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Pyo JS, Min KW, Oh IH, Lim DH, Son BK. Clinicopathological significance and the associated signaling pathway of p21-activated kinase 1 (PAK1) in colorectal cancer. Pathol Res Pract 2023; 251:154820. [PMID: 37801909 DOI: 10.1016/j.prp.2023.154820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/11/2023] [Accepted: 09/14/2023] [Indexed: 10/08/2023]
Abstract
The aim of this study was to evaluate the clinicopathological significance and associated signaling pathways of p21-activated kinase 1 (PAK1) in colorectal cancer (CRC). PAK1 immunohistochemical expression was investigated in 246 human CRC tissues to evaluate its clinicopathological significance and prognostic role. Correlations between PAK1 and the immunoscore, HIF-1α, and pFOXO1 were also evaluated. PAK1 was expressed in 169 of 246 CRC tissues (68.7%). PAK1 expression significantly correlated with the metastatic lymph node ratio (P = 0.023). However, PAK1 expression did not correlate with tumor size, tumor location, tumor differentiation, lymphovascular and perineural invasion, or distant metastasis. PAK1 expression was significantly higher in CRC with a low immunoscore than in CRC with a high immunoscore (P = 0.017). In addition, there were significant correlations between PAK1, HIF-1α, and pFOXO1 expression (P = 0.001 and P = 0.024, respectively). Patients with PAK1 expression had worse overall and recurrence-free survival than those without PAK1 expression (P 0.001 and P = 0.001, respectively). PAK1 expression was significantly correlated with worse prognosis in CRCs patients. In addition, PAK1 expression was significantly correlated with a low immunoscore and high expression of HIF-1α and pFOXO1 in CRCs.
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Affiliation(s)
- Jung-Soo Pyo
- Department of Pathology, Uijeongbu Eulji Medical Center, Eulji University School of Medicine, Gyeonggi-do, Republic of Korea
| | - Kyueng-Whan Min
- Department of Pathology, Uijeongbu Eulji Medical Center, Eulji University School of Medicine, Gyeonggi-do, Republic of Korea
| | - Il Hwan Oh
- Department of Internal Medicine, Uijeongbu Eulji Medical Center, Eulji University School of Medicine, Gyeonggi-do, Republic of Korea
| | - Dae Hyun Lim
- Department of Internal Medicine, Uijeongbu Eulji Medical Center, Eulji University School of Medicine, Gyeonggi-do, Republic of Korea
| | - Byoung Kwan Son
- Department of Internal Medicine, Uijeongbu Eulji Medical Center, Eulji University School of Medicine, Gyeonggi-do, Republic of Korea.
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Kothapalli KSD, Park HG, Kothapalli NSL, Brenna JT. FADS2 function at the major cancer hotspot 11q13 locus alters fatty acid metabolism in cancer. Prog Lipid Res 2023; 92:101242. [PMID: 37597812 DOI: 10.1016/j.plipres.2023.101242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 07/31/2023] [Accepted: 08/15/2023] [Indexed: 08/21/2023]
Abstract
Dysregulation of fatty acid metabolism and de novo lipogenesis is a key driver of several cancer types through highly unsaturated fatty acid (HUFA) signaling precursors such as arachidonic acid. The human chromosome 11q13 locus has long been established as the most frequently amplified in a variety of human cancers. The fatty acid desaturase genes (FADS1, FADS2 and FADS3) responsible for HUFA biosynthesis localize to the 11q12-13.1 region. FADS2 activity is promiscuous, catalyzing biosynthesis of several unsaturated fatty acids by Δ6, Δ8, and Δ4 desaturation. Our main aim here is to review known and putative consequences of FADS2 dysregulation due to effects on the 11q13 locus potentially driving various cancer types. FADS2 silencing causes synthesis of sciadonic acid (5Z,11Z,14Z-20:3) in MCF7 cells and breast cancer in vivo. 5Z,11Z,14Z-20:3 is structurally identical to arachidonic acid (5Z,8Z,11Z,14Z-20:4) except it lacks the internal Δ8 double bond required for prostaglandin and leukotriene synthesis, among other eicosanoids. Palmitic acid has substrate specificity for both SCD and FADS2. Melanoma, prostate, liver and lung cancer cells insensitive to SCD inhibition show increased FADS2 activity and sapienic acid biosynthesis. Elevated serum mead acid levels found in hepatocellular carcinoma patients suggest an unsatisfied demand for arachidonic acid. FADS2 circular RNAs are at high levels in colorectal and lung cancer tissues. FADS2 circular RNAs are associated with shorter overall survival in colorectal cancer patients. The evidence thusfar supports an effort for future research on the role of FADS2 as a tumor suppressor in a range of neoplastic disorders.
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Affiliation(s)
- Kumar S D Kothapalli
- Dell Pediatric Research Institute, Dell Medical School and Department of Nutritional Sciences, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA.
| | - Hui Gyu Park
- Dell Pediatric Research Institute, Dell Medical School and Department of Nutritional Sciences, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA
| | | | - J Thomas Brenna
- Dell Pediatric Research Institute, Dell Medical School and Department of Nutritional Sciences, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA.
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Gao Y, Guan L, Jia R, Xiao W, Han Y, Li Y, Tang P, Yu Z, Zhang H. High expression of PPFIA1 in human esophageal squamous cell carcinoma correlates with tumor metastasis and poor prognosis. BMC Cancer 2023; 23:417. [PMID: 37158817 PMCID: PMC10169376 DOI: 10.1186/s12885-023-10872-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 04/21/2023] [Indexed: 05/10/2023] Open
Abstract
BACKGROUND PTPRF interacting protein alpha 1 (PPFIA1) is reportedly related to the occurrence and progression of several kinds of malignancies. However, its role in esophageal squamous cell carcinoma (ESCC) is unclear. This current study investigated the prognostic significance and biological functions of PPFIA1 in ESCC. METHODS Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), and Gene Expression Omnibus (GEO) were used to investigate PPFIA1 expression in esophageal cancer. The relationship between PPFIA1 expression and clinicopathological characteristics and patient survival was evaluated in GSE53625 dataset, and verified in the cDNA array based on qRT-PCR and tissue microarray (TMA) dataset based on immunohistochemistry. The impact of PPFIA1 on the migration and invasion of cancer cells were investigated by wound-healing and transwell assays, respectively. RESULTS The expression of PPFIA1 was obviously increased in ESCC tissues versus adjacent esophageal tissues according to online database analyses (all P < 0.05). High PPFIA1 expression was closely related to several clinicopathological characteristics, including tumor location, histological grade, tumor invasion depth, lymph node metastasis, and tumor-node-metastasis (TNM) stage. High PPFIA1 expression was related to worse outcomes and was identified as an independent prognostic factor of overall survival in ESCC patients (GSE53625 dataset, P = 0.019; cDNA array dataset, P < 0.001; TMA dataset, P = 0.039). Downregulation of PPFIA1 expression can significantly reduce the migration and invasion ability of ESCC cells. CONCLUSION PPFIA1 is related to the migration and invasion of ESCC cells, and can be used as a potential biomarker to evaluate the prognosis of ESCC patients.
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Affiliation(s)
- Yongyin Gao
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin, 300060, China
| | - Lizhao Guan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Ran Jia
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and PeKing Union Medical College, Shenzhen, 518116, China
| | - Wanyi Xiao
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin, 300060, China
| | - Youming Han
- Binhai Hospital of Tianjin Medical University General Hospital, Tianjin, 300456, China
| | - Yue Li
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin, 300060, China
| | - Peng Tang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin, 300060, China.
| | - Zhentao Yu
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and PeKing Union Medical College, Shenzhen, 518116, China.
| | - Hongdian Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin, 300060, China.
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Prognostic significance and immune correlates of FADD in penile squamous cell carcinoma. Virchows Arch 2023; 482:869-878. [PMID: 36813950 DOI: 10.1007/s00428-023-03514-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/25/2022] [Accepted: 02/03/2023] [Indexed: 02/24/2023]
Abstract
Penile squamous cell carcinoma (PSCC) with a poor prognosis lacks reliable biomarkers for stratifying patients. Fas-associated death domain (FADD) could regulate cell proliferation and has shown promising diagnostic and prognostic significance in multiple cancers. However, researchers have not determined how FADD exerts its effect on PSCC. In this study, we set out to investigate the clinical features of FADD and the prognostic impact of PSCC. Additionally, we also assessed the role of affecting the immune environment in PSCC. Immunohistochemistry was carried out to evaluate the protein expression of FADD. The difference between FADDhigh and FADDlow was explored by RNA sequencing from available cases. The immune environment evaluation of CD4, CD8, and Foxp3 was performed by immunohistochemical. In this study, we found that FADD was overexpressed in 19.6 (39/199) patients, and the overexpression of FADD was associated with phimosis (p=0.007), N stage (p<0.001), clinical stage (p=0.001), and histologic grade (p=0.005). The overexpression of FADD was an independent prognostic factor for both PFS (HR 3.976, 95% CI 2.413-6.553, p<0.001) and OS (HR 4.134, 95% CI 2.358-7.247, p<0.001). In addition, overexpression of FADD was mainly linked to T cell activation and PD-L1 expression combined with PD-L1 checkpoint in cancer. Further validation demonstrated that overexpression of FADD was positively correlated with the infiltration of Foxp3 in PSCC (p=0.0142). It is the first time to show that overexpression of FADD is an adjunct biomarker with poor prognosis in PSCC and could also serve as a tumor immune environment regulator.
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Liu Y, Li X, Zhou X, Wang J, Ao X. FADD as a key molecular player in cancer progression. Mol Med 2022; 28:132. [DOI: 10.1186/s10020-022-00560-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/05/2022] [Accepted: 10/19/2022] [Indexed: 11/11/2022] Open
Abstract
AbstractCancer is a leading disease-related cause of death worldwide. Despite advances in therapeutic interventions, cancer remains a major global public health problem. Cancer pathogenesis is extremely intricate and largely unknown. Fas-associated protein with death domain (FADD) was initially identified as an adaptor protein for death receptor-mediated extrinsic apoptosis. Recent evidence suggests that FADD plays a vital role in non-apoptotic cellular processes, such as proliferation, autophagy, and necroptosis. FADD expression and activity of are modulated by a complicated network of processes, such as DNA methylation, non-coding RNA, and post-translational modification. FADD dysregulation has been shown to be closely associated with the pathogenesis of numerous types of cancer. However, the detailed mechanisms of FADD dysregulation involved in cancer progression are still not fully understood. This review mainly summarizes recent findings on the structure, functions, and regulatory mechanisms of FADD and focuses on its role in cancer progression. The clinical implications of FADD as a biomarker and therapeutic target for cancer patients are also discussed. The information reviewed herein may expand researchers’ understanding of FADD and contribute to the development of FADD-based therapeutic strategies for cancer patients.
