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Joshi P, Waghmare S. Molecular signaling in cancer stem cells of tongue squamous cell carcinoma: Therapeutic implications and challenges. World J Stem Cells 2023; 15:438-452. [PMID: 37342225 PMCID: PMC10277967 DOI: 10.4252/wjsc.v15.i5.438] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/21/2023] [Accepted: 04/07/2023] [Indexed: 05/26/2023] Open
Abstract
Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with high mortality rates. Amongst oral cavity cancers, tongue carcinoma is a very common and aggressive oral cavity carcinoma. Despite the implementation of a multimodality treatment regime including surgical intervention, chemo-radiation as well as targeted therapy, tongue carcinoma shows a poor overall 5-year survival pattern, which is attributed to therapy resistance and recurrence of the disease. The presence of a rare population, i.e., cancer stem cells (CSCs) within the tumor, are involved in therapy resistance, recurrence, and distant metastasis that results in poor survival patterns. Therapeutic agents targeting CSCs have been in clinical trials, although they are unable to reach into therapy stage which is due to their failure in trials. A more detailed understanding of the CSCs is essential for identifying efficient targets. Molecular signaling pathways, which are differentially regulated in the CSCs, are one of the promising targets to manipulate the CSCs that would provide an improved outcome. In this review, we summarize the current understanding of molecular signaling associated with the maintenance and regulation of CSCs in tongue squamous cell carcinoma in order to emphasize the need of the hour to get a deeper understanding to unravel novel targets.
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Affiliation(s)
- Priyanka Joshi
- Stem Cell Biology Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
| | - Sanjeev Waghmare
- Stem Cell Biology Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
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The Multifaceted Therapeutic Mechanisms of Curcumin in Osteosarcoma: State-of-the-Art. JOURNAL OF ONCOLOGY 2021; 2021:3006853. [PMID: 34671398 PMCID: PMC8523229 DOI: 10.1155/2021/3006853] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/24/2021] [Indexed: 12/16/2022]
Abstract
Osteosarcoma is a major form of malignant bone tumor that typically occurs in young adults and children. The combination of aggressive surgical strategies and chemotherapy has led to improvements in survival time, although individuals with recurrent or metastatic conditions still have an extremely poor prognosis. This disappointing situation strongly indicates that testing novel, targeted therapeutic agents is imperative to prevent the progression of osteosarcoma and enhance patient survival time. Curcumin, a naturally occurring phenolic compound found in Curcuma longa, has been shown to have a wide variety of anti-tumor, anti-oxidant, and anti-inflammatory activities in many types of cancers including osteosarcoma. Curcumin is a highly pleiotropic molecule that can modulate intracellular signaling pathways to regulate cell proliferation, inflammation, and apoptosis. These signaling pathways include RANK/RANKL, Notch, Wnt/β-catenin, apoptosis, autophagy, JAK/STAT, and HIF-1 pathways. Additionally, curcumin can regulate the expression of various types of microRNAs that are involved in osteosarcoma. Therefore, curcumin may be a potential candidate for the prevention and treatment of osteosarcoma. This comprehensive review not only covers the use of curcumin in the treatment of osteosarcoma and its anti-cancer molecular mechanisms but also reveals the novel delivery strategies and combination therapies with the aim to improve the therapeutic effect of curcumin.
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Cutaneous Effects of Notch Inhibitor Therapy: A Report of Two Cases. Case Rep Dermatol Med 2020; 2020:8842242. [PMID: 32695530 PMCID: PMC7352146 DOI: 10.1155/2020/8842242] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/01/2020] [Accepted: 06/08/2020] [Indexed: 12/22/2022] Open
Abstract
As aberrant Notch signaling has been linked to cancerous growth, Notch inhibitors represent a novel category of targeted oncological therapy. Notch pathways in tumor cells may contribute to proliferation or limit apoptosis and differentiation. Healthy skin differentiation and homeostasis are reliant on normal Notch expression, and disruption of this signaling has been implicated in dermatological conditions such as hidradenitis suppurativa, psoriasis, atopic dermatitis, and lichen planus. Here, we describe two cases of patients with cutaneous side effects from Notch inhibitor treatment for adenoid cyst carcinoma (ACC) and review the role of Notch signaling in skin disease. By illuminating connections between medication side effects and disease pathogenesis, our goal is to increase awareness of the cutaneous side effects of Notch inhibitor treatment.
