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Ding H, Ding ZG, Liu S, Mao XN, Lu XS. Ras-related protein Rab24 plays a predictive role in hepatocellular carcinoma and enhanced tumor proliferation. World J Gastroenterol 2025; 31:101585. [PMID: 40062325 PMCID: PMC11886508 DOI: 10.3748/wjg.v31.i8.101585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 12/04/2024] [Accepted: 01/06/2025] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND Ras-related protein Rab24, which belongs to the small GTPase family, plays a crucial role in regulating intracellular protein trafficking. Dysregulation of Rab24 has been recently identified in hepatocellular carcinoma (HCC). However, its clinical significance and tumor related effects remain to be further clarified. AIM To explore the expression pattern of Rab24 and its role in HCC progression. METHODS The expression profile of Rab24 was tested in HCC tissues together with adjacent tissues from transcriptional, mRNA, and protein levels. The prognostic role of Rab24 in HCC was assessed by univariate and multivariate analyses. Clinical outcomes were evaluated by the Kaplan-Meier analysis and log-rank test. The effect of Rab24 on cell proliferation was tested through cellular experiments and xenograft experiments. RESULTS Rab24 expression was elevated in HCC tissues compared to adjacent liver tissues. High expression of Rab24 was significantly associated with larger tumor size and advanced tumor stage. Moreover, HCC patients with high Rab24 expression showed poorer overall survival, and Rab24 was identified as an independent prognosis factor according to multivariate analysis. By using overexpression and shRNA knockdown strategies in HCC cell lines, we found that Rab24 can promote HCC proliferation. Finally, we validated that silencing Rab24 significantly attenuated xenograft growth in vivo. CONCLUSION Our study demonstrated that high expression of Rab24 was significantly correlated with poorer prognosis of HCC patients, indicating the potential of Rab24 as a novel clinical biomarker and therapeutic target.
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Affiliation(s)
- Han Ding
- Department of Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, The Affiliated to Fudan University, Shanghai 200032, China
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Zhi-Guo Ding
- Department of General Surgery, The Third People’s Hospital of Yangzhou, Yangzhou 225126, Jiangsu Province, China
| | - Song Liu
- Department of General Surgery, The Fourth Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
| | - Xu-Nan Mao
- Medical College, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
| | - Xing-Sheng Lu
- Department of General Surgery, The Fourth Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
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Li S, Feng M, Wang F, Liu D, Li M, Dai J, Yang Y, Chai Y, Chen W. Mycobacterium tuberculosis infection may increase the degrees of malignancy in lung adenocarcinoma. Front Immunol 2025; 16:1537520. [PMID: 40061944 PMCID: PMC11885956 DOI: 10.3389/fimmu.2025.1537520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 02/04/2025] [Indexed: 05/13/2025] Open
Abstract
Background The early diagnosis and management of lung adenocarcinoma co-existing with tuberculosis (LAC-TB) presents significant challenges in clinical settings. This is compounded by a paucity of robust clinical evidence elucidating the interactions between these two conditions. Methods This study included 14 patients diagnosed with LAC-TB, with an equal distribution among those with pulmonary tuberculosis (TB) and those with peripheral lymph node TB. Controls included patients with simple TB and those with lung adenocarcinoma (LAC). Histopathologic examinations confirmed typical changes in each group. Immunohistochemistry analyzed immune markers, focusing on PD-L1, while genomic analysis identified differential mutant genes. Results Pathological evaluations showed that LAC-TB and LAC groups expressed TTF-1 and Napsin A in their adenocarcinoma specimens. Notably, a higher proportion of patients in the LAC-TB group had a Ki-67 proliferation index of ≥10%. Subsequent Molecular analyses revealed significant differences in RALGAPA1 gene expression, with the LAC-TB group also exhibiting a greater median count of missense mutations, single nucleotide polymorphisms, and overall mutations, suggesting a higher malignancy level than the LAC group. Additionally, the LAC-TB group showed an increased tumor mutational burden, indicating a potentially better response to immunotherapy. Immunohistochemical assessments indicated that Mycobacterium tuberculosis (MTB) infection correlated with reduced infiltration of T cells and CD4+ T cells, alongside an upregulation of PD-L1 expression in LAC. Notably, PD-L1 was strongly expressed in the TB granuloma and surrounding areas. Conclusion Our findings suggest that MTB infection may increase the malignancy of LAC, with the pronounced expression of PD-L1 in granuloma regions constituting a pivotal mechanism underlying this relationship.
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Affiliation(s)
- Shanshan Li
- Department of Pathology, The Eighth Medical Center, General Hospital of the Chinese People's Liberation Army (PLA), Beijing, China
| | - Mengru Feng
- Department of Pathology, The Eighth Medical Center, General Hospital of the Chinese People's Liberation Army (PLA), Beijing, China
| | - Fenghua Wang
- Department of Pathology, The Eighth Medical Center, General Hospital of the Chinese People's Liberation Army (PLA), Beijing, China
| | - Dongxu Liu
- Department of Pathology, The Eighth Medical Center, General Hospital of the Chinese People's Liberation Army (PLA), Beijing, China
| | - Mingyan Li
- Department of Pathology, The Eighth Medical Center, General Hospital of the Chinese People's Liberation Army (PLA), Beijing, China
| | - Jinlong Dai
- Department of Pathology, The Eighth Medical Center, General Hospital of the Chinese People's Liberation Army (PLA), Beijing, China
| | - Yan Yang
- Department of Radiology, The Eighth Medical Center, General Hospital of the Chinese People's Liberation Army (PLA), Beijing, China
| | - Yinghui Chai
- Department of Clinical Laboratory, The Eighth Medical Center, General Hospital of the Chinese People's Liberation Army (PLA), Beijing, China
| | - Wen Chen
- Department of Pathology, The Eighth Medical Center, General Hospital of the Chinese People's Liberation Army (PLA), Beijing, China
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Jin H, Qin S, He J, Xiao J, Li Q, Mao Y, Zhao L. Systematic pan-cancer analysis identifies RALA as a tumor targeting immune therapeutic and prognostic marker. Front Immunol 2022; 13:1046044. [PMID: 36466919 PMCID: PMC9713825 DOI: 10.3389/fimmu.2022.1046044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 11/02/2022] [Indexed: 10/07/2023] Open
Abstract
INTRODUCTION RALA is a member of the small GTPase Ras superfamily and has been shown to play a role in promoting cell proliferation and migration in most tumors, and increase the resistance of anticancer drugs such as imatinib and cisplatin. Although many literatures have studied the cancer-promoting mechanism of RALA, there is a lack of relevant pan-cancer analysis. METHODS This study systematically analyzed the differential expression and mutation of RALA in pan-cancer, including different tissues and cancer cell lines, and studied the prognosis and immune infiltration associated with RALA in various cancers. Next, based on the genes co-expressed with RALA in pan-cancer, we selected 241 genes with high correlation for enrichment analysis. In terms of pan-cancer, we also analyzed the protein-protein interaction pathway of RALA and the application of small molecule drug Guanosine-5'-Diphosphate. We screened hepatocellular cancer (HCC) to further study RALA. RESULTS The results indicated that RALA was highly expressed in most cancers. RALA was significantly correlated with the infiltration of B cells and macrophages, as well as the expression of immune checkpoint molecules such as CD274, CTLA4, HAVCR2 and LAG3, suggesting that RALA can be used as a kind of new pan-cancer immune marker. The main functions of 241 genes are mitosis and protein localization to nucleosome, which are related to cell cycle. For HCC, the results displayed that RALA was positively correlated with common intracellular signaling pathways such as angiogenesis and apoptosis. DISCUSSION In summary, RALA was closely related to the clinical prognosis and immune infiltration of various tumors, and RALA was expected to become a broad-spectrum molecular immune therapeutic target and prognostic marker for pan-cancer.
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Affiliation(s)
- Haoer Jin
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Pathology, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Sha Qin
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Pathology, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Jiang He
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Juxiong Xiao
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qingling Li
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Pathology, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yitao Mao
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Luqing Zhao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Pathology, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Van Campenhout R, Leroy K, Cooreman A, Tabernilla A, Cogliati B, Kadam P, Vinken M. Connexin-Based Channels in the Liver. Compr Physiol 2022; 12:4147-4163. [PMID: 35950654 DOI: 10.1002/cphy.c220007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Connexin proteins oligomerize in hexameric structures called connexin hemichannels, which then dock to form gap junctions. Gap junctions direct cell-cell communication by allowing the exchange of small molecules and ions between neighboring cells. In this way, hepatic gap junctions support liver homeostasis. Besides serving as building blocks for gap junctions, connexin hemichannels provide a pathway between the intracellular and the extracellular environment. The activation of connexin hemichannels is associated with acute and chronic liver pathologies. This article discusses the role of gap junctions and connexin hemichannels in the liver. © 2022 American Physiological Society. Compr Physiol 12:1-17, 2022.