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Lei K, Luo M, Tu Z, Lv S, Liu J, Gong C, Ye M, Wu M, Sheng Y, Long X, Li J, Zhu X, Huang K. Comprehensive analysis of the prognostic implications and functional exploration of PAK gene family in human cancer. Cancer Cell Int 2022; 22:275. [PMID: 36064705 PMCID: PMC9442929 DOI: 10.1186/s12935-022-02689-6] [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: 05/05/2022] [Accepted: 08/18/2022] [Indexed: 11/30/2022] Open
Abstract
Background The p21-activated kinase (PAK) family (PAKs) plays a key role in the formation and development of human tumors. However, a systematic analysis of PAKs in human cancers is lacking and the potential role of PAKs in cancer immunity has not been explored. Methods We used datasets from in The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression database (GTEx). Results Based on TCGA datasets most PAKs show noteworthy differences in expression between tumors and corresponding normal tissues or across different tumor tissues. Patients with high expression of PAKs often show a worse prognosis. However, copy number variation, mutation, and DNA methylation of PAKs have limited impact on tumor development. Further analysis showed that the impact of PAKs on immunity varies with the type of tumor and the respective tumor microenvironment. PAK1 and PAK4 may be stronger predictors of immune characteristics, and are more suitable as drugs and molecular therapeutic targets. Furthermore, Cox regression analysis revealed that a PAK gene signature could be used as an independent prognostic factor for lower grade glioma (LGG) and glioblastoma (GBM). Gene set enrichment analysis (GSEA) analysis indicated that PAK genes may affect the occurrence and development of GBM through the PI3K signaling pathway. Further experiments verified that PAK1 and AKT1 have a significant interaction in GBM cells, and inhibiting the overactivation of PAK1 can significantly inhibit the proliferation of GBM cells. Conclusions Our study provides a rationale for further research on the prognostic and therapeutic potential of PAKs in human tumors. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02689-6.
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Affiliation(s)
- Kunjian Lei
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Min Luo
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,East China Institute of Digital Medical Engineering, Shangrao, 334000, Jiangxi, People's Republic of China
| | - Zewei Tu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,East China Institute of Digital Medical Engineering, Shangrao, 334000, Jiangxi, People's Republic of China
| | - Shigang Lv
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Junzhe Liu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Chuandong Gong
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Minhua Ye
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Miaojing Wu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Yilei Sheng
- Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Xiaoyan Long
- East China Institute of Digital Medical Engineering, Shangrao, 334000, Jiangxi, People's Republic of China
| | - Jingying Li
- Department of Comprehensive Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.
| | - Xingen Zhu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China. .,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.
| | - Kai Huang
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China. .,Institute of Neuroscience, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.
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Li S, Chen R, Luo W, Lin J, Chen Y, Wang Z, Lin W, Li B, Wang J, Yang J. Identification of a Four Cancer Stem Cell-Related Gene Signature and Establishment of a Prognostic Nomogram Predicting Overall Survival of Pancreatic Adenocarcinoma. Comb Chem High Throughput Screen 2022; 25:2070-2081. [PMID: 35048799 DOI: 10.2174/1386207325666220113142212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/10/2021] [Accepted: 11/19/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cancer stem cells (CSCs) are now being considered as the initial component in the development of pancreatic adenocarcinoma (PAAD). Our aim was to develop a CSCrelated signature to assess the prognosis of PAAD patients for the optimization of treatment. METHODS Differentially expressed genes (DEGs) between pancreatic tumor and normal tissue in the Cancer Genome Atlas (TCGA) were screened out, and the weighted gene correlation network analysis (WGCNA) was employed to identify the CSC-related gene sets. Then, univariate, Lasso Cox regression analyses and multivariate Cox regression were applied to construct a prognostic signature using the CSC-related genes. Its prognostic performance was validated in TCGA and ICGC cohorts. Furthermore, Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors in PAAD, and a prognostic nomogram was established. RESULTS The Kaplan-Meier analysis, ROC curve and C-index indicated the good performance of the CSC-related signature at predicting overall survival (OS). Univariate Cox regression and multivariate Cox regression revealed that the CSC-related signature was an independent prognostic factor in PAAD. The nomogram was superior to the risk model and AJCC stage in predicting OS. In terms of mutation and tumor immunity, patients in the high-risk group had higher tumor mutation burden (TMB) scores than patients in the low-risk group, and the immune score and the ESTIMATE score were significantly lower in the high-risk group. Moreover, according to the results of principal component analysis (PCA) and Gene Set Enrichment Analysis (GSEA), the low-risk and high-risk groups displayed different stemness statuses based on the risk model. CONCLUSION Our study identified four CSC-related gene signatures and established a prognostic nomogram that reliably predicts OS in PAAD. The findings may support new ideas for screening therapeutic targets to inhibit stem characteristics and the development of PAAD.
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Affiliation(s)
- Shuanghua Li
- Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China
| | - Rui Chen
- Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China
| | - Wang Luo
- Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China
| | - Jinyu Lin
- Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China
| | - Yunlong Chen
- Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China
| | - Zhuangxiong Wang
- Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China
| | - Wenjun Lin
- Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China
| | - Baihong Li
- Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China
| | - Junfeng Wang
- Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China
| | - Jian Yang
- Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China
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Park HG, Kim JH, Dancer AN, Kothapalli KS, Brenna JT. The aromatase inhibitor letrozole restores FADS2 function in ER+ MCF7 human breast cancer cells. Prostaglandins Leukot Essent Fatty Acids 2021; 171:102312. [PMID: 34303883 DOI: 10.1016/j.plefa.2021.102312] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 12/26/2022]
Abstract
PURPOSE Plasticity in fatty acid metabolism is increasingly recognized as a major feature influencing cancer progression and efficacy of treatments. Estrogen receptor positive MCF7 human breast cancer cells have long been known to have no FADS2-mediated Δ6-desaturase activity. Our objective was to examine the effect of estrogen and the "antiestrogen" aromatase inhibitor letrozole, on Δ5- and Δ6-desaturase synthesized fatty acids in vitro. METHODS Eicosa-11,14-dienoic acid (20:2n-6), a known substrate for both FADS1 and FADS2, was used as a sentinel of relative FADS2 and FADS1 activity. MCF7 cells and four additional estrogen responsive wild type cell lines (HepG2, SK-N-SH, Y79 and Caco2) were studied. FAME were quantified by GC-FID and structures identified by GCCACI-MS/MS. RESULTS In all five cell lines, estrogen caused a dose dependent decrease in sciadonic acid (5,11,14-20:3, ScA) via apparent inhibition of FADS1 activity, and had no effect on FADS2 catalyzed synthesis of dihomo-gamma linolenic acid (8,11,14-20:3; DGLA). In MCF7 cells, letrozole caused a dose dependent increase in FADS2-catalyzed DGLA synthesis, which plateaued in SK-N-SH cells. CONCLUSION Letrozole restores Δ6-desaturase mediated synthesis of the anti-inflammatory PGE1-precursor DGLA in vitro and is the first endocrine-active agent to have opposing effects on FADS1 and FADS2 catalyzed activities.
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Affiliation(s)
- Hui Gyu Park
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA
| | - Jae Hun Kim
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA
| | - Andrew N Dancer
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA
| | - Kumar S Kothapalli
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA
| | - J Thomas Brenna
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA.
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Manasa P, Sidhanth C, Krishnapriya S, Vasudevan S, Ganesan TS. Oncogenes in high grade serous adenocarcinoma of the ovary. Genes Cancer 2020; 11:122-136. [PMID: 33488950 PMCID: PMC7805537 DOI: 10.18632/genesandcancer.206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 10/15/2020] [Indexed: 12/19/2022] Open
Abstract
High grade serous ovarian cancer is characterized by relatively few mutations occurring at low frequency, except in TP53. However other genetic aberrations such as copy number variation alter numerous oncogenes and tumor suppressor genes. Oncogenes are positive regulators of tumorigenesis and play a critical role in cancer cell growth, proliferation, and survival. Accumulating evidence suggests that they are crucial for the development and the progression of high grade serous ovarian carcinoma (HGSOC). Though many oncogenes have been identified, no successful inhibitors targeting these molecules and their associated pathways are available. This review discusses oncogenes that have been identified recently in HGSOC using different screening strategies. All the genes discussed in this review have been functionally characterized both in vitro and in vivo and some of them are able to transform immortalized ovarian surface epithelial and fallopian tube cells upon overexpression. However, it is necessary to delineate the molecular pathways affected by these oncogenes for the development of therapeutic strategies.
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Affiliation(s)
- Pacharla Manasa
- Laboratory for Cancer Biology, Department of Medical Oncology and Clinical Research Cancer Institute (WIA), Chennai, India
| | - Chirukandath Sidhanth
- Laboratory for Cancer Biology, Department of Medical Oncology and Clinical Research Cancer Institute (WIA), Chennai, India
| | - Syama Krishnapriya
- Laboratory for Cancer Biology, Department of Medical Oncology and Clinical Research Cancer Institute (WIA), Chennai, India
| | - Sekar Vasudevan
- Laboratory for Cancer Biology, Department of Medical Oncology and Clinical Research Cancer Institute (WIA), Chennai, India
| | - Trivadi S Ganesan
- Laboratory for Cancer Biology, Department of Medical Oncology and Clinical Research Cancer Institute (WIA), Chennai, India
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High expression of MYEOV reflects poor prognosis in non-small cell lung cancer. Gene 2020; 770:145337. [PMID: 33278551 DOI: 10.1016/j.gene.2020.145337] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 09/09/2020] [Accepted: 11/27/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND The myeloma overexpressed gene (MYEOV) plays a critical role in tumorigenesis in a variety of cancers. However, little is known of the prognosis and immune infiltration associated with MYEOV in non-small cell lung cancer (NSCLC). METHODS We used several databases (Oncomine, TCGA, and GEO) to analysis the expression, prognosis, and immune infiltration, associated with MYEOV in NSCLC. We also used RT-qPCR and immunohistochemistry to investigate the expression and prognosis of MYEOV in NSCLC. RESULTS Compared with normal tissues, high MYEOV expression in NSCLC was observed in Oncomine database, and was validated in the TCGA database. High MYEOV expression was significantly associated with different subtypes of NSCLC. Moreover, high MYEOV expression was closely related with a poorer overall survival in NSCLC in TCGA cohort, and was validated in GEO database. Simultaneously, high expression of MYEOV correlates with clinical relevance of NSCLC. Specifically, MYEOV expression was negatively correlated with infiltrating levels of tumor purity and B cells in LUAD. MYEOV expression was negatively correlated with infiltrating levels of tumor purity, and positively associated with CD8 + T cells, CD4 + T cells, dendritic cells, and neutrophils in LUSC. GSEA also revealed that high MYEOV expression were enriched in certain cancer-specific pathways. In addition, RT-qPCR and immunohistochemistry showed MYEOV expression was higher in NSCLC compared to the normal tissues. Finally, high MYEOV expression was closely related with poorer overall survival of NSCLC in an independent validation cohort. CONCLUSION Our analyses indicate that MYEOV can be used as a prognostic biomarker for determining prognosis and immune infiltration in NSCLC.
