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Lu Y, Sun Q, Guan Q, Zhang Z, He Q, He J, Ji Z, Tian W, Xu X, Liu Y, Yin Y, Zheng C, Lian S, Xu B, Wang P, Jiang R, Sun B. The XOR-IDH3α axis controls macrophage polarization in hepatocellular carcinoma. J Hepatol 2023; 79:1172-1184. [PMID: 37473847 DOI: 10.1016/j.jhep.2023.06.022] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 05/30/2023] [Accepted: 06/21/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND & AIMS Tumor-associated macrophages (TAMs) are indispensable in the hepatocellular carcinoma (HCC) tumor microenvironment. Xanthine oxidoreductase (XOR), also known as xanthine dehydrogenase (XDH), participates in purine metabolism, uric acid production, and macrophage polarization to a pro-inflammatory phenotype. However, the role of XOR in HCC-associated TAMs is unclear. METHODS We evaluated the XOR level in macrophages isolated from HCC tissues and paired adjacent tissues. We established diethylnitrosamine/carbon tetrachloride (CCl4)-induced and orthotopically implanted HCC mouse models using mice with Xdh-specific depletion in the myeloid cell lineage (Xdhf/fLyz2cre) or Kupffer cells (Xdhf/fClec4fcre). We determined metabolic differences using specific methodologies, including metabolomics and metabolic flux. RESULTS We found that XOR expression was downregulated in HCC TAMs and positively correlated with patient survival, which was strongly related to the characteristics of the tumor microenvironment, especially hypoxia. Using HCC-inflicted mice (Xdhf/fLyz2cre and Xdhf/fClec4fcre), we revealed that XOR loss in monocyte-derived TAMs rather than Kupffer cells promoted their M2 polarization and CD8+ T-cell exhaustion, which exacerbated HCC progression. In addition, the tricarboxylic acid cycle was disturbed, and the generation of α-ketoglutarate was enhanced within XOR-depleted macrophages. XOR inhibited α-ketoglutarate production by interacting with IDH3α catalytic sites (K142 and Q139). The increased IDH3α activity caused increased adenosine and kynurenic acid production in TAMs, which enhanced the immunosuppressive effects of TAMs and CD8+ T cells. CONCLUSIONS The XOR-IDH3α axis mediates TAM polarization and HCC progression and may be a small-molecule therapeutic or immunotherapeutic target against suppressive HCC TAMs. IMPACT AND IMPLICATIONS Immunotherapies have been widely applied to the treatment of hepatocellular carcinoma (HCC), but to date they have been associated with unsatisfactory efficacy. The tumor microenvironment of HCC is full of different infiltrating immune cells. Tumor-associated macrophages (TAMs) are vital components in the tumor microenvironment and are involved in HCC progression. Herein, we confirm the downregulation of XOR expression in TAMs isolated from human HCC. The loss of XOR in monocyte-derived macrophages increases IDH3 activity and results in an increase in α-ketoglutarate production, which can promote M2-like polarization. Additionally, XOR-null TAMs derived from monocytes promote CD8+ T-cell exhaustion via the upregulation of immunosuppressive metabolites, including adenosine and kynurenic acid. Given the prevalence and high rate of incidence of HCC and the need for improved therapeutic options for patients, our findings identify potential therapeutic targets that may be further studied to develop improved therapies.
