proteins was detected. Molecular genetic testing was performed utilizing the amplification-refractory mutation system (ARMS) and high-throughput sequencing technology. RESULTS In this cohort of 58 cases, there was a trend toward a female predominance in ARID1A loss (P = 0.084), and BRM (SMARCA2) loss was associated with lymphatic invasion (P = 0.043). A significant positive correlation was observed between ARID1A loss and dMMR (P = 0.021), and BRG1 (SMARCA4) loss was more prevalent in poorly differentiated PSBA (P = 0.023). ARID1A loss was positively correlated with PIK3CA gene mutation (r = 0.551, P < 0.001), and loss of MMR protein expression was also positively correlated with PIK3CA gene mutation (r = 0.354, P = 0.006). Additionally, BRM (SMARCA2) loss showed a significant positive correlation with NRAS gene mutation (r = 0.293, P = 0.025) and a significant negative correlation with KRAS gene mutation (r = -0.281, P = 0.033). Univariate analysis indicated a trend toward poor prognosis with BRM (SMARCA2) loss (P = 0.097). CONCLUSION This study represents the initial description of loss of the SWI/SNF complex expression in PSBA, which is rare and primarily originates in the jejunum and ileum. Further investigations are warranted to elucidate potential targets of PIK3CA inhibitors for dMMR PSBA and ARID1A loss of expression in PSBA.
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Affiliation(s)
- Minying Deng
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Rongkui Luo
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Huimei Wang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ayizimugu Abuduwaili
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Dongxian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xinyi Zhang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Lei Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiaolei Zhang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhiping Niu
- Department of Environmental Health, School of Public Health, Fudan University, Shanghai 200032, China
| | - Jieakesu Su
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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Molefi T, Mabonga L, Hull R, Mwazha A, Sebitloane M, Dlamini Z. The Histomorphology to Molecular Transition: Exploring the Genomic Landscape of Poorly Differentiated Epithelial Endometrial Cancers. Cells 2025; 14:382. [PMID: 40072110 PMCID: PMC11898822 DOI: 10.3390/cells14050382] [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: 12/06/2024] [Revised: 03/01/2025] [Accepted: 03/03/2025] [Indexed: 03/15/2025] Open
Abstract
The peremptory need to circumvent challenges associated with poorly differentiated epithelial endometrial cancers (PDEECs), also known as Type II endometrial cancers (ECs), has prompted therapeutic interrogation of the prototypically intractable and most prevalent gynecological malignancy. PDEECs account for most endometrial cancer-related mortalities due to their aggressive nature, late-stage detection, and poor response to standard therapies. PDEECs are characterized by heterogeneous histopathological features and distinct molecular profiles, and they pose significant clinical challenges due to their propensity for rapid progression. Regardless of the complexities around PDEECs, they are still being administered inefficiently in the same manner as clinically indolent and readily curable type-I ECs. Currently, there are no targeted therapies for the treatment of PDEECs. The realization of the need for new treatment options has transformed our understanding of PDEECs by enabling more precise classification based on genomic profiling. The transition from a histopathological to a molecular classification has provided critical insights into the underlying genetic and epigenetic alterations in these malignancies. This review explores the genomic landscape of PDEECs, with a focus on identifying key molecular subtypes and associated genetic mutations that are prevalent in aggressive variants. Here, we discuss how molecular classification correlates with clinical outcomes and can refine diagnostic accuracy, predict patient prognosis, and inform therapeutic strategies. Deciphering the molecular underpinnings of PDEECs has led to advances in precision oncology and protracted therapeutic remissions for patients with these untamable malignancies.
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Affiliation(s)
- Thulo Molefi
- Discipline of Obstetrics and Gynaecology, School of Clinical Medicine, University of KwaZulu-Natal, Durban 4002, South Africa;
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP) Pan African Research Institute (PACRI), University of Pretoria, Hartfield, Pretoria 0028, South Africa
- Department of Medical Oncology, University of Pretoria, Hatfield, Pretoria 0028, South Africa
| | - Lloyd Mabonga
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP) Pan African Research Institute (PACRI), University of Pretoria, Hartfield, Pretoria 0028, South Africa
| | - Rodney Hull
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP) Pan African Research Institute (PACRI), University of Pretoria, Hartfield, Pretoria 0028, South Africa
| | - Absalom Mwazha
- Department of Anatomical Pathology, National Health Laboratory Services, Durban 4058, South Africa
| | - Motshedisi Sebitloane
- Discipline of Obstetrics and Gynaecology, School of Clinical Medicine, University of KwaZulu-Natal, Durban 4002, South Africa;
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP) Pan African Research Institute (PACRI), University of Pretoria, Hartfield, Pretoria 0028, South Africa
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Zheng K, Jin G, Cao R, Gao Y, Xu J, Chai R, Kang Y. Targeting on the PI3K/mTOR: a potential treatment strategy for clear cell ovarian carcinoma. Cancer Chemother Pharmacol 2025; 95:21. [PMID: 39792198 PMCID: PMC11723846 DOI: 10.1007/s00280-024-04748-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 12/29/2024] [Indexed: 01/12/2025]
Abstract
PURPOSE Ovarian clear cell carcinoma is a highly malignant gynecological tumor characterized by a high rate of chemotherapy resistance and poor prognosis. The PI3K/AKT/mTOR pathway is well-known to be closely related to the progression of various malignancies, and recent studies have indicated that this pathway may play a critical role in the progression and worsening of OCCC. METHODS In this study, we investigated the combined effects of WX390, a dual inhibitor of PI3K/mTOR, and cisplatin on OCCC through both in vitro and in vivo experiments to further elucidate their therapeutic effects. RESULTS WX390 significantly inhibited the proliferation of human OCCC cell lines ES2 and OVISE, while promoting apoptosis. Furthermore, the combination of WX390 with CDDP exhibited a synergistic effect, markedly increasing the sensitivity of OCCC cells to chemotherapeutic agents and significantly suppressing tumor growth in PDX models. Western blot and RNA-seq analyses revealed that WX390 robustly inhibited the PI3K/AKT/mTOR pathway, interrupt autophagy, altered cell cycle dynamics, and induced apoptosis. CONCLUSION This study comprehensively assessed the efficacy of WX390 across multiple models of OCCC, laying a solid foundation for the development of new therapeutic strategies for this challenging malignancy.
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Affiliation(s)
- Kewei Zheng
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Guanqin Jin
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Rui Cao
- Department of Gynecology, Dalian Obstetrics and Gynecology Hospital, Dalian, 116033, China
| | - Yi Gao
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Jing Xu
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Ranran Chai
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Yu Kang
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
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Al Ageeli E. Dual Roles of microRNA-122 in Hepatocellular Carcinoma and Breast Cancer Progression and Metastasis: A Comprehensive Review. Curr Issues Mol Biol 2024; 46:11975-11992. [PMID: 39590305 PMCID: PMC11592835 DOI: 10.3390/cimb46110711] [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: 09/27/2024] [Revised: 10/17/2024] [Accepted: 10/22/2024] [Indexed: 11/28/2024] Open
Abstract
microRNA-122 (miR-122) plays crucial yet contrasting roles in hepatocellular carcinoma (HCC) and breast cancer (BC), two prevalent and aggressive malignancies. This review synthesizes current research on miR-122's functions in these cancers, focusing on its potential as a diagnostic, prognostic, and therapeutic target. A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus databases. In HCC, miR-122 is downregulated in most cases, suppressing oncogenic pathways and reducing tumor growth and metastasis. Restoring miR-122 levels has shown promising therapeutic potential, increasing sensitivity to treatments like sorafenib. In contrast, in BC, miR-122 plays a pro-metastatic role, especially in triple-negative breast cancer (TNBC) and metastatic lesions. miR-122's ability to influence key pathways, such as the Wnt/β-catenin and NF-κB pathways in HCC, and its role in enhancing the Warburg effect in BC underline its significance in cancer biology. miR-122, a key factor in breast cancer radioresistance, suppresses tumors in radiosensitive cells. Inhibiting miR-122 could reverse resistance and potentially overcome radiotherapy resistance. Given its context-dependent functions, miR-122 could serve as a potential therapeutic target, where restoring or inhibiting its expression may help in treating HCC and BC, respectively. The dual roles of miR-122 underscore its significance in cancer biology and its potential in precision medicine.
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Affiliation(s)
- Essam Al Ageeli
- Department of Basic Medical Sciences (Medical Genetics), Faculty of Medicine, Jazan University, Jazan 45142, Saudi Arabia
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Angelico G, Attanasio G, Colarossi L, Colarossi C, Montalbano M, Aiello E, Di Vendra F, Mare M, Orsi N, Memeo L. ARID1A Mutations in Gastric Cancer: A Review with Focus on Clinicopathological Features, Molecular Background and Diagnostic Interpretation. Cancers (Basel) 2024; 16:2062. [PMID: 38893181 PMCID: PMC11171396 DOI: 10.3390/cancers16112062] [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: 04/02/2024] [Revised: 05/23/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
AT-rich interaction domain 1 (ARID1A) is a pivotal gene with a significant role in gastrointestinal tumors which encodes a protein referred to as BAF250a or SMARCF1, an integral component of the SWI/SNF (SWItch/sucrose non-fermentable) chromatin remodeling complex. This complex is instrumental in regulating gene expression by modifying the structure of chromatin to affect the accessibility of DNA. Mutations in ARID1A have been identified in various gastrointestinal cancers, including colorectal, gastric, and pancreatic cancers. These mutations have the potential to disrupt normal SWI/SNF complex function, resulting in aberrant gene expression and potentially contributing to the initiation and progression of these malignancies. ARID1A mutations are relatively common in gastric cancer, particularly in specific adenocarcinoma subtypes. Moreover, such mutations are more frequently observed in specific molecular subtypes, such as microsatellite stable (MSS) cancers and those with a diffuse histological subtype. Understanding the presence and implications of ARID1A mutations in GC is of paramount importance for tailoring personalized treatment strategies and assessing prognosis, particularly given their potential in predicting patient response to novel treatment strategies including immunotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors.