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Affiliation(s)
- Raf Van Campenhout
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Kaat Leroy
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Axelle Cooreman
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Andrés Tabernilla
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Bruno Cogliati
- School of Veterinary Medicine and Animal Science, Department of Pathology, University of São Paulo, São Paulo, Brazil
| | - Prashant Kadam
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Mathieu Vinken
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
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Tian L, Zhao L, Sze KM, Kam CS, Ming VS, Wang X, Zhang VX, Ho DW, Cheung T, Chan L, Ng IO. Dysregulation of RalA signaling through dual regulatory mechanisms exerts its oncogenic functions in hepatocellular carcinoma. Hepatology 2022; 76:48-65. [PMID: 34767674 PMCID: PMC9299834 DOI: 10.1002/hep.32236] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 10/14/2021] [Accepted: 11/05/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Ras-like (Ral) small guanosine triphosphatases (GTPases), RalA and RalB, are proto-oncogenes directly downstream of Ras and cycle between the active guanosine triphosphate-bound and inactive guanosine diphosphate-bound forms. RalGTPase-activating protein (RalGAP) complex exerts a negative regulation. Currently, the role of Ral up-regulation in cancers remains unclear. We aimed to examine the clinical significance, functional implications, and underlying mechanisms of RalA signaling in HCC. APPROACH AND RESULTS Our in-house and The Cancer Genome Atlas RNA sequencing data and quantitative PCR data revealed significant up-regulation of RalA in patients' HCCs. Up-regulation of RalA was associated with more aggressive tumor behavior and poorer prognosis. Consistently, knockdown of RalA in HCC cells attenuated cell proliferation and migration in vitro and tumorigenicity and metastasis in vivo. We found that RalA up-regulation was driven by copy number gain and uncovered that SP1 and ETS proto-oncogene 2 transcription factor cotranscriptionally drove RalA expression. On the other hand, RalGAPA2 knockdown increased the RalA activity and promoted intrahepatic and extrahepatic metastasis in vivo. Consistently, we observed significant RalGAPA2 down-regulation in patients' HCCs. Intriguingly, HCC tumors showing simultaneous down-regulation of RalGAPA2 and up-regulation of RalA displayed a significant association with more aggressive tumor behavior in terms of more frequent venous invasion, more advanced tumor stage, and poorer overall survival. Of note, Ral inhibition by a Ral-specific inhibitor RBC8 suppressed the oncogenic functions in a dose-dependent manner and sensitized HCC cells to sorafenib treatment, with an underlying enhanced inhibition of mammalian target of rapamycin signaling. CONCLUSIONS Our results provide biological insight that dysregulation of RalA signaling through dual regulatory mechanisms supports its oncogenic functions in HCC. Targeting RalA may serve as a potential alternative therapeutic approach alone or in combination with currently available therapy.
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Affiliation(s)
- Lu Tian
- Department of PathologyThe University of Hong KongHong Kong,State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Luqing Zhao
- Department of PathologyThe University of Hong KongHong Kong,State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong,Present address:
Department of PathologyXiangya School of MedicineCentral South UniversityChangshaHunanChina
| | - Karen Man‐Fong Sze
- Department of PathologyThe University of Hong KongHong Kong,State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Charles Shing Kam
- Department of PathologyThe University of Hong KongHong Kong,State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Vanessa Sheung‐In Ming
- Department of PathologyThe University of Hong KongHong Kong,State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Xia Wang
- Department of PathologyThe University of Hong KongHong Kong,State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Vanilla Xin Zhang
- Department of PathologyThe University of Hong KongHong Kong,State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Daniel Wai‐Hung Ho
- Department of PathologyThe University of Hong KongHong Kong,State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Tan‐To Cheung
- State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong,Department of SurgeryThe University of Hong KongHong Kong
| | - Lo‐Kong Chan
- Department of PathologyThe University of Hong KongHong Kong,State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Irene Oi‐Lin Ng
- Department of PathologyThe University of Hong KongHong Kong,State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
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Richardson DS, Spehar JM, Han DT, Chakravarthy PA, Sizemore ST. The RAL Enigma: Distinct Roles of RALA and RALB in Cancer. Cells 2022; 11:cells11101645. [PMID: 35626682 PMCID: PMC9139244 DOI: 10.3390/cells11101645] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 11/16/2022] Open
Abstract
RALA and RALB are highly homologous small G proteins belonging to the RAS superfamily. Like other small GTPases, the RALs are molecular switches that can be toggled between inactive GDP-bound and active GTP-bound states to regulate diverse and critical cellular functions such as vesicle trafficking, filopodia formation, mitochondrial fission, and cytokinesis. The RAL paralogs are activated and inactivated by a shared set of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) and utilize similar sets of downstream effectors. In addition to their important roles in normal cell biology, the RALs are known to be critical mediators of cancer cell survival, invasion, migration, and metastasis. However, despite their substantial similarities, the RALs often display striking functional disparities in cancer. RALA and RALB can have redundant, unique, or even antagonistic functions depending on cancer type. The molecular basis for these discrepancies remains an important unanswered question in the field of cancer biology. In this review we examine the functions of the RAL paralogs in normal cellular physiology and cancer biology with special consideration provided to situations where the roles of RALA and RALB are non-redundant.
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Liu S, Shi C, Wang X, Ma X, Gao P. Low expression of RalGAPs associates with the poorer overall survival of head and neck squamous cell carcinoma. Transl Cancer Res 2022; 10:5085-5094. [PMID: 35116360 PMCID: PMC8799020 DOI: 10.21037/tcr-21-1489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 11/18/2021] [Indexed: 02/05/2023]
Abstract
Background The role of Ral and RalGAPs on the progression of head and neck squamous cell carcinoma (HNSC) remains unclear. Methods The predesigned siRNAs against RalGAPs were transfected into cells to evaluate the effect on RalA activation. The Data from TCGA and GTEx were combined to analyze the pan-cancer gene expression of RalA and RalGAPs in cancer and adjacent normal tissues. Kaplan-Meier analysis was used to assess the predictive value of RalA and RalGAPs expression on the overall survival of patients with HNSC. Methylation-specific PCR in vitro and next-generation bisulfite sequencing in vivo were used to evaluate the association between DNA methylation and the down-regulation of RalGAPs. Results RalGAPs negatively regulated RalA activation. HNSC patients with low level of RalGAPα2 had worse overall survival. The promoter of RalGAPα2 was widely methylated in comparison to RalGAPα1 and the DNA methylation level of RalGAPα2 promoter was increased in HNSC tissues and associated with the presence of neck lymph node metastasis. Conclusions RalA and RalGAPs could act as a specific predictor to assess the prognosis of HNSC. DNA methylation might be a potential mechanism that downregulated the RalGAPα2 expression.
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Affiliation(s)
- Shan Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Congyu Shi
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiaoyi Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiangrui Ma
- Department of Oral and Maxillofacial Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Pan Gao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of General and Emergency Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Fixing the GAP: the role of RhoGAPs in cancer. Eur J Cell Biol 2022; 101:151209. [DOI: 10.1016/j.ejcb.2022.151209] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/29/2022] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
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Wang Y, He M, Li X, Chai J, Jiang Q, Peng C, He G, Huang W. Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole-Based RalA Inhibitors Against Hepatocellular Carcinoma. Front Chem 2021; 9:700956. [PMID: 34869198 PMCID: PMC8634879 DOI: 10.3389/fchem.2021.700956] [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: 04/27/2021] [Accepted: 09/29/2021] [Indexed: 02/05/2023] Open
Abstract
The activation of Ras small GTPases, including RalA and RalB, plays an important role in carcinogenesis, tumor progress, and metastasis. In the current study, we report the discovery of a series of 6-sulfonylamide-pyrano [2,3-c]-pyrazole derivatives as novel RalA inhibitors. ELISA-based biochemical assay results indicated that compounds 4k–4r suppressed RalA/B binding capacities to their substrates. Cellular proliferation assays indicated that these RalA inhibitors potently inhibited the proliferation of HCC cell lines, including HepG2, SMMC-7721, Hep3B, and Huh-7 cells. Among the evaluated compounds, 4p displayed good inhibitory capacities on RalA (IC50 = 0.22 μM) and HepG2 cells (IC50 = 2.28 μM). Overall, our results suggested that a novel small-molecule RalA inhibitor with a 6-sulfonylamide-pyrano [2, 3-c]-pyrazole scaffold suppressed autophagy and cell proliferation in hepatocellular carcinoma, and that it has potential for HCC-targeted therapy.