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Affiliation(s)
- Yijun Lu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Qikai Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qifei Guan
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Zechuan Zhang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Qifeng He
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jianbo He
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Zetao Ji
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Wenfang Tian
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaoliang Xu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yang Liu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yin Yin
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Chang Zheng
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Senlin Lian
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Bing Xu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Pin Wang
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
| | - Runqiu Jiang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
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You Y, Wen D, Zeng L, Lu J, Xiao X, Chen Y, Song H, Liu Z. ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression. Int J Biol Sci 2022; 18:5001-5018. [PMID: 35982895 PMCID: PMC9379398 DOI: 10.7150/ijbs.70149] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 06/30/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma is one of the most common malignant tumors.M6A is a novel epigenetic modification that have been emerged as vital regulators for the progression of HCC. However, the regulatory role, clinical significance and the details of the modification, such as the impact on the local tumor environment, remain largely unclear. Our study showed that ALKBH5 was highly expressed in HCC and high ALKBH5 expression predicted a worse prognosis of HCC patients. Prediction of ALKBH5 function by tissue samples and single cell sequencing Gene Set Variation Analysis. Primary CD3 + T lymphocytes and bone marrow-derived macrophages were used to evaluate the effect of ALKBH5 on immune microenvironment. The results indicated that ALKBH5 promote HCC cell proliferation, metastasis and PD-L1+macrophage recruitment. Mechanistically the results showed that ALKBH5 regulates MAP3K8 expression in a m6A dependent manner which mediates the proliferation and metastasis of HCC cells. ALKBH5 also promotes the activation of JNK and ERK pathways through upregulating MAP3K8, thus regulating the expression of IL-8 and promoting macrophage recruitment. Taken together, these data show that ALKBH5 promotes HCC growth, metastasis and macrophage recruitment through ALKBH5/MAP3K8 axis and it may serve as a potential diagnostic marker and target for treatment of HCC patients.
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Affiliation(s)
- Yu You
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Diguang Wen
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Lu Zeng
- Department of Gastroenterology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Jiao Lu
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Xiao Xiao
- Department of Gastroenterology, Chongqing University Central Hospital (Chongqing Emergency Medical Center), Chongqing 400010, China
| | - Yucheng Chen
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Hua Song
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Zuojin Liu
- Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
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Sansone V, Le Grazie M, Roselli J, Polvani S, Galli A, Tovoli F, Tarocchi M. Telomerase reactivation is associated with hepatobiliary and pancreatic cancers. Hepatobiliary Pancreat Dis Int 2020; 19:420-428. [PMID: 32386990 DOI: 10.1016/j.hbpd.2020.04.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 04/15/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Human telomerase reverse transcriptase (hTERT) and its components play a significant role in cancer progression, but recent data demonstrated that telomeres and telomerase alterations could be found in other diseases; increasing evidence suggests a key role of this enzyme in the fields of hepatobiliary and pancreatic diseases. DATA SOURCES We performed a PubMed search with the following keywords: telomerase, hepatocellular carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma by December 2019. We reviewed the relevant publications that analyzed the correlation between telomerase activity and hepatobiliary and pancreatic diseases. RESULTS Telomerase reactivation plays a significant role in the development and progression of hepatobiliary and pancreatic tumors and could be used as a diagnostic biomarker for hepatobiliary and pancreatic cancers, as a predictor for prognosis and a promising therapeutic target. CONCLUSIONS Our review summarized the evidence about the critical role of hTERT in cancerous and precancerous lesions of the alteration and its activity in hepatobiliary and pancreatic diseases.