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Affiliation(s)
- Giuseppe Angelico
- Department of Medicine and Surgery, Kore University of Enna, 94100 Enna, Italy;
| | - Giulio Attanasio
- Department of Medical, Surgical Sciences and Advanced Technologies G.F. Ingrassia, Anatomic Pathology, University of Catania, 95123 Catania, Italy;
| | - Lorenzo Colarossi
- Pathology Unit, Department of Experimental Oncology, Mediterranean Institute of Oncology, 95029 Catania, Italy; (L.C.); (C.C.); (E.A.)
| | - Cristina Colarossi
- Pathology Unit, Department of Experimental Oncology, Mediterranean Institute of Oncology, 95029 Catania, Italy; (L.C.); (C.C.); (E.A.)
| | - Matteo Montalbano
- Pathology Unit, Department of Experimental Oncology, Mediterranean Institute of Oncology, 95029 Catania, Italy; (L.C.); (C.C.); (E.A.)
- PhD Program in Precision Medicine, University of Palermo, 90144 Palermo, Italy
| | - Eleonora Aiello
- Pathology Unit, Department of Experimental Oncology, Mediterranean Institute of Oncology, 95029 Catania, Italy; (L.C.); (C.C.); (E.A.)
| | - Federica Di Vendra
- Department of Chemical, Biological and Environmental Chemistry, University of Messina, 98122 Messina, Italy
| | - Marzia Mare
- Medical Oncology Unit, Department of Experimental Oncology, Mediterranean Institute of Oncology, Viagrande, 95029 Catania, Italy
| | - Nicolas Orsi
- Leeds Institute of Medical Research, St James’s University Hospital, The University of Leeds, Leeds LS9 7TF, UK;
| | - Lorenzo Memeo
- Pathology Unit, Department of Experimental Oncology, Mediterranean Institute of Oncology, 95029 Catania, Italy; (L.C.); (C.C.); (E.A.)
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Liu Z, Jing C, Kong F. From clinical management to personalized medicine: novel therapeutic approaches for ovarian clear cell cancer. J Ovarian Res 2024; 17:39. [PMID: 38347608 PMCID: PMC10860311 DOI: 10.1186/s13048-024-01359-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 01/26/2024] [Indexed: 02/15/2024] Open
Abstract
Ovarian clear-cell cancer is a rare subtype of epithelial ovarian cancer with unique clinical and biological features. Despite optimal cytoreductive surgery and platinum-based chemotherapy being the standard of care, most patients experience drug resistance and a poor prognosis. Therefore, novel therapeutic approaches have been developed, including immune checkpoint blockade, angiogenesis-targeted therapy, ARID1A synthetic lethal interactions, targeting hepatocyte nuclear factor 1β, and ferroptosis. Refining predictive biomarkers can lead to more personalized medicine, identifying patients who would benefit from chemotherapy, targeted therapy, or immunotherapy. Collaboration between academic research groups is crucial for developing prognostic outcomes and conducting clinical trials to advance treatment for ovarian clear-cell cancer. Immediate progress is essential, and research efforts should prioritize the development of more effective therapeutic strategies to benefit all patients.
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Affiliation(s)
- Zesi Liu
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, Liaoning Province, China
| | - Chunli Jing
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116000, Liaoning Province, China
| | - Fandou Kong
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, Liaoning Province, China.
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Li JJ, Lee CS. The Role of the AT-Rich Interaction Domain 1A Gene ( ARID1A) in Human Carcinogenesis. Genes (Basel) 2023; 15:5. [PMID: 38275587 PMCID: PMC10815128 DOI: 10.3390/genes15010005] [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: 11/13/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 01/27/2024] Open
Abstract
The switch/sucrose non-fermentable (SWI/SNF) (SWI/SNF) complex uses energy from ATP hydrolysis to mobilise nucleosomes on chromatin. Components of SWI/SNF are mutated in 20% of all human cancers, of which mutations in AT-rich binding domain protein 1A (ARID1A) are the most common. ARID1A is mutated in nearly half of ovarian clear cell carcinoma and around one-third of endometrial and ovarian carcinomas of the endometrioid type. This review will examine in detail the molecular functions of ARID1A, including its role in cell cycle control, enhancer regulation, and the prevention of telomerase activity. ARID1A has key roles in the maintenance of genomic integrity, including DNA double-stranded break repair, DNA decatenation, integrity of the cohesin complex, and reduction in replication stress, and is also involved in mismatch repair. The role of ARID1A loss in the pathogenesis of some of the most common human cancers is discussed, with a particular emphasis on gynaecological cancers. Finally, several promising synthetic lethal strategies, which exploit the specific vulnerabilities of ARID1A-deficient cancer cells, are briefly mentioned.
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Affiliation(s)
- Jing Jing Li
- Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia
| | - Cheok Soon Lee
- Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
- Discipline of Pathology, School of Medicine, Western Sydney University, Sydney, NSW 2560, Australia
- South Western Sydney Clinical School, University of New South Wales, Liverpool, NSW 2170, Australia
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW 2010, Australia
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Lu S, Duan R, Cong L, Song Y. The effects of ARID1A mutation in gastric cancer and its significance for treatment. Cancer Cell Int 2023; 23:296. [PMID: 38008753 PMCID: PMC10676575 DOI: 10.1186/s12935-023-03154-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 11/21/2023] [Indexed: 11/28/2023] Open
Abstract
Gastric cancer (GC) has emerged as a significant issue in public health all worldwide as a result of its high mortality rate and dismal prognosis. AT-rich interactive domain 1 A (ARID1A) is a vital component of the switch/sucrose-non-fermentable (SWI/SNF) chromatin remodeling complex, and ARID1A mutations occur in various tumors, leading to protein loss and decreased expression; it then affects the tumor biological behavior or prognosis. More significantly, ARID1A mutations will likely be biological markers for immune checkpoint blockade (ICB) treatment and selective targeted therapy. To provide theoretical support for future research on the stratification of individuals with gastric cancer with ARID1A as a biomarker to achieve precision therapy, we have focused on the clinical significance, predictive value, underlying mechanisms, and possible treatment strategies for ARID1A mutations in gastric cancer in this review.
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Affiliation(s)
- Shan Lu
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
| | - Ruifeng Duan
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
| | - Liang Cong
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
| | - Ying Song
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China.
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Abstract
Ovarian clear cell carcinoma is a rare subtype of epithelial ovarian cancer with unique clinicopathological features. The most common genetic aberration observed is loss of function ARID1A mutations. Advanced and recurrent ovarian clear cell carcinoma is characterized by resistance to standard-of-care cytotoxic chemotherapy and a poor prognosis. Despite the distinct molecular features of ovarian clear cell carcinoma, current treatments for this subtype of epithelial ovarian cancer are based on clinical trials which predominantly recruited patients with high grade serous ovarian carcinoma. These factors have encouraged researchers to develop novel treatment strategies specifically for ovarian clear cell carcinoma which are currently being tested in the context of clinical trials. These new treatment strategies currently focus on three key areas: immune checkpoint blockade, targeting angiogenesis, and exploiting ARID1A synthetic lethal interactions. Rational combinations of these strategies are being assessed in clinical trials. Despite the progress made in identifying new treatments for ovarian clear cell carcinoma, predictive biomarkers to better define those patients likely to respond to new treatments remain to be elucidated. Additional future challenges which may be addressed through international collaboration include the need for randomized trials in a rare disease and establishing the relative sequencing of these novel treatments.
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Affiliation(s)
- James Stewart
- Royal Marsden Hospital NHS Trust, London, UK
- Gene Function Laboratory, Insitute of Cancer Research, London, UK
| | | | - Susana Banerjee
- Royal Marsden Hospital NHS Trust, London, UK
- Division of Clinical Studies, Institute of Cancer Research, London, UK
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Loe AKH, Zhu L, Kim TH. Chromatin and noncoding RNA-mediated mechanisms of gastric tumorigenesis. Exp Mol Med 2023; 55:22-31. [PMID: 36653445 PMCID: PMC9898530 DOI: 10.1038/s12276-023-00926-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 11/08/2022] [Accepted: 11/22/2022] [Indexed: 01/20/2023] Open
Abstract
Gastric cancer (GC) is one of the most common and deadly cancers in the world. It is a multifactorial disease highly influenced by environmental factors, which include radiation, smoking, diet, and infectious pathogens. Accumulating evidence suggests that epigenetic regulators are frequently altered in GC, playing critical roles in gastric tumorigenesis. Epigenetic regulation involves DNA methylation, histone modification, and noncoding RNAs. While it is known that environmental factors cause widespread alterations in DNA methylation, promoting carcinogenesis, the chromatin- and noncoding RNA-mediated mechanisms of gastric tumorigenesis are still poorly understood. In this review, we focus on discussing recent discoveries addressing the roles of histone modifiers and noncoding RNAs and the mechanisms of their interactions in gastric tumorigenesis. A better understanding of epigenetic regulation would likely facilitate the development of novel therapeutic approaches targeting specific epigenetic regulators in GC.