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Li JY, Huang WX, Zhou X, Chen J, Li Z. Numb inhibits epithelial-mesenchymal transition via RBP-Jκ-dependent Notch1/PTEN/FAK signaling pathway in tongue cancer. BMC Cancer 2019; 19:391. [PMID: 31023264 PMCID: PMC6482548 DOI: 10.1186/s12885-019-5605-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 04/12/2019] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Oral cancer has been estimated as the sixth most frequent solid cancer all over the world, in which tongue squamous cell carcinoma (TSCC) is the most common type of oral cancers. However, the mechanism of TSCC metastasizing to lymph node and distant sites has not been completely understood. METHODS In this study, RT-qPCR method was used to detect the mRNA level of Numb, PTEN and Notch1 genes, as well as EMT-associated genes. Western blot assay was utilized to detect protein level of these genes. In addition, we determined cell proliferation by MTT assay and employed transwell invasion assay and wound healing assay to probe the abilities of invasion and migration, respectively. To investigate the role of PTEN, its inhibitor VO-Ohpic trihydrate was used to treat SCC-4 and CAL27 cells. RESULTS We found that Numb expression was downregulated in SCC-9 and CAL-27 cells compared to NHOK cells. Instead, Notch1 level in SCC-9 and CAL-27 cells were higher than that in NHOK cells. Furthermore, the results showed that Numb overexpression significantly suppressed proliferation, migration and invasion of SCC-9 and CAL-27 cells via regulating Notch1 signaling and EMT-related genes expression. By contrast, we observed that RBP-Jκ knockdown had an inhibitory role in proliferation, migration and invasion of SCC-9 and CAL-27 cells. In cells with Numb overexpression or RBP-Jκ knockdown, p-FAK and EMT-related genes were remarkably regulated. CONCLUSIONS Our findings provide new mechanism of understanding the metastasis of TSCC and help develop therapeutic strategies for treating tongue cancer.
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Affiliation(s)
- Jin-Yun Li
- Department of Head and Neck Surgery, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No.283, Tongzipo Road, Yuelu District, Changsha, 410013 Hunan Province People’s Republic of China
| | - Wen-Xiao Huang
- Department of Head and Neck Surgery, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No.283, Tongzipo Road, Yuelu District, Changsha, 410013 Hunan Province People’s Republic of China
| | - Xiao Zhou
- Department of Head and Neck Surgery, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No.283, Tongzipo Road, Yuelu District, Changsha, 410013 Hunan Province People’s Republic of China
| | - Jie Chen
- Department of Head and Neck Surgery, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No.283, Tongzipo Road, Yuelu District, Changsha, 410013 Hunan Province People’s Republic of China
| | - Zan Li
- Department of Head and Neck Surgery, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No.283, Tongzipo Road, Yuelu District, Changsha, 410013 Hunan Province People’s Republic of China
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Jue C, Zhifeng W, Zhisheng Z, Lin C, Yayun Q, Feng J, Hao G, Shintaro I, Hisamitsu T, Shiyu G, Yanqing L. Vasculogenic mimicry in hepatocellular carcinoma contributes to portal vein invasion. Oncotarget 2018; 7:77987-77997. [PMID: 27793002 PMCID: PMC5363638 DOI: 10.18632/oncotarget.12867] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 10/12/2016] [Indexed: 01/10/2023] Open
Abstract
Portal vein invasion (PVI) is common in hepatocellular carcinoma (HCC) and largely contributes to tumor recurrence after radical tumor resection or liver transplantation. Vasculogenic mimicry (VM) was an independent vascular system lined with tumor cells and associated with poor prognosis of HCC. The present study was conducted to evaluate the relationship between VM and portal vein invasion. A total of 44 HCC cases receiving anatomic liver resection were included in the study and were divided into groups with and without PVI. The prevalence of VM in each group was examined by CD34-PAS dual staining. The regulatory molecules of VM formation such as Notch1, Vimentin and matrix metalloproteinases (MMPs) were investigated by immunohistochemical staining. Analysis was performed to explore the association of PVI, VM and the VM regulatory molecules. PVI was found in 40.91% (18/44) cases and VM was found in 38.64% (17/44) cases in total samples. The incidence of VM was 72.22% (13/18) in PVI group while it was 15.38% (4/26) in non-PVI group (P<0.001), VM formation was positively correlated with PVI (r=0.574, P<0.001). The VM forming regulatory molecules such as Notch1, Vimentin, MMP-2 and MMP-9 were found to be correlated with PVI in HCC patients. Taken together, our results suggested that VM formation, alone with its regulatory molecules, is the promoting factor of PVI in hepatocellular carcinoma.
