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Han S, Tian Z, Tian H, Han H, Zhao J, Jiao Y, Wang C, Hao H, Wang S, Fu J, Xue D, Sun H, Li P. HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer. Cell Death Discov 2023; 9:181. [PMID: 37301856 DOI: 10.1038/s41420-023-01476-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 04/29/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
Hepatoma-derived growth factor (HDGF) expression is associated with poor prognosis in non-small cell lung cancer (NSCLC); however, whether HDGF affects gefitinib resistance in NSCLC remains unknown. This study aimed to explore the role of HDGF in gefitinib resistance in NSCLC and to discover the underlying mechanisms. Stable HDGF knockout or overexpression cell lines were generated to perform experiments in vitro and in vivo. HDGF concentrations were determined using an ELISA kit. HDGF overexpression exacerbated the malignant phenotype of NSCLC cells, while HDGF knockdown exerted the opposite effects. Furthermore, PC-9 cells, which were initially gefitinib-sensitive, became resistant to gefitinib treatment after HDGF overexpression, whereas HDGF knockdown enhanced gefitinib sensitivity in H1975 cells, which were initially gefitinib-resistant. Higher levels of HDGF in plasma or tumor tissue also indicated gefitinib resistance. The effects of HDGF on promoting the gefitinib resistance were largely attenuated by MK2206 (Akt inhibitor) or U0126 (ERK inhibitor). Mechanistically, gefitinib treatment provoked HDGF expression and activated the Akt and ERK pathways, which were independent of EGFR phosphorylation. In summary, HDGF contributes to gefitinib resistance by activating the Akt and ERK signaling pathways. The higher HDGF levels may predict poor efficacy for TKI treatment, thus it has the potential to serve as a new target for overcoming tyrosine kinase inhibitor resistance in combating NSCLC.
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Affiliation(s)
- Shuyan Han
- Department of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Zhihua Tian
- Central Laboratory, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Huifang Tian
- Central Laboratory, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Haibo Han
- The Tissue Bank, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jun Zhao
- Department of Thoracic Medical Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Yanna Jiao
- Department of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Chunli Wang
- Department of Oncology, Infectious Disease Hospital of Heilongjiang Province, Harbin, 150030, China
| | - Huifeng Hao
- Department of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Shan Wang
- Department of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jialei Fu
- Department of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Dong Xue
- Department of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Hong Sun
- Department of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Pingping Li
- Department of Integration of Chinese and Western Medicine, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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Niu Y, She Z, Su C, Zhao Q, Wang S, Xiao B. The effects and the mechanisms of naringenin from Artemisia ordosica Krasch on allergic rhinitis based on mast cell degranulation model and network pharmacology. J Pharm Pharmacol 2021; 74:397-408. [PMID: 34969089 DOI: 10.1093/jpp/rgab166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 11/05/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVES The ethyl acetate extraction of Artemisia ordosica Krasch (AOK) root showed anti-allergic rhinitis (AR) effect, while the active compounds and pharmacological targets were unknown. METHODS The P815 degranulation was established by cell counting kit 8 assay, β-hexosaminidase releasing assay and toluidine blue staining. The flavonoids were screened in vitro. Then toluidine blue staining and ELISA were carried out to investigate the anti-inflammatory effects of the active compound. Network pharmacology was implemented to explain the mechanisms of the active compound. iGEMDOCK was used to investigate the binding between active compound and hub targets. KEY FINDINGS C48/80 was the optimum reagent in triggering P815 degranulation. Naringenin could significantly decrease P815 degranulation. Meanwhile, naringenin could remarkably increase the IL-4 and decrease the tumour necrosis factor-α. The effect of naringenin on AR was achieved by regulating multiple targets (e.g. AKT1, MAPK3, VEGFA) and pathways (e.g. pathways in cancer, VEGF signalling pathway). Nine hub proteins were obtained by topological analysis. Multiple hydrogen bonds and van der Waals forces were formed between the naringenin and the residues of hub proteins. CONCLUSIONS Naringenin might be one of the effective ingredients of AOK against AR. And its effects could achieve through regulating multiple targets and pathways.