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Affiliation(s)
- Adrian Kwan Ho Loe
- grid.42327.300000 0004 0473 9646Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4 Canada ,grid.17063.330000 0001 2157 2938Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 Canada
| | - Lexin Zhu
- grid.42327.300000 0004 0473 9646Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4 Canada ,grid.17063.330000 0001 2157 2938Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 Canada
| | - Tae-Hee Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada. .,Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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Bhattacharya A. Epigenetic modifications and regulations in gastrointestinal diseases. EPIGENETICS IN ORGAN SPECIFIC DISORDERS 2023:497-543. [DOI: 10.1016/b978-0-12-823931-5.00005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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Yakovlev VA, Sullivan SA, Fields EC, Temkin SM. PARP inhibitors in the treatment of ARID1A mutant ovarian clear cell cancer: PI3K/Akt1-dependent mechanism of synthetic lethality. Front Oncol 2023; 13:1124147. [PMID: 36910637 PMCID: PMC9992988 DOI: 10.3389/fonc.2023.1124147] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/13/2023] [Indexed: 02/24/2023] Open
Abstract
Introduction Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme involved in the repair of DNA single-strand breaks (SSB). The recent development of poly(ADP-ribose) polymerase inhibitors (PARPi) results from over 45 years of studies. When the activity of PARP1 or PARP2 is compromised, DNA SSB lesions are unresolved and can be converted to DNA double-strand breaks (DSBs) by the cellular transcription mechanisms. ARID1A (also called BAF250a) is an important component of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex. ARID1A gene demonstrates >50% of mutation rate in ovarian clear-cell carcinomas (OCCC). Mutated or downregulated ARID1A significantly compromises the Homologous Recombination Repair (HRR) of DNA DSB. Results The present study demonstrated that downregulated or mutated ARID1A attenuates DNA HRR through stimulation of the PI3K/Akt1 pathway and makes tumor cells highly sensitive to PARPi and PARPi/ionizing radiation (IR) combination. We showed that PI3K/Akt1 pathway plays an important role in the sensitization of cancer cell lines with compromised function of ARID1A to PARPi treatment. Discussion We believe that using of PARPi monotherapy or in combination with radiation therapy is an appealing strategy for treating ARID1A-mutated cancers, as well as many other types of PI3K/Akt1-driven cancers.
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Affiliation(s)
- Vasily A Yakovlev
- Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Stephanie A Sullivan
- Gynecologic Oncology Division, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Emma C Fields
- Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Sarah M Temkin
- Gynecologic Oncology Division, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
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Lei ZN, Teng QX, Tian Q, Chen W, Xie Y, Wu K, Zeng Q, Zeng L, Pan Y, Chen ZS, He Y. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther 2022; 7:358. [PMID: 36209270 PMCID: PMC9547882 DOI: 10.1038/s41392-022-01190-w] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/14/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.
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Affiliation(s)
- Zi-Ning Lei
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qin Tian
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Wei Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA
| | - Kaiming Wu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Qianlin Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
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14
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Li R, Xiong G, Zhao J, Yang L. Targeting the alterations of ARID1A in pancreatic cancer: tumorigenesis, prediction of treatment, and prognostic value. Am J Transl Res 2022; 14:5952-5964. [PMID: 36247295 PMCID: PMC9556451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/01/2022] [Indexed: 06/16/2023]
Abstract
The chromatin remodeling gene AT-rich interactive domain 1A (ARID1A), encoding a subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, is one of the most frequently mutated chromatin regulators across a broad spectrum of cancers. Most of the ARID1A alterations are inactivating, leading to the loss or reduced expression of the protein. Recently, ARID1A has been demonstrated as a tumor suppressor gene in pancreatic ductal adenocarcinoma (PDAC), as its inactive alterations attribute to carcinogenesis. Importantly, ARID1A alterations are revealed as predictive biomarkers for the selection of targeted therapy and immune checkpoint blockade (ICB) therapy. In PDAC, the application of ARID1A alterations in stratifying patients for precise treatment has also been widely explored in preclinical and early clinic studies with encouraging preliminary results. Furthermore, the prognostic value of ARID1A mutations in PDAC has been suggested by various studies. In this review, we focus on the functions of ARID1A alterations in PDAC, particularly their functions during carcinogenesis and their predictive value in treatment selection and prognosis, to provide a comprehensive overview on our current understanding of ARID1A alterations in PDAC.
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Affiliation(s)
- Ruichao Li
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, China
| | - Guangbing Xiong
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, China
| | - Jun Zhao
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, China
| | - Lin Yang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, China
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15
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Epigenetic gene alterations in metastatic solid tumours: results from the prospective precision medicine MOSCATO and MATCH-R trials. Eur J Cancer 2022; 173:133-145. [PMID: 35872509 DOI: 10.1016/j.ejca.2022.06.014] [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: 04/28/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Although the role of epigenetic alterations in oncogenesis has been well studied, their prevalence in metastatic solid tumours is still poorly described. We therefore aimed at: (i) describing the presence of epigenetic gene alterations (EGA) - defined by an alteration in a gene encoding an epigenetic regulator; and (ii) evaluating their relationship with clinical characteristics and outcome in patients (pts) included in prospective molecular profiling trials. MATERIALS AND METHODS On-purpose tumour biopsies from pts with metastatic solid tumours enrolled in the Gustave Roussy-sponsored MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials were molecularly profiled using whole exome sequencing (WES). Alterations in 176 epigenetic genes were assessed and classified as pathogenic variants (PV) or non-pathogenic variants by a molecular tumour board. Clinical characteristics and outcome were collected. RESULTS Between Dec 2011 and Oct 2016, WES was successfully performed in 292 pts presenting various solid tumours. We found 496 epigenetic gene alterations in 134 patients (49%), including 237 pathogenic variants in 86 patients; 63 tumour samples (47%) presented ≥3 EGAs. The median number of previous treatment lines was 3 (1-10). The most frequently altered genes were KMT2D and KMT2C (16% each), ARID1A and SETD2 (10% each) and KMT2A (8%).; 31% of EGA co-occurred with a driver gene alteration (p < 0.001). Outcome was not correlated with the presence of EGA. CONCLUSIONS Epigenetic alterations occur frequently in metastatic solid tumours. With the current development of epigenetic modifiers, they increasingly represent actionable targets. Such genes should now be systematically analysed in molecular profiling studies.
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16
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Nekkanti A, Chakraborty P, Ghosh A, Iquebal MA, Jaiswal S, Baranwal VK. Transcriptomic Changes of Bemisia tabaci Asia II 1 Induced by Chilli Leaf Curl Virus Trigger Infection and Circulation in Its Vector. Front Microbiol 2022; 13:890807. [PMID: 35572639 PMCID: PMC9096263 DOI: 10.3389/fmicb.2022.890807] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 03/25/2022] [Indexed: 11/24/2022] Open
Abstract
Bemisia tabaci (Hemiptera: Aleyrodidae) is a highly efficient vector in the spread of chilli leaf curl virus (ChiLCV, Begomovirus) which is a major constraint in the production of chilli in South Asia. Transcriptome analysis of B. tabaci post-6 h acquisition of ChiLCV showed differential expression of 80 (29 upregulated and 51 downregulated) genes. The maximum number of DEGs are categorized under the biological processes category followed by cellular components and molecular functions. KEGG analysis of DEGs showed that the genes are involved in the functions like metabolism, signaling pathways, cellular processes, and organismal systems. The expression of highly expressed 20 genes post-ChiLCV acquisition was validated in RT-qPCR. DEGs such as cytosolic carboxypeptidase 3, dual-specificity protein phosphatase 10, 15, dynein axonemal heavy chain 17, fasciclin 2, inhibin beta chain, replication factor A protein 1, and Tob1 were found enriched and favored the virus infection and circulation in B. tabaci. The present study provides an improved understanding of the networks of molecular interactions between B. tabaci and ChiLCV. The candidate genes of B. tabaci involved in ChiLCV transmission would be novel targets for the management of the B. tabaci-begomovirus complex.
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Affiliation(s)
- Aarthi Nekkanti
- Advanced Centre for Plant Virology, Indian Agricultural Research Institute, New Delhi, India.,Division of Entomology, Indian Agricultural Research Institute, New Delhi, India
| | - Prosenjit Chakraborty
- Advanced Centre for Plant Virology, Indian Agricultural Research Institute, New Delhi, India
| | - Amalendu Ghosh
- Advanced Centre for Plant Virology, Indian Agricultural Research Institute, New Delhi, India
| | - Mir Asif Iquebal
- Centre for Agricultural Bioinformatics, Indian Agricultural Statistics Research Institute, New Delhi, India
| | - Sarika Jaiswal
- Centre for Agricultural Bioinformatics, Indian Agricultural Statistics Research Institute, New Delhi, India
| | - Virendra Kumar Baranwal
- Advanced Centre for Plant Virology, Indian Agricultural Research Institute, New Delhi, India
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17
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Dong X, Song S, Li Y, Fan Y, Wang L, Wang R, Huo L, Scott A, Xu Y, Pizzi MP, Ma L, Wang Y, Jin J, Zhao W, Yao X, Johnson R, Wang L, Wang Z, Peng G, Ajani JA. Loss of ARID1A activates mTOR signaling and SOX9 in gastric adenocarcinoma-rationale for targeting ARID1A deficiency. Gut 2022; 71:467-478. [PMID: 33785559 PMCID: PMC9724309 DOI: 10.1136/gutjnl-2020-322660] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 02/20/2021] [Accepted: 03/02/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Gastric adenocarcinoma (GAC) is a lethal disease with limited therapeutic options. Genetic alterations in chromatin remodelling gene AT-rich interactive domain 1A (ARID1A) and mTOR pathway activation occur frequently in GAC. Targeting the mechanistic target of rapamycin (mTOR) pathway in unselected patients has failed to show survival benefit. A deeper understanding of GAC might identify a subset that can benefit from mTOR inhibition. METHODS Genomic alterations in ARID1A were analysed in GAC. Mouse gastric epithelial cells from CK19-Cre-Arid1Afl/fl and wild-type mice were used to determine the activation of oncogenic genes due to loss of Arid1A. Functional studies were performed to determine the significance of loss of ARID1A and the sensitivity of ARID1A-deficient cancer cells to mTOR inhibition in GAC. RESULTS More than 30% of GAC cases had alterations (mutations or deletions) of ARID1A and ARID1A expression was negatively associated with phosphorylation of S6 and SOX9 in GAC tissues and patient-derived xenografts (PDXs). Activation of mTOR signalling (increased pS6) and SOX9 nuclear expression were strongly increased in Arid1A-/- mouse gastric tissues which could be curtailed by RAD001, an mTOR inhibitor. Knockdown of ARID1A in GAC cell lines increased pS6 and nuclear SOX9 and increased sensitivity to an mTOR inhibitor which was further amplified by its combination with fluorouracil both in vitro and in vivo in PDXs. CONCLUSIONS The loss of ARID1A activates pS6 and SOX9 in GAC, which can be effectively targeted by an mTOR inhibitor. Therefore, our studies suggest a new therapeutic strategy of clinically targeting the mTOR pathway in patients with GAC with ARID1A deficiency.