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Affiliation(s)
- Chen Jue
- Institution of Integrated Traditional Chinese and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China.,Department of Oncology, The Second People's Hospital of Taizhou Affiliated to Yangzhou University, Taizhou, Jiangsu, China.,Department of Physiology, School of Medicine, Showa University, Tokyo, Japan
| | - Wu Zhifeng
- Department of Oncology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Zhang Zhisheng
- Department of Oncology, The Second People's Hospital of Taizhou Affiliated to Yangzhou University, Taizhou, Jiangsu, China
| | - Cui Lin
- Department of Oncology, The Second People's Hospital of Taizhou Affiliated to Yangzhou University, Taizhou, Jiangsu, China
| | - Qian Yayun
- Institution of Integrated Traditional Chinese and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Jin Feng
- Institution of Integrated Traditional Chinese and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Gu Hao
- Institution of Integrated Traditional Chinese and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Ishikawa Shintaro
- Department of Physiology, School of Medicine, Showa University, Tokyo, Japan
| | - Tadashi Hisamitsu
- Department of Physiology, School of Medicine, Showa University, Tokyo, Japan
| | - Guo Shiyu
- Department of Physiology, School of Medicine, Showa University, Tokyo, Japan
| | - Liu Yanqing
- Institution of Integrated Traditional Chinese and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China
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Curcumin and Osteosarcoma: Can Invertible Polymeric Micelles Help? MATERIALS 2016; 9:ma9070520. [PMID: 28773642 PMCID: PMC5456898 DOI: 10.3390/ma9070520] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 06/21/2016] [Accepted: 06/23/2016] [Indexed: 12/16/2022]
Abstract
Systematic review of experimental and clinical data on the use of curcumin in the treatment of osteosarcoma is presented. The current status of curcumin's therapeutic potential against bone cancer is analyzed in regard to using polymeric micelles (including recently developed invertible, responsive, micelles) as a platform for curcumin delivery to treat osteosarcoma. The potential of micellar assemblies from responsive macromolecules in a controlled delivery of curcumin to osteosarcoma cells, and the release using a new inversion mechanism is revealed.
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Jin MM, Ye YZ, Qian ZD, Zhang YB. Notch signaling molecules as prognostic biomarkers for non-small cell lung cancer. Oncol Lett 2015; 10:3252-3260. [PMID: 26722321 DOI: 10.3892/ol.2015.3662] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 07/28/2015] [Indexed: 12/19/2022] Open
Abstract
Notch family proteins have been reported to be associated with the initiation and development of various types of tumors. The present study used a prospective design to investigate the role of Notch proteins as novel biomarkers that are capable of predicting the survival outcome for patients with non-small cell lung cancer (NSCLC). The protein expression of Notch 1, Notch 3 and their ligands, Jagged 1 and Delta-like 4, was examined using immunohistochemistry in NSCLC tissues and adjacent non-cancerous lung tissues from 101 patients who underwent surgical treatment. The expression was also correlated with clinicopathological parameters and overall survival (OS). High Notch 1 protein expression was observed in 55.4% (56/101) of NSCLC samples and high Notch 3 expression was observed in 53.5% (54/101). The nuclear expression of Notch 3 was significantly associated with the lymph node status (P=0.0026) and tumor-node-metastasis (TNM) stage (P<0.0001), while the coexpression of Notch 1 plus Notch 3 was associated with lymph node status (P=0.0056), TNM stage (P=0.0001) and the histological grading (P=0.0359). In the survival analyses, the high expression of Notch 1 and Notch 3 exhibited an additive effect toward a poorer OS compared with a subtype with low coexpression for the two proteins (P<0.001), with high nuclear Notch 3 expression in the NSCLC patients maintaining independent prognostic significance for the outcome on multivariate analysis. These data further demonstrate a central role for Notch signaling in NSCLC and the significance of Notch 3 as a prognostic indicator of a poorer survival for patients with resected NSCLC.