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Affiliation(s)
- Yixuan Niu
- Department of pharmacy, Ordos Central Hospital, Ordos, China
| | - Zhanfei She
- Department of pharmacy, Ordos Central Hospital, Ordos, China
| | - Changhai Su
- Department of pharmacy, Ordos Central Hospital, Ordos, China
| | - Qingchun Zhao
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Shumin Wang
- Department of pharmacy, Ordos Central Hospital, Ordos, China
| | - Bin Xiao
- Department of pharmacy, Ordos Central Hospital, Ordos, China
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Qiu L, Ma Y, Chen X, Zhou L, Zhang H, Zhong G, Zhang L, Tang J. Heparin-binding growth factor (HDGF) drives radioresistance in breast cancer by activating the STAT3 signaling pathway. J Transl Med 2021; 19:344. [PMID: 34376200 PMCID: PMC8353798 DOI: 10.1186/s12967-021-03021-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 08/03/2021] [Indexed: 12/12/2022] Open
Abstract
Although reports implicate radioresistance as an important obstacle for the management of breast cancer, its molecular mechanism is elusive. Herein, we found that high HDGF levels are expressed significantly in breast cancer and exhibit a positive association with poor survival prognosis. Heparin-binding growth factor (HDGF) was upregulated in radioresistant breast cancer cells, however, its knockdown could reduce breast cancer radioresistant both in vitro and in vivo. Additionally, the binding of RXRα to HDGF promoter blocked HDGF transcriptional activity, consequently inhibiting breast cancer radioresistance. The enhanced radioresistant activity of HDGF is induced by TKT and STAT3, impacting the STAT3-Tyr705 and STAT3-Ser727 phosphorylation and STAT3 transcriptional activity. Notably, HDGF depletion renders radioresistant hypersensitive to the drug that targets STAT3 phosphorylation. This article demonstrates the novel function of HDGF as a promising molecular target for predicting radioresistance in breast cancer.
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Affiliation(s)
- Lingyun Qiu
- Oncology Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Yan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Xiaohua Chen
- Department of Radiation Oncology, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China
| | - Liheng Zhou
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Haibo Zhang
- Oncology Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Guansheng Zhong
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China
| | - Lei Zhang
- Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.
| | - Jianming Tang
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China.
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Ma Y, Xu XL, Huang HG, Li YF, Li ZG. LncRNA TDRG1 promotes the aggressiveness of gastric carcinoma through regulating miR-873-5p/HDGF axis. Biomed Pharmacother 2019; 121:109425. [PMID: 31726370 DOI: 10.1016/j.biopha.2019.109425] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 08/31/2019] [Accepted: 08/31/2019] [Indexed: 02/07/2023] Open
Abstract
Gastric carcinoma (GC) is still one of the most common digestive system neoplasms and the primary reason for malignant cancer-associated death. Long non-coding RNAs (lncRNAs) have been reported to play critical roles in GC progression. In this study, we demonstrated that lncRNA testis development-related gene 1 (TDRG1) is markedly upregulated in clinical GC tissues and GC cells. High level of lncRNA TDRG1 correlates with the metastasis and prognosis of patients with GC. Overexpression of lncRNA TDRG1 promotes GC growth and metastatic-related traits in vitro and in vivo, and silencing TDRG1 causes opposite results. We future find that TDRG1 is inversely associated with miR-873-5p and positively modulates the expression of hepatoma-derived growth factor (HDGF), a functional target gene of miR-873-5p. Finally, lncRNA TDRG1 regulates the progression of GC through regulating miR-873-5p/HDGF pathway. Taken together, our data uncover the crucial function of TDRG1-miR-873-5p-HDGF axis in human gastric cancer.