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Affiliation(s)
- Xiaochuan Dong
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030;,Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yuan Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030;,Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, 110001, P.R. China
| | - Yibo Fan
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Lulu Wang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Ruiping Wang
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Longfei Huo
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Ailing Scott
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Yan Xu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030;,Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, 110001, P.R. China
| | - Melissa Pool Pizzi
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Lang Ma
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Ying Wang
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Jiankang Jin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Wei Zhao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Xiaodan Yao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Randy Johnson
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Linghua Wang
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, 110001, P.R. China
| | - Guang Peng
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Jaffer A. Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030;,Corresponding authors: Shumei Song, MD, Ph.D, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009; phone: 713-834-6144; fax: 713-745-1163; . Jaffer A. Ajani, MD, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009; phone: 713-792-3685; fax: 713-792-8864;
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18
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Tessiri S, Techasen A, Kongpetch S, Namjan A, Loilome W, Chan-on W, Thanan R, Jusakul A. Therapeutic targeting of ARID1A and PI3K/AKT pathway alterations in cholangiocarcinoma. PeerJ 2022; 10:e12750. [PMID: 35070505 PMCID: PMC8761367 DOI: 10.7717/peerj.12750] [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: 08/23/2021] [Accepted: 12/15/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Genetic alterations in ARID1A were detected at a high frequency in cholangiocarcinoma (CCA). Growing evidence indicates that the loss of ARID1A expression leads to activation of the PI3K/AKT pathway and increasing sensitivity of ARID1A-deficient cells for treatment with the PI3K/AKT inhibitor. Therefore, we investigated the association between genetic alterations of ARID1A and the PI3K/AKT pathway and evaluated the effect of AKT inhibition on ARID1A-deficient CCA cells. METHODS Alterations of ARID1A, PI3K/AKT pathway-related genes, clinicopathological data and overall survival of 795 CCA patients were retrieved from cBio Cancer Genomics Portal (cBioPortal) databases. The association between genetic alterations and clinical data were analyzed. The effect of the AKT inhibitor (MK-2206) on ARID1A-deficient CCA cell lines and stable ARID1A-knockdown cell lines was investigated. Cell viability, apoptosis, and expression of AKT signaling were analyzed using an MTT assay, flow cytometry, and Western blots, respectively. RESULTS The analysis of a total of 795 CCA samples revealed that ARID1A alterations significantly co-occurred with mutations of EPHA2 (p < 0.001), PIK3CA (p = 0.047), and LAMA1 (p = 0.024). Among the EPHA2 mutant CCA tumors, 82% of EPHA2 mutant tumors co-occurred with ARID1A truncating mutations. CCA tumors with ARID1A and EPHA2 mutations correlated with better survival compared to tumors with ARID1A mutations alone. We detected that 30% of patients with PIK3CA driver missense mutations harbored ARID1A-truncated mutations and 60% of LAMA1-mutated CCA co-occurred with truncating mutations of ARID1A. Interestingly, ARID1A-deficient CCA cell lines and ARID1A-knockdown CCA cells led to increased sensitivity to treatment with MK-2206 compared to the control. Treatment with MK-2206 induced apoptosis in ARID1A-knockdown KKU-213A and HUCCT1 cell lines and decreased the expression of pAKTS473 and mTOR. CONCLUSION These findings suggest a dependency of ARID1A-deficient CCA tumors with the activation of the PI3K/AKT-pathway, and that they may be more vulnerable to selective AKT pathway inhibitors which can be used therapeutically.
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Affiliation(s)
- Supharada Tessiri
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand,Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand
| | - Anchalee Techasen
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sarinya Kongpetch
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand,Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Achira Namjan
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand,Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand
| | - Watcharin Loilome
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand,Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Waraporn Chan-on
- Center for Research and Innovation, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand
| | - Raynoo Thanan
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Apinya Jusakul
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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19
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Alemi F, Raei Sadigh A, Malakoti F, Elhaei Y, Ghaffari SH, Maleki M, Asemi Z, Yousefi B, Targhazeh N, Majidinia M. Molecular mechanisms involved in DNA repair in human cancers: An overview of PI3k/Akt signaling and PIKKs crosstalk. J Cell Physiol 2021; 237:313-328. [PMID: 34515349 DOI: 10.1002/jcp.30573] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/17/2021] [Accepted: 08/20/2021] [Indexed: 12/14/2022]
Abstract
The cellular genome is frequently subjected to abundant endogenous and exogenous factors that induce DNA damage. Most of the Phosphatidylinositol 3-kinase-related kinases (PIKKs) family members are activated in response to DNA damage and are the most important DNA damage response (DDR) proteins. The DDR system protects the cells against the wrecking effects of these genotoxicants and repairs the DNA damage caused by them. If the DNA damage is severe, such as when DNA is the goal of chemo-radiotherapy, the DDR drives cells toward cell cycle arrest and apoptosis. Some intracellular pathways, such as PI3K/Akt, which is overactivated in most cancers, could stimulate the DDR process and failure of chemo-radiotherapy with the increasing repair of damaged DNA. This signaling pathway induces DNA repair through the regulation of proteins that are involved in DDR like BRCA1, HMGB1, and P53. In this review, we will focus on the crosstalk of the PI3K/Akt and PIKKs involved in DDR and then discuss current achievements in the sensitization of cancer cells to chemo-radiotherapy by PI3K/Akt inhibitors.
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Affiliation(s)
- Forough Alemi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aydin Raei Sadigh
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faezeh Malakoti
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yusuf Elhaei
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Hamed Ghaffari
- Department of Orthopedics, Shohada Medical Research & Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Masomeh Maleki
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Bahman Yousefi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
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20
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Wang J, Yan HB, Zhang Q, Liu WY, Jiang YH, Peng G, Wu FZ, Liu X, Yang PY, Liu F. Enhancement of E-cadherin expression and processing and driving of cancer cell metastasis by ARID1A deficiency. Oncogene 2021; 40:5468-5481. [PMID: 34290402 DOI: 10.1038/s41388-021-01930-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/04/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023]
Abstract
The ARID1A gene, which encodes a subunit of the SWI/SNF chromatin remodeling complex, has been found to be frequently mutated in many human cancer types. However, the function and mechanism of ARID1A in cancer metastasis are still unclear. Here, we show that knockdown of ARID1A increases the ability of breast cancer cells to proliferate, migrate, invade, and metastasize in vivo. The ARID1A-related SWI/SNF complex binds to the second exon of CDH1 and negatively modulates the expression of E-cadherin/CDH1 by recruiting the transcriptional repressor ZEB2 to the CDH1 promoter and excluding the presence of RNA polymerase II. The silencing of CDH1 attenuated the migration, invasion, and metastasis of breast cancer cells in which ARID1A was silenced. ARID1A depletion increased the intracellular enzymatic processing of E-cadherin and the production of C-terminal fragment 2 (CTF2) of E-cadherin, which stabilized β-catenin by competing for binding to the phosphorylation and degradation complex of β-catenin. The matrix metalloproteinase inhibitor GM6001 inhibited the production of CTF2. In zebrafish and nude mice, ARID1A silencing or CTF2 overexpression activated β-catenin signaling and promoted migration/invasion and metastasis of cancer cells in vivo. The inhibitors GM6001, BB94, and ICG-001 suppressed the migration and invasion of cancer cells with ARID1A-deficiency. Our findings provide novel insights into the mechanism of ARID1A metastasis and offer a scientific basis for targeted therapy of ARID1A-deficient cancer cells.
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Affiliation(s)
- Jie Wang
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China
| | - Hai-Bo Yan
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China
| | - Qian Zhang
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China
| | - Wei-Yan Liu
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China
| | - Ying-Hua Jiang
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China
| | - Gang Peng
- Institutes of Brain Science, Fudan University, Shanghai, China
| | - Fei-Zhen Wu
- Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xin Liu
- Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Peng-Yuan Yang
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China.
- Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
- Department of Chemistry, Fudan University, Shanghai, China.
| | - Feng Liu
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China.
- Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
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21
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Kucukhuseyin O, Cakiris A, Hakan MT, Horozoglu C, Tuzun E, Yaylim I. Impact of calcitriol and an AKT inhibitor, AT7867, on survival of rat C6 glioma cells. BIOTECHNOL BIOTEC EQ 2021. [DOI: 10.1080/13102818.2021.1912641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Affiliation(s)
- Ozlem Kucukhuseyin
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Aris Cakiris
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Mehmet Tolgahan Hakan
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Cem Horozoglu
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Erdem Tuzun
- Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Ilhan Yaylim
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
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22
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Xu S, Tang C. The Role of ARID1A in Tumors: Tumor Initiation or Tumor Suppression? Front Oncol 2021; 11:745187. [PMID: 34671561 PMCID: PMC8521028 DOI: 10.3389/fonc.2021.745187] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/08/2021] [Indexed: 01/08/2023] Open
Abstract
Genes encoding subunits of SWItch/Sucrose Non-Fermenting (SWI/SNF) chromatin remodeling complexes are collectively mutated in 20% of all human cancers, among which the AT-rich interacting domain-containing protein 1A (ARID1A, also known as BAF250a, B120, C1orf4, Osa1) that encodes protein ARID1A is the most frequently mutated, and mutations in ARID1A have been found in various types of cancer. ARID1A is thought to play a significant role both in tumor initiation and in tumor suppression, which is highly dependent upon context. Recent molecular mechanistic research has revealed that ARID1A participates in tumor progression through its effects on control of cell cycle, modulation of cellular functions such as EMT, and regulation of various signaling pathways. In this review, we synthesize a mechanistic understanding of the role of ARID1A in human tumor initiation as well as in tumor suppression and further discuss the implications of these new discoveries for potential cancer intervention. We also highlight the mechanisms by which mutations affecting the subunits in SWI/SNF complexes promote cancer.