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Affiliation(s)
- Meng-Meng Jin
- Department of Respiratory Medicine, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Yuan-Zi Ye
- Department of Respiratory Medicine, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Zhen-Dong Qian
- Department of Respiratory Medicine, Colored Metal General Staff Hospital of Tongling, Tongling, Anhui 244000, P.R. China
| | - Yan-Bei Zhang
- Department of Respiratory Medicine, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
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Jimenez L, Jayakar SK, Ow TJ, Segall JE. Mechanisms of Invasion in Head and Neck Cancer. Arch Pathol Lab Med 2015; 139:1334-48. [PMID: 26046491 DOI: 10.5858/arpa.2014-0498-ra] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
CONTEXT The highly invasive properties demonstrated by head and neck squamous cell carcinoma (HNSCC) are often associated with locoregional recurrence and lymph node metastasis in patients and is a key factor leading to an expected 5-year survival rate of approximately 50% for patients with advanced disease. It is important to understand the features and mediators of HNSCC invasion so that new treatment approaches can be developed. OBJECTIVES To provide an overview of the characteristics, mediators, and mechanisms of HNSCC invasion. DATA SOURCES A literature review of peer-reviewed articles in PubMed on HNSCC invasion. CONCLUSIONS Histologic features of HNSCC tumors can help predict prognosis and influence clinical treatment decisions. Cell surface receptors, signaling pathways, proteases, invadopodia function, epithelial-mesenchymal transition, microRNAs, and tumor microenvironment are all involved in the regulation of the invasive behavior of HNSCC cells. Identifying effective HNSCC invasion inhibitors has the potential to improve outcomes for patients by reducing the rate of spread and increasing responsiveness to chemoradiation.
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Affiliation(s)
| | | | | | - Jeffrey E Segall
- From the Departments of Pathology (Mss Jimenez and Jayakar, and Drs Ow and Segall) and Anatomy and Structural Biology (Mss Jimenez and Jayakar, and Dr Segall), Albert Einstein College of Medicine, Bronx, New York
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Abstract
Notch signaling is an evolutionarily conserved cell signaling pathway involved in cell fate during development, stem cell renewal and differentiation in postnatal tissues. Roles for Notch in carcinogenesis, in the biology of cancer stem cells and tumor angiogenesis have been reported. These features identify Notch as a potential therapeutic target in oncology. Based on the molecular structure of Notch receptor, Notch ligands and Notch activators, a set of Notch pathway inhibitors have been developed. Most of these inhibitors had shown anti-tumor effects in preclinical studies. At the same time, the combinatorial effect of these inhibitors with current chemotherapeutical drugs is still under study in different clinical trials. In this review, we describe the basics of Notch signaling and the role of Notch in normal and cancer stem cells as a logic way to develop different Notch inhibitors and their current stage of progress for cancer patient's treatment.