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Affiliation(s)
- Yan Ma
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Xiu Lian Xu
- The First Department of General Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Hai Ge Huang
- Department of Gastroenterological Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi Zhuang Autonomous Region, China
| | - Yan Feng Li
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
| | - Zhi Guo Li
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
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Yang Y, Liang S, Li Y, Gao F, Zheng L, Tian S, Yang P, Li L. Hepatoma-derived growth factor functions as an unfavorable prognostic marker of human gliomas. Oncol Lett 2018; 14:7179-7184. [PMID: 29344149 PMCID: PMC5754909 DOI: 10.3892/ol.2017.7180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 09/05/2017] [Indexed: 01/28/2023] Open
Abstract
Hepatoma-derived growth factor (HDGF) regulates various cellular processes involved in the onset and development of tumors. To evaluate the role of HDGF in human gliomas, western blotting analysis, immunohistochemistry staining and reverse transcription-quantitative polymerase chain reaction were performed to detect HDGF protein and mRNA expression levels in glioma and intractable epileptic brain tissue. Various clinicopathological characteristics, including age, gender, World health Organization grade, HDGF expression level, Karnofsky performance Status (KPS) and Ki-67 index were obtained from medical records. The correlation between HDGF expression and these clinicopathological characteristics was statistically evaluated. Following this, multivariate liner regression was used to evaluate their effect on patient survival time. HDGF expression, at the protein and mRNA levels, was observed to be more upregulated in glioma tissues compared with intractable epileptic brain tissue without tumor. Furthermore, the level of HDGF expression was positively associated with the grade of malignancy [grades II~IV, Ki-67 index ≥20% or KPS <80 (P<0.05)] and poor prognosis in glioma patients. Notably, the univariate survival analysis identified a negative correlation between HDGF-expression and survival time (P<0.01) and multivariate liner regression demonstrated that HDGF expression is an independent prognostic factor for gliomas (P=0.01). Overall, HDGF upregulation may be a crucial step in the development and invasion of glioma. Further survival analysis highlighted its prognostic value for this malignancy, implying its potential as a promising therapeutic target for gliomas.
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Affiliation(s)
- Yang Yang
- Department of Neurosurgery, The 451st Hospital of Chinese People's Liberation Army, Xi'an, Shaanxi 710054, P.R. China
| | - Shengru Liang
- Department of Gynaecology and Obstetrics, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Yuqian Li
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Fei Gao
- Department of Neurosurgery, The 3rd Hospital of Chinese People's Liberation, Army, Baoji, Shaanxi 721000, P.R. China
| | - Longlong Zheng
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Shilai Tian
- Department of Neurosurgery, Donggang Branch of The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Pu Yang
- Department of Neurosurgery, The 451st Hospital of Chinese People's Liberation Army, Xi'an, Shaanxi 710054, P.R. China
| | - Lihong Li
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
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Yang GY, Zhang AQ, Wang J, Li CH, Wang XQ, Pan K, Zhou C, Dong JH. Hepatoma-derived growth factor promotes growth and metastasis of hepatocellular carcinoma cells. Cell Biochem Funct 2017; 34:274-85. [PMID: 27273265 DOI: 10.1002/cbf.3189] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Revised: 03/21/2016] [Accepted: 04/05/2016] [Indexed: 12/19/2022]
Abstract