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23
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Wang R, Chen M, Ye X, Poon K. Role and potential clinical utility of ARID1A in gastrointestinal malignancy. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2020; 787:108360. [PMID: 34083049 DOI: 10.1016/j.mrrev.2020.108360] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 11/26/2020] [Accepted: 11/29/2020] [Indexed: 12/12/2022]
Abstract
ARID1A (AT-rich interactive domain 1A) is a newly discovered tumor suppressor gene, and its encoded product is an important component of the SWI/SNF chromatin remodeling complex. ARID1A plays an important role in cell proliferation, invasion and metastasis, apoptosis, cell cycle regulation, epithelial mesenchymal transition, and the regulation of other of biological behaviors. Recently, ARID1A mutations have been increasingly reported in esophageal adenocarcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, cholangiocarcinoma, pancreatic cancer, and other malignant tumors of the digestive system. This article reviews the relationship between ARID1A mutation and the molecular mechanisms of carcinogenesis, including microsatellite instability and the PI3K/ATK signaling pathway, and relates these mechanisms to the prognostic assessment of digestive malignancy. Further, this review describes the potential for molecular pathologic epidemiology (MPE) to provide new insights into environment-tumor-host interactions.
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Affiliation(s)
- Ruihua Wang
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, 518000, Guangdong Province, China.
| | - Mei Chen
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, 518000, Guangdong Province, China.
| | - Xiaojun Ye
- Program of Food Science and Technology, Division of Science and Technology, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, 519085, Guangdong Province, China.
| | - Karen Poon
- Program of Food Science and Technology, Division of Science and Technology, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, 519085, Guangdong Province, China.
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24
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Vigodner M, Lucas B, Kemeny S, Schwartz T, Levy R. Identification of sumoylated targets in proliferating mouse spermatogonia and human testicular seminomas. Asian J Androl 2020; 22:569-577. [PMID: 32217837 PMCID: PMC7705977 DOI: 10.4103/aja.aja_11_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 01/17/2020] [Indexed: 11/19/2022] Open
Abstract
Spermatogenesis is regulated by a complex network of posttranslation modifications. Sumoylation (a modification by small ubiquitin-like modifiers, or SUMO proteins) was identified as an important cellular event in different cell types. SUMO proteins are highly expressed in the testis, and their role during spermatogenesis has begun to be elucidated. Given the important role of sumoylation in the regulation of mitosis and cancer progression in other tissues, the aim of the current study was to identify the targets of SUMO in proliferating mouse spermatogonia and human seminoma tissues and to initially examine the level of sumoylation in relation to the proliferative activity of the tissues. Using freshly purified spermatogonia and C18-4 spermatogonia cell line, mass spectrometry analysis identified several SUMO targets implicated into the proliferation of spermatogonia (such as heat shock protein 60 [HSP60] and prohibitin). Tissue array and western blot approaches showed that SUMO expression is a prominent feature of human seminomas and that the proliferative activity of the tumor tissues was positively correlated with the level of SUMO expression. Downregulation of sumoylation with si-RNA was not sufficient to significantly affect the proliferation of C18-4 spermatogonia; however, SUMO overexpression increased the proliferation rate of the cells. These data suggest that cells are more sensitive to an elevated level of SUMO, and that this situation may lead to an upregulated cellular proliferation and, possibly, cancer. Mass spectrometry analysis identified around a hundred SUMO targets in seminoma samples. Notably, many of the identified proteins (such as proliferating cell nuclear antigen [PCNA], DNA topoisomerase 2-alpha [Top2A], prohibitin, 14-3-3 protein, and others) were implicated in oncogenic transformation and cancer progression.
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Affiliation(s)
- Margarita Vigodner
- Department of Biology, Stern College, Yeshiva University, New York, NY 10016, USA
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Benjamin Lucas
- Department of Biology, Stern College, Yeshiva University, New York, NY 10016, USA
| | - Stav Kemeny
- Department of Biology, Stern College, Yeshiva University, New York, NY 10016, USA
| | - Tamar Schwartz
- Department of Biology, Stern College, Yeshiva University, New York, NY 10016, USA
| | - Rebecca Levy
- Department of Biology, Stern College, Yeshiva University, New York, NY 10016, USA
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25
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Ebrahimi V, Soleimanian A, Ebrahimi T, Azargun R, Yazdani P, Eyvazi S, Tarhriz V. Epigenetic modifications in gastric cancer: Focus on DNA methylation. Gene 2020; 742:144577. [DOI: 10.1016/j.gene.2020.144577] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 03/10/2020] [Indexed: 12/12/2022]
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26
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The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat Rev Clin Oncol 2020; 17:435-448. [PMID: 32303701 DOI: 10.1038/s41571-020-0357-3] [Citation(s) in RCA: 406] [Impact Index Per Article: 81.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2020] [Indexed: 12/11/2022]
Abstract
Cancer genome-sequencing studies have revealed a remarkably high prevalence of mutations in genes encoding subunits of the SWI/SNF chromatin-remodelling complexes, with nearly 25% of all cancers harbouring aberrations in one or more of these genes. A role for such aberrations in tumorigenesis is evidenced by cancer predisposition in both carriers of germline loss-of-function mutations and genetically engineered mouse models with inactivation of any of several SWI/SNF subunits. Whereas many of the most frequently mutated oncogenes and tumour-suppressor genes have been studied for several decades, the cancer-promoting role of mutations in SWI/SNF genes has been recognized only more recently, and thus comparatively less is known about these alterations. Consequently, increasing research interest is being focused on understanding the prognostic and, in particular, the potential therapeutic implications of mutations in genes encoding SWI/SNF subunits. Herein, we review the burgeoning data on the mechanisms by which mutations affecting SWI/SNF complexes promote cancer and describe promising emerging opportunities for targeted therapy, including immunotherapy with immune-checkpoint inhibitors, presented by these mutations. We also highlight ongoing clinical trials open specifically to patients with cancers harbouring mutations in certain SWI/SNF genes.
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27
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Fang WL, Wu CH, Tseng CH, Huang KH, Chen MH, Li AY, Wu CW. The clinical significance of ARID1A mutations in gastric cancer patients. FORMOSAN JOURNAL OF SURGERY 2020. [DOI: 10.4103/fjs.fjs_66_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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28
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De P, Dey N. Mutation-Driven Signals of ARID1A and PI3K Pathways in Ovarian Carcinomas: Alteration Is An Opportunity. Int J Mol Sci 2019; 20:ijms20225732. [PMID: 31731647 PMCID: PMC6888220 DOI: 10.3390/ijms20225732] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/08/2019] [Accepted: 11/13/2019] [Indexed: 12/24/2022] Open
Abstract
The chromosome is a functionally dynamic structure. The dynamic nature of chromosome functionally connects it to almost every event within a cell, in health and sickness. Chromatin remodeling system acts in unison with the cell survival pathway in mediating a variety of cellular functions, including mitosis, differentiation, DNA damage repair, and apoptosis. In humans, the 16 SWI/SNF complexes are a class of nucleosome remodelers, and ARID1A, an epigenetic tumor suppressor, is a member of mammalian 17 chromatin remodeling complex, SWI/SNF. Alterations of chromatin remodeling system contribute to tumorigenic events in various cancers, including ovarian cancers. Oncogenic changes of genes of the PI3K pathway are one of the potential genetic determinants of ovarian carcinomas. In this review, we present the data demonstrating the co-occurrence of mutations of ARID1A and the PI3K pathway in our cohort of ovarian cancers from the Avera Cancer Institute (SD, USA). Taking into account data from our cohort and the cBioPortal, we interrogate the opportunity provided by this co-occurrence in the context of mutation-driven signals in the life cycle of a tumor cell and its response to the targeted anti-tumor drugs.
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Affiliation(s)
- Pradip De
- Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57105, USA;
- Department of Internal Medicine, SSOM, University of South Dakota, Sioux Falls, SD 57105, USA
- VieCure, Greenwood Village, CO 80112, USA
| | - Nandini Dey
- Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57105, USA;
- Department of Internal Medicine, SSOM, University of South Dakota, Sioux Falls, SD 57105, USA
- Correspondence:
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29
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Chabanon RM, Morel D, Postel-Vinay S. Exploiting epigenetic vulnerabilities in solid tumors: Novel therapeutic opportunities in the treatment of SWI/SNF-defective cancers. Semin Cancer Biol 2019; 61:180-198. [PMID: 31568814 DOI: 10.1016/j.semcancer.2019.09.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 09/23/2019] [Accepted: 09/24/2019] [Indexed: 12/12/2022]
Abstract
Mammalian switch/sucrose non-fermentable (mSWI/SNF) family complexes are pivotal elements of the chromatin remodeling machinery, which contribute to the regulation of several major cellular functions. Large-scale exome-wide sequencing studies have identified mutations in genes encoding mSWI/SNF subunits in 20% of all human cancers, establishing mSWI/SNF deficiency as a recurrent oncogenic alteration. Accumulating evidence now supports that several mSWI/SNF defects represent targetable vulnerabilities in cancer; notably, recent research advances have unveiled unexpected synthetic lethal opportunities that foster the development of novel biomarker-driven and mechanism-based therapeutic approaches for the treatment of mSWI/SNF-deficient tumors. Here, we review the latest breakthroughs and discoveries that inform our understanding of the mSWI/SNF complexes biology in carcinogenesis, and discuss the most promising therapeutic strategies to target mSWI/SNF defects in human solid malignancies.
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Affiliation(s)
- Roman M Chabanon
- Université Paris Saclay, Université Paris-Sud, Faculté de médicine, Le Kremlin Bicêtre, France; ATIP-Avenir Group, Inserm Unit U981, Gustave Roussy, Villejuif, France; The Breast Cancer Now Toby Robins Breast Cancer Research Centre, France; CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Daphné Morel
- Université Paris Saclay, Université Paris-Sud, Faculté de médicine, Le Kremlin Bicêtre, France; ATIP-Avenir Group, Inserm Unit U981, Gustave Roussy, Villejuif, France
| | - Sophie Postel-Vinay
- Université Paris Saclay, Université Paris-Sud, Faculté de médicine, Le Kremlin Bicêtre, France; ATIP-Avenir Group, Inserm Unit U981, Gustave Roussy, Villejuif, France; DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, Villejuif, France.
