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Yao QX, Li ZY, Kang HL, He X, Kang M. Effect of acacetin on inhibition of apoptosis in Helicobacter pylori-infected gastric epithelial cell line. World J Gastrointest Oncol 2024; 16:3624-3634. [PMID: 39171164 PMCID: PMC11334024 DOI: 10.4251/wjgo.v16.i8.3624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/15/2024] [Accepted: 05/31/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) infection can cause extensive apoptosis of gastric epithelial cells, serving as a critical catalyst in the progression from chronic gastritis, gastrointestinal metaplasia, and atypical gastric hyperplasia to gastric carcinoma. Prompt eradication of H. pylori is paramount for ameliorating the pathophysiological conditions associated with chronic inflammation of the gastric mucosa and the primary prevention of gastric cancer. Acacetin, which has multifaceted pharmacological activities such as anti-cancer, anti-inflammatory, and antioxidative properties, has been extensively investigated across various domains. Nevertheless, the impact and underlying mechanisms of action of acacetin on H. pylori-infected gastric mucosal epithelial cells remain unclear. AIM To explore the defensive effects of acacetin on apoptosis in H. pylori-infected GES-1 cells and to investigate the underlying mechanisms. METHODS GES-1 cells were treated with H. pylori and acacetin in vitro. Cell viability was assessed using the CCK-8 assay, cell mortality rate via lactate dehydrogenase assay, alterations in cell migration and healing capacities through the wound healing assay, rates of apoptosis via flow cytometry and TUNEL staining, and expression levels of apoptosis-associated proteins through western blot analysis. RESULTS H. pylori infection led to decreased GES-1 cell viability, increased cell mortality, suppressed cell migration, increased rate of apoptosis, increased expressions of Bax and cle-caspase3, and decreased Bcl-2 expression. Conversely, acacetin treatment enhanced cell viability, mitigated apoptosis induced by H. pylori infection, and modulated the expression of apoptosis-regulatory proteins by upregulating Bcl-2 and downregulating Bax and cleaved caspase-3. CONCLUSION Acacetin significantly improved GES-1 cell viability and inhibited apoptosis in H. pylori-infected GES-1 cells, thereby exerting a protective effect on gastric mucosal epithelial cells.
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Affiliation(s)
- Qi-Xi Yao
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Zi-Yu Li
- Department of Orthopaedics, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Hou-Le Kang
- Department of Emergency, Luzhou People’s Hospital, Luzhou 646000, Sichuan Province, China
| | - Xin He
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Min Kang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
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Zhang X, Zhao L, Zhang H, Zhang Y, Ju H, Wang X, Ren H, Zhu X, Dong Y. The immunosuppressive microenvironment and immunotherapy in human glioblastoma. Front Immunol 2022; 13:1003651. [PMID: 36466873 PMCID: PMC9712217 DOI: 10.3389/fimmu.2022.1003651] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/01/2022] [Indexed: 08/09/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most malignant intracranial tumor in adults, characterized by extensive infiltrative growth, high vascularization, and resistance to multiple therapeutic approaches. Among the many factors affecting the therapeutic effect, the immunosuppressive GBM microenvironment that is created by cells and associated molecules via complex mechanisms plays a particularly important role in facilitating evasion of the tumor from the immune response. Accumulating evidence is also revealing a close association of the gut microbiota with the challenges in the treatment of GBM. The gut microbiota establishes a connection with the central nervous system through bidirectional signals of the gut-brain axis, thus affecting the occurrence and development of GBM. In this review, we discuss the key immunosuppressive components in the tumor microenvironment, along with the regulatory mechanism of the gut microbiota involved in immunity and metabolism in the GBM microenvironment. Lastly, we concentrate on the immunotherapeutic strategies currently under investigation, which hold promise to overcome the hurdles of the immunosuppressive tumor microenvironment and improve the therapeutic outcome for patients with GBM.