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Kothapalli KSD, Park HG, Brenna JT. Polyunsaturated fatty acid biosynthesis pathway and genetics. implications for interindividual variability in prothrombotic, inflammatory conditions such as COVID-19 ✰,✰✰,★,★★. Prostaglandins Leukot Essent Fatty Acids 2020; 162:102183. [PMID: 33038834 PMCID: PMC7527828 DOI: 10.1016/j.plefa.2020.102183] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/29/2020] [Accepted: 09/29/2020] [Indexed: 12/15/2022]
Abstract
COVID-19 symptoms vary from silence to rapid death, the latter mediated by both a cytokine storm and a thrombotic storm. SARS-CoV (2003) induces Cox-2, catalyzing the synthesis, from highly unsaturated fatty acids (HUFA), of eicosanoids and docosanoids that mediate both inflammation and thrombosis. HUFA balance between arachidonic acid (AA) and other HUFA is a likely determinant of net signaling to induce a healthy or runaway physiological response. AA levels are determined by a non-protein coding regulatory polymorphisms that mostly affect the expression of FADS1, located in the FADS gene cluster on chromosome 11. Major and minor haplotypes in Europeans, and a specific functional insertion-deletion (Indel), rs66698963, consistently show major differences in circulating AA (>50%) and in the balance between AA and other HUFA (47-84%) in free living humans; the indel is evolutionarily selective, probably based on diet. The pattern of fatty acid responses is fully consistent with specific genetic modulation of desaturation at the FADS1-mediated 20:3→20:4 step. Well established principles of net tissue HUFA levels indicate that the high linoleic acid and low alpha-linoleic acid in populations drive the net balance of HUFA for any individual. We predict that fast desaturators (insertion allele at rs66698963; major haplotype in Europeans) are predisposed to higher risk and pathological responses to SARS-CoV-2 could be reduced with high dose omega-3 HUFA.
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Affiliation(s)
- Kumar S D Kothapalli
- Dell Pediatric Research Institute, Depts of Pediatrics, of Chemistry, and of Nutrition, University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, United States.
| | - Hui Gyu Park
- Dell Pediatric Research Institute, Depts of Pediatrics, of Chemistry, and of Nutrition, University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, United States.
| | - J Thomas Brenna
- Dell Pediatric Research Institute, Depts of Pediatrics, of Chemistry, and of Nutrition, University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, United States; Division of Nutritional Sciences, Cornell University, Ithaca, NY, United States.
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12
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GAB2 and GAB3 are expressed in a tumor stage-, grade- and histotype-dependent manner and are associated with shorter progression-free survival in ovarian cancer. J Cell Commun Signal 2020; 15:57-70. [PMID: 32888136 DOI: 10.1007/s12079-020-00582-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 08/31/2020] [Indexed: 02/06/2023] Open
Abstract
Ovarian cancer is the most lethal gynecological malignancy and molecular mechanisms of its progression and metastasis are not completely understood. Some members of GAB (GRB2-associated binding) protein family have been reported to be involved in tumor cell proliferation and metastasis in various cancer types. In the present study, we analyzed the expression of GAB proteins (GAB1, GAB2 and GAB3) in ovarian cancer compared to normal ovarian tissue, in terms of tumor stage, tumor grade and histological type. Differential expression analyses performed in R programming environment using multiple transcriptome datasets (n = 1449) showed that GAB1 expression is decreased in ovarian cancer independently of tumor stage, grade and histotype. Unlike GAB1, expression of GAB2 and GAB3 are increased from early stage to late stage and from low grade to high grade in epithelial ovarian cancer. GAB2 and GAB3 also showed histotype-dependent expression. GAB3 was computed as a top gene whose expression most significantly changed between tumor cells from primary tumor, metastases and ascites. High expression of GAB2 and GAB3 was shown to be associated with shorter progression-free survival in ovarian cancer. This study shows that GAB2 and GAB3 can be important regulators of tumor progression and metastasis in ovarian cancer.
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13
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Qiao XR, Zhang X, Mu L, Tian J, Du Y. GRB2-associated binding protein 2 regulates multiple pathways associated with the development of prostate cancer. Oncol Lett 2020; 20:99. [PMID: 32831918 PMCID: PMC7439102 DOI: 10.3892/ol.2020.11960] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 05/18/2020] [Indexed: 12/24/2022] Open
Abstract
The development of prostate cancer is complicated and involves a number of tumor-associated gene expression level abnormalities. Gene chip technology is a high-throughput method that can detect gene expression levels in different tissues and cells on a large scale. In the present study, gene chip technology was used to screen differentially expressed genes in PC-3 human prostate cancer cells following GRB-associated binding protein 2 (GAB2) gene knockdown, and the corresponding biological information was analyzed to investigate the role of GAB2 in prostate cancer. The PC-3 human prostate cancer cell GAB2 gene was knocked out and gene chip hybridization and bioinformatics methods were used to analyze the classical pathway and predict upstream regulatory molecules, disease and function associations and genetic interaction networks. According to the screening conditions |fold change|>1 and P<0.05, 1,242 differential genes were screened; 665 genes were upregulated, and 577 genes were downregulated. Ingenuity Pathway Analysis software demonstrated that GAB2 regulates pathways, such as the superpathway of cholesterol biosynthesis and p53 signaling in cells, and serves a role in diseases and functions such as 'non-melanoma solid tumors', 'viral infections' and 'morbidity or mortality'. In the occurrence and development of prostate cancer, factors such as the activation of genes involved in the proliferative cycle, abnormalities in metabolism-associated enzyme gene activities and viral infection play key roles. The present study provides novel research directions and therapeutic targets for prostate cancer.
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Affiliation(s)
- Xiang-Rui Qiao
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.,Key Laboratory of Molecular Cardiology, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China
| | - Xinwei Zhang
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China.,Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Lijun Mu
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China
| | - Juanhua Tian
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China
| | - Yuefeng Du
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China.,Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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14
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Bautista L, Knippler CM, Ringel MD. p21-Activated Kinases in Thyroid Cancer. Endocrinology 2020; 161:bqaa105. [PMID: 32609833 PMCID: PMC7417880 DOI: 10.1210/endocr/bqaa105] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 06/24/2020] [Indexed: 02/07/2023]
Abstract
The family of p21-activated kinases (PAKs) are oncogenic proteins that regulate critical cellular functions. PAKs play central signaling roles in the integrin/CDC42/Rho, ERK/MAPK, PI3K/AKT, NF-κB, and Wnt/β-catenin pathways, functioning both as kinases and scaffolds to regulate cell motility, mitosis and proliferation, cytoskeletal rearrangement, and other cellular activities. PAKs have been implicated in both the development and progression of a wide range of cancers, including breast cancer, pancreatic melanoma, thyroid cancer, and others. Here we will discuss the current knowledge on the structure and biological functions of both group I and group II PAKs, as well as the roles that PAKs play in oncogenesis and progression, with a focus on thyroid cancer and emerging data regarding BRAF/PAK signaling.
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Affiliation(s)
- Luis Bautista
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, and Cancer Biology Program, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio
| | - Christina M Knippler
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, and Cancer Biology Program, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio
- Department of Hematology and Medical Oncology, Emory University and Winship Cancer Institute, Atlanta, Georgia
| | - Matthew D Ringel
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, and Cancer Biology Program, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio
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15
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Tang R, Ji J, Ding J, Huang J, Gong B, Zhang X, Li F. Overexpression of MYEOV predicting poor prognosis in patients with pancreatic ductal adenocarcinoma. Cell Cycle 2020; 19:1602-1610. [PMID: 32420813 PMCID: PMC7469688 DOI: 10.1080/15384101.2020.1757243] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 04/08/2020] [Accepted: 04/10/2020] [Indexed: 01/28/2023] Open
Abstract
Myeloma Overexpressed (MYEOV) is closely related to cell growth and differentiation in many cancer types. However, the role of this protein-coding gene in pancreatic ductal adenocarcinoma (PDAC) has rarely been investigated. In this study, we demonstrated that MYEOV was higher expressed in tumor tissues compared with adjacent normal pancreas tissues (ANPTs) both in mRNA and protein levels. We also performed bioinformatic analysis and found high MYEOV expression was positively correlated with tumor differentiation (P = 0.004), lymph node metastasis (P = 0.016) and TNM stage (P = 0.001). Moreover, Kaplan-Meier and Cox proportional-hazards analyses indicated that high MYEOV expression was significantly associated with poor survival in patients with PDAC and that MYEOV was an independent prognostic factor for overall survival in patients with PDAC. Geneset Enrichment Analysis (GSEA) result showed that high expression of MYEOV facilitates glycolysis of tumor cells in PDAC and validated in cellular assays. In conclusion, our results suggest that MYEOV acts as an oncogene in PDAC and can therefore serve as a biomarker for the prognosis of patients with PDAC.