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Affiliation(s)
- Yuting Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mingyao He
- State Key Laboratory of Biotherapy and Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,State Key Laboratory of Biotherapy and Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinlong Chai
- State Key Laboratory of Biotherapy and Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Qinglin Jiang
- School of Pharmacy and Sichuan Province College Key Laboratory of Structure-Specific Small Molecule Drugs, Chengdu Medical College, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Biotherapy and Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Gu He
- State Key Laboratory of Biotherapy and Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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RAS GTPase signalling to alternative effector pathways. Biochem Soc Trans 2021; 48:2241-2252. [PMID: 33125484 DOI: 10.1042/bst20200506] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 09/21/2020] [Accepted: 09/23/2020] [Indexed: 02/07/2023]
Abstract
RAS GTPases are fundamental regulators of development and drivers of an extraordinary number of human cancers. RAS oncoproteins constitutively signal through downstream effector proteins, triggering cancer initiation, progression and metastasis. In the absence of targeted therapeutics to mutant RAS itself, inhibitors of downstream pathways controlled by the effector kinases RAF and PI3K have become tools in the treatment of RAS-driven tumours. Unfortunately, the efficacy of this approach has been greatly minimized by the prevalence of acquired drug resistance. Decades of research have established that RAS signalling is highly complex, and in addition to RAF and PI3K these small GTPase proteins can interact with an array of alternative effectors that feature RAS binding domains. The consequence of RAS binding to these effectors remains relatively unexplored, but these pathways may provide targets for combinatorial therapeutics. We discuss here three candidate alternative effectors: RALGEFs, RASSF5 and AFDN, detailing their interaction with RAS GTPases and their biological significance. The metastatic nature of RAS-driven cancers suggests more attention should be granted to these alternate pathways, as they are highly implicated in the regulation of cell adhesion, polarity, cell size and cytoskeletal architecture.
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Apken LH, Oeckinghaus A. The RAL signaling network: Cancer and beyond. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 361:21-105. [PMID: 34074494 DOI: 10.1016/bs.ircmb.2020.10.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The RAL proteins RALA and RALB belong to the superfamily of small RAS-like GTPases (guanosine triphosphatases). RAL GTPases function as molecular switches in cells by cycling through GDP- and GTP-bound states, a process which is regulated by several guanine exchange factors (GEFs) and two heterodimeric GTPase activating proteins (GAPs). Since their discovery in the 1980s, RALA and RALB have been established to exert isoform-specific functions in central cellular processes such as exocytosis, endocytosis, actin organization and gene expression. Consequently, it is not surprising that an increasing number of physiological functions are discovered to be controlled by RAL, including neuronal plasticity, immune response, and glucose and lipid homeostasis. The critical importance of RAL GTPases for oncogenic RAS-driven cellular transformation and tumorigenesis still attracts most research interest. Here, RAL proteins are key drivers of cell migration, metastasis, anchorage-independent proliferation, and survival. This chapter provides an overview of normal and pathological functions of RAL GTPases and summarizes the current knowledge on the involvement of RAL in human disease as well as current therapeutic targeting strategies. In particular, molecular mechanisms that specifically control RAL activity and RAL effector usage in different scenarios are outlined, putting a spotlight on the complexity of the RAL GTPase signaling network and the emerging theme of RAS-independent regulation and relevance of RAL.
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Affiliation(s)
- Lisa H Apken
- Institute of Molecular Tumor Biology, Faculty of Medicine, University of Münster, Münster, Germany
| | - Andrea Oeckinghaus
- Institute of Molecular Tumor Biology, Faculty of Medicine, University of Münster, Münster, Germany.
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12
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Welberry C, Macdonald I, McElveen J, Parsy-Kowalska C, Allen J, Healey G, Irving W, Murray A, Chapman C. Tumor-associated autoantibodies in combination with alpha-fetoprotein for detection of early stage hepatocellular carcinoma. PLoS One 2020; 15:e0232247. [PMID: 32374744 PMCID: PMC7202612 DOI: 10.1371/journal.pone.0232247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 04/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) continues to be a leading challenge in modern oncology. Early detection via blood-based screening tests has the potential to cause a stage-shift at diagnosis and improve clinical outcomes. Tumor associated autoantibodies (TA-AAbs) have previously shown the ability to distinguish HCC from patients with high-risk liver disease. This research aimed to further show the utility of TA-AAbs as biomarkers of HCC and assess their use in combination with Alpha-fetoprotein (AFP) for detection of HCC across multiple tumor stages. METHODS Levels of circulating G class antibodies to 44 recombinant tumor associated antigens and circulating AFP were measured in the serum of patients with HCC, non-cancerous chronic liver disease (NCCLD) and healthy controls via enzyme-linked immunosorbent assay (ELISA). TA-AAb cut-offs were set at the highest Youden's J statistic at a specificity ≥95.00%. Panels of TA-AAbs were formed using net reclassification improvement. AFP was assessed at a cut-off of 200 ng/ml. RESULTS Sensitivities ranged from 1.01% to 12.24% at specificities of 95.96% to 100.00% for single TA-AAbs. An ELISA test measuring a panel of 10 of these TA-AAbs achieved a combined sensitivity of 36.73% at a specificity of 89.89% when distinguishing HCC from NCCLD controls. At a cut-off of 200 ng/ml, AFP achieved a sensitivity of 31.63% at a specificity of 100.00% in the same cohort. Combination of the TA-AAb panel with AFP significantly increased the sensitivity for stage one (40.00%) and two (55.00%) HCC over the TA-AAb panel or AFP alone. CONCLUSIONS A panel of TA-AAbs in combination with AFP could be clinically relevant as a replacement for measuring levels of AFP alone in surveillance and diagnosis strategies. The increased early stage sensitivity could lead to a stage shift with positive prognostic outcomes.
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Affiliation(s)
- Christopher Welberry
- Oncimmune ltd, Nottingham, United Kingdom
- School of Medicine, University of Nottingham, Nottingham, United Kingdom
- * E-mail: ,
| | | | | | | | - Jared Allen
- Oncimmune ltd, Nottingham, United Kingdom
- School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | | | - William Irving
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom
| | | | - Caroline Chapman
- School of Medicine, University of Nottingham, Nottingham, United Kingdom
- Bowel Cancer Screening Program, Nottingham University NHS Trust, Nottingham, United Kingdom
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13
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Wang P, Zhang W, Wang L, Liang W, Cai A, Gao Y, Chen L. RCC2 Interacts with Small GTPase RalA and Regulates Cell Proliferation and Motility in Gastric Cancer. Onco Targets Ther 2020; 13:3093-3103. [PMID: 32341655 PMCID: PMC7166089 DOI: 10.2147/ott.s228914] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 12/29/2019] [Indexed: 12/20/2022] Open
Abstract
Background Regulator of chromosome condensation 2 (RCC2), also known as TD-60, is associated with various human malignant cancers. RCC2 has been shown to exhibit guanine exchange factor (GEF) activity and contribute to early mitosis. However, the role and mechanism of RCC2 in gastric cancer remain unclear. Materials and Methods RCC2 expression in gastric cancer was studied using qPCR, Western blotting and immunochemistry staining of clinical specimens, and its roles in the cytobiology, mouse model and related molecular pathways were evaluated using gastric cell lines. Results RCC2 was frequently overexpressed in gastric cancer. RCC2 knockdown significantly inhibited cell proliferation, migration and invasion in vitro, which was further confirmed by the RCC2 overexpression results in gastric cancer cells. Moreover, RCC2 knockdown inhibited tumor progression in vivo. Further study revealed the interaction between RCC2 and RalA. The level of RalA-GTP was decreased in gastric cancer cells after RCC2 knockdown, while an increased phosphorylation level in MAPK/JNK was found. Furthermore, the changes in the level of RalA-GTP as well as cell proliferation, migration and invasion abilities were further confirmed using RBC8, a specific small-molecule inhibitor of the intracellular actions of Ral GTPases, in gastric cancer cells. Conclusion RCC2 plays an important role in gastric cancer. RCC2 knockdown inhibits cell growth, cell motility and tumor progression, which may act through RalA and affect the MAPK/JNK pathway.
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Affiliation(s)
- Pengpeng Wang
- School of Medicine, Nankai University, Tianjin 300071, People's Republic of China.,Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, People's Republic of China
| | - Wang Zhang
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, People's Republic of China
| | - Lili Wang
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, People's Republic of China
| | - Wenquan Liang
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, People's Republic of China
| | - Aizhen Cai
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, People's Republic of China
| | - Yunhe Gao
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, People's Republic of China
| | - Lin Chen
- School of Medicine, Nankai University, Tianjin 300071, People's Republic of China.,Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, People's Republic of China
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14
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Wagner M, Skorobogatko Y, Pode-Shakked B, Powell CM, Alhaddad B, Seibt A, Barel O, Heimer G, Hoffmann C, Demmer LA, Perilla-Young Y, Remke M, Wieczorek D, Navaratnarajah T, Lichtner P, Klee D, Shamseldin HE, Al Mutairi F, Mayatepek E, Strom T, Meitinger T, Alkuraya FS, Anikster Y, Saltiel AR, Distelmaier F. Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities. Am J Hum Genet 2020; 106:246-255. [PMID: 32004447 DOI: 10.1016/j.ajhg.2020.01.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 01/06/2020] [Indexed: 12/30/2022] Open
Abstract
Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.