We aimed to elucidate the effects of hepatoma-derived growth factor (HDGF) on growth and metastasis of hepatocellular carcinoma (HCC) cells. Tissue microarrays with 236 HCC specimens and 18 extrahepatic metastases were utilized to detect the HDGF expression by immunohistochemistry. Meanwhile, HDGF expressions in HCC cell lines with different metastatic potentials were examined using immunofluorescence staining, real-time PCR and western blotting. After HDGF silencing, the growth and metastatic potentials of HCC cells were evaluated by soft agar assay, invasion assay, together with tumorigenicity assay in nude mice. The gelatin zymography was performed by detecting MMP-2 and MMP-9 levels. Additionally, western blotting was conducted to determine the levels of total and phosphorylated ERK1/2, JNK, p38 and Akt. The results showed that HDGF was overexpressed in HCC metastasis tumour, and the expression increased with the differentiation degree of tumours (Grade I 44.0%, Grade II 48.4% and Grade III 65.6%). Consistently, HDGF levels were positively associated with the metastatic capability of HCC cells (MHCC97L < MHCC97H < HCCLM3). The growth and metastasis were suppressed by HDGF-siRNA. Gelatinolytic activities were enhanced in the three metastatic HCC cell lines, but had no significant difference among them. The tumourigenicity and metastatic capability of HCCLM3 cells in nude mice were inhibited after silencing HDGF. Meanwhile, HDGF-siRNA specifically suppressed the total and phosphorylated protein levels of ERK1/2, while not JNK, p38 and Akt. In conclusion, HDGF was overexpressed in HCC patients and cells, and HDGF might be closely correlated with HCC metastasis via regulating ERK signalling pathway. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Guang-Yun Yang
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Ai-Qun Zhang
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Jing Wang
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Chong-Hui Li
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Xian-Qiang Wang
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Ke Pan
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Cheng Zhou
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Jia-Hong Dong
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
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Shetty A, Dasari S, Banerjee S, Gheewala T, Zheng G, Chen A, Kajdacsy-Balla A, Bosland MC, Munirathinam G. Hepatoma-derived growth factor: A survival-related protein in prostate oncogenesis and a potential target for vitamin K2. Urol Oncol 2016; 34:483.e1-483.e8. [PMID: 27692835 DOI: 10.1016/j.urolonc.2016.05.027] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 05/22/2016] [Accepted: 05/24/2016] [Indexed: 12/18/2022]
Abstract
Hepatoma-derived growth factor (HDGF) is a heparin-binding growth factor, which has previously been shown to be expressed in a variety of cancers. HDGF overexpression has also previously been correlated with a poor prognosis in several cancers. The significance of HDGF in prostate cancer, however, has not been investigated. Here, we show that HDGF is overexpressed in both androgen-sensitive LNCaP cells and androgen-insensitive DU145, 22RV1, and PC-3 cells. Forced overexpression enhanced cell viability of RWPE-1 cells, whereas HDGF knockdown reduced cell proliferation in human prostate cancer cells. We also show that HDGF may serve as a survival-related protein as ectopic overexpression of HDGF in RWPE cells up-regulated the expression of antiapoptosis proteins cyclin E and BCL-2, whereas simultaneously down-regulating proapoptotic protein BAX. Western blot analysis also showed that HDGF overexpression modulated the activity of phospho-AKT as well as NF-kB, and these results correlated with in vitro migration and invasion assays. We next assessed the therapeutic potential of HDGF inhibition with a HDGF monoclonal antibody and vitamin k2, showing reduced cell proliferation as well as inhibition of NF-kB expression in HDGF overexpressed RWPE cells treated with a HDGF monoclonal antibody and vitamin K2. Collectively, our results suggest that HDGF is a relevant protein in prostate oncogenesis and may serve as a potential therapeutic target in prostate cancer.
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Affiliation(s)
- Aditya Shetty
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL
| | - Subramanyam Dasari
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL
| | - Souresh Banerjee
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL
| | - Taher Gheewala
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL
| | - Guoxing Zheng
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL
| | - Aoshuang Chen
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL
| | | | - Maarten C Bosland
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Gnanasekar Munirathinam
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL.