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Affiliation(s)
- Rui Tang
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Jianmei Ji
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Jun Ding
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Jinxin Huang
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Biao Gong
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Xiwen Zhang
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Fu Li
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
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16
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FADD in Cancer: Mechanisms of Altered Expression and Function, and Clinical Implications. Cancers (Basel) 2019; 11:cancers11101462. [PMID: 31569512 PMCID: PMC6826683 DOI: 10.3390/cancers11101462] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/25/2019] [Accepted: 09/27/2019] [Indexed: 12/15/2022] Open
Abstract
FADD was initially described as an adaptor molecule for death receptor-mediated apoptosis, but subsequently it has been implicated in nonapoptotic cellular processes such as proliferation and cell cycle control. During the last decade, FADD has been shown to play a pivotal role in most of the signalosome complexes, such as the necroptosome and the inflammasome. Interestingly, various mechanisms involved in regulating FADD functions have been identified, essentially posttranslational modifications and secretion. All these aspects have been thoroughly addressed in previous reviews. However, FADD implication in cancer is complex, due to pleiotropic effects. It has been reported either as anti- or protumorigenic, depending on the cell type. Regulation of FADD expression in cancer is a complex issue since both overexpression and downregulation have been reported, but the mechanisms underlying such alterations have not been fully unveiled. Posttranslational modifications also constitute a relevant mechanism controlling FADD levels and functions in tumor cells. In this review, we aim to provide detailed, updated information on alterations leading to changes in FADD expression and function in cancer. The participation of FADD in various biological processes is recapitulated, with a mention of interesting novel functions recently proposed for FADD, such as regulation of gene expression and control of metabolic pathways. Finally, we gather all the available evidence regarding the clinical implications of FADD alterations in cancer, especially as it has been proposed as a potential biomarker with prognostic value.
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17
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Hollis RL, Churchman M, Michie CO, Rye T, Knight L, McCavigan A, Perren T, Williams ARW, McCluggage WG, Kaplan RS, Jayson GC, Oza A, Harkin DP, Herrington CS, Kennedy R, Gourley C. High EMSY expression defines a BRCA-like subgroup of high-grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum. Cancer 2019; 125:2772-2781. [PMID: 31154673 PMCID: PMC6771827 DOI: 10.1002/cncr.32079] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 01/11/2019] [Accepted: 01/15/2019] [Indexed: 11/14/2022]
Abstract
BACKGROUND Approximately half of high-grade serous ovarian carcinomas (HGSOCs) demonstrate homologous recombination repair (HR) pathway defects, resulting in a distinct clinical phenotype comprising hypersensitivity to platinum, superior clinical outcome, and greater sensitivity to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. EMSY, which is known to be amplified in breast and ovarian cancers, encodes a protein reported to bind and inactivate BRCA2. Thus, EMSY overexpression may mimic BRCA2 mutation, resulting in HR deficiency. However, to our knowledge, the phenotypic consequences of EMSY overexpression in HGSOC patients has not been explored. METHODS Here we investigate the impact of EMSY expression on clinical outcome and sensitivity to platinum-based chemotherapy using available data from transcriptomically characterized HGSOC cohorts. RESULTS High EMSY expression was associated with better clinical outcome in a cohort of 265 patients with HGSOC from Edinburgh (overall survival multivariable hazard ratio, 0.58 [95% CI, 0.38-0.88; P = .011] and progression-free survival multivariable hazard ratio, 0.62 [95% CI, 0.40-0.96; P = .030]). Superior outcome also was demonstrated in the Medical Research Council ICON7 clinical trial and multiple publicly available data sets. Patients within the Edinburgh cohort who had high EMSY expression were found to demonstrate greater rates of complete response to multiple platinum-containing chemotherapy regimens (radiological complete response rate of 44.4% vs 12.5% at second exposure; P = .035) and corresponding prolonged time to disease progression (median, 151.5 days vs 60.5 days after third platinum exposure; P = .004). CONCLUSIONS Patients with HGSOCs demonstrating high EMSY expression appear to experience prolonged survival and greater platinum sensitivity, reminiscent of BRCA-mutant cases. These data are consistent with the notion that EMSY overexpression may render HGSOCs HR deficient.
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Affiliation(s)
- Robert L. Hollis
- Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUnited Kingdom
| | - Michael Churchman
- Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUnited Kingdom
| | - Caroline O. Michie
- Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUnited Kingdom
| | - Tzyvia Rye
- Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUnited Kingdom
| | | | | | - Timothy Perren
- St. James's Institute of OncologySt. James's University HospitalLeedsUnited Kingdom
| | | | - W. Glenn McCluggage
- Center for Cancer Research and Cell BiologyQueen's University of BelfastBelfastUnited Kingdom
- Department of PathologyBelfast Health and Social Care TrustBelfastUnited Kingdom
| | - Richard S. Kaplan
- Medical Research Council Clinical Trials Unit at University College LondonLondonUnited Kingdom
| | - Gordon C. Jayson
- Division of Molecular and Clinical Cancer SciencesUniversity of ManchesterManchesterUnited Kingdom
| | - Amit Oza
- Cancer Clinical Research Unit, Division of Medical Oncology and Hematology, Princess Margaret Cancer CentreUniversity of TorontoTorontoOntarioCanada
| | - D. Paul Harkin
- Almac DiagnosticsCraigavonUnited Kingdom
- Center for Cancer Research and Cell BiologyQueen's University of BelfastBelfastUnited Kingdom
| | - C. Simon Herrington
- Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUnited Kingdom
- Department of PathologyUniversity of EdinburghEdinburghUnited Kingdom
- Division of Pathology, Centre for Comparative Pathology, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUnited Kingdom
| | - Richard Kennedy
- Almac DiagnosticsCraigavonUnited Kingdom
- Center for Cancer Research and Cell BiologyQueen's University of BelfastBelfastUnited Kingdom
| | - Charlie Gourley
- Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUnited Kingdom
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18
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Fang Z, Li T, Chen W, Wu D, Qin Y, Liu M, Wu G, He L, Li H, Gu H. Gab2 promotes cancer stem cell like properties and metastatic growth of ovarian cancer via downregulation of miR-200c. Exp Cell Res 2019; 382:111462. [PMID: 31194976 DOI: 10.1016/j.yexcr.2019.06.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 06/05/2019] [Accepted: 06/08/2019] [Indexed: 11/24/2022]
Abstract
Scaffolding adaptor Gab2 is overexpressed in a subset of high-grade ovarian cancer. Our published work shows that Gab2 via PI3K enhances migratory behaviors and epithelial to mesenchymal transition (EMT) features of ovarian cancer cells in vitro. However, it is still unclear how Gab2/PI3K pathway reuglates EMT characteristics and whether Gab2 promotes the growth of ovarian cancer stem cell (CSC)-like population and metastatic growth. In this study, we examined the effects of Gab2 expression on CSC-like cell growth using Aldefluor and tumorshpere assays commonly used for assessing ovarian cancer cells with CSC properties. Gab2 overexpression increased the number of ALDH+ cells and tumorsphere formation in two different ovarian cancer cell lines OVCAR5 and OVCAR8, whereas knockdown of Gab2 decreased the number of ALDH+ cells and tumorsphere formation in Caov-3 cells. Furthermore, Gab2 promoted metastatic tumor growth of OVCAR5 in nude mice. Mechanistically, we uncovered that Gab2 via PI3K specifically inhibited miR-200c expression. miR-200c downregulation contributed to the Gab2-enhanced cell migratory behaviors, EMT properties, and the expansion of ALDH+ cells and tumorspheres. Furthermore, Gab2 promoted CD44 expression and cell migration/invasion through miR-200c downregulation. Our findings support a model that Gab2-PI3K pathway via miR-200c downregulation promotes CD44 expression, EMT characteristics, and CSC-like cell growth. Therapies involving miR-200c or targeting CD44 should help treat ovarian cancer with high Gab2 expression.
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Affiliation(s)
- Zenghui Fang
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Tong Li
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Wanzhou Chen
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Du Wu
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Yaqian Qin
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Min Liu
- Department of Orthopedics, Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325200, China
| | - Guang Wu
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Licai He
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Hongzhi Li
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Haihua Gu
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China.
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19
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Kondrashova O, Scott CL. Clarifying the role of EMSY in DNA repair in ovarian cancer. Cancer 2019; 125:2720-2724. [PMID: 31154666 DOI: 10.1002/cncr.32135] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 03/13/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Olga Kondrashova
- Cancer Biology and Stem Cells Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Genetics & Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Clare L Scott
- Cancer Biology and Stem Cells Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Royal Women's Hospital, University of Melbourne, Melbourne, Victoria, Australia
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20
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PARP Inhibitors in Ovarian Cancer: The Route to "Ithaca". Diagnostics (Basel) 2019; 9:diagnostics9020055. [PMID: 31109041 PMCID: PMC6627688 DOI: 10.3390/diagnostics9020055] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 05/12/2019] [Accepted: 05/16/2019] [Indexed: 12/14/2022] Open
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.
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21
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Chromatin-remodeling factor, RSF1, controls p53-mediated transcription in apoptosis upon DNA strand breaks. Cell Death Dis 2018; 9:1079. [PMID: 30348983 PMCID: PMC6197202 DOI: 10.1038/s41419-018-1128-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 10/02/2018] [Accepted: 10/08/2018] [Indexed: 12/14/2022]
Abstract
Remodeling and spacing factor 1 (RSF1), which is one of chromatin-remodeling factors, has been linked to the DNA damage response (DDR) and DNA repair. However, the biological consequence of RSF1 deficiency in DDR in vivo and its molecular mechanisms remain unknown. Because defective DDR is related to neuropathological phenotypes, we developed neural-specific Rsf1 knockout mice. Rsf1 deficiency did not result in any neuropathological abnormalities, but prevented neural apoptosis triggered by excessive DNA strand breaks during neurogenesis. Likewise, cell death was significantly reduced in RSF1 deficient human cell lines after DNA damage, and the global transcriptome of these cells revealed that the expressions of p53 downstream genes were significantly reduced upon DNA strand breaks. Inactivation of these genes resulted from decreased binding of p53/p300 complex and subsequent reduction of H3 acetylation at their promoters. Our data show that RSF1 is necessary for p53-dependent gene expression in response to DNA strand breaks via controlling the accessibility of p53/p300 complex to its target genes and contributes to the maintenance of cellular integrity.
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22
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Wang K, Baldwin GS, Nikfarjam M, He H. p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation. World J Gastroenterol 2018; 24:3709-3723. [PMID: 30197477 PMCID: PMC6127653 DOI: 10.3748/wjg.v24.i33.3709] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/22/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemo-therapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases (PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemo-resistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.