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15
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Wang Y, Lv K, Zhao M, Chen H, Ji G, Zhang Y, Wang T, Cao H, Li Y, Qu L. Analysis of miRNA expression profiles in the liver of Clock Δ19 mutant mice. PeerJ 2019; 7:e8119. [PMID: 31799078 PMCID: PMC6885354 DOI: 10.7717/peerj.8119] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 10/29/2019] [Indexed: 12/31/2022] Open
Abstract
The circadian clock controls the physiological functions of many tissues including the liver via an autoregulatory transcriptional−translational feedback loop, of which CLOCK is a core positive component. In addition, many studies have indicated that microRNAs (miRNAs) regulate liver function. However, how CLOCK-regulated miRNAs are linked to liver function remains largely unknown. In this study, miRNAs expression profiles were performed in the liver of ClockΔ19 mutant mice. Compared to wild type mice, totals of 61 and 57 putative CLOCK-regulated miRNAs were differentially expressed (fold change absolute value ≥2) at zeitgeber time 2 and zeitgeber time 14, respectively. According to the pathway analyses, the target genes of differentially expressed miRNAs were mainly involved in pathways in cancer, the PI3K-Akt signaling pathway and the MAPK signaling pathway. Protein−protein interaction analyses revealed that the hub genes were primarily associated with pathway in cancer and circadian rhythms. Expression validation showed that while the expression levels of miR-195 and miR-340 were up-regulated, the rhythms of these two miRNAs were always maintained. The expression level of nr1d2 mRNA was down-regulated. We identified a number of prospective CLOCK-regulated miRNAs that play roles in the various physiological processes of the liver, providing a reference to better understanding the potential regulatory mechanisms in the liver.
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Affiliation(s)
- Yanli Wang
- School of Life Sciences, Northwestern Polytechnical University, Xian, Shaanxi, China
| | - Ke Lv
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Mei Zhao
- Institute of Psychology, Chinese Academy of Sciences, Beijing, China
| | - Hailong Chen
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Guohua Ji
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yongliang Zhang
- School of Life Sciences, Northwestern Polytechnical University, Xian, Shaanxi, China
| | - Tingmei Wang
- School of Life Sciences, Northwestern Polytechnical University, Xian, Shaanxi, China
| | - Hongqing Cao
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yinghui Li
- School of Life Sciences, Northwestern Polytechnical University, Xian, Shaanxi, China.,State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Lina Qu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
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16
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Yang Q, Lang C, Wu Z, Dai Y, He S, Guo W, Huang S, Du H, Ren D, Peng X. MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:391. [PMID: 31488180 PMCID: PMC6729064 DOI: 10.1186/s13046-019-1374-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 08/09/2019] [Indexed: 01/22/2023]
Abstract
Background Clinically, prostate cancer (PCa) exhibits a high avidity to metastasize to bone. Myc-associated zinc-finger protein (MAZ) is a well-documented oncogene involved in the progression and metastasis of multiple cancer types, even in PCa. However, the clinical significance and biological roles of MAZ in bone metastasis of PCa remain unclear. Methods MAZ expression was examined in PCa tissues with bone metastasis, PCa tissues without bone metastasis and metastatic bone tissues by real-time PCR and immunohistochemistry (IHC), respectively. Statistical analysis was performed to evaluate the clinical correlation between MAZ expression and clinicopathological features and bone metastasis-free survival in PCa patients. Biological roles of MAZ in bone metastasis of PCa were investigated both in vitro by transwell assay, and in vivo by a mouse model of left cardiac ventricle inoculation. The bioinformatics analysis, western blot, pull-down assays, chromatin immunoprecipitation (ChIP) and luciferase reporter assays were applied to demonstrate and examine the relationship between MAZ and its potential downstream signalling pathway. TaqMan copy number assay was performed to identify the underlying mechanism responsible for MAZ overexpression in PCa tissues. Results MAZ expression is elevated in PCa tissues with bone metastasis compared with that in PCa tissues without bone metastasis, and is further increased in metastatic bone tissues. High expression of MAZ positively correlates with poor overall and bone metastasis-free survival in PCa patients. Upregulating MAZ elevates, while silencing MAZ represses the invasion and migration abilities of PCa cells in vitro and bone metastasis ability in vivo. Our results further reveal that MAZ promotes bone metastasis of PCa dependent on KRas signalling, although MAZ transcriptionally upregulates KRas and HRas expression, where the Ral guanine nucleotide exchange factor (RalGEF) signaling is responsible for the different roles of KRas and HRas in mediating the pro-bone metastasis of MAZ in PCa. Finally, our results indicate that recurrent gains contribute to MAZ overexpression in a small portion of PCa tissues. Conclusion These results indicate that the MAZ/Kras/ RalGEF signalling axis plays a crucial role in promoting PCa cell bone metastasis, suggesting a potential therapeutic utility of MAZ in bone metastasis of PCa. Electronic supplementary material The online version of this article (10.1186/s13046-019-1374-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Qing Yang
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, 510080, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, 510080, Guangdong Province, China
| | - Chuandong Lang
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, 510080, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, 510080, Guangdong Province, China
| | - Zhengquan Wu
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, 510080, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, 510080, Guangdong Province, China
| | - Yuhu Dai
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, 510080, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, 510080, Guangdong Province, China
| | - Shaofu He
- Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, Guangdong Province, China
| | - Wei Guo
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, 510080, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, 510080, Guangdong Province, China
| | - Shuai Huang
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Hong Du
- Department of Pathology, The First People's Hospital of Guangzhou City, Guangzhou, 510180, Guangdong, China
| | - Dong Ren
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, 510080, Guangdong Province, China. .,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, 510080, Guangdong Province, China.
| | - Xinsheng Peng
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, 510080, Guangdong Province, China. .,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, 510080, Guangdong Province, China.
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17
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Wang D, Huang Z, Li L, Yuan Y, Xiang L, Wu X, Ni C, Yu W. Intracarotid cold saline infusion contributes to neuroprotection in MCAO‑induced ischemic stroke in rats via serum and glucocorticoid‑regulated kinase 1. Mol Med Rep 2019; 20:3942-3950. [PMID: 31485662 DOI: 10.3892/mmr.2019.10599] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 07/16/2019] [Indexed: 11/05/2022] Open
Abstract
Intracarotid cold saline infusion (ICSI) brings about neuroprotective effects in ischemic stroke. However, the involvement of serum and glucocorticoid‑regulated kinase 1 (SGK1) in the underlying mechanism of ICSI is not fully understood; therefore, we used the rat middle cerebral artery occlusion (MCAO) model to investigate the neuroprotective effects of ICSI on ischemic stroke in rats, as well as the involvement of SGK1 in these effects. ICSI decreased infarct size and brain swelling, as determined by 2,3,5‑triphenyltetrazolium chloride staining and the dry‑wet weight method, respectively. The results of terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL) and Nissl staining showed that ICSI also suppressed apoptosis and increased the relative integral optical density (IOD) values of Nissl bodies in the rat MCAO model. Regarding the mechanism, the results of immunohistochemistry and western blotting revealed that ICSI upregulated SGK1 expression and downregulated beclin‑1 and LC‑3 expression in the rat MCAO model. In addition, SGK1 knockdown increased ICSI‑mediated infarct size and brain swelling, promoted apoptosis, and reduced the IOD values of Nissl bodies in the rat MCAO model. In addition, we found that SGK1 knockdown upregulated beclin‑1 and LC‑3 expression mediated by ICSI. Overall, ICSI had a neuroprotective effect on ischemic stroke after reperfusion by upregulating SGK1 and inhibiting autophagy.