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Bao C, Wang J, Ma W, Wang X, Cheng Y. HDGF: a novel jack-of-all-trades in cancer. Future Oncol 2015; 10:2675-85. [PMID: 25236340 DOI: 10.2217/fon.14.194] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
HDGF is an important regulator of a broad range of cancer cell activities and plays important roles in cancer cell transformation, apoptosis, angiogenesis and metastasis. Such a divergent influence of HDGF on cancer cell activities derives from its multiple inter- and sub-cellular localizations where it interacts with a range of different binding partners. Interestingly, high levels of HDGF could be detected in patients' serum of some cancers. This review is focused on the role of HDGF in tumorigenesis and metastasis, and provides insight for application in clinical cancer therapy as well as its clinical implications as a prognostic marker in cancer progression.
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Affiliation(s)
- Cihang Bao
- Department of Radiation Oncology, Qilu Hospital of Shandong University, 107 Wenhua Road West, Jinan 250012, China
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Enomoto H, Nakamura H, Liu W, Nishiguchi S. Hepatoma-Derived Growth Factor: Its Possible Involvement in the Progression of Hepatocellular Carcinoma. Int J Mol Sci 2015; 16:14086-14097. [PMID: 26101867 PMCID: PMC4490540 DOI: 10.3390/ijms160614086] [Citation(s) in RCA: 28] [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: 05/25/2015] [Revised: 06/11/2015] [Accepted: 06/17/2015] [Indexed: 02/05/2023] Open
Abstract
The development of hepatocellular carcinoma (HCC) is an important complication of viral infection induced by hepatitis virus C, and our major research theme is to identify a new growth factor related to the progression of HCC. HDGF (hepatoma-derived growth factor) is a novel growth factor that belongs to a new gene family. HDGF was initially purified from the conditioned medium of a hepatoma cell line. HDGF promotes cellular proliferation as a DNA binding nuclear factor and a secreted protein acting via a receptor-mediated pathway. HDGF is a unique multi-functional protein that can function as a growth factor, angiogenic factor and anti-apoptotic factor and it participates in the development and progression of various malignant diseases. The expression level of HDGF may be an independent prognostic factor for predicting the disease-free and overall survival in patients with various malignancies, including HCC. Furthermore, the overexpression of HDGF promotes the proliferation of HCC cells, while a reduction in the HDGF expression inhibits the proliferation of HCC cells. This article provides an overview of the characteristics of HDGF and describes the potential role of HDGF as a growth-promoting factor for HCC.
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Affiliation(s)
- Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa-cho 1-1, Nishinomiya, Hyogo 663-8501, Japan.
| | - Hideji Nakamura
- Department of Gastroenterology and Hepatology, Nissay Hospital, Itachibori 6-3-8, Nishi-ku, Osaka 550-0012, Japan.
| | - Weidong Liu
- Department of Hepatology and Infectious Diseases, the Second Affiliated Hospital, Shantou University Medical College, No. 69, Dongxiabei, Jinping, Shantou 515041, China.
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa-cho 1-1, Nishinomiya, Hyogo 663-8501, Japan.
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Liu Y, Sun J, Yang G, Liu Z, Guo S, Zhao R, Xu K, Wu X, Zhang Z. Downregulation of the expression of HDGF attenuates malignant biological behaviors of hilar cholangiocarcinoma cells. Mol Med Rep 2015; 12:4713-4719. [PMID: 26081074 DOI: 10.3892/mmr.2015.3922] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Accepted: 05/13/2015] [Indexed: 11/05/2022] Open
Abstract
Hepatoma-derived growth factor (HDGF) has been reported to be a potential predictive and prognostic marker for several types of cancer and important in malignant biological behaviors. However, its role in human hilar cholangiocarcinoma remains to be elucidated. Our previous study demonstrated that high expression levels of HDGF in hilar cholangiocarcinoma tissues correlates with tumor progression and patient outcome. The present study aimed to elucidate the detailed functions of the HDGF protein. This was performed by downregulating the protein expression of HDGF in the FRH0201 hilar cholangiocarcinoma cell line by RNA interference (RNAi) in vitro, and revealed that downregulation of the HDGF protein significantly inhibited the malignant biological behavior of the FRH0201 cells. In addition, further investigation revealed that downregulation of the protein expression of HDGF significantly decreased the secretion of vascular endothelial growth factor, which may be the mechanism partially responsible for the inhibition of malignant biological behaviors. These findings demonstrated that HDGF is important in promoting malignant biological behaviors, including proliferation, migration and invasion of hilar cholangiocarcinoma FRH0201 cells. Inhibition of the expression of HDGF downregulated the malignant biological behaviors, suggesting that downregulation of the protein expression of HDGF by RNAi may be a novel therapeutic approach to inhibit the progression of hilar cholangiocarcinoma.