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Affiliation(s)
- Vito Sansone
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
| | - Marco Le Grazie
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50139 Firenze, Italy
| | - Jenny Roselli
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50139 Firenze, Italy
| | - Simone Polvani
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50139 Firenze, Italy
| | - Andrea Galli
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50139 Firenze, Italy
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Mirko Tarocchi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50139 Firenze, Italy
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Lian W, Lian H, Li Q, Hu A, Liu S. The venom of spider Haplopelma hainanum suppresses proliferation and induces apoptosis in hepatic cancer cells by caspase activation in vitro. JOURNAL OF ETHNOPHARMACOLOGY 2018; 225:169-177. [PMID: 29928971 DOI: 10.1016/j.jep.2018.06.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 06/09/2018] [Accepted: 06/15/2018] [Indexed: 06/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Spiders and spider venoms have been used in traditional Chinese medicine to treat various ailments for more than 1000 years. For instance, several large spiders have been utilized by the Li People, who mainly live in Hainan Island of China, in their own unique traditional Chinese medicine therapy. Recent studies have indicated that spider venoms may be an important source of bioactive compounds for anti-tumor treatments. However, the specific mechanisms underlying these activities are not yet completely understood. AIM OF THE STUDY The present study investigated how the venom of the spider Haplopelma hainanum regulate proliferation and apoptosis in HepG2 cells via the underlying molecular mechanisms. MATERIALS AND METHODS We treated HepG2 cells with various concentrations of the spider venom (0, 10, 50, 100 and 200 μg/mL) for 48 h, and then analyzed anti-proliferation activity, apoptosis-inducing effects, mitochondrial membrane potential (Δψm) and changes in the pro-apoptotic pathway. The anti-proliferation activity was detected by the MTT assay and Western blotting. Flow cytometry was used to analyze both apoptosis and mitochondrial membrane potential. The key pro-apoptotic molecules in the caspase-3 and -9 dependent mitochondrial pathway, including Bcl2 family, were assessed through realtime PCR, Western blotting and enzymatic test. RESULTS Obvious morphological changes induced by the spider venom included decreased cell numbers, shorter cell length and reduced cell adhesion. MTT and Western blotting demonstrated that the spider venom potently suppressed cell proliferation in a dose- and time-dependent manner with IC50 of 126.00 μg/mL for 48 h. In addition, the spider venom caused a reduction in the mitochondrial membrane potential and cytochrome c release from mitochondria to cytoplasm under the participation of Bax. Finally, cytochrome c activated caspase-3 and caspase-9, and induced the apoptosis in the HepG2 cells. CONCLUSION The results indicated that the venom of H. hainanum exhibited potent inhibition effects in HepG2 cells through suppressing proliferation, reducing the mitochondrial membrane potential, activating caspase-3 and caspase-9, and inducing the apoptosis through a mitochondrial-dependent pathway.
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Affiliation(s)
- Weiguang Lian
- Department of Laboratory Animal Science, Hebei Medical University, Key Lab of Laboratory Animal Science of Hebei Province, Shijiazhuang 050017, China.
| | - Hongguang Lian
- Department of Dermatology, the Second Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China.
| | - Qian Li
- Department of Dermatology, the Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China.
| | - An Hu
- Department of Laboratory Animal Science, Hebei Medical University, Key Lab of Laboratory Animal Science of Hebei Province, Shijiazhuang 050017, China.
| | - Shufeng Liu
- Department of Laboratory Animal Science, Hebei Medical University, Key Lab of Laboratory Animal Science of Hebei Province, Shijiazhuang 050017, China.
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Hou J, Wang L, Wu D. The root of Actinidia chinensis inhibits hepatocellular carcinomas cells through LAMB3. Cell Biol Toxicol 2018; 34:321-332. [PMID: 29127567 DOI: 10.1007/s10565-017-9416-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 10/05/2017] [Indexed: 12/14/2022]
Abstract
The root of Actinidia chinensis, as traditional Chinese medicine, has been shown to inhibit cell proliferation in numerous cancer cells. However, the mechanisms underlying its inhibitory activity remain unclear. Death rates of hepatocellular carcinoma (HCC) are increasing, but therapies for advanced HCC are not well developed. We choose the extract from root of Actinidia chinensis (ERAC) to treat the HCC cell lines in vitro, displaying distinct effects on cell proliferation, S-phase cell cycle arrest, and apoptosis. LAMB3, the gene encoding laminin subunit beta-3, plays a key role in the proliferation suppression and S-phase cell cycle arrest of HepG2 cells treated with ERAC. The downstream genes ITGA3, CCND2, and TP53 in LAMB3 pathway show the same response to ERAC as LAMB3. Thus, LAMB3 pathways, along with extracellular matrix-receptor interaction, pathways in cancer, and focal adhesion, are involved in the ERAC-induced suppressive response in HepG2.