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Affiliation(s)
- Dazhi Wang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Zhi Huang
- Department of Interventional Radiology, The Second Affiliated Hospital of Guizhou Medical University, Kaili, Guizhou 556000, P.R. China
| | - Lei Li
- Department of General Courses, People's Armed College of Guizhou University, Guiyang, Guizhou 550025, P.R. China
| | - Yingnan Yuan
- School of Medical Imaging, Guizhou Medical University, Guiyang, Guizhou 550002, P.R. China
| | - Lei Xiang
- School of Medical Imaging, Guizhou Medical University, Guiyang, Guizhou 550002, P.R. China
| | - Xiaowen Wu
- School of Medical Imaging, Guizhou Medical University, Guiyang, Guizhou 550002, P.R. China
| | - Caifang Ni
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Wenfeng Yu
- Key Laboratory of Molecular Biology, Guizhou Medical University, Guiyang, Guizhou 550002, P.R. China
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18
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Gong S, Chen Y, Meng F, Zhang Y, Wu H, Li C, Zhang G. RCC2, a regulator of the RalA signaling pathway, is identified as a novel therapeutic target in cisplatin-resistant ovarian cancer. FASEB J 2019; 33:5350-5365. [PMID: 30768358 DOI: 10.1096/fj.201801529rr] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Currently, cisplatin (DDP) is the first-line chemotherapeutic agent used for treatment of ovarian cancer, but gradually acquired drug resistance minimizes its therapeutic outcomes. We aimed to identify crucial genes associated with DDP resistance in ovarian cancer and uncover potential mechanisms. Two sets of gene expression data were downloaded from Gene Expression Omnibus, and bioinformatics analysis was conducted. In our study, the differentially expressed genes between DDP-sensitive and DDP-resistant ovarian cancer were screened in GSE15709 and GSE51373 database, and chromosome condensation 2 regulator (RCC2) and nucleoporin 160 were identified as 2 genes that significantly up-regulated in DDP-resistant ovarian cancer cell lines compared with DDP-sensitive cell lines. Moreover, RCC2, Ral small GTPase (RalA), and Ral binding protein-1 (RalBP1) expression was found to be significantly higher in DDP-resistant ovarian cancer tissues than in DDP-sensitive tissues. RCC2 plays a positive role in cell proliferation, apoptosis, and migration in DDP-resistant ovarian cancer cell lines in vitro and in vivo. Furthermore, RCC2 could interact with RalA, thus promoting its downstream effector RalBP1. RalA knockdown could reverse the effects of RCC2 overexpression on DDP-resistant ovarian cancer cell proliferation, apoptosis, and migration. Similarly, RalA overexpression could alleviate the effects of RCC2 knockdown in DDP-resistant ovarian cancer cells. Taken together, RCC2 may function as an oncogene, regulating the RalA signaling pathway, and intervention of RCC2 expression might be a promising therapeutic strategy for DDP-resistant ovarian cancer.-Gong, S., Chen, Y., Meng, F., Zhang, Y., Wu, H., Li, C., Zhang, G. RCC2, a regulator of the RalA signaling pathway, is identified as a novel therapeutic target in cisplatin-resistant ovarian cancer.
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Affiliation(s)
- Shipeng Gong
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yongning Chen
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fanliang Meng
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yadi Zhang
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huan Wu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; and
| | - Chanyuan Li
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guangping Zhang
- Department of Gynecology, People's Hospital of Huadu District, Guangzhou, China
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19
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Zheng Y, Liu Y, Zhao S, Zheng Z, Shen C, An L, Yuan Y. Large-scale analysis reveals a novel risk score to predict overall survival in hepatocellular carcinoma. Cancer Manag Res 2018; 10:6079-6096. [PMID: 30538557 PMCID: PMC6252784 DOI: 10.2147/cmar.s181396] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a major cause of cancer mortality and an increasing incidence worldwide; however, there are very few effective diagnostic approaches and prognostic biomarkers. Materials and methods One hundred forty-nine pairs of HCC samples from Gene Expression Omnibus (GEO) were obtained to screen differentially expressed genes (DEGs) between HCC and normal samples. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene ontology enrichment analyses, and protein–protein interaction network were used. Cox proportional hazards regression analysis was used to identify significant prognostic DEGs, with which a gene expression signature prognostic prediction model was identified in The Cancer Genome Atlas (TCGA) project discovery cohort. The robustness of this panel was assessed in the GSE14520 cohort. We verified details of the gene expression level of the key molecules through TCGA, GEO, and qPCR and used immunohistochemistry for substantiation in HCC tissues. The methylation states of these genes were also explored. Results Ninety-eight genes, consisting of 13 upregulated and 85 downregulated genes, were screened out in three datasets. KEGG and Gene ontology analysis for the DEGs revealed important biological features of each subtype. Protein–protein interaction network analysis was constructed, consisting of 64 nodes and 115 edges. A subset of four genes (SPINK1, TXNRD1, LCAT, and PZP) that formed a prognostic gene expression signature was established from TCGA and validated in GSE14520. Next, the expression details of the four genes were validated with TCGA, GEO, and clinical samples. The expression panels of the four genes were closely related to methylation states. Conclusion This study identified a novel four-gene signature biomarker for predicting the prognosis of HCC. The biomarkers may also reveal molecular mechanisms underlying development of the disease and provide new insights into interventional strategies.
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Affiliation(s)
- Yujia Zheng
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yulin Liu
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Songfeng Zhao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,
| | - Zhetian Zheng
- School of Computer Science, Yangtze University, Jingzhou, Hubei, China
| | - Chunyi Shen
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Li An
- Institute of Quality Standard and Testing Technology for Agro-products, Henan Academy of Agricultural Sciences, Zhengzhou, China,
| | - Yongliang Yuan
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,
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20
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Zago G, Veith I, Singh MK, Fuhrmann L, De Beco S, Remorino A, Takaoka S, Palmeri M, Berger F, Brandon N, El Marjou A, Vincent-Salomon A, Camonis J, Coppey M, Parrini MC. RalB directly triggers invasion downstream Ras by mobilizing the Wave complex. eLife 2018; 7:40474. [PMID: 30320548 PMCID: PMC6226288 DOI: 10.7554/elife.40474] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 10/14/2018] [Indexed: 12/27/2022] Open
Abstract
The two Ral GTPases, RalA and RalB, have crucial roles downstream Ras oncoproteins in human cancers; in particular, RalB is involved in invasion and metastasis. However, therapies targeting Ral signalling are not available yet. By a novel optogenetic approach, we found that light-controlled activation of Ral at plasma-membrane promotes the recruitment of the Wave Regulatory Complex (WRC) via its effector exocyst, with consequent induction of protrusions and invasion. We show that active Ras signals to RalB via two RalGEFs (Guanine nucleotide Exchange Factors), RGL1 and RGL2, to foster invasiveness; RalB contribution appears to be more important than that of MAPK and PI3K pathways. Moreover, on the clinical side, we uncovered a potential role of RalB in human breast cancers by determining that RalB expression at protein level increases in a manner consistent with progression toward metastasis. This work highlights the Ras-RGL1/2-RalB-exocyst-WRC axis as appealing target for novel anticancer strategies. Cancers develop when cells in the body divide rapidly in an uncontroled manner. It is generally possible to cure cancers that remain contained within a small area. However, if the tumor cells start to move, the cancer may spread in the body and become life threatening. Currently, most of the anti-cancer treatments act to reduce the multiplication of these cells, but not their ability to migrate. A signal protein called Ras stimulates human cells to grow and move around. In healthy cells, the activity of Ras is tightly controled to ensure cells only divide and migrate at particular times, but in roughly 30% of all human cancers, Ras is abnormally active. Ras switches on another protein, named RalB, which is also involved in inappropriate cell migration. Yet, it is not clear how RalB is capable to help Ras trigger the migration of cells. Zago et al. used an approach called optogenetics to specifically activate the RalB protein in human cells using a laser that produces blue light. When activated, the light-controlled RalB started abnormal cell migration; this was used to dissect which molecules and mechanisms were involved in the process. Taken together, the experiments showed that, first, Ras ‘turns on’ RalB by changing the location of two proteins that control RalB. Then, the activated RalB regulates the exocyst, a group of proteins that travel within the cell. In turn, the exocyst recruits another group of proteins, named the Wave complex, which is part of the molecular motor required for cells to migrate. Zago et al. also found that, in patients, the RalB protein was present at abnormally high levels in samples of breast cancer cells that had migrated to another part of the body. Overall, these findings indicate that the role of RalB protein in human cancers is larger than previously thought, and they highlight a new pathway that could be a target for new anti-cancer drugs.