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Affiliation(s)
- Yanfeng Liu
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jingxian Sun
- Department of Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250011, P.R. China
| | - Guangyun Yang
- Department of Hepatobiliary Surgery, The General Hospital of PLA, Beijing 100853, P.R. China
| | - Zhaojian Liu
- Institute of Cell Biology, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China
| | - Sen Guo
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Rui Zhao
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Kesen Xu
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xiaopeng Wu
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Zhaoyang Zhang
- Department of Emergency Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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Tao F, Ye MF, Sun AJ, Lv JQ, Xu GG, Jing YM, Wang W. Prognostic significance of nuclear hepatoma-derived growth factor expression in gallbladder cancer. World J Gastroenterol 2014; 20:9564-9569. [PMID: 25071353 PMCID: PMC4110590 DOI: 10.3748/wjg.v20.i28.9564] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 03/11/2014] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the expression of nuclear hepatoma-derived growth factor (HDGF) in benign and malignant gallbladder lesions and to determine its clinicopathological significance.
METHODS: We studied 40 patients with gallbladder cancer (GBC) and a control group of 40 patients with cholelithiasis. All diagnoses of GBC and cholelithiasis were confirmed by histopathological examination after surgery. None of the patients received chemotherapy or radiotherapy before surgery. All tissue samples were fixed in 4% formalin immediately after removal and embedded in paraffin for immunohistochemical staining. The HDGF expression in the GBC and cholelithiasis specimens was examined by immunohistochemical staining. The relationship between the HDGF expression and the clinicopathological parameters of GBC was analyzed.
RESULTS: Nuclear HDGF expression was significantly higher (77.5%) in GBC than in chronic cholelithiasis (21.5%, P < 0.001). High nuclear HDGF levels were associated with histopathological subtype (P < 0.05), clinical stage (P < 0.01), and perineural invasion (P < 0.01) but not with sex, age, history of gallstones, or lymph node metastasis. A univariate Kaplan-Meier analysis showed that positive nuclear HDGF expression was associated with decreased overall survival (P < 0.01). Multivariate Cox regression analysis showed that nuclear HDGF expression and lymph node metastasis were independent risk factors for disease-free survival.
CONCLUSION: The expression of nuclear HDGF might be closely related to the carcinogenesis, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma.
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Identification of Hepatoma-Derived Growth Factor as a Potential Prognostic and Diagnostic Marker for Extrahepatic Cholangiocarcinoma. World J Surg 2013; 37:2419-27. [DOI: 10.1007/s00268-013-2132-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Downregulated expression of hepatoma-derived growth factor (HDGF) reduces gallbladder cancer cell proliferation and invasion. Med Oncol 2013; 30:587. [PMID: 23609195 DOI: 10.1007/s12032-013-0587-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 04/13/2013] [Indexed: 01/10/2023]
Abstract
Hepatoma-derived growth factor (HDGF), a heparin-binding growth factor, has a wide range of biological functions, including mitogenic activity and vascular development. Recent studies demonstrated that HDGF also acted as an oncogene with aberrantly increased activity in multiple human cancers; however, little is known about the biological function of HDGF in gallbladder cancer (GBC). In this study, we focused on the clinical significance and biological functions of HDGF in GBC and found that Nuclear HDGF protein overexpression was frequently detected in GBC tissues. Patients with nuclear HDGF-positive tumors had worse overall survival than patients with HDGF-negative tumors. Furthermore, treatment of GBC lines with HDGF-targeting siRNA oligonucleotides (HDGF-siRNA) significantly reduced the proliferation of GBC-SD and SGC-996 cell lines and diminished both anchorage-independent growth on soft agar and cell migration. These data indicate that HDGF acts as a putative oncogene in GBC and could be a novel diagnostic and therapeutic target for GBC.