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30
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Chen J, Liu K, Liu Y, Wang X, Zhang Z. Targeting mTORC1/2 with OSI-027 inhibits proliferation and migration of keloid keratinocytes. Exp Dermatol 2019; 28:270-275. [PMID: 30650200 DOI: 10.1111/exd.13882] [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: 08/18/2018] [Revised: 01/02/2019] [Accepted: 01/11/2019] [Indexed: 12/14/2022]
Abstract
Keloid is a dermal proliferative disorder characterized by the excessive proliferation and migration of keratinocytes and fibroblasts. Over-activation of the serine/threonine protein kinase, mammalian target of rapamycin (mTOR), plays a pivotal role in the process. Here, we show that both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) were hyper-activated in keloid-derived primary keratinocytes. Further, OSI-027, an mTOR kinase inhibitor, potently inhibited proliferation and migration of keloid keratinocytes. At the molecular level, OSI-027 disrupted the assembly of mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-Rictor-mLST8). Further, OSI-027 almost completely blocked the phosphorylation of the mTORC1 substrates, S6K1, S6 and 4EBP1, and the mTORC2 substrate, AKT, at Ser-473. The OSI-027 treatment of keloid keratinocytes showed more effectively inhibited cell proliferation and migration compared to the mTORC1 inhibitor, rapamycin. Moreover, restoring mTORC1 activation by the introduction of the constitutively active S6K1 only partly alleviated OSI-027-induced inhibition of keloid keratinocytes. Notably, mTOR2 inhibition by Rictor siRNAs also inhibited keloid keratinocyte proliferation and migration, but less efficiently than OSI-027. Together, our results imply that concurrent targeting of mTORC1/2 by OSI-027 potently inhibits the proliferation and the migration of keloid keratinocytes. Thus, OSI-027 may have translational value for the treatment of keloid.
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Affiliation(s)
- Jun Chen
- Department of Dermatology and Dermatologic Surgery, Shanghai Ninth People's Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Center for Specialty Strategy Research of Shanghai, JiaoTong University China Hospital Development Institute, Shanghai, China
| | - Ke Liu
- Department of Dermatology and Dermatologic Surgery, Shanghai Ninth People's Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Center for Specialty Strategy Research of Shanghai, JiaoTong University China Hospital Development Institute, Shanghai, China
| | - Yang Liu
- Department of Dermatology and Dermatologic Surgery, Shanghai Ninth People's Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Center for Specialty Strategy Research of Shanghai, JiaoTong University China Hospital Development Institute, Shanghai, China
| | - Xue Wang
- Department of Dermatology and Dermatologic Surgery, Shanghai Ninth People's Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Center for Specialty Strategy Research of Shanghai, JiaoTong University China Hospital Development Institute, Shanghai, China
| | - Zhen Zhang
- Department of Dermatology and Dermatologic Surgery, Shanghai Ninth People's Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Center for Specialty Strategy Research of Shanghai, JiaoTong University China Hospital Development Institute, Shanghai, China
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31
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Bei S, Li F, Li H, Li J, Zhang X, Sun Q, Feng L. Inhibition of gastric cancer cell growth by a PI3K-mTOR dual inhibitor GSK1059615. Biochem Biophys Res Commun 2019; 511:13-20. [PMID: 30765226 DOI: 10.1016/j.bbrc.2019.02.032] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 02/07/2019] [Indexed: 12/29/2022]
Abstract
Gastric cancer (GC) is a common malignancy. Developing novel and efficient anti-GC agents is urgent. GSK1059615 is a PI3K (phosphatidylinositol 3-kinase) and mTOR (mammalian target of rapamycin) dual inhibitor. It activity in human GC cells is tested here. In AGS cells and primary human GC cells, GSK1059615 potently inhibited cell growth, survival, proliferation and cell cycle progression. Further, significant apoptosis activation was detected in GSK1059615-treated GC cells. Contrarily in the primary human gastric epithelial cells, GSK1059615 failed to induce significant cytotoxicity and apoptosis. GSK1059615 blocked PI3K-AKT-mTOR cascade activation, inducing microRNA-9 downregulation but LMX1A (LIM homeobox transcription factor 1α) upregulation in GC cells. Significantly, GSK1059615 administration (i.p., daily, at 10 or 30 mg/kg) in nude mice potently inhibited subcutaneous AGS xenograft growth. AKT-mTOR inhibition and LMX1A upregulation were detected in AGS xenograft tissues with GSK1059615 administration. Together, we conclude that GSK1059615 inhibits GC cell growth in vitro and in vivo.
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Affiliation(s)
- Songhua Bei
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Fan Li
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Huanqin Li
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Jian Li
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Xiaohong Zhang
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Qi Sun
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China.
| | - Li Feng
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China.
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32
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Zhou H, Tan S, Li H, Lin X. Expression and significance of EBV, ARID1A and PIK3CA in gastric carcinoma. Mol Med Rep 2019; 19:2125-2136. [PMID: 30747208 PMCID: PMC6390055 DOI: 10.3892/mmr.2019.9886] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 12/14/2018] [Indexed: 12/13/2022] Open
Abstract
AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) serve important roles in the formation and development of numerous malignancies including gastric cancer. Accumulating evidence has demonstrated that Epstein-Barr virus (EBV) is a pathogenic virus associated with gastric cancer. The present study aimed to investigate the association between EBV infection, and the expression levels of ARID1A and PIK3CA in gastric cancer. EBER in situ hybridization was performed to detect EBV infection. Immunohistochemistry was used to assess the expression levels of ARID1A and PIK3CA in gastric cancer and adjacent normal tissues. A total of 58 gastric cancer and 10 adjacent normal tissues were tested for genetic mutations via single nucleotide polymorphism genotyping assays. Fluorescent polymerase chain reaction was used to detect EBV infection; 9.3% (28/300) of gastric cancer samples were positive for EBV, whereas, all adjacent normal tissues were negative. ARID1A and PIK3CA were negatively correlated in gastric cancer (r=−0.167). The expression levels of ARID1A and PIK3CA in gastric cancer were significantly associated with the depth of invasion of gastric cancer. A total of 62.1% (36/58) of tumor samples exhibited mutations in ARID1A, whereas, 13.8% (8/58) presented mutations in PIK3CA. Notably, EBV-associated gastric cancer (EBVaGC) samples with PIK3CA mutations additionally exhibited ARID1A mutations. Although in the present study it was identified that ARID1A and PIK3CA were negatively correlated in EBVaGC, further studies are required to investigate the association among ARID1A, PIK3CA and EBV in gastric cancer.
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Affiliation(s)
- Huan Zhou
- Department of Pathology, Central South University, Xiangya School of Medicine, Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
| | - Shun Tan
- Department of Pathology, Central South University, Xiangya School of Medicine, Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
| | - Hong Li
- Department of Pathology, Central South University, Xiangya School of Medicine, Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
| | - Xiangtao Lin
- Department of Pathology, Central South University, Xiangya School of Medicine, Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
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Fukayama M, Kunita A, Kaneda A. Gastritis-Infection-Cancer Sequence of Epstein-Barr Virus-Associated Gastric Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1045:437-457. [PMID: 29896679 DOI: 10.1007/978-981-10-7230-7_20] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epstein-Barr virus-associated gastric cancer (EBVaGC) is a representative EBV-infected epithelial neoplasm, which is now included as one of the four subtypes of The Cancer Genome Atlas molecular classification of gastric cancer. In this review, we portray a gastritis-infection-cancer sequence of EBVaGC. This virus-associated type of gastric cancer demonstrates clonal growth of EBV-infected epithelial cells within the mucosa of atrophic gastritis. Its core molecular abnormality is the EBV-specific hyper-epigenotype of CpG island promoter methylation, which induces silencing of tumor suppressor genes. This is due to the infection-induced disruption of the balance between DNA methylation and DNA demethylation activities. Abnormalities in the host cell genome, including phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit α (PIK3CA), AT-rich interaction domain 1A (ARID1A), and programmed death-ligand 1 (PD-L1), are associated with the development and progression of EBVaGC. Furthermore, posttranscriptional modulation affects the transformation processes of EBV-infected cells, such as epithelial mesenchymal transition and anti-apoptosis, via cellular and viral microRNAs (miRNAs). Once established, cancer cells of EBVaGC remodel their microenvironment, at least partly, via the delivery of exosomes containing cellular and viral miRNAs. After exosomes are incorporated, these molecules change the functions of stromal cells, tuning the microenvironment for EBVaGC. During this series of events, EBV hijacks and uses cellular machineries, such as DNA methylation and the miRNA delivery system. This portrait of gastritis-infection-cancer sequences highlights the survival strategies of EBV in the stomach epithelial cells and may be useful for the integration of therapeutic modalities against EBV-driven gastric cancer.
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Affiliation(s)
- Masashi Fukayama
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Akiko Kunita
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Atsushi Kaneda
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
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Zhang J, Guo L, Zhang Q, Liu K, Dong Z. Aloe emodin suppresses EGF‑induced neoplastic cell transformation by inhibiting the ERK/MSK1 and AKT/GSK3β signaling pathways. Mol Med Rep 2018; 18:5215-5220. [PMID: 30272294 DOI: 10.3892/mmr.2018.9517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 11/06/2017] [Indexed: 11/06/2022] Open
Abstract
Natural compounds which can block cell transformation due to potential for chemoprevention have received increased attention. The present study aimed to investigate whether aloe emodin, which is present in aloe latex or the roots of the Rheum palmatum L. are able to block epidermal growth factor (EGF)‑ and tissue plasminogen activator‑induced JB6 C141 cell transformation. The aloe emodin treatment was applied to the JB6 C141 cell neoplastic model. The toxicity of aloe emodin was determined. The present study detected the expression level of AKT serine/threonine kinase 1 (AKT), lysine‑tRNA ligase MSK1 (MSK1) and cyclin D1 using western blotting. The cell proliferation and cell cycle distribution were also monitored. And when 95‑maximal effective dose ranged between 1 and 15 µM, the cell death was evident. Aloe emodin‑treated cells had an impaired anchorage‑independent growth capability, leading to a dose‑dependent reduction of colony formation. Western blotting revealed that aloe emodin had a significant effect on phosphorylation of pyruvate dehydrogenase kinase 1 and glycogen synthase kinase 3β (GSK3β) and AKT was inhibited. The present study determined that the proliferation of JB6 C141 cells was reduced in a dose‑dependent manner and the effect may be associated with its inhibition of the G1/S cell cycle transition. Cyclin D1 transcriptional activity was reduced to 25%, 24 h following aloe emodin treatment. The protein expression of cyclin D1 was inhibited. The findings of the present study indicated that aloe emodin may be able to suppress neoplastic cell transformation by inhibiting the extracellular‑signal regulated kinase/MSK1 and AKT/GSK3β signaling pathways. It may be a potential natural compound for chemoprevention.