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Affiliation(s)
- Giulia Zago
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,ART Group, Inserm U830, Paris, France
| | - Irina Veith
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,ART Group, Inserm U830, Paris, France
| | - Manish Kumar Singh
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,ART Group, Inserm U830, Paris, France
| | - Laetitia Fuhrmann
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,Department of Pathology, Institut Curie, Paris, France
| | - Simon De Beco
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,LOCCO Group, UMR168, Paris, France
| | - Amanda Remorino
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,LOCCO Group, UMR168, Paris, France
| | - Saori Takaoka
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,ART Group, Inserm U830, Paris, France
| | - Marjorie Palmeri
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,ART Group, Inserm U830, Paris, France
| | - Frédérique Berger
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,Department of Biostatistics, Institut Curie, Paris, France
| | - Nathalie Brandon
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,ART Group, Inserm U830, Paris, France
| | - Ahmed El Marjou
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,Protein Expression and Purification Core Facility, Paris, France
| | - Anne Vincent-Salomon
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,Department of Pathology, Institut Curie, Paris, France
| | - Jacques Camonis
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,ART Group, Inserm U830, Paris, France
| | - Mathieu Coppey
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,LOCCO Group, UMR168, Paris, France
| | - Maria Carla Parrini
- Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.,ART Group, Inserm U830, Paris, France
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21
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Terai K, Bi D, Liu Z, Kimura K, Sanaat Z, Dolatkhah R, Soleimani M, Jones C, Bright A, Esfandyari T, Farassati F. A Novel Oncolytic Herpes Capable of Cell-Specific Transcriptional Targeting of CD133± Cancer Cells Induces Significant Tumor Regression. Stem Cells 2018; 36:1154-1169. [PMID: 29658163 DOI: 10.1002/stem.2835] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 02/16/2017] [Accepted: 03/10/2017] [Indexed: 12/11/2022]
Abstract
The topic of cancer stem cells (CSCs) is of significant importance due to its implications in our understanding of the tumor biology as well as the development of novel cancer therapeutics. However, the question of whether targeting CSCs can hamper the growth of tumors remains mainly unanswered due to the lack of specific agents for this purpose. To address this issue, we have developed the first mutated version of herpes simplex virus-1 that is transcriptionally targeted against CD133+ cells. CD133 has been portrayed as one of the most important markers in CSCs involved in the biology of a number of human cancers, including liver, brain, colon, skin, and pancreas. The virus developed in this work, Signal-Smart 2, showed specificity against CD133+ cells in three different models (hepatocellular carcinoma, colorectal cancer, and melanoma) resulting in a loss of viability and invasiveness of cancer cells. Additionally, the virus showed robust inhibitory activity against in vivo tumor growth in both preventive and therapeutic mouse models as well as orthotopic model highly relevant to potential clinical application of this virus. Therefore, we conclude that targeting CD133+ CSCs has the potential to be pursued as a novel strategy against cancer. Stem Cells 2018;36:1154-1169.
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Affiliation(s)
- Kaoru Terai
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Danse Bi
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Zhengian Liu
- Midwest Biomedical Research Foundation, Kansas City Veterans Affairs Medical Center, Kansas, Missouri, USA
| | - Kyle Kimura
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Zohreh Sanaat
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Roya Dolatkhah
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Mina Soleimani
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Christopher Jones
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Allison Bright
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Tuba Esfandyari
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Faris Farassati
- Midwest Biomedical Research Foundation, Kansas City Veterans Affairs Medical Center, Kansas, Missouri, USA.,Saint Luke's Cancer Institute-Saint Luke's Marion Bloch Neuroscience Institute, Kansas, Missouri, USA
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22
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Shabbir A, Esfandyari T, Farassati F. Cancer stem cells, the ultimate targets in cancer therapy. Onco Targets Ther 2018; 11:183-184. [PMID: 29379299 PMCID: PMC5757206 DOI: 10.2147/ott.s154431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Ahmed Shabbir
- Midwest Biomedical Research Foundation, Kansas City Veterans Affairs Medical Center
| | - Tuba Esfandyari
- Department of Medicine, School of Medicine, The University of Kansas
| | - Faris Farassati
- Midwest Biomedical Research Foundation, Kansas City Veterans Affairs Medical Center.,Saint Luke's Cancer Institute.,Saint Luke's Marion Bloch Neuroscience Institute, Saint Luke's Health System, Kansas City, MO, USA
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23
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Zhang Y, Wang C, Huang W, Haruehanroengra P, Peng C, Sheng J, Han B, He G. Application of organocatalysis in bioorganometallic chemistry: asymmetric synthesis of multifunctionalized spirocyclic pyrazolone–ferrocene hybrids as novel RalA inhibitors. Org Chem Front 2018. [DOI: 10.1039/c8qo00422f] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Asymmetric construction of chiral spirocyclic pyrazolone–ferrocene hybrids has been developed. The lead compound displayed potent RalA inhibition.
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Affiliation(s)
- Yuehua Zhang
- State Key Laboratory of Biotherapy and Cancer Center
- West China Hospital
- Sichuan University
- Chengdu 610041
- China
| | - Chunting Wang
- State Key Laboratory of Biotherapy and Cancer Center
- West China Hospital
- Sichuan University
- Chengdu 610041
- China
| | - Wei Huang
- School of Pharmacy
- Chengdu University of Traditional Chinese Medicine
- Chengdu 611137
- China
| | - Phensinee Haruehanroengra
- Department of Chemistry and The RNA Institute
- University at Albany
- State University of New York
- Albany
- USA
| | - Cheng Peng
- School of Pharmacy
- Chengdu University of Traditional Chinese Medicine
- Chengdu 611137
- China
| | - Jia Sheng
- Department of Chemistry and The RNA Institute
- University at Albany
- State University of New York
- Albany
- USA
| | - Bo Han
- School of Pharmacy
- Chengdu University of Traditional Chinese Medicine
- Chengdu 611137
- China
- Department of Chemistry and The RNA Institute
| | - Gu He
- State Key Laboratory of Biotherapy and Cancer Center
- West China Hospital
- Sichuan University
- Chengdu 610041
- China
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24
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Abstract
More than a hundred proteins comprise the RAS superfamily of small GTPases. This family can be divided into RAS, RHO, RAB, RAN, ARF, and RAD subfamilies, with each shown to play distinct roles in human cells in both health and disease. The RAS subfamily has a well-established role in human cancer with the three genes, HRAS, KRAS, and NRAS being the commonly mutated in tumors. These RAS mutations, most often functionally activating, are especially common in pancreatic, lung, and colorectal cancers. Efforts to inhibit RAS and related GTPases have produced inhibitors targeting the downstream effectors of RAS signaling, including inhibitors of the RAF-mitogen-activated protein kinase/extracellular signal-related kinase (ERK)-ERK kinase pathway and the phosphoinositide-3-kinase-AKT-mTOR kinase pathway. A third effector arm of RAS signaling, mediated by RAL (RAS like) has emerged in recent years as a critical driver of RAS oncogenic signaling and has not been targeted until recently. RAL belongs to the RAS branch of the RAS superfamily and shares a high structural similarity with RAS. In human cells, there are two genes, RALA and RALB, both of which have been shown to play roles in the proliferation, survival, and metastasis of a variety of human cancers, including lung, colon, pancreatic, prostate, skin, and bladder cancers. In this review, we summarize the latest knowledge of RAL in the context of human cancer and the recent advancements in the development of cancer therapeutics targeting RAL small GTPases.
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Affiliation(s)
- Chao Yan
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China (C.Y.); Departments of Surgery (Urology) and Pharmacology, University of Colorado, Aurora, Colorado (D.T.); and University of Colorado Comprehensive Cancer Center, Aurora, Colorado (D.T.)
| | - Dan Theodorescu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China (C.Y.); Departments of Surgery (Urology) and Pharmacology, University of Colorado, Aurora, Colorado (D.T.); and University of Colorado Comprehensive Cancer Center, Aurora, Colorado (D.T.)
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25
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Moghadam AR, Patrad E, Tafsiri E, Peng W, Fangman B, Pluard TJ, Accurso A, Salacz M, Shah K, Ricke B, Bi D, Kimura K, Graves L, Najad MK, Dolatkhah R, Sanaat Z, Yazdi M, Tavakolinia N, Mazani M, Amani M, Ghavami S, Gartell R, Reilly C, Naima Z, Esfandyari T, Farassati F. Ral signaling pathway in health and cancer. Cancer Med 2017; 6:2998-3013. [PMID: 29047224 PMCID: PMC5727330 DOI: 10.1002/cam4.1105] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 04/10/2017] [Accepted: 04/14/2017] [Indexed: 12/12/2022] Open
Abstract
The Ral (Ras-Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.