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Affiliation(s)
- Xuehua Zhang
- Department of Immunology, Binzhou Medical University, Yantai, China
| | - Leilei Zhao
- Department of Immunology, Binzhou Medical University, Yantai, China
| | - He Zhang
- Department of Immunology, Qiqihar Medical University, Qiqihar, China
| | - Yurui Zhang
- Department of Immunology, Binzhou Medical University, Yantai, China
| | - Huanyu Ju
- Department of Immunology, Harbin Medical University, Harbin, China
| | - Xiaoyu Wang
- Department of Neurology, Hongda Hospital, Jinxiang, China
| | - Huan Ren
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Xiao Zhu
- School of Computer and Control Engineering, Yantai University, Yantai, China
| | - Yucui Dong
- Department of Immunology, Binzhou Medical University, Yantai, China
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Zhou B, Lu Y, Zhao Z, Shi T, Wu H, Chen W, Zhang L, Zhang X. B7-H4 expression is upregulated by PKCδ activation and contributes to PKCδ-induced cell motility in colorectal cancer. Cancer Cell Int 2022; 22:147. [PMID: 35410218 PMCID: PMC8996430 DOI: 10.1186/s12935-022-02567-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 03/31/2022] [Indexed: 12/24/2022] Open
Abstract
Introduction B7-H4 is overexpressed in colorectal cancer (CRC) and plays an important role in tumor growth and immunosuppression. However, the exact mechanism that regulates B7-H4 expression remains largely unknown. Here, we investigated whether protein kinase C δ (PKCδ) regulates the expression of B7-H4 in CRC. Methods By using immunohistochemical (IHC) and immunofluorescence (IF) staining, we analyzed the expression of B7-H4 and phospho-PKCδ (p-PKCδ) in 225 colorectal tumor samples and determined the clinical significance of the expression patterns. In vitro experiments were performed with the CRC cell lines HCT116 and SW620 to detect the effect of PKCδ activation on B7-H4 expression, and xenograft-bearing mice were treated with rottlerin to monitor the expression of B7-H4 and tumor metastasis. Results The B7-H4 expression level was significantly correlated with the p-PKCδ level (r = 0.378, P < 0.001) in tumor tissues. Coexpression of p-PKCδ and B7-H4 was significantly associated with moderate/poor differentiation (P = 0.024), lymph node metastasis (P = 0.001) and advanced Dukes’ stage (P = 0.002). Western blot analysis showed that Phorbol-12-Myristate-13-Acetate (TPA) increased B7-H4 expression in a concentration-dependent manner and that rottlerin abrogated the TPA-induced increase in B7-H4 expression. The protein levels of B7-H4 and p-STAT3 were significantly reduced by a PKCδ-specific siRNA. Moreover, the STAT3 inhibitor cryptotanshinone significantly decreased the B7-H4 protein level in CRC cells. Knockdown of B7-H4 or PKCδ suppressed cell migration and motility. Rottlerin also inhibited B7-H4 expression and tumor metastasis in vivo. Conclusion The B7-H4 expression level is significantly correlated with the p-PKCδ level and tumor metastasis in CRC samples. B7-H4 expression is upregulated by STAT3 activation via PKCδ and plays roles in PKCδ-induced cancer cell motility and metastasis, suggesting that the PKCδ/STAT3/B7-H4 axis may be a potential therapeutic target for CRC. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02567-1.
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Affiliation(s)
- Bin Zhou
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Soochow University, Suzhou, Jiangsu, China
| | - Youwei Lu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Zhiming Zhao
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Tongguo Shi
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Soochow University, Suzhou, Jiangsu, China
| | - Hongya Wu
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Soochow University, Suzhou, Jiangsu, China
| | - Weichang Chen
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Soochow University, Suzhou, Jiangsu, China
| | - Liang Zhang
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China. .,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Soochow University, Suzhou, Jiangsu, China. .,College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. .,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China. .,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Soochow University, Suzhou, Jiangsu, China.