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Affiliation(s)
- Juan Zhang
- Department of Pathology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Lihua Guo
- Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Quanwu Zhang
- Department of Pathology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Kangdong Liu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Ziming Dong
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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35
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Luo D, Xu X, Li J, Chen C, Chen W, Wang F, Xie Y, Li F. The PDK1/c‑Jun pathway activated by TGF‑β induces EMT and promotes proliferation and invasion in human glioblastoma. Int J Oncol 2018; 53:2067-2080. [PMID: 30106127 DOI: 10.3892/ijo.2018.4525] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 07/23/2018] [Indexed: 11/05/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common primary malignant tumor affecting the human brain. Despite improvements in therapeutic technologies, patients with GBM have a poor clinical result and the molecular mechanisms responsible for the development of GBM have not yet been fully elucidated. 3-phosphoinositide dependent protein kinase 1 (PDK1) is upregulated in various tumors and promotes tumor invasion. In glioma, transforming growth factor-β (TGF‑β) promotes cell invasion; however, whether TGF‑β directly regulates PDK1 protein and promotes proliferation and invasion is not yet clear. In this study, PDK1 levels were measured in glioma tissues using tissue microarray (TMA) by immunohistochemistry (IHC) and RT‑qPCR. Kaplan-Meier analyses were used to calculate the survival rate of patients with glioma. In vitro, U251 and U87 glioma cell lines were used for functional analyses. Cell proliferation and invasion were analyzed using siRNA transfection, MTT assay, RT‑qPCR, western blot analysis, flow cytometry and invasion assay. In vivo, U251 glioma cell xenografts were established. The results revealed that PDK1 protein was significantly upregulated in glioma tissues compared with non-tumorous tissues. Furthermore, the higher PDK1 levels were associated with a large tumor size (>5.0 cm), a higher WHO grade and a shorter survival of patients with GBM. Univariate and multivariate analyses indicated that PDK1 was an independent prognostic factor. In vivo, PDK1 promoted glioma tumor xenograft growth. In vitro, functional analyses confirmed that TGF‑β upregulated PDK1 protein expression and PDK1 promoted cell migration and invasion, and functioned as an oncogene in GBM, by upregulating c‑Jun protein and inducing epithelial-mesenchymal transition (EMT). c‑Jun protein were overexpressed in glioma tissues and positively correlated with PDK1 levels. Moreover, our findings were further validated by the online Oncomine database. On the whole, the findings of this study indicate that in GBM, PDK1 functions as an oncogene, promoting proliferation and invasion.
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Affiliation(s)
- Dingyuan Luo
- Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Xinke Xu
- Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510120, P.R. China
| | - Junliang Li
- Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510120, P.R. China
| | - Cheng Chen
- Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510120, P.R. China
| | - Wei Chen
- Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510120, P.R. China
| | - Fangyu Wang
- Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510120, P.R. China
| | - Yanping Xie
- Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510120, P.R. China
| | - Fangcheng Li
- Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510120, P.R. China
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Luo Q, Wu X, Zhang Y, Shu T, Ding F, Chen H, Zhao P, Chang W, Zhu X, Liu Z. ARID1A ablation leads to multiple drug resistance in ovarian cancer via transcriptional activation of MRP2. Cancer Lett 2018; 427:9-17. [PMID: 29660381 DOI: 10.1016/j.canlet.2018.04.013] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 04/10/2018] [Accepted: 04/11/2018] [Indexed: 01/01/2023]
Abstract
Multiple Drug Resistance (MDR) of ovarian cancer is a severe trouble for clinical treatment and always contributes to a bad prognosis. AT-rich interaction domain 1 A (ARID1A) has been recognized as a bona fide tumor suppressor gene in recent years, with the highest mutation rate in ovarian cancer. Previous study illustrated that ARID1A expression is negatively correlated with chemoresistance of ovarian cancer cases. However, the specific role of ARID1A in chemoresistance of ovarian cancer remains elusive. In this study, we showed that ARID1A knockdown in ovarian cancer cells significantly reduced their apoptosis rate and led to MDR, while ectopic expression of ARID1A showed opposite effects. ARID1A depletion transcriptionally activates the expression of multidrug resistance-associated protein 2 (MRP2) following chromatin remodeling. Furthermore, IHC analysis of ovarian cancer samples confirmed that ARID1A expression was strong negatively correlated with MRP2 expression. Both ARID1A and MRP2 expression levels are correlated with sensitivity to platinum. Collectively, our results illustrated that ARID1A loss in ovarian cancer leads to MDR through upregulation of MRP2, providing an opportunity to overcome the ARID1A loss induced chemoresistance of ovarian cancer by targeting MRP2.
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Affiliation(s)
- Qingyu Luo
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiaowei Wu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yiping Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tong Shu
- Department of Gynecological Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fang Ding
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hongyan Chen
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Pengfei Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Wan Chang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiaolin Zhu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Zhu M, Zhang Q, Wang X, Kang L, Yang Y, Liu Y, Yang L, Li J, Yang L, Liu J, Li Y, Zu L, Shen Y, Qi Z. Metformin potentiates anti-tumor effect of resveratrol on pancreatic cancer by down-regulation of VEGF-B signaling pathway. Oncotarget 2018; 7:84190-84200. [PMID: 27705937 PMCID: PMC5356654 DOI: 10.18632/oncotarget.12391] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Accepted: 09/25/2016] [Indexed: 12/12/2022] Open
Abstract
Our previous study showed that resveratrol (RSV) exhibited not only anti-tumor effect, but also had potential tumor promotion effect on pancreatic cancer (Paca) cells through up-regulation of VEGF-B. We determined whether metformin (MET) could potentiate the anti-tumor effect of RSV on PaCa in this study. Combination of RSV (100 μmol/l) and MET (20 mmol/l) significantly inhibited tumor growth and increased apoptosis of human PaCa in comparison with RSV or MET alone treatment in PaCa cell lines (Miapaca-2, Panc-1 and Capan-2). Combination of RSV (60 mg/kg, gavage) and MET (250 mg/kg, i.p.) significantly inhibited tumor growth in PaCa bearing nude mice (subcutaneous injection of 5 × 106 Miapaca-2 cells) in comparison with RSV or MET alone treatment on day 40. Combination treatment significantly decreased VEGF-B expression and inhibited activity of GSK-3β when compared to the RSV alone treatment. Up-regulated expressions of Bax, cleaved caspase-3 and down-regulated expression of Bcl-2 were observed in RSV+ MET group in comparison with RSV group either in vitro or in vivo. Inhibition of VEGF-B by VEGF-B small interfering RNA (siRNA) mimicked the effects of MET on PaCa cells. These results suggested that MET, a potential pharmacological inhibitor of VEGF-B signaling pathway, potentiated the anti-tumor effect of RSV on PaCa, and combination of MET and RSV would be a promising modality for clinical PaCa therapy.
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Affiliation(s)
- Mengmeng Zhu
- Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China
| | - Qiong Zhang
- Department of Microbiology, School of Laboratory Medicine, Tianjin Medical University, Tianjin, China
| | - Xiaoling Wang
- Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China
| | - Licheng Kang
- Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China
| | - Yinan Yang
- Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China
| | - Yuansheng Liu
- Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China
| | - Lei Yang
- Tianjin Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Tianjin, China
| | - Jing Li
- Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China
| | - Liang Yang
- Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China
| | - Jie Liu
- Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China
| | - Yin Li
- Department of Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, China
| | - Lingling Zu
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenviroment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yanna Shen
- Department of Microbiology, School of Laboratory Medicine, Tianjin Medical University, Tianjin, China
| | - Zhi Qi
- Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China
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Yang L, Yang G, Ding Y, Dai Y, Xu S, Guo Q, Xie A, Hu G. Inhibition of PI3K/AKT Signaling Pathway Radiosensitizes Pancreatic Cancer Cells with ARID1A Deficiency in Vitro. J Cancer 2018; 9:890-900. [PMID: 29581767 PMCID: PMC5868153 DOI: 10.7150/jca.21306] [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: 06/03/2017] [Accepted: 01/29/2018] [Indexed: 01/05/2023] Open
Abstract
Pancreatic cancer is among the most aggressive human cancers, and is resistant to regular chemotherapy and radiotherapy. The AT-rich interactive domain containing protein 1A (ARID1A) gene, a crucial chromatin remodeling gene, mutates frequently in a broad spectrum of cancers, including pancreatic cancer. Recent evidence suggests that ARID1A acts as tumor suppressor and plays an important role in DNA damage repair (DDR). However, the effect of ARID1A on the radiosensitivity of pancreatic cancer remains unclear. Herein, we investigated the involvement of ARID1A depletion in the radioresistance of pancreatic cancer cells, and explored the underlying mechanisms. The results reveal that knockdown of ARID1A enhances the radioresistance of pancreatic cancer cells through suppressing apoptosis, impairing G2-M checkpoint arrest, strengthening DDR, and accompanying activation of PI3K/AKT signaling pathway. Moreover, upon inhibition of PI3K/AKT pathway by PI3K-inhibitor LY294002 or AKT-inhibitor mk2206, the radiosensitivity of ARID1A-deficient pancreatic cancer cells is improved in vitro via increased apoptosis and weakened DDR. Taken together, these data suggest that loss of ARID1A expression enhances radioresistance of pancreatic cancer through activation of PI3K/AKT pathway, which maybe a promising target for radiosensitization of ARID1A-deficient pancreatic cancer.