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Affiliation(s)
- Kai Wang
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| | - Graham S Baldwin
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| | - Mehrdad Nikfarjam
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| | - Hong He
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
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23
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Fang L, Wu S, Zhu X, Cai J, Wu J, He Z, Liu L, Zeng M, Song E, Li J, Li M, Guan H. MYEOV functions as an amplified competing endogenous RNA in promoting metastasis by activating TGF-β pathway in NSCLC. Oncogene 2018; 38:896-912. [PMID: 30181549 PMCID: PMC6756124 DOI: 10.1038/s41388-018-0484-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 07/06/2018] [Accepted: 08/10/2018] [Indexed: 01/13/2023]
Abstract
Non-small cell lung cancer (NSCLC) remains a major cause of death worldwide. As metastatic disease is primarily responsible for the poor clinical outcome of NSCLC, it is important to understand the process, and its underlying molecular mechanism as well, via which NSCLC cells disseminate. In this study, we identified a new competing endogenous RNA (ceRNA), namely, the MYEOV transcript, and found that it is upregulated in NSCLC and associated with a poor prognosis of the disease. We further uncovered that the MYEOV ceRNA plays a critical role in the invasion and metastasis of NSCLC cells. Intriguingly, the MYEOV ceRNA exerted its pro-metastatic function independent of its protein-coding capacity, but in a miR-30c-2-3p binding-dependent manner. Further experiments demonstrated that the MYEOV ceRNA sequestered miR-30c-2-3p from binding its targets TGFBR2 and USP15 mRNAs, which in turn leading to constitutive activation of TGF-β signaling and tumor progression in NSCLC. By identifying a new layer of regulatory modality for TGF-β signaling, our findings extend the current understanding on the molecular mechanism mediating NSCLC progression and highlight a potential role of MYEOV transcript to serve as the therapeutic target.
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Affiliation(s)
- Lishan Fang
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.,Central Laboratory of The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Shanshan Wu
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.,Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xun Zhu
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China
| | - Junchao Cai
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.,Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jueheng Wu
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.,Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zhenjian He
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Lei Liu
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.,Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Musheng Zeng
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Erwei Song
- Department of Breast Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jun Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Mengfeng Li
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China. .,Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
| | - Hongyu Guan
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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24
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Park HG, Zhang JY, Foster C, Sudilovsky D, Schwed DA, Mecenas J, Devapatla S, Lawrence P, Kothapalli KSD, Brenna JT. A rare eicosanoid precursor analogue, sciadonic acid (5Z,11Z,14Z-20:3), detected in vivo in hormone positive breast cancer tissue. Prostaglandins Leukot Essent Fatty Acids 2018; 134:1-6. [PMID: 29886893 PMCID: PMC5999340 DOI: 10.1016/j.plefa.2018.05.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 05/10/2018] [Accepted: 05/10/2018] [Indexed: 02/06/2023]
Abstract
Numerous genetic alterations of HSA 11q13 are found frequently in several cancer types, including breast cancer (BC). The 11q13 locus harbors FADS2 encoding Δ6 desaturation which is not functional in several cancer cell lines, including hormone positive MCF7 BC cells. In vitro, the non-functional FADS2 activity unmasks 18:2n-6 elongation to 20:2n-6 and Δ5 desaturation by FADS1 to yield 5Z,11Z,14Z-20:3 (sciadonic acid) rather than 5Z,8Z,11Z,14Z-20:4 (arachidonic acid). In this pilot study we aimed to determine whether 5,11,14-20:3 appears in vivo in hormone positive human BC tissue. Fatty acids were profiled in surgically removed human breast tumor and adjacent normal tissue (n = 9). Sciadonic acid was detected in three of nine breast tumor samples and was below detect limits in normal breast tissue. The internal Δ8 double bond of arachidonic acid is required for normal eicosanoid synthesis but is missing in sciadonic acid. This pilot study demonstrates for the first time in vivo sciadonic acid in hormone positive BC tissue, warranting a larger survey study to further evaluate its appearance and the functional implications.
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Affiliation(s)
- H G Park
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Dell Pediatric Research Institute and Dept. of Pediatrics, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA
| | - J Y Zhang
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA
| | - C Foster
- Cayuga Medical Center, 101 Dates Drive, Ithaca, NY 14850, USA
| | - D Sudilovsky
- Cayuga Medical Center, 101 Dates Drive, Ithaca, NY 14850, USA
| | - D A Schwed
- Cayuga Medical Center, 101 Dates Drive, Ithaca, NY 14850, USA
| | - J Mecenas
- Cayuga Medical Center, 101 Dates Drive, Ithaca, NY 14850, USA
| | - S Devapatla
- Cayuga Medical Center, 101 Dates Drive, Ithaca, NY 14850, USA
| | - P Lawrence
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | - K S D Kothapalli
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Dell Pediatric Research Institute and Dept. of Pediatrics, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA.
| | - J T Brenna
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Dell Pediatric Research Institute and Dept. of Pediatrics, Dell Medical School, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA; Department of Chemistry, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA.
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25
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Liu K, Beck D, Thoms JAI, Liu L, Zhao W, Pimanda JE, Zhou X. Annotating function to differentially expressed LincRNAs in myelodysplastic syndrome using a network-based method. Bioinformatics 2018; 33:2622-2630. [PMID: 28472271 DOI: 10.1093/bioinformatics/btx280] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 04/22/2017] [Indexed: 02/01/2023] Open
Abstract
Motivation Long non-coding RNAs (lncRNAs) have been implicated in the regulation of diverse biological functions. The number of newly identified lncRNAs has increased dramatically in recent years but their expression and function have not yet been described from most diseases. To elucidate lncRNA function in human disease, we have developed a novel network based method (NLCFA) integrating correlations between lncRNA, protein coding genes and noncoding miRNAs. We have also integrated target gene associations and protein-protein interactions and designed our model to provide information on the combined influence of mRNAs, lncRNAs and miRNAs on cellular signal transduction networks. Results We have generated lncRNA expression profiles from the CD34+ haematopoietic stem and progenitor cells (HSPCs) from patients with Myelodysplastic syndromes (MDS) and healthy donors. We report, for the first time, aberrantly expressed lncRNAs in MDS and further prioritize biologically relevant lncRNAs using the NLCFA. Taken together, our data suggests that aberrant levels of specific lncRNAs are intimately involved in network modules that control multiple cancer-associated signalling pathways and cellular processes. Importantly, our method can be applied to prioritize aberrantly expressed lncRNAs for functional validation in other diseases and biological contexts. Availability and implementation The method is implemented in R language and Matlab. Contact xizhou@wakehealth.edu. Supplementary information Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Keqin Liu
- Department of Radiology, Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Dominik Beck
- Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, 2052, Australia.,Centre for Health Technologies and School of Software, University of Technology Sydney, Sydney, NSW, 2007, Australia
| | - Julie A I Thoms
- Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, 2052, Australia
| | - Liang Liu
- Department of Radiology, Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Weiling Zhao
- Department of Radiology, Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - John E Pimanda
- Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, 2052, Australia.,Centre for Health Technologies and School of Software, University of Technology Sydney, Sydney, NSW, 2007, Australia.,Department of Haematology, Prince of Wales Hospital, Randwick, NSW, 2031, Australia
| | - Xiaobo Zhou
- Department of Radiology, Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
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26
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LaPak KM, Vroom DC, Garg AA, Guan X, Hays JL, Song JW, Burd CE. Melanoma-associated mutants within the serine-rich domain of PAK5 direct kinase activity to mitogenic pathways. Oncotarget 2018; 9:25386-25401. [PMID: 29875996 PMCID: PMC5986637 DOI: 10.18632/oncotarget.25356] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 04/26/2018] [Indexed: 02/07/2023] Open
Abstract
The overexpression and hyperactivity of p21-activated serine/threonine kinases (PAKs) is known to facilitate tumorigenesis; however, the contribution of cancer-associated PAK mutations to tumor initiation and progression remains unclear. Here, we identify p21-activated serine/threonine kinase 5 (PAK5) as the most frequently altered PAK family member in human melanoma. More than 60% of melanoma-associated PAK5 gene alterations are missense mutations, and distribution of these variants throughout the protein coding sequence make it difficult to distinguish oncogenic drivers from passengers. To address this issue, we stably introduced the five most common melanoma-associated PAK5 missense mutations into human immortalized primary melanocytes (hMELTs). While expression of these mutants did not promote single-cell migration or induce temozolomide resistance, a subset of variants drove aberrant melanocyte proliferation. These mitogenic mutants, PAK5 S364L and D421N, clustered within an unstructured, serine-rich domain of the protein and inappropriately activated ERK and PKA through kinase-independent and -dependent mechanisms, respectively. Together, our findings establish the ability of mutant PAK5 to enhance PKA and MAPK signaling in melanocytes and localize the engagement of mitogenic pathways to a serine-rich region of PAK5.
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Affiliation(s)
- Kyle M LaPak
- Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA
| | - Dennis C Vroom
- Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA
| | - Ayush A Garg
- Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH, USA
| | - Xiangnan Guan
- Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA
| | - John L Hays
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Jonathan W Song
- Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH, USA
| | - Christin E Burd
- Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA.,Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
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27
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Clinical importance of the EMSY gene expression and polymorphisms in ovarian cancer. Oncotarget 2018; 9:17735-17755. [PMID: 29707144 PMCID: PMC5915152 DOI: 10.18632/oncotarget.24878] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 02/28/2018] [Indexed: 11/25/2022] Open
Abstract
EMSY, a BRCA2–associated protein, is amplified and overexpressed in various sporadic cancers. This is the first study assessing the clinical impact of its expression and polymorphisms on ovarian cancer (OvCa) outcome in the context of the chemotherapy regimen used. In 134 frozen OvCa samples, we assessed EMSY mRNA expression with Reverse Transcription-quantitative PCR, and also investigated the EMSY gene sequence using SSCP and/or PCR-sequencing. Clinical relevance of changes in EMSY mRNA expression and DNA sequence was evaluated in two subgroups treated with either taxane/platinum (TP, n=102) or platinum/cyclophosphamide (PC, n=32). High EMSY expression negatively affected overall survival (OS), disease-free survival (DFS) and sensitivity to treatment (PS) in the TP-treated subgroup (p-values: 0.001, 0.002 and 0.010, respectively). Accordingly, our OvCa cell line studies showed that the EMSY gene knockdown sensitized A2780 and IGROV1 cells to paclitaxel. Interestingly, EMSY mRNA expression in surviving cells was similar as in the control cells. Additionally, we identified 24 sequence alterations in the EMSY gene, including the previously undescribed: c.720G>C, p.(Lys240Asn); c.1860G>A, p.(Lys620Lys); c.246-76A>G; c.421+68A>C. In the PC-treated subgroup, a heterozygous genotype comprising five SNPs (rs4300410, rs3814711, rs4245443, rs2508740, rs2513523) negatively correlated with OS (p-value=0.009). The same SNPs exhibited adverse borderline associations with PS in the TP-treated subgroup. This is the first study providing evidence that high EMSY mRNA expression is a negative prognostic and predictive factor in OvCa patients treated with TP, and that the clinical outcome may hinge on certain SNPs in the EMSY gene as well.