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Bremer S, Klein K, Sedlmaier A, Abouzied M, Gieselmann V, Franken S. Hepatoma-derived growth factor and nucleolin exist in the same ribonucleoprotein complex. BMC BIOCHEMISTRY 2013; 14:2. [PMID: 23305559 PMCID: PMC3551658 DOI: 10.1186/1471-2091-14-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Accepted: 01/02/2013] [Indexed: 12/26/2022]
Abstract
BACKGROUND Hepatoma-derived growth factor (HDGF) is a protein which is highly expressed in a variety of tumours. HDGF has mitogenic, angiogenic, neurotrophic and antiapoptotic activity but the molecular mechanisms by which it exerts these activities are largely unknown nor has its biological function in tumours been elucidated. Mass spectrometry was performed to analyse the HDGFStrep-tag interactome. By Pull-down-experiments using different protein and nucleic acid constructs the interaction of HDGF and nucleolin was investigated further. RESULTS A number of HDGFStrep-tag copurifying proteins were identified which interact with RNA or are involved in the cellular DNA repair machinery. The most abundant protein, however, copurifying with HDGF in this approach was nucleolin. Therefore we focus on the characterization of the interaction of HDGF and nucleolin in this study. We show that expression of a cytosolic variant of HDGF causes a redistribution of nucleolin into the cytoplasm. Furthermore, formation of HDGF/nucleolin complexes depends on bcl-2 mRNA. Overexpression of full length bcl-2 mRNA increases the number of HDGF/nucleolin complexes whereas expression of only the bcl-2 coding sequence abolishes interaction completely. Further examination reveals that the coding sequence of bcl-2 mRNA together with either the 5' or 3' UTR is sufficient for formation of HDGF/nucleolin complexes. When bcl-2 coding sequence within the full length cDNA is replaced by a sequence coding for secretory alkaline phosphatase complex formation is not enhanced. CONCLUSION The results provide evidence for the existence of HDGF and nucleolin containing nucleoprotein complexes which formation depends on the presence of specific mRNAs. The nature of these RNAs and other components of the complexes should be investigated in future.
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Affiliation(s)
- Stephanie Bremer
- Institute of Biochemistry and Molecular Biology, University of Bonn, Nussallee 11, Bonn, 53115, Germany
| | - Katharina Klein
- Institute of Biochemistry and Molecular Biology, University of Bonn, Nussallee 11, Bonn, 53115, Germany
| | - Angela Sedlmaier
- Institute of Biochemistry and Molecular Biology, University of Bonn, Nussallee 11, Bonn, 53115, Germany
| | - Mekky Abouzied
- Faculty of Pharmacy, University of El-Minia, El-Minia, Egypt
| | - Volkmar Gieselmann
- Institute of Biochemistry and Molecular Biology, University of Bonn, Nussallee 11, Bonn, 53115, Germany
| | - Sebastian Franken
- Institute of Biochemistry and Molecular Biology, University of Bonn, Nussallee 11, Bonn, 53115, Germany
- Present address: Life-Science-Inkubator, Ludwig-Erhard-Allee 2, Bonn, 53175, Germany
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Niu Z, Li X, Hu B, Li R, Wang L, Wu L, Wang X. Small interfering RNA targeted to secretory clusterin blocks tumor growth, motility, and invasion in breast cancer. Acta Biochim Biophys Sin (Shanghai) 2012; 44:991-8. [PMID: 23099883 DOI: 10.1093/abbs/gms091] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Clusterin/apolipoprotein J (Clu) is a ubiquitously expressed secreted heterodimeric glycoprotein that is implicated in several physiological processes. It has been reported that the elevated level of secreted clusterin (sClu) protein is associated with poor survival in breast cancer patients and can induce metastasis in rodent models. In this study, we investigated the