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Bolandi N, Derakhshani A, Hemmat N, Baghbanzadeh A, Asadzadeh Z, Afrashteh Nour M, Brunetti O, Bernardini R, Silvestris N, Baradaran B. The Positive and Negative Immunoregulatory Role of B7 Family: Promising Novel Targets in Gastric Cancer Treatment. Int J Mol Sci 2021; 22:ijms221910719. [PMID: 34639059 PMCID: PMC8509619 DOI: 10.3390/ijms221910719] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/28/2021] [Accepted: 10/01/2021] [Indexed: 12/30/2022] Open
Abstract
Gastric cancer (GC), with a heterogeneous nature, is the third leading cause of death worldwide. Over the past few decades, stable reductions in the incidence of GC have been observed. However, due to the poor response to common treatments and late diagnosis, this cancer is still considered one of the lethal cancers. Emerging methods such as immunotherapy with immune checkpoint inhibitors (ICIs) have transformed the landscape of treatment for GC patients. There are presently eleven known members of the B7 family as immune checkpoint molecules: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Gi24, DD1α, Dies1 SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and Ig-like domain-containing receptor 2 (ILDR2). Interaction of the B7 family of immune-regulatory ligands with the corresponding receptors resulted in the induction and inhibition of T cell responses by sending co-stimulatory and co-inhibitory signals, respectively. Manipulation of the signals provided by the B7 family has significant potential in the management of GC.
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Affiliation(s)
- Nadia Bolandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia 571478334, Iran
| | - Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
| | - Mina Afrashteh Nour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia 571478334, Iran
| | - Oronzo Brunetti
- Medical Oncology Unit—IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
| | - Renato Bernardini
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95100 Catania, Italy;
| | - Nicola Silvestris
- Medical Oncology Unit—IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
- Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari, 70124 Bari, Italy
- Correspondence: (N.S.); (B.B.); Tel.: +98-413-3371440 (B.B.); Fax: +98-413-3371311 (B.B.)
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 516615731, Iran
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran
- Correspondence: (N.S.); (B.B.); Tel.: +98-413-3371440 (B.B.); Fax: +98-413-3371311 (B.B.)
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Li C, Qin Y, Zhong Y, Qin Y, Wei Y, Li L, Xie Y. Fentanyl inhibits the progression of gastric cancer through the suppression of MMP-9 via the PI3K/Akt signaling pathway. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:118. [PMID: 32175411 PMCID: PMC7049026 DOI: 10.21037/atm.2019.12.161] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 12/30/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Fentanyl is a drug commonly used for perioperative and postoperative analgesia. Previous studies have confirmed that fentanyl can affect the progression of gastric cancer; however, this effect has not yet been elucidated. The purpose of our study was thus to investigate the role of fentanyl in gastric cancer and clarify its potential mechanisms. METHODS A CCK-8 assay was used to determine the proliferation of MGC-803 cells, while Transwell assay and wound healing assay were used to determine the invasion and migration abilities, respectively. Apoptosis and the cell cycle were assessed by flow cytometry, and the ultrastructure of the cells was examined with a transmission electron microscope. The mRNA expression levels of serine-threonine protein kinase 1 (Akt-1), matrix metalloproteinase-9 (MMP-9), and death-associated protein kinase 1 (DAPK1) were evaluated by real-time (RT) quantitative PCR. The protein expression of p-Akt, MMP-9, and caspase-9 was detected by western blot analysis. To study the interaction of fentanyl with the phosphatidylinositol-3-kinase (PI3K)/Akt/MMP-9 pathway, PI3K inhibitor (LY294002) and MMP-9 inhibitor (SB-3CT) were used to treat the MGC-803 cells. RESULTS Findings indicated that fentanyl inhibits the proliferation, invasion, and migration of MGC-803 cells. Specifically, fentanyl inhibits the expression of MMP-9 and enhances the expression of apoptosis-promoting factors such as caspase-9 and DAPK1 through the PI3K/Akt signaling pathway. Cell cycle arrest was observed in the G0/G1 phase. Furthermore, the inhibition of PI3K/Akt/MMP-9 by LY294002 and SB-3CT enhanced the anticancer effects of fentanyl. CONCLUSIONS Fentanyl inhibits the proliferation, invasion and migration of gastric cancer cells by inhibiting the PI3K/Akt/MMP-9 pathway, which could be very useful for gastric cancer treatment.