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Affiliation(s)
- Ingrid Espinoza
- University of Mississippi, Cancer Institute, Jackson, Mississippi
| | - Lucio Miele
- University of Mississippi, Cancer Institute, Jackson, Mississippi
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MicroRNA-125b inhibitor sensitizes human primary glioblastoma cells to chemotherapeutic drug temozolomide on invasion. In Vitro Cell Dev Biol Anim 2013; 49:599-607. [PMID: 23835866 DOI: 10.1007/s11626-013-9644-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Accepted: 05/20/2013] [Indexed: 12/13/2022]
Abstract
Malignant gliomas are treated with a combination of surgery, radiation, and temozolomide (TMZ), but these therapies ultimately fail due to tumor recurrence. In this study, we aimed to identify the combined effects of miR-125b and TMZ involved in the invasive pathogenesis of glioblastoma cells. The effects of miR-125b and TMZ on cell invasion were analyzed by Transwell assays. Unexpectedly, either overexpression or downregulation of miR-125b has no function on glioblastoma cell invasion. However, knockdown of miR-125b could enhance the effects of TMZ on glioblastoma cell invasion. Conversely, overexpression of miR-125b could decrease such effects of TMZ. Further research on the mechanism demonstrated that such function of miR-125b knockdown on enhancing the effects of TMZ was involved in downregulation of Notch1. Notch1 was overexpressed in glioblastoma cells, and found by us that downregulation of Notch1 expression decreased the cell invasion of glioblastoma cells. Knockdown of miR-125b combined with TMZ enhancely downregulated Notch1 and inhibited cell invasion of malignant glioblastoma. These findings indicate that the combination of miR-125b inhibitor and TMZ treatment could effectively inhibit the glioblastoma cell invasion by inhibiting Notch1 expression.
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Zhou L, Zhang N, Song W, You N, Li Q, Sun W, Zhang Y, Wang D, Dou K. The significance of Notch1 compared with Notch3 in high metastasis and poor overall survival in hepatocellular carcinoma. PLoS One 2013; 8:e57382. [PMID: 23468978 PMCID: PMC3585338 DOI: 10.1371/journal.pone.0057382] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Accepted: 01/21/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The prognosis for patients with hepatocellular carcinoma (HCC) is poor, and the mechanisms underlying the development of HCC remain unclear. Notch1 and Notch3 may be involved in malignant transformation, although their roles remain unknown. MATERIALS AND METHODS HCC tissues were stained with anti-Notch1 or -Notch3 antibody. The migration and invasion capacities of the cells were measured with transwell cell culture chambers. RT-PCR was used to measure the expression of Notch1 and Notch3 mRNA. Additionally, western blot analysis was used to assess the protein expression of Notch1, Notch3, CD44v6, E-cadherin, matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator (uPA). RNA interference was used to down-regulate the expression of Notch1 and Notch3. Cell viability was assessed using MTT. RESULTS Based on immunohistochemistry, high Notch1 expression was correlated with tumor size, tumor grade, metastasis, venous invasion and AJCC TNM stage. High Notch3 expression was only strongly correlated with metastasis, venous invasion and satellite lesions. Kaplan-Meier curves demonstrated that patients with high Notch1 or Notch3 expression were at a significantly increased risk for shortened survival time. In vitro, the down-regulation of Notch1 decreased the migration and invasion capacities of HCC cells by regulating CD44v6, E-cadherin, MMP-2, MMP-9, and uPA via the COX-2 and ERK1/2 pathways. Down-regulation of Notch3 only decreased the invasion capacity of HCC cells by regulating MMP-2 and MMP-9 via the ERK1/2 pathway. CONCLUSIONS Based on the migration and invasion of HCC, we hypothesize that targeting Notch1 may be more useful than Notch3 for designing novel preventive and therapeutic strategies for HCC in the near future.
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Affiliation(s)
- Liang Zhou
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shannxi, People’s Republic of China
| | - Ning Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shannxi, People’s Republic of China
| | - Wenjie Song
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shannxi, People’s Republic of China
| | - Nan You
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shannxi, People’s Republic of China
| | - Qingjun Li
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shannxi, People’s Republic of China
| | - Wei Sun
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shannxi, People’s Republic of China
| | - Yong Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shannxi, People’s Republic of China
| | - Desheng Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shannxi, People’s Republic of China
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shannxi, People’s Republic of China
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