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28
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Fan G. FER mediated HGF-independent regulation of HGFR/MET activates RAC1-PAK1 pathway to potentiate metastasis in ovarian cancer. Small GTPases 2018; 11:155-159. [PMID: 29099290 DOI: 10.1080/21541248.2017.1379931] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
Uncontrolled metastasis significantly contributes to high lethality of patients suffering from ovarian cancer. To date, the detailed molecular mechanisms which account for ovarian tumor cell spreading and metastasis remain largely unknown. In a recent study, we have demonstrated that aberrantly high expression of the non-receptor tyrosine kinase FER is responsible for ovarian tumor cell metastasis both in vitro and in vivo. Mechanistically, we indentified Hepatocyte Growth Factor Receptor HGFR/MET as a novel substrate of FER, and through which the kinase FER modulates ovarian cancer cell motility and invasiveness in a ligand-independent manner. We also observed aberrantly high expression of PAK1 kinase in cancer cells, and RNAi-mediated knockdown of FER kinase inactivated the RAC1-PAK1 signaling pathway and decreased metastatic potential of CAOV4 ovarian cancer cells. Overall, our study revealed a previously uncharacterized, pro-metastatic role of the kinase FER in ovarian cancer through the MET-RAC1-PAK1 pathway. Further efforts are essential to investigating beneficial outcomes towards targeting the RAC1-PAK1 signaling pathway in reducing metastatic burden of this deadly disease.
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Affiliation(s)
- Gaofeng Fan
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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29
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Wang H, He H, Meng H, Cui Y, Wang W. Effects of Grb2-associated binding protein 2-specific siRNA on the migration and invasion of MG-63 osteosarcoma cells. Oncol Lett 2018; 15:926-930. [PMID: 29422967 PMCID: PMC5772958 DOI: 10.3892/ol.2017.7375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 04/13/2017] [Indexed: 12/19/2022] Open
Abstract
To investigate the association between the expression of growth factor receptor binding protein 2-associated binding protein 2 (Gab2) in human osteosarcoma as well as the effects of Gab2 on invasion and metastasis, human MG-63 osteosarcoma cells were transfected with small interfering (si)RNA plasmid. Gab2 protein and mRNA expression levels were detected using western blotting and reverse transcription-polymerase chain reaction, respectively. The cell migration and invasion abilities were detected using in vitro chemotaxis and invasion assays, respectively, following siRNA vector expression. Gab2 was markedly expressed in MG-63 cells. The Gab2 protein and mRNA expression levels of the cells transfected with Gab2 siRNA (siGab2/MG-63) were reduced compared with those of the cells transfected with scrambled siRNA (Scr/MG-63). The chemotaxis assay demonstrated that the migration capacity of siGab2/MG-63 cells induced by 10 µg/l epidermal growth factor, was significantly reduced compared with that of the MG-63 and Scr/MG-63 cells (P<0.01). In comparison with Scr/MG-63 and MG-63 cells, a reduced number of siGab2/MG-63 cells invaded the Matrigel matrix, demonstrating that the in vitro invasion capacity was significantly decreased (P<0.01). Decreasing Gab2 expression levels using siRNA interference inhibited the migration and invasion ability of human MG-63 osteosarcoma cells.
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Affiliation(s)
- Huan Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Hui He
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Hongmei Meng
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yang Cui
- Department of Orthopedic Surgery, The First Hospital of Qiqihar, Qiqihar, Heilongjiang 161000, P.R. China
| | - Wenbo Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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30
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Zhang X, Dong Z, Zhang C, Ung CY, He S, Tao T, Oliveira AM, Meves A, Ji B, Look AT, Li H, Neel BG, Zhu S. Critical Role for GAB2 in Neuroblastoma Pathogenesis through the Promotion of SHP2/MYCN Cooperation. Cell Rep 2017; 18:2932-2942. [PMID: 28329685 DOI: 10.1016/j.celrep.2017.02.065] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 01/17/2017] [Accepted: 02/21/2017] [Indexed: 11/26/2022] Open
Abstract
Growing evidence suggests a major role for Src-homology-2-domain-containing phosphatase 2 (SHP2/PTPN11) in MYCN-driven high-risk neuroblastoma, although biologic confirmation and a plausible mechanism for this contribution are lacking. Using a zebrafish model of MYCN-overexpressing neuroblastoma, we demonstrate that mutant ptpn11 expression in the adrenal gland analog of MYCN transgenic fish promotes the proliferation of hyperplastic neuroblasts, accelerates neuroblastomagenesis, and increases tumor penetrance. We identify a similar mechanism in tumors with wild-type ptpn11 and dysregulated Gab2, which encodes a Shp2 activator that is overexpressed in human neuroblastomas. In MYCN transgenic fish, Gab2 overexpression activated the Shp2-Ras-Erk pathway, enhanced neuroblastoma induction, and increased tumor penetrance. We conclude that MYCN cooperates with either GAB2-activated or mutant SHP2 in human neuroblastomagenesis. Our findings further suggest that combined inhibition of MYCN and the SHP2-RAS-ERK pathway could provide effective targeted therapy for high-risk neuroblastoma patients with MYCN amplification and aberrant SHP2 activation.
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Affiliation(s)
- Xiaoling Zhang
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA
| | - Zhiwei Dong
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA
| | - Cheng Zhang
- Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA
| | - Choong Yong Ung
- Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA
| | - Shuning He
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Ting Tao
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Andre M Oliveira
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55902, USA
| | - Alexander Meves
- Department of Dermatology, Mayo Clinic, Rochester, MN 55902, USA
| | - Baoan Ji
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA
| | - A Thomas Look
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Hu Li
- Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA
| | - Benjamin G Neel
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA.
| | - Shizhen Zhu
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.
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31
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Jelinic P, Eccles LA, Tseng J, Cybulska P, Wielgos M, Powell SN, Levine DA. The EMSY threonine 207 phospho-site is required for EMSYdriven suppression of DNA damage repair. Oncotarget 2017; 8:13792-13804. [PMID: 28099152 PMCID: PMC5355139 DOI: 10.18632/oncotarget.14637] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 01/04/2017] [Indexed: 01/07/2023] Open
Abstract
BRCA1 and BRCA2 are essential for the repair of double-strand DNA breaks, and alterations in these genes are a hallmark of breast and ovarian carcinomas. Other functionally related genes may also play important roles in carcinogenesis. Amplification of EMSY, a putative BRCAness gene, has been suggested to impair DNA damage repair by suppressing BRCA2 function. We employed direct repeat GFP (DR-GFP) and RAD51 foci formation assays to show that EMSY overexpression impairs the repair of damaged DNA, suggesting that EMSY belongs to the family of BRCAness proteins. We also identified a novel phospho-site at threonine 207 (T207) and demonstrated its role in EMSY-driven suppression of DNA damage repair. In vitro kinase assays established that protein kinase A (PKA) directly phosphorylates the T207 phospho-site. Immunoprecipitation experiments suggest that EMSY-driven suppression of DNA damage repair is a BRCA2-independent process. The data also suggest that EMSY amplification is a BRCAness feature, and may help to expand the population of patients who could benefit from targeted therapies that are also effective in BRCA1/2-mutant cancers.
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Affiliation(s)
- Petar Jelinic
- Laura and Isaac Perlmutter Cancer Center, Division of Gynecologic Oncology, Department of OB/GYN, NYU Langone Medical Center, New York, USA
| | - Laura A Eccles
- Departments of Radiation Oncology and Molecular Biology, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Jill Tseng
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Paulina Cybulska
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Monicka Wielgos
- Laura and Isaac Perlmutter Cancer Center, Division of Gynecologic Oncology, Department of OB/GYN, NYU Langone Medical Center, New York, USA
| | - Simon N Powell
- Departments of Radiation Oncology and Molecular Biology, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Douglas A Levine
- Laura and Isaac Perlmutter Cancer Center, Division of Gynecologic Oncology, Department of OB/GYN, NYU Langone Medical Center, New York, USA
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32
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Thillai K, Lam H, Sarker D, Wells CM. Deciphering the link between PI3K and PAK: An opportunity to target key pathways in pancreatic cancer? Oncotarget 2017; 8:14173-14191. [PMID: 27845911 PMCID: PMC5355171 DOI: 10.18632/oncotarget.13309] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 10/27/2016] [Indexed: 02/07/2023] Open
Abstract
The development of personalised therapies has ushered in a new and exciting era of cancer treatment for a variety of solid malignancies. Yet pancreatic ductal adenocarcinoma (PDAC) has failed to benefit from this paradigm shift, remaining notoriously refractory to targeted therapies. Chemotherapy is the cornerstone of management but can offer only modest survival benefits of a few months with 5-year survival rates rarely exceeding 3%. Despite these disappointing statistics, significant strides have been made towards understanding the complex biology of pancreatic cancer, with deep genomic sequencing identifying novel genetic aberrations and key signalling pathways. The PI3K-PDK1-AKT pathway has received great attention due to its prominence in carcinogenesis. However, efforts to target several components of this network have resulted in only a handful of drugs demonstrating any survival benefit in solid tumors; despite promising pre-clinical results. p-21 activated kinase 4 (PAK4) is a gene that is recurrently amplified or overexpressed in PDAC and both PAK4 and related family member PAK1, have been linked to aberrant RAS activity, a common feature in pancreatic cancer. As regulators of PI3K, PAKs have been highlighted as a potential prognostic marker and therapeutic target. In this review, we discuss the biology of pancreatic cancer and the close interaction between PAKs and the PI3K pathway. We also suggest proposals for future research that may see the development of effective targeted therapies that could finally improve outcomes for this disease.