effects of sClu inhibition with small interfering RNAs (siRNAs) on cell motility, invasion, and growth in vitro and in vivo. MDA-MB-231 cells were transfected with pSuper-siRNA/sClu. Cell survival and proliferation were examined by 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and clonogenic survival assay. The results showed that sClu silencing significantly inhibited the proliferation of MDA-MB-231 cells. The invasion and migration ability were also dramatically decreased, which was detected by matrigel assays. TUNEL staining and caspase-3 activity assay demonstrated that sClu silencing also could increase the apoptosis rate of cells, resulting in the inhibition of cell growth. We also determined the effects of sClu silencing on tumor growth and metastatic progression in an orthotopic breast cancer model. The results showed that orthotopic primary tumors derived from MDA-MB-231/pSuper sClu siRNA cells grew significantly slower than tumors derived from parental MDA-MB-231 or MDA-MB-231/pSuper scramble siRNA cells, and metastasize less to the lungs. These data suggest that secretory clusterin plays a significant role in tumor growth and metastatic progression. Knocking-down sClu gene expression may provide a valuable method for breast cancer therapy.
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Affiliation(s)
- Zhaohe Niu
- Department of Breast Surgery, Affiliated Hospital of Qingdao Medical College, Qingdao University, Qingdao 266003, China
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Zhang J, Qi J, Guo Y, Guo Y, Fu W, Zhou B, Wu G, Han L, He A. [Aberrant expression of HDGF and its prognostic values in surgically resected non-small cell lung cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2011; 14:211-8. [PMID: 21426662 PMCID: PMC5999669 DOI: 10.3779/j.issn.1009-3419.2011.03.06] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND AND OBJECTIVE Our previous studies revealed that hepatoma-derived growth factor (HDGF) is highly expressed in non-small cell lung cancer (NSCLC) cells, playing important roles in promoting NSCLC cells growth and invasion. The aim of this study is to detect the expression of HDGF in 158 cases of surgically resected NSCLC and evaluate its clinical significance. METHODS Immunohistochemical SP method was used to detect the expression of HDGF in 158 NSCLC tissues and 12 normal control lung tissues. Survival analysis was further conducted. RESULTS HDGF was found significantly highly expressed in 158 NSCLC tissues compared with normal control lung tissues (P < 0.001). The 5-year survival rate was 38.2% in HDGF high expression cases, compared with 63.1% in HDGF low expression cases, the difference was statistically significant (P=0.009). Linear correlation analysis discovered a significantly negative correlation between HDGF expression and the survival time (r=-0.183, P=0.022). COX proportion hazard model analysis revealed that pathological stages and HDGF expression were independent prognostic factors for this group of 158 resected NSCLC cases. CONCLUSIONS HDGF is highly expressed in human NSCLC tissues, predicting worse prognosis in resected NSCLCs. It might be useful molecular biomarker for predicting the prognosis of resected NSCLCs.
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Affiliation(s)
- Jun Zhang
- China Medical University Lung Cancer Center, the First Hospital of China Medical University, Shenyang, China.
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Liu YF, Zhao R, Guo S, Wang XQ, Lian PL, Chen YG, Xu KS. Expression and Clinical Significance of Hepatoma-Derived Growth Factor as a Prognostic Factor in Human Hilar Cholangiocarcinoma. Ann Surg Oncol 2010; 18:872-9. [DOI: 10.1245/s10434-010-1303-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Indexed: 12/17/2022]
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