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Affiliation(s)
- Chunlai Li
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Yi Qin
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Yu Zhong
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Yinying Qin
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Yi Wei
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
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Wang JR, Li TZ, Wang C, Li SM, Luo YH, Piao XJ, Feng YC, Zhang Y, Xu WT, Zhang Y, Zhang T, Wang SN, Xue H, Wang HX, Cao LK, Jin CH. Liquiritin inhibits proliferation and induces apoptosis in HepG2 hepatocellular carcinoma cells via the ROS-mediated MAPK/AKT/NF-κB signaling pathway. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:1987-1999. [PMID: 31956937 DOI: 10.1007/s00210-019-01763-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 11/01/2019] [Indexed: 12/11/2022]
Abstract
Liquiritin (LIQ), a major constituent of Glycyrrhiza Radix, exhibits various pharmacological activities. In this study, to explore the potential anti-cancer effects and its underlying molecular mechanisms of LIQ in hepatocellular carcinoma (HCC) cells. LIQ significantly decreased viability and induced apoptosis in HepG2 cells by decreasing mitochondrial membrane potential and regulating Bcl-2 family proteins, cytochrome c, cle-caspase-3, and cle-PARP. The cell cycle analysis and western blot analysis revealed that LIQ induced G2/M phase arrest through increased expression of p21 and decreased levels of p27, cyclin B, and CDK1/2. The flow cytometry and western blot analysis also suggested that LIQ promoted the accumulation of ROS in HepG2 cells and up-regulated the phosphorylation expression levels of p38 kinase, c-Jun N-terminal kinase (JNK), and inhibitor of NF-κB (IκB-α); the phosphorylation levels of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), signal transducer activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) were down-regulated. However, these effects were reversed by N-acetyl-L-cysteine (NAC), MAPK, and AKT inhibitors. The findings demonstrated that LIQ induced cell cycle arrest and apoptosis via the ROS-mediated MAPK/AKT/NF-κB signaling pathway in HepG2 cells, and the LIQ may serve as a potential therapeutic agent for the treatment of human HCC.
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Affiliation(s)
- Jia-Ru Wang
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
| | - Tian-Zhu Li
- Molecular Medicine Research Center, School of Basic Medical Science, Chifeng University, Chifeng, 024000, China
| | - Cheng Wang
- Pharmacy Department, Daqing Oilfield General Hospital, Daqing, 163001, China
| | - Shu-Mei Li
- Hemodialysis Center, Daqing Oilfield General Hospital, Daqing, 163001, China
| | - Ying-Hua Luo
- Department of Grass Science, College of Animal Science & Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
| | - Xian-Ji Piao
- Department of Gynaecology and Obstetrics, the Fifth Affiliated Hospital of Harbin Medical University, Daqing, 163316, China
| | - Yu-Chao Feng
- Department of Food Science and Engineering, College of Food Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
| | - Yi Zhang
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
| | - Wan-Ting Xu
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
| | - Yu Zhang
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
| | - Tong Zhang
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
| | - Shi-Nong Wang
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
| | - Hui Xue
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
| | - Hong-Xing Wang
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
| | - Long-Kui Cao
- Department of Food Science and Engineering, College of Food Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China. .,National Coarse Cereals Engineering Research Center, Daqing, 163319, Heilongjiang, China.
| | - Cheng-Hao Jin
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China. .,Department of Food Science and Engineering, College of Food Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China. .,National Coarse Cereals Engineering Research Center, Daqing, 163319, Heilongjiang, China.