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Affiliation(s)
- Adel Rezaei Moghadam
- Department of Human Anatomy and Cell ScienceUniversity of ManitobaWinnipegCanada
| | - Elham Patrad
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Elham Tafsiri
- Department of Pediatrics, Columbia Presbyterian Medical CenterNew YorkNew York
| | - Warner Peng
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Benjamin Fangman
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Timothy J Pluard
- Saint Luke's HospitalUniversity of Missouri at Kansas CityKansas CityMissouri
| | - Anthony Accurso
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Michael Salacz
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Kushal Shah
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Brandon Ricke
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Danse Bi
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Kyle Kimura
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Leland Graves
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Marzieh Khajoie Najad
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Roya Dolatkhah
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Zohreh Sanaat
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Mina Yazdi
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Naeimeh Tavakolinia
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Mohammad Mazani
- Pasteur Institute of IranTehranIran
- Ardabil University of Medical Sciences, BiochemistryArdabilIran
| | - Mojtaba Amani
- Pasteur Institute of IranTehranIran
- Ardabil University of Medical Sciences, BiochemistryArdabilIran
| | - Saeid Ghavami
- Department of Human Anatomy and Cell ScienceUniversity of ManitobaWinnipegCanada
| | - Robyn Gartell
- Department of Pediatrics, Columbia Presbyterian Medical CenterNew YorkNew York
| | - Colleen Reilly
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Zaid Naima
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Tuba Esfandyari
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Faris Farassati
- Research Service (151)Kansas City Veteran Affairs Medical Center & Midwest Biomedical Research Foundation4801 E Linwood BlvdKansas CityMissouri64128‐2226
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26
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Nakamoto Y. Promising new strategies for hepatocellular carcinoma. Hepatol Res 2017; 47:251-265. [PMID: 27558453 DOI: 10.1111/hepr.12795] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 08/16/2016] [Accepted: 08/19/2016] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. It usually arises based on a background of chronic liver diseases, defined as the hypercarcinogenic state. The current treatment options for HCC ranging from locoregional treatments to chemotherapies, including sorafenib, effectively regulate the limited sizes and numbers of the nodules. However, these treatments remain unsatisfactory because they have insufficient antitumor effects on the large and numerous nodules associated with HCC and because of a high recurrence rate in the surrounding inflamed liver. To develop novel and promising therapies with higher antitumor effects, recent progress in identifying molecular targets and developing immunological procedures for HCC are reviewed. The molecular targets discussed include the intracellular signaling pathways of protein kinase B/mammalian target of rapamycin and RAS/RAF/mitogen-activated protein kinase, Wnt/β-catenin and glutamine synthetase, insulin-like growth factor, signal transducer and activator of transcription 3, nuclear factor-κB and telomerase reverse transcriptase, and c-MET. Immunological studies have focused mainly on target identification, T cells, natural killer cells, dendritic cells, natural killer T cells, and vaccine development.
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Affiliation(s)
- Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
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27
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Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro. Angiogenesis 2016; 20:39-54. [PMID: 27699500 PMCID: PMC5306362 DOI: 10.1007/s10456-016-9527-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 09/28/2016] [Indexed: 12/24/2022]
Abstract
During prolonged hypoxic conditions, endothelial cells change their gene expression to adjust to the low oxygen environment. This process is mainly regulated by the hypoxia-inducible factors, HIF-1α and HIF-2α. Although endothelial cells do not form sprouts during prolonged hypoxic culturing, silencing of HIF-2α partially restores sprout formation. The present study identifies novel HIF-2α-target genes that may regulate endothelial sprouting during prolonged hypoxia. The gene expression profile of primary human microvascular endothelial cells (hMVECs) that were cultured at 20 % oxygen was compared to hMVECs that were cultured at 1 % oxygen for 14 days by using genome-wide RNA-sequencing. The differentially regulated genes in hypoxia were compared to the genes that were differentially regulated upon silencing of HIF-2α in hypoxia. Surprisingly, KEGG pathway analysis showed that metabolic pathways were enriched within genes upregulated in response to hypoxia and enriched within genes downregulated upon HIF-2α silencing. Moreover, 51 HIF-2α-regulated genes were screened for their role in endothelial sprouting in hypoxia, of which four genes ARRDC3, MME, PPARG and RALGPS2 directly influenced endothelial sprouting during prolonged hypoxic culturing. The manipulation of specific downstream targets of HIF-2α provides a new, but to be further evaluated, perspective for restoring reduced neovascularization in several pathological conditions, such as diabetic ulcers or other chronic wounds, for improvement of vascularization of implanted tissue-engineered scaffolds.
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28
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Ouyang Y, Pan J, Tai Q, Ju J, Wang H. Transcriptomic changes associated with DKK4 overexpression in pancreatic cancer cells detected by RNA-Seq. Tumour Biol 2016; 37:10827-38. [PMID: 26880586 DOI: 10.1007/s13277-015-4379-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 11/04/2015] [Indexed: 11/27/2022] Open
Abstract
The promotion of tumor development by Dickkopf 4 (DKK4) is receiving increased attention. However, the association between DKK4 and pancreatic cancer remains unclear. DKK4 expression was measured in pancreatic ductal adenocarcinoma tissues using qRT-PCR and immunohistochemistry. A DKK4-overexpressing pancreatic cancer cell line was established, and the differentially expressed genes (DEGs) that were induced by DKK4 were identified using transcriptome sequencing. The association between the identified DEGs and pancreatic cancer was assessed using gene ontology (GO), pathway analysis, pathway interaction networks, differentially expressed gene interaction network analysis, and co-expression gene networks. Finally, the accuracy of the analyses was validated using serial paraffin and frozen sections of clinical samples. DKK4 is highly expressed in pancreatic cancer tissues. DEGs of overexpression DKK4 of PANC-1 are mostly upregulated. GO and pathway analysis showed that DKK4 are associated with tumor and organ development and immune inflammation. The mitogen-activated protein kinase (MAPK) signaling pathway was the main signal transduction pathway that showed significant enrichment in overexpression DKK4 of PANC-1. The results of GO, pathway analyses, and differentially expressed gene interaction network identified genes that are closely associated with tumor development, including MAPK3, PIK3R3, VAV3, JAG1, and Notch3. The immunohistochemistry and immunofluorescence results suggested that DKK4 is co-expressed with MAPK3 and VAV3 in pancreatic cancer tissues. The results presented here show for the first time that DKK4 is highly expressed in pancreatic cancer tissues. Bioinformatics analysis of a DKK4-overexpressing of PANC-1 identified several oncogenes that are closely associated with tumors, and the MAPK signaling pathway is the core signal transduction pathway. DKK4 can be co-expressed with MAPK3 and VAV3 in pancreatic ductal adenocarcinoma tissues. Thus, DKK4 may have function on the development and progression of pancreatic cancer.
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Affiliation(s)
- Yongsheng Ouyang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Juncheng Pan
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Qiang Tai
- Organ transplantation centre, First Affiliated Hospital Sun Yat-sen University, 58 #, 2nd ZhongShan Road, Guangzhou, GD, 510080, China.
| | - Jingfang Ju
- Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, 11794, USA.
| | - Huaizhi Wang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China.
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29
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Delire B, Stärkel P. The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications. Eur J Clin Invest 2015; 45:609-23. [PMID: 25832714 DOI: 10.1111/eci.12441] [Citation(s) in RCA: 191] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 03/27/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is still a major health problem, often diagnosed at an advanced stage. The multikinase inhibitor sorafenib is to date the sole approved systemic therapy. Several signalling pathways are implicated in tumour development and progression. Among these pathways, the Ras/MAPK pathway is activated in 50-100% of human HCCs and is correlated with a poor prognosis. The aim of this work was to review the main intracellular mechanisms leading to aberrant Ras pathway activation in HCC and the potential therapeutic implications. MATERIALS AND METHODS This review is based on the material found on PubMed up to December 2014. 'Ras signaling, Ras dysregulation, Ras inhibition, MAPK pathway, cancer, hepatocarcinoma and liver cancer' alone or in combination were the main terms used for online research. RESULTS Multiple mechanisms lead to the deregulation of the Ras pathway in liver cancer. Ras and Raf gene mutations are rare events in human hepatocarcinogenesis in contrast to experimental models in rodents. Downregulation of several Ras/MAPK pathway inhibitors such as GAPs, RASSF proteins, DUSP1, Sprouty and Spred proteins is largely implicated in the aberrant activation of this pathway in the context of wild-type Ras and Raf genes. Epigenetic or post-transcriptional mechanisms lead to the downregulation of these tumour suppressor genes. CONCLUSION Ras/MAPK pathway effectors may be considered as potential therapeutic targets in the field of HCC. In particular after the arrival of sorafenib, more Ras/MAPK inhibitors have emerged and are still in preclinical or clinical investigation for HCC therapy.
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Affiliation(s)
- Bénédicte Delire
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Catholic University of Louvain, Brussels, Belgium
| | - Peter Stärkel
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Catholic University of Louvain, Brussels, Belgium.,Department of Gastroenterology, Saint-Luc Academic Hospital and Institute of Clinical Research, Catholic University of Louvain, Brussels, Belgium
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30
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Shirakawa R, Horiuchi H. Ral GTPases: crucial mediators of exocytosis and tumourigenesis. J Biochem 2015; 157:285-99. [DOI: 10.1093/jb/mvv029] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 02/07/2015] [Indexed: 11/12/2022] Open
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31
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The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer. Acta Pharmacol Sin 2015; 36:291-7. [PMID: 25557115 DOI: 10.1038/aps.2014.129] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 10/30/2014] [Indexed: 12/21/2022]
Abstract
Activating RAS mutations are common in human tumors. These mutations are often markers for resistance to therapy and subsequent poor prognosis. So far, targeting the RAF-MEK-ERK and PI3K-AKT signaling pathways downstream of RAS is the only promising approach in the treatment of cancer patients harboring RAS mutations. RAL GTPase, another downstream effector of RAS, is also considered as a therapeutic option for the treatment of RAS-mutant cancers. The RAL GTPase family comprises RALA and RALB, which can have either divergent or similar functions in different tumor models. Recent studies on non-small cell lung cancer (NSCLC) have showed that different RAS mutations selectively activate specific effector pathways. This observation requires broader validation in other tumor tissue types, but if true, will provide a new approach to the treatment of RAS-mutant cancer patients by targeting specific downstream RAS effectors according to the type of RAS mutation. It also suggests that RAL GTPase inhibition will be an important treatment strategy for tumors harboring RAS glycine to cysteine (G12C) or glycien to valine (G12V) mutations, which are commonly found in NSCLC and pancreatic cancer.