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Affiliation(s)
- Jiayun Hou
- Zhongshan Hospital Institute of Clinical Science, Shanghai Institute of Clinical Bioinformatics; Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Lingyan Wang
- Zhongshan Hospital Institute of Clinical Science, Shanghai Institute of Clinical Bioinformatics; Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Duojiao Wu
- Zhongshan Hospital Institute of Clinical Science, Shanghai Institute of Clinical Bioinformatics; Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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Le Grazie M, Biagini MR, Tarocchi M, Polvani S, Galli A. Chemotherapy for hepatocellular carcinoma: The present and the future. World J Hepatol 2017; 9:907-920. [PMID: 28824742 PMCID: PMC5545136 DOI: 10.4254/wjh.v9.i21.907] [Citation(s) in RCA: 149] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 06/20/2017] [Accepted: 07/03/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it’s still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatin- and gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.
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Hao J, Li Z, Zhang C, Yu W, Tang Z, Li Y, Feng X, Gao Y, Liu Q, Huang W, Guo W, Deng W. Targeting NF-κB/AP-2β signaling to enhance antitumor activity of cisplatin by melatonin in hepatocellular carcinoma cells. Am J Cancer Res 2017; 7:13-27. [PMID: 28123844 PMCID: PMC5250677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 05/12/2016] [Indexed: 06/06/2023] Open
Abstract
Cisplatin is a common chemotherapeutic drug for cancer treatment, but its effect is limited because of its cytotoxicity and chemoresistance. The combinational use of cisplatin with some natural compounds has provided a potential option to improve its effect and lower its side effects in cancer treatment. Here, we investigated the role of melatonin in the regulation of cisplatin-mediated antitumor activity in hepatocellular carcinoma cells. The combined treatment of cisplatin with melatonin significantly inhibited cell proliferation and resulted in a corresponding decrease of the IC50 values of cisplatin in four hepatocellular carcinoma cell lines. Cotreatment with melatonin also increased the cisplatin-induced apoptosis in hepatocellular carcinoma cells compared with cisplatin treatment alone. Further mechanism studies showed that the combined treatment of melatonin and cisplatin enhanced the cleavage of caspase-3, caspase-9 and poly-(ADP-ribose) polymerase (PARP), decreased the expression of Bcl-2 and p-IKKα/β, suppressed the nuclear translocation of NF-κB p50/p65 proteins, and abrogated the binding of p65 to COX-2 promoter, thereby inhibiting COX-2 expression. Furthermore, melatonin was found to synergistically enhance cisplatin-mediated inhibition of AP-2β and hTERT expression. Overexpression of AP-2β reversely rescued this inhibition mediated by the combined treatment of these two drugs. Collectively, our results demonstrated that melatonin sensitizes the cisplatin-mediated growth suppression of cells via the inactivation of NF-κB/COX-2 and AP-2β/hTERT signaling in hepatocellular carcinoma cells.
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Affiliation(s)
- Jiaojiao Hao
- Institute of Cancer Stem Cell, Dalian Medical UniversityDalian, China
| | - Zhenglin Li
- Institute of Cancer Stem Cell, Dalian Medical UniversityDalian, China
| | - Changlin Zhang
- Sun Yat-sen University Cancer Centre; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer MedicineGuangzhou, China
| | - Wendan Yu
- Institute of Cancer Stem Cell, Dalian Medical UniversityDalian, China
| | - Zhipeng Tang
- Institute of Cancer Stem Cell, Dalian Medical UniversityDalian, China
| | - Yixin Li
- Sun Yat-sen University Cancer Centre; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer MedicineGuangzhou, China
| | - Xu Feng
- Institute of Cancer Stem Cell, Dalian Medical UniversityDalian, China
| | - Yue Gao
- Institute of Cancer Stem Cell, Dalian Medical UniversityDalian, China
| | - Quentin Liu
- Institute of Cancer Stem Cell, Dalian Medical UniversityDalian, China
- Sun Yat-sen University Cancer Centre; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer MedicineGuangzhou, China
| | - Wenlin Huang
- Sun Yat-sen University Cancer Centre; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer MedicineGuangzhou, China
- State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc.Guangzhou, China
| | - Wei Guo
- Institute of Cancer Stem Cell, Dalian Medical UniversityDalian, China