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Affiliation(s)
- Lin Yang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Guanghai Yang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yingjun Ding
- Department of Physiology, University of Oklahoma Health Sciences Center, 975 N 10 th St, Oklahoma City, OK, US, 73104
| | - Yuhong Dai
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Sanpeng Xu
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Qiuyun Guo
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Aini Xie
- Department of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Guangyuan Hu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Lee D, Yu EJ, Ham IH, Hur H, Kim YS. AKT inhibition is an effective treatment strategy in ARID1A-deficient gastric cancer cells. Onco Targets Ther 2017; 10:4153-4159. [PMID: 28860825 PMCID: PMC5574587 DOI: 10.2147/ott.s139664] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND The At-rich interactive domain 1A (ARID1A) is frequently mutated in gastric cancers (GCs) with a poor prognosis. Growing evidence indicates that loss of ARID1A expression leads to activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway by AKT phosphorylation. We aim to investigate the different sensitivity for the AKT inhibitor in ARID1A-deficient GC cells. METHODS After transfection using siRNA or shRNA, the effect of ARID1A knockdown on the PI3K/AKT signaling pathway was evaluated by Western blot analysis. ARID1A-knockdown cells were treated with AKT inhibitor (GSK690693), 5-fluorouracil, or cisplatin, alone or in combination. Viability and apoptosis were analyzed using EZ-CYTOX cell viability assay and flow cytometry, respectively. RESULTS ARID1A depletion accelerated the phosphorylation of AKT and S6 in a dose-dependent manner and led to an increased proliferation of MKN-1, MKN-28, and KATO-III GC cells (P<0.001). ARID1A-deficient cells were more vulnerable to GSK690693 in comparison to the controls (P<0.001), even at very low doses. Flow cytometry confirmed the increased apoptosis in ARID1A-deficient cells treated with GSK690693 (0.01 μmol/L; P<0.001). In contrast to our expectations, ARID1A depletion did not cause resistance to 5-fluorouracil or cisplatin. Addition of GSK690693 to the conventional chemotherapy induced more decreased cell viability in ARID1A-knockdown cells (P<0.01). CONCLUSION Loss of ARID1A expression is a surrogate marker for the activation of the AKT signaling pathway and is also a reliable biomarker to predict the response for the AKT inhibitor. We anticipate that appropriate patient selection based on ARID1A expression in the tumor tissue will increase the drug sensitivity for the AKT inhibition and improve the clinical outcome.
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Affiliation(s)
- Dakeun Lee
- Department of Pathology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Eun Ji Yu
- Department of Pathology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - In-Hye Ham
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
- Brain Korea 21 Plus Research Center for Biomedical Sciences, Ajou University, Suwon, Republic of Korea
| | - Hoon Hur
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
- Brain Korea 21 Plus Research Center for Biomedical Sciences, Ajou University, Suwon, Republic of Korea
| | - You-Sun Kim
- Department of Biochemistry, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, Republic of Korea
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Kimura A, Toyoda T, Nishi Y, Nasu M, Ohta A, Osafune K. Small molecule AT7867 proliferates PDX1-expressing pancreatic progenitor cells derived from human pluripotent stem cells. Stem Cell Res 2017; 24:61-68. [PMID: 28843156 DOI: 10.1016/j.scr.2017.08.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 07/28/2017] [Accepted: 08/11/2017] [Indexed: 10/19/2022] Open
Abstract
While pancreatic islet transplantation achieves insulin independence in type 1 diabetes (T1D) patients, its widespread application is limited by donor tissue scarcity. Pancreatic progenitor cells (PPCs) give rise to all cell types in the pancreas during development. PPCs derived from human pluripotent stem cells have been shown to differentiate into functional β cells both in vitro and in vivo, and to reverse hyperglycemia, at least in mice. Therefore, PPCs have great potential to serve as an alternative cell source for cell therapy, and the identification of compounds that facilitate PPC proliferation could provide stable and large-scale pancreatic cell preparation systems in clinical settings. Here, we developed and performed cell-based screens to identify small molecules that induce the proliferation of hiPSC-derived PDX1-expressing PPCs. The screening identified AT7867, which promoted PPC proliferation approximately five-fold within six days through the maintenance of a high Ki67+ cell ratio. The induced proliferation by AT7867 does not result in DNA damage, as revealed by pHH2AX staining, and is observed specifically in PPCs but not other cell types. The established platform utilizing small molecules for PPC proliferation may contribute to the development of cell therapy for T1D using a regenerative medicine approach.
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Affiliation(s)
- Azuma Kimura
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Taro Toyoda
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
| | - Yohei Nishi
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Makoto Nasu
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Akira Ohta
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Kenji Osafune
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
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Zheng Y, Jiang L, Hu Y, Xiao C, Xu N, Zhou J, Zhou X. Metallothionein 1H (MT1H) functions as a tumor suppressor in hepatocellular carcinoma through regulating Wnt/β-catenin signaling pathway. BMC Cancer 2017; 17:161. [PMID: 28241806 PMCID: PMC5330125 DOI: 10.1186/s12885-017-3139-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 02/15/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Metallothionein 1H (MT1H) expression level is downregulated in several kinds of tumors, including hepatocellular cancer (HCC). However, its biological functions and underlying mechanisms in HCC is largely unknown. The current study aimed to demonstrate the expression status, biological roles and potential mechanisms of MT1H in HCC. METHODS We investigated the expression level of MT1H in the Cancer Genome Atlas (TCGA) dataset and a panel of 12 paired tumor/non-tumor tissues. In vitro, gain-of-function experiments were performed to examine the role of MT1H on HCC cell proliferation, invasion, and migration. Using bioinformatics assay, reporter assays, quantitative real-time PCR, and western blotting, we explored the possible mechanisms underlying the role of MT1H in HCC cells. In vivo nude mice experiments were performed to assess the anti-proliferative role of MT1H in HCC. RESULTS Downregulation of MT1H was observed in TCGA dataset and a panel of 12 paired tumor/non-tumor tissues. Ectopic overexpression of MT1H in HepG2 and Hep3B cells inhibited cell proliferation, invasion, and migration. Gene Set Enrichment Analysis (GSEA) showed that MT1H might involve in regulation of Wnt/β-catenin pathway. Top/Fop reporter assay confirmed that MT1H had an effect on Wnt/β-catenin signaling. Real-time PCR showed MT1H expression decreased the expression of Wnt/β-catenin target genes. Western blotting assay showed that overexpression of MT1H inhibited the nuclear translocation of β-catenin and that the Akt/GSK-3β axis mediated the modulatory role of MT1H on Wnt/β-catenin signaling in HCC. In vivo nude mice experiments demonstrated that MT1H suppressed the proliferation of HCC cells. Taken together, MT1H suppressed the proliferation, invasion and migration of HCC cells via regulating Wnt/β-catenin signaling pathway. CONCLUSIONS This study demonstrated that through inhibiting Wnt/β-catenin pathway, MT1H suppresses the proliferation and invasion of HCC cells. MT1H may be a potential target for HCC therapy.
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Affiliation(s)
- Yulong Zheng
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Lihua Jiang
- Department of Neurology, The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, 31006, China
| | - Yongxian Hu
- Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Cheng Xiao
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Nong Xu
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Jianying Zhou
- Department of Respiratory Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang, 310003, China.
| | - Xinhui Zhou
- Department of Gynecology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang, 310003, China.
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Zhang S, Deng Z, Yao C, Huang P, Zhang Y, Cao S, Li X. AT7867 Inhibits Human Colorectal Cancer Cells via AKT-Dependent and AKT-Independent Mechanisms. PLoS One 2017; 12:e0169585. [PMID: 28081222 PMCID: PMC5231330 DOI: 10.1371/journal.pone.0169585] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 12/19/2016] [Indexed: 11/18/2022] Open
Abstract
AKT is often hyper-activated in human colorectal cancers (CRC). This current study evaluated the potential anti-CRC activity by AT7867, a novel AKT and p70S6K1 (S6K1) dual inhibitor. We showed that AT7867 inhibited survival and proliferation of established (HT-29, HCT116 and DLD-1 lines) and primary human CRC cells. Meanwhile, it provoked caspase-dependent apoptosis in the CRC cells. Molecularly, AT7867 blocked AKT-S6K1 activation in CRC cells. Restoring AKT-S6K1 activation, via expression of a constitutively-active AKT1 ("ca-AKT1"), only partially attenuated AT7867-induced HT-29 cell death. Further studies demonstrated that AT7867 inhibited sphingosine kinase 1 (SphK1) activity to promote pro-apoptotic ceramide production in HT-29 cells. Such effects by AT7867 were independent of AKT inhibition. AT7867-indued ceramide production and subsequent HT-29 cell apoptosis were attenuated by co-treatment of sphingosine-1-phosphate (S1P), but were potentiated with the glucosylceramide synthase (GCS) inhibitor PDMP. In vivo, intraperitoneal injection of AT7867 inhibited HT-29 xenograft tumor growth in nude mice. AKT activation was also inhibited in AT7867-treated HT-29 tumors. Together, the preclinical results suggest that AT7867 inhibits CRC cells via AKT-dependent and -independent mechanisms.
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Affiliation(s)
- Shihu Zhang
- Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhengming Deng
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Chen Yao
- Orthopedic Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Ping Huang
- Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yi Zhang
- Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shibing Cao
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiangcheng Li
- Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Niu ZS, Niu XJ, Wang WH. Genetic alterations in hepatocellular carcinoma: An update. World J Gastroenterol 2016; 22:9069-9095. [PMID: 27895396 PMCID: PMC5107590 DOI: 10.3748/wjg.v22.i41.9069] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 09/20/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.
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MESH Headings
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Genomic Instability
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Molecular Diagnostic Techniques
- Molecular Targeted Therapy
- Mutation
- Patient Selection
- Phenotype
- Polymorphism, Single Nucleotide
- Precision Medicine
- Predictive Value of Tests
- Signal Transduction
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