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32
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Chan LH, Luk ST, Ma S. Turning hepatic cancer stem cells inside out--a deeper understanding through multiple perspectives. Mol Cells 2015; 38:202-9. [PMID: 25666349 PMCID: PMC4363719 DOI: 10.14348/molcells.2015.2356] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 01/02/2015] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC), a highly malignant disease and the third leading cause of all cancer mortalities worldwide, often responses poorly to current treatments and results in dismal outcomes due to frequent chemoresistance and tumor relapse. The heterogeneity of HCC is an important attribute of the disease. It is the outcome of many factors, including the cross-talk between tumor cells within the tumor microenvironment and the acquisition and accumulation of genetic and epigenetic alterations in tumor cells. In addition, there is accumulating evidence in recent years to show that the malignancy of HCC can be attributed partly to the presence of cancer stem cell (CSC). CSCs are capable to self-renew, differentiate and initiate tumor formation. The regulation of the stem cell-like properties by several important signaling pathways have been found to endow the tumor cells with an increased level of tumorigenicity, chemoresistance, and metastatic ability. In this review, we will discuss the recent findings on hepatic CSCs, with special emphasis on their putative origins, relationship with hepatitis viruses, regulatory signaling networks, tumor microenvironment, and how these factors control the stemness of hepatic CSCs. We will also discuss some novel therapeutic strategies targeted at hepatic CSCs for combating HCC and perspectives of future investigation.
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Affiliation(s)
- Lok-Hei Chan
- Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong
| | - Steve T. Luk
- Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong
| | - Stephanie Ma
- Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong
- State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
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33
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Kim JH, Sohn BH, Lee HS, Kim SB, Yoo JE, Park YY, Jeong W, Lee SS, Park ES, Kaseb A, Kim BH, Kim WB, Yeon JE, Byun KS, Chu IS, Kim SS, Wang XW, Thorgeirsson SS, Luk JM, Kang KJ, Heo J, Park YN, Lee JS. Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation. PLoS Med 2014; 11:e1001770. [PMID: 25536056 PMCID: PMC4275163 DOI: 10.1371/journal.pmed.1001770] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Accepted: 11/07/2014] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications. METHODS AND FINDINGS Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (n = 396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3-3.7; p = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (p = 0.005) but not with late recurrence (p = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (<1 y after surgical resection) (hazard ratio, 1.7; 95% confidence interval, 1.1-2.6; p = 0.01). The potential significance of STAT3 activation in late recurrence was predicted by gene network analysis and validated later. We also developed and validated 4- and 20-gene predictors from the full 233-gene predictor. The main limitation of the study is that most of the patients in our study were hepatitis B virus-positive. Further investigations are needed to test our prediction models in patients with different etiologies of HCC, such as hepatitis C virus. CONCLUSIONS Two independently developed predictors reflected well the differences between early and late recurrence of HCC at the molecular level and provided new biomarkers for risk stratification. Please see later in the article for the Editors' Summary.
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Affiliation(s)
- Ji Hoon Kim
- Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Bo Hwa Sohn
- Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Hyun-Sung Lee
- Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Sang-Bae Kim
- Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Jeong Eun Yoo
- Department of Pathology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Yun-Yong Park
- ASAN Institute for Life Sciences, Asan Medical Center, Department of Medicine, University of Ulsan College of Medicine, Seoul, Korea
| | - Woojin Jeong
- Department of Life Sciences, Division of Life and Pharmaceutical Sciences, Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul, Korea
| | - Sung Sook Lee
- Department of Hematology-Oncology, Inje University Haeundae Paik Hospital, Busan, Korea
| | - Eun Sung Park
- Institute for Medical Convergence, Yonsei University College of Medicine, Seoul, Korea
| | - Ahmed Kaseb
- Department of GI Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Baek Hui Kim
- Department of Pathology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Wan Bae Kim
- Department of Surgery, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jong Eun Yeon
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Kwan Soo Byun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - In-Sun Chu
- Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Sung Soo Kim
- Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Snorri S. Thorgeirsson
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - John M. Luk
- Department of Pharmacology, National University of Singapore, Singapore
| | - Koo Jeong Kang
- Department of Surgery, Keimyung University School of Medicine, Daegu, Korea
| | - Jeonghoon Heo
- Departments of Molecular Biology and Immunology, Kosin University College of Medicine, Busan, Korea
| | - Young Nyun Park
- Department of Pathology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Ju-Seog Lee
- Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
- * E-mail:
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34
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Gentry LR, Martin TD, Reiner DJ, Der CJ. Ral small GTPase signaling and oncogenesis: More than just 15minutes of fame. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:2976-2988. [PMID: 25219551 DOI: 10.1016/j.bbamcr.2014.09.004] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 09/03/2014] [Accepted: 09/04/2014] [Indexed: 01/26/2023]
Abstract
Since their discovery in 1986, Ral (Ras-like) GTPases have emerged as critical regulators of diverse cellular functions. Ral-selective guanine nucleotide exchange factors (RalGEFs) function as downstream effectors of the Ras oncoprotein, and the RalGEF-Ral signaling network comprises the third best characterized effector of Ras-dependent human oncogenesis. Because of this, Ral GTPases as well as their effectors are being explored as possible therapeutic targets in the treatment of RAS mutant cancer. The two Ral isoforms, RalA and RalB, interact with a variety of downstream effectors and have been found to play key and distinct roles in both normal and neoplastic cell physiology including regulation of vesicular trafficking, migration and invasion, tumor formation, metastasis, and gene expression. In this review we provide an overview of Ral biochemistry and biology, and we highlight recent discoveries.
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Affiliation(s)
- Leanna R Gentry
- University of North Carolina at Chapel Hill, Department of Pharmacology, Chapel Hill, NC, USA
| | | | - David J Reiner
- Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA
| | - Channing J Der
- University of North Carolina at Chapel Hill, Department of Pharmacology, Chapel Hill, NC, USA; University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
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35
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Ezzeldin M, Borrego-Diaz E, Taha M, Esfandyari T, Wise AL, Peng W, Rouyanian A, Asvadi Kermani A, Soleimani M, Patrad E, Lialyte K, Wang K, Williamson S, Abdulkarim B, Olyaee M, Farassati F. RalA signaling pathway as a therapeutic target in hepatocellular carcinoma (HCC). Mol Oncol 2014; 8:1043-53. [PMID: 24785097 DOI: 10.1016/j.molonc.2014.03.020] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 03/12/2014] [Accepted: 03/24/2014] [Indexed: 12/23/2022] Open
Abstract
Ral (Ras like) leads an important proto-oncogenic signaling pathway down-stream of Ras. In this work, RalA was found to be significantly overactivated in hepatocellular carcinoma (HCC) cells and tissues as compared to non-malignant samples. Other elements of RalA pathway such as RalBP1 and RalGDS were also expressed at higher levels in malignant samples. Inhibition of RalA by gene-specific silencing caused a robust decrease in the viability and invasiveness of HCC cells. Additionally, the use of geranyl-geranyl transferase inhibitor (GGTI, an inhibitor of Ral activation) and Aurora kinase inhibitor II resulted in a significant decrease in the proliferation of HCC cells. Furthermore, RalA activation was found to be at a higher level of activation in HCC stem cells that express CD133. Transgenic mouse model for HCC (FXR-Knockout) also revealed an elevated level of RalA-GTP in the liver tumors as compared to background animals. Finally, subcutaneous mouse model for HCC confirmed effectiveness of inhibition of aurora kinase/RalA pathway in reducing the tumorigenesis of HCC cells in vivo. In conclusion, RalA overactivation is an important determinant of malignant phenotype in differentiated and stem cells of HCC and can be considered as a target for therapeutic intervention.
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Affiliation(s)
- Mohamad Ezzeldin
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Emma Borrego-Diaz
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Mohammad Taha
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Tuba Esfandyari
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Amanda L Wise
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Warner Peng
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Alex Rouyanian
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Atabak Asvadi Kermani
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Mina Soleimani
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Elham Patrad
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Kristina Lialyte
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Kun Wang
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Stephen Williamson
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Bashar Abdulkarim
- The University of Kansas Medical Center, Department of Surgery, Kansas City, KS, USA
| | - Mojtaba Olyaee
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Faris Farassati
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
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