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Affiliation(s)
- Kiruthikah Thillai
- Division of Cancer Studies, King's College London, London, United Kingdom.,Department of Medical Oncology, Guy's and St Thomas' NHS Trust, London, United Kingdom
| | - Hoyin Lam
- Division of Cancer Studies, King's College London, London, United Kingdom
| | - Debashis Sarker
- Division of Cancer Studies, King's College London, London, United Kingdom.,Department of Medical Oncology, Guy's and St Thomas' NHS Trust, London, United Kingdom
| | - Claire M Wells
- Division of Cancer Studies, King's College London, London, United Kingdom
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Cheng J, Zhong Y, Chen S, Sun Y, Huang L, Kang Y, Chen B, Chen G, Wang F, Tian Y, Liu W, Feng GS, Lu Z. Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways. FASEB J 2017; 31:5530-5542. [PMID: 28842424 PMCID: PMC5690380 DOI: 10.1096/fj.201700120rr] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Accepted: 08/07/2017] [Indexed: 12/12/2022]
Abstract
Our previous studies have found that Growth factor receptor-bound protein 2-associated binding protein 2 (Gab2)-a docking protein-governs the development of fatty liver disease. Here, we further demonstrate that Gab2 mediates hepatocarcinogenesis. Compared with a faint expression in para-carcinoma tissue, Gab2 was highly expressed in ∼60-70% of human hepatocellular carcinoma (HCC) specimens. Deletion of Gab2 dramatically suppressed diethylnitrosamine-induced HCC in mice. The oncogenic effects of Gab2 in HepG2 cells were promoted by Gab2 overexpression but were rescued by Gab2 knockdown. Furthermore, Gab2 knockout in HepG2 cells restrained cell proliferation, migration and tumor growth in nude mice. Signaling pathway analysis with protein kinase inhibitors demonstrated that oncogenic regulation by Gab2 in hepatic cells involved multiple signaling molecules, including ERK, Akt, and Janus kinases (Jaks), especially those that mediate inflammatory signaling. IL-6 signaling was increased by Gab2 overexpression and impaired by Gab2 deletion via regulation of Jak2 and signal transducer and activator of transcription 3 phosphorylation and the expression of downstream genes, such as Bcl-2 (B-cell lymphoma 2), c-Myc, MMP7 (matrix metalloproteinase-7), and cyclin D1in vitro and in vivo These data indicate that Gab2 mediates the pathologic progression of HCC by integrating multiple signaling pathways and suggest that Gab2 might be a powerful therapeutic target for HCC.-Cheng, J., Zhong, Y., Chen, S., Sun, Y., Huang, L., Kang, Y., Chen, B., Chen, G., Wang, F., Tian, Y., Liu, W., Feng, G.-S., Lu, Z. Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways.
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Affiliation(s)
- Jianghong Cheng
- School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China
| | - Yanhong Zhong
- School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China
| | - Shuai Chen
- School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China
| | - Yan Sun
- School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China
| | - Lantang Huang
- School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China
| | - Yujia Kang
- School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China
| | - Baozhen Chen
- Department of Pathology, Fujian Provincial Tumor Hospital, Fuzhou, China
| | - Gang Chen
- Department of Pathology, Fujian Provincial Tumor Hospital, Fuzhou, China
| | - Fengli Wang
- School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China
| | - Yingpu Tian
- School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China
| | - Wenjie Liu
- School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China
| | - Gen-Sheng Feng
- Division of Biological Sciences, Department of Pathology, University of California, San Diego, La Jolla, California, USA
| | - Zhongxian Lu
- School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China;
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Wang L, Lu J, Wu H, Wang L, Liang X, Liang Z, Liu T. Expression of signaling adaptor proteins predicts poor prognosis in pancreatic ductal adenocarcinoma. Diagn Pathol 2017; 12:42. [PMID: 28558797 PMCID: PMC5450263 DOI: 10.1186/s13000-017-0633-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Accepted: 05/12/2017] [Indexed: 11/17/2022] Open
Abstract
Background Adaptor proteins bridge the gap between cell surface receptors and their downstream signaling elements. The clinicopathological and prognostic values of adaptor proteins remain poorly understood. The purpose of the present study was to explore the expression and prognostic value of three adaptor proteins: GRB2-associated binding protein 2 (GAB2), CRK-like protein (CRKL) and fibroblast growth factor receptor substrate 2 (FRS2) in pancreatic ductal adenocarcinoma (PDAC). Methods The expression of GAB2, CRKL, and FRS2 in 77 formalin fixed paraffin embedded (FFPE) samples from 77 PDAC patients, along with three paired fresh PDAC and matched normal tissues from 3 PDAC patients was analyzed by immunohistochemistry and western blot, respectively. The association between the expression of the three proteins and the clinicopathological factors of PDAC was assessed by χ2 test. The correlation between the expression levels of the three proteins was analyzed by Spearman rank correlation analyses; Kaplan-Meier survival analyses were also performed. Results IHC was successful in 75, 76, and 77 cases for GAB2, CRKL, and FRS2, respectively. Of which, the positive rate of GAB2, CRKL, and FRS2 protein expression was 40.00% (30/75), 53.95% (41/76) and 35.06% (27/77), respectively. The positive rate of GAB2, CRKL and FRS2 co-expression was 16.88% (13/77). Though there was no association between GAB2 expression, CRKL expression, FRS2 expression, GAB2/CRKL/FRS2 co-expression and the clinicopathological parameters of PDAC, positive correlations were observed between the expressions of the three proteins. Further, univariate survival analysis showed that positive expression of GAB2, CRKL and FRS2 and co-expression of GAB2/CRKL/FRS2 of PDAC predicted poor clinical outcomes, and multivariate survival analysis suggested that positive expression of GAB2 and positive co-expression of GAB2/CRKL/FRS2 were independent prognostic factors for disease-free survival (DFS) and overall survival (OS), respectively. Conclusion In conclusion, GAB2, CRKL, and FRS2 may be potential prognosticators and therapeutic targets for PDAC patients.
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Affiliation(s)
- Lili Wang
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Junliang Lu
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Huanwen Wu
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Li Wang
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Xiaolong Liang
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Zhiyong Liang
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Tonghua Liu
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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Wang C, Gu C, Jeong KJ, Zhang D, Guo W, Lu Y, Ju Z, Panupinthu N, Yang JY, Gagea MM, Ng PKS, Zhang F, Mills GB. YAP/TAZ-Mediated Upregulation of GAB2 Leads to Increased Sensitivity to Growth Factor-Induced Activation of the PI3K Pathway. Cancer Res 2017; 77:1637-1648. [PMID: 28202507 DOI: 10.1158/0008-5472.can-15-3084] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 11/29/2016] [Accepted: 01/06/2017] [Indexed: 11/16/2022]
Abstract
The transcription regulators YAP and TAZ function as effectors of the HIPPO signaling cascade, critical for organismal development, cell growth, and cellular reprogramming, and YAP/TAZ is commonly misregulated in human cancers. The precise mechanism by which aberrant YAP/TAZ promotes tumor growth remains unclear. The HIPPO tumor suppressor pathway phosphorylates YAP and TAZ, resulting in cytosolic sequestration with subsequent degradation. Here, we report that the PI3K/AKT pathway, which is critically involved in the pathophysiology of endometrial cancer, interacts with the HIPPO pathway at multiple levels. Strikingly, coordinate knockdown of YAP and TAZ, mimicking activation of the HIPPO pathway, markedly decreased both constitutive and growth factor-induced PI3K pathway activation by decreasing levels of the GAB2 linker molecule in endometrial cancer lines. Furthermore, targeting YAP/TAZ decreased endometrial cancer tumor growth in vivo In addition, YAP and TAZ total and phosphoprotein levels correlated with clinical characteristics and outcomes in endometrial cancer. Thus, YAP and TAZ, which are inhibited by the HIPPO tumor suppressor pathway, modify PI3K/AKT pathway signaling in endometrial cancer. The cross-talk between these key pathways identifies potential new biomarkers and therapeutic targets in endometrial cancer. Cancer Res; 77(7); 1637-48. ©2017 AACR.
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Affiliation(s)
- Chao Wang
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China. .,Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Chao Gu
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.,Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kang Jin Jeong
- Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Dong Zhang
- Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wei Guo
- Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yiling Lu
- Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Zhenlin Ju
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nattapon Panupinthu
- Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Ji Yeon Yang
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mihai Mike Gagea
- Department of Veterinary Medicine & Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Patrick Kwok Shing Ng
- Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Fan Zhang
- Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gordon B Mills
- Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
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MicroRNA-494 inhibits breast cancer progression by directly targeting PAK1. Cell Death Dis 2017; 8:e2529. [PMID: 28055013 PMCID: PMC5386359 DOI: 10.1038/cddis.2016.440] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 11/03/2016] [Accepted: 11/17/2016] [Indexed: 12/21/2022]
Abstract
MicroRNA (miRNA) is involved in the progression and metastasis of diverse human cancers, including breast cancer, as strong evidence has been found that miRNAs can act as oncogenes or tumor suppressor genes. Here, we show that miR-494 is decreased in human breast cancer specimens and breast cancer cell lines. Ectopic expression of miR-494 in basal-like breast cancer cell lines MDA-MB-231-LUC-D2H3LN and BT-549 inhibits clonogenic ability and metastasis-relevant traits in vitro. Moreover, ectopic expression of miR-494 suppresses neoplasm initiation as well as pulmonary metastasis in vivo. Further studies have identified PAK1, as a direct target gene of miR-494, contributes to the functions of miR-494. Remarkably, the expression of PAK1 is inversely correlated with the level of miR-494 in human breast cancer samples. Furthermore, re-expression of PAK1 partially reverses miR-494-mediated proliferative and clonogenic inhibition as well as migration and invasion suppression in breast cancer cells. Taken together, these findings highlight an important role for miR-494 in the regulation of progression and metastatic potential of breast cancer and suggest a potential application of miR-494 in breast cancer treatment.