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Jiang Y, Cai G, Lin J, Zhang J, Bo Z, Li Y, Wang C, Tong Y. B7-H4 is highly expressed in aggressive Epstein-Barr virus positive diffuse large B-cell lymphoma and inhibits apoptosis through upregulating Erk1/2 and Akt signalling pathways. Infect Agent Cancer 2019; 14:20. [PMID: 31406503 PMCID: PMC6686556 DOI: 10.1186/s13027-019-0234-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 07/22/2019] [Indexed: 11/22/2022] Open
Abstract
Background B7-H4 is among the B7 family members which may serve as a new targetable immune checkpoint molecule. It was reported that high level of serum B7-H4 level may be correlated with lymphoma. Nevertheless, the role of B7-H4 in Epstein-Barr Virus-Positive diffuse large B cell lymphoma (EBV+DLBCL) has not been addressed although it has been suggested that B7-H4 could promote tumor growth and metastatic progression in certain cancers. Methods Between January 2005 and November 2017 at the department of Hematology, Shanghai Jiao Tong University School of Medicine affiliated Shanghai General Hospital 260 DLBCL samples were analyzed for EBV-encoded small RNA (EBV-EBER) by in situ hybridization. The expression level of B7-H4 in DLBCL tumor tissue was evaluated by immunohistochemistry. Furthermore, the role of B7-H4 in DLBCL was further investigated in DLBCL cell line. Results EBV+DLBCL patients suffered from markedly lower overall survival (OS) and progression-free survival (PFS) rates in our study. We showed that B7-H4 was significantly overexpressed in 16 EBV+-subgroup cases out of 260 DLBCL patients. We further found that EBV infection in lymphoblast cells led to enhanced expression of B7-H4 followed by increased cell viability and reduced apoptosis. In contrast, inhibition of B7-H4 simultaneously impaired cell viability and induced apoptosis. Mechanistically, inhibiting B7-H4 resulted in decreased phosphorylation Erk 1/2 and Akt. Conclusion Our study reveals a critical role of B7-H4 in EBV+DLBCL development by regulating cell survival and apoptosis through the Erk and Akt signalling pathways. Targetting B7-H4 may be promising in the therapy of EBV+DLBCL.
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Affiliation(s)
- Ying Jiang
- 1Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080 People's Republic of China
| | - Gangli Cai
- Department of Hematology, JinHua Hospital of TCM, 439 Shuangxi West Road, Jinhua, 321017 People's Republic of China
| | - Jun Lin
- 3Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080 People's Republic of China
| | - Jing Zhang
- 4Department of Integrated Therapy, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032 People's Republic of China
| | - Zhilei Bo
- 1Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080 People's Republic of China
| | - Ying Li
- 1Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080 People's Republic of China
| | - Chun Wang
- 1Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080 People's Republic of China
| | - Yin Tong
- 1Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080 People's Republic of China
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Genomic Characteristics of Invasive Mucinous Adenocarcinomas of the Lung and Potential Therapeutic Targets of B7-H3. Cancers (Basel) 2018; 10:cancers10120478. [PMID: 30513627 PMCID: PMC6316015 DOI: 10.3390/cancers10120478] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 11/27/2018] [Accepted: 11/28/2018] [Indexed: 12/20/2022] Open
Abstract
Pulmonary invasive mucinous adenocarcinoma (IMA) is considered a variant of lung adenocarcinomas based on the current World Health Organization classification of lung tumors. However, the molecular mechanism driving IMA development and progression is not well understood. Thus, we surveyed the genomic characteristics of IMA in association with immune-checkpoint expression to investigate new potential therapeutic strategies. Tumor cells were collected from surgical specimens of primary IMA, and sequenced to survey 53 genes associated with lung cancer. The mutational profiles thus obtained were compared in silico to conventional adenocarcinomas and other histologic carcinomas, thereby establishing the genomic clustering of lung cancers. Immunostaining was also performed to compare expression of programmed death ligand 1 (PD-L1) and B7-H3 in IMA and conventional adenocarcinomas. Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) were detected in 75% of IMAs, but in only 11.6% of conventional adenocarcinomas. On the other hand, the frequency of mutations in epidermal growth factor receptor (EGFR) and tumor protein p53 (TP53) genes was 5% and 10%, respectively, in the former, but 48.8% and 34.9%, respectively, in the latter. Clustering of all 78 lung cancers indicated that IMA is distinct from conventional adenocarcinoma or squamous cell carcinoma. Strikingly, expression of PD-L1 in ≥1% of cells was observed in only 6.1% of IMAs, but in 59.7% of conventional adenocarcinomas. Finally, 42.4% and 19.4% of IMAs and conventional adenocarcinomas, respectively, tested positive for B7-H3. Although currently classified as a variant of lung adenocarcinoma, it is also reasonable to consider IMA as fundamentally distinct, based on mutation profiles and genetic clustering as well as immune-checkpoint status. The immunohistochemistry data suggest that B7-H3 may be a new and promising therapeutic target for immune checkpoint therapy.
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