| | - Wuguo Deng
- Sun Yat-sen University Cancer Centre; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer MedicineGuangzhou, China
- State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc.Guangzhou, China
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Activation of TGF-β1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis. Sci Rep 2015; 5:16552. [PMID: 26559755 PMCID: PMC4642271 DOI: 10.1038/srep16552] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 10/15/2015] [Indexed: 02/07/2023] Open
Abstract
Activation of hepatic stellate cells (HSCs) by transforming growth factor-β1 (TGF-β1) initiates HBV-associated fibrogenesis. The mechanism of TGF-β1 modulating HSC activation is not fully uncovered. We hypothesized a positive feedback signaling loop of TGF-β1-CD147 promoting liver fibrogenesis by activation of HSCs. Human HSC cell line LX-2 and spontaneous liver fibrosis model derived from HBV transgenic mice were used to evaluate the activation of molecules in the signaling loop. Wound healing and cell contraction assay were performed to detect the CD147-overexpressed HSC migration and contraction. The transcriptional regulation of CD147 by TGF-β1/Smad4 was determined using dual-luciferase reporter assay and chromatin immunoprecipitation. We found that a positive reciprocal regulation between TGF-β1 and CD147 mediated HSC activation. CD147 over-expression promoted HSC migration and accelerated TGF-β1-induced cell contraction. Phosphorylation of Smad2 and Smad3 in cooperation with Smad4 mediated the TGF-β1-regulated CD147 expression. Smad4 activated the transcription by direct interaction with CD147 promoter. Meanwhile, CD147 modulated the activated phenotype of HSCs through the ERK1/2 and Sp1 which up-regulated α-SMA, collagen I, and TGF-β1 synthesis. These findings indicate that TGF-β1-CD147 loop plays a key role in regulating the HSC activation and combination of TGF-β receptor inhibitor and anti-CD147 antibody might be promised to reverse fibrogenesis.
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Picariello L, Grappone C, Polvani S, Galli A. Telomerase activity: An attractive target for cancer therapeutics. World J Pharmacol 2014; 3:86-96. [DOI: 10.5497/wjp.v3.i4.86] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 10/01/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
Telomeres are non-coding tandem repeats of 1000-2000 TTAGGG nucleotide DNA sequences on the 3’ termini of human chromosomes where they serve as protective “caps” from degradation and loss of genes. The “cap” at the end of chromosome required to protect its integrity is a 150-200 nucleotide-long single stranded G-rich 3’ overhang that forms two higher order structures, a T-loop with Sheltering complex, or a G-quadruplex complex. Telomerase is a human ribonucleoprotein reverse transcriptase that continually added single stranded TTAGGG DNA sequences onto the single strand 3’ of telomere in the 5’ to 3’ direction. Telomerase activity is detected in male germ line cells, proliferative cells of renewal tissues, some adult pluripotent stem cells, embryonic cells, but in most somatic cells is not detected. Re-expression or up-regulation of telomerase in tumours cells is considered as a critical step in cell tumorigenesis and telomerase is widely considered as a tumour marker and a target for anticancer drugs. Different approaches have been used in anticancer therapeutics targeting telomerase. Telomerase inhibitors can block directly Human TElomerase Reverse Transcriptase (hTERT) or Human TElomerase RNA telomerase subunits activity, or G-quadruplex and Sheltering complex components, shortening telomeres and inhibiting cell proliferation. Telomerase can become an immune target and GV1001, Vx-001, I540 are the most widespread vaccines used with encouraging results. Another method is to use hTERT promoter to drive suicide gene expression or to control a lytic virus replication. Recently telomerase activity was used to activate pro-drugs such as Acycloguanosyl 5’-thymidyltriphosphate, a synthetic ACV-derived molecule when it is activated by telomerase it does not require any virus or host active immune response to induce suicide gene therapy. Advantage of all these therapies is that target only neoplastic cells without any effects in normal cells, avoiding toxicity and adverse effects of the current chemotherapy. However, as not all the approaches are equally efficient, further studies will be necessary.
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