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Prudnikova TY, Chernoff J. The Group I Pak inhibitor Frax-1036 sensitizes 11q13-amplified ovarian cancer cells to the cytotoxic effects of Rottlerin. Small GTPases 2016; 8:193-198. [PMID: 27427770 DOI: 10.1080/21541248.2016.1213089] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The p21-activated kinases (PAKs) are Cdc42/Rac-activated serine-threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt, and Wnt/β-catenin cascades. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including breast, ovary, prostate, and brain cancer. PAK1 genomic amplification at 11q13 is the most common mechanism of Pak1 hyperactivation, though Pak1 mRNA and/or protein may be overexpressed in the absence of gene amplification. In previous in vitro and in vivo studies we have shown that ovarian cancer cells with amplified/overexpressed Pak1 were significantly more sensitive to pharmacologic inhibition of Pak1 compared to cells without 11q13 amplification. In the present study we examined if additional signaling pathways might be targeted in tandem with the Group I Pak inhibitor Frax-1036 in ovarian cancer cells. Using the ICCB Known Bioactives Library, we found that the cytotoxic effect of Frax-1036 was significantly higher in combination with the PKCδ inhibitor, Rottlerin, suggesting that Pak inhibitors might be combined with other agents to treat 11q13-amplified ovarian cancer.
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Affiliation(s)
| | - Jonathan Chernoff
- a Cancer Biology Program, Fox Chase Cancer Center , Philadelphia , PA , USA
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Jenner ZB, Sood AK, Coleman RL. Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy. Future Oncol 2016; 12:1439-56. [PMID: 27087632 PMCID: PMC4976841 DOI: 10.2217/fon-2016-0002] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 04/04/2016] [Indexed: 12/28/2022] Open
Abstract
Rucaparib camsylate (CO-338; 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt) is a PARP1, 2 and 3 inhibitor. Phase I studies identified a recommended Phase II dose of 600 mg orally twice daily. ARIEL2 Part 1 established a tumor genomic profiling test for homologous recombination loss of heterozygosity quantification using a next-generation sequencing companion diagnostic (CDx). Rucaparib received US FDA Breakthrough Therapy designation for treatment of platinum-sensitive BRCA-mutated advanced ovarian cancer patients who received greater than two lines of platinum-based therapy. Comparable to rucaparib development, other PARP inhibitors, such as olaparib, niraparib, veliparib and talazoparib, are developing CDx tests for targeted therapy. PARP inhibitor clinical trials and CDx assays are discussed in this review, as are potential PARP inhibitor combination therapies and likely resistance mechanisms.
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Affiliation(s)
- Zachary B Jenner
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- McGovern Medical School, formerly The University of Texas Health Science Center at Houston (UTHealth) Medical School, Houston, TX, USA
| | - Anil K Sood
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Robert L Coleman
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Parvathy M, Sreeja S, Kumar R, Pillai MR. Potential role of p21 Activated Kinase 1 (PAK1) in the invasion and motility of oral cancer cells. BMC Cancer 2016; 16 Suppl 1:293. [PMID: 27229476 PMCID: PMC4896241 DOI: 10.1186/s12885-016-2263-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Oral cancer malignancy consists of uncontrolled division of cells primarily in and around the floor of the oral cavity, gingiva, oropharynx, lower lip and base of the tongue. According to GLOBOCAN 2012 report, oral cancer is one of the most common cancers among males and females in India. Even though significant advancements have been made in the field of oral cancer treatment modalities, the overall prognosis for the patients has not improved in the past few decades and hence, this demands a new thrust for the identification of novel therapeutic targets in oral cancer. p21 Activated Kinases (PAKs) are potential therapeutic targets that are involved in numerous physiological functions. PAKs are serine-threonine kinases and they serve as important regulators of cytoskeletal dynamics and cell motility, transcription through MAP kinase cascades, death and survival signalling, and cell-cycle progression. Although PAKs are known to play crucial roles in cancer progression, the role and clinical significance of PAKs in oral cancer remains poorly understood. RESULTS Our results suggest that PAK1 is over-expressed in oral cancer cell lines. Stimulation of Oral Squamous Cell Carcinoma (OSCC) cells with serum growth factors leads to PAK1 re-localization and might cause a profound cytoskeletal remodelling. PAK1 was also found to be involved in the invasion, migration and cytoskeletal remodelling of OSCC cells. CONCLUSIONS Our study revealed that PAK1 may play a crucial role in the progression of OSCC. Studying the role of PAK1 and its substrates is likely to enhance our understanding of oral carcinogenesis and potential therapeutic value of PAKs in oral cancer.
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Affiliation(s)
- Muraleedharan Parvathy
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Sreeharshan Sreeja
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Rakesh Kumar
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.,Department of Biochemistry and Molecular Medicine, George Washington University, Washington DC, USA
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Liprin-α1 is a regulator of vimentin intermediate filament network in the cancer cell adhesion machinery. Sci Rep 2016; 6:24486. [PMID: 27075696 PMCID: PMC4830931 DOI: 10.1038/srep24486] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 03/30/2016] [Indexed: 12/13/2022] Open
Abstract
PPFIA1 is located at the 11q13 region, which is one of the most commonly amplified regions in several epithelial cancers including head and neck squamous cell carcinoma and breast carcinoma. Considering the location of PPFIA1 in this amplicon, we examined whether protein encoded by PPFIA1, liprin-α1, possesses oncogenic properties in relevant carcinoma cell lines. Our results indicate that liprin-α1 localizes to different adhesion and cytoskeletal structures to regulate vimentin intermediate filament network, thereby altering the invasion and growth properties of the cancer cells. In non-invasive cells liprin-α1 promotes expansive growth behavior with limited invasive capacity, whereas in invasive cells liprin-α1 has significant impact on mesenchymal cancer cell invasion in three-dimensional collagen. Current results identify liprin-α1 as a novel regulator of the tumor cell intermediate filaments with differential oncogenic properties in actively proliferating or motile cells.
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41
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Tian LQ, Liu EQ, Zhu XD, Wang XG, Li J, Xu GM. MicroRNA-197 inhibits cell proliferation by targeting GAB2 in glioblastoma. Mol Med Rep 2016; 13:4279-88. [PMID: 27035789 DOI: 10.3892/mmr.2016.5076] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 12/29/2015] [Indexed: 11/06/2022] Open
Abstract
Glioblastoma is the most common type of primary brain tumor in adults, and is usually fatal in a short duration. Acquiring a better understanding of the pathogenic mechanisms of glioblastoma is essential to the design of effective therapeutic strategies. Grb2-associated binding protein 2 (GAB2) is a member of the daughter of sevenless/Gab family of scaffolding adapters, and has been reported to be important in the development and progression of human cancer. Previously, it has been reported that GAB2 is expressed at high levels in glioma, and may serve as a useful prognostic marker for glioma and a novel therapeutic target for glioma invasion intervention. Elucidating why GAB2 is overexpressed in glioma, and investigating how to downregulate it will assist in further understanding the pathogenesis and progression of the disease, and to offer novel targets for therapy. The present study used in situ hybridization to detect microRNA (miR)‑197 expression levels and Targetscan to predict that the 3'-UTR of GAB2 was targeted by miR-197. Northern blotting and reverse transcription‑quantitative polymerase chain reaction were also conducted in the current study. miR-197 is downregulated in glioblastoma tissues, compared with adjacent normal tissues, however it involvement continues to be detected in the disease. The results of the present study demonstrated that miR‑197, as a tumor suppressor gene, inhibited proliferation by regulating GAB2 in glioblastoma cells. Furthermore, GAB2 was not only upregulated in glioma, but its expression levels were also associated with the grades of glioma severity. In addition, overexpression of GAB2 suppressed the expression of miR‑197 in glioblastoma cells. Therefore, restoration of miR‑197 and targeting GAB2 may be used, in conjunction with other therapies, to prevent the progression of glioblastoma.
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Affiliation(s)
- Li-Qiang Tian
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - En-Qin Liu
- Department of Infectious Diseases, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
| | - Xi-De Zhu
- Department of Neurosurgery, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
| | - Xin-Gong Wang
- Department of Neurosurgery, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
| | - Jian Li
- Department of Neurosurgery, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
| | - Guang-Ming Xu
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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Kumar R, Li DQ. PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology. Adv Cancer Res 2016; 130:137-209. [PMID: 27037753 DOI: 10.1016/bs.acr.2016.01.002] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Since the initial recognition of a mechanistic role of p21-activated kinase 1 (PAK1) in breast cancer invasion, PAK1 has emerged as one of the widely overexpressed or hyperactivated kinases in human cancer at-large, allowing the PAK family to make in-roads in cancer biology, tumorigenesis, and cancer therapeutics. Much of our current understanding of the PAK family in cancer progression relates to a central role of the PAK family in the integration of cancer-promoting signals from cell membrane receptors as well as function as a key nexus-modifier of complex, cytoplasmic signaling network. Another core aspect of PAK signaling that highlights its importance in cancer progression is through PAK's central role in the cross talk with signaling and interacting proteins, as well as PAK's position as a key player in the phosphorylation of effector substrates to engage downstream components that ultimately leads to the development cancerous phenotypes. Here we provide a comprehensive review of the recent advances in PAK cancer research and its downstream substrates in the context of invasion, nuclear signaling and localization, gene expression, and DNA damage response. We discuss how a deeper understanding of PAK1's pathobiology over the years has widened research interest to the PAK family and human cancer, and positioning the PAK family as a promising cancer therapeutic target either alone or in combination with other therapies. With many landmark findings and leaps in the progress of PAK cancer research since the infancy of this field nearly 20 years ago, we also discuss postulated advances in the coming decade as the PAK family continues to shape the future of oncobiology.
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Affiliation(s)
- R Kumar
- School of Medicine and Health Sciences, George Washington University, Washington, DC, United States; Rajiv Gandhi Center of Biotechnology, Thiruvananthapuram, India.
| | - D-Q Li
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China; Key Laboratory of Breast Cancer in Shanghai, Shanghai Medical College, Fudan University, Shanghai, China; Key Laboratory of Epigenetics in Shanghai, Shanghai Medical College, Fudan University, Shanghai, China.
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Luo LY, Hahn WC. Oncogenic Signaling Adaptor Proteins. J Genet Genomics 2015; 42:521-529. [PMID: 26554907 PMCID: PMC4643408 DOI: 10.1016/j.jgg.2015.09.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/31/2015] [Accepted: 09/02/2015] [Indexed: 02/08/2023]
Abstract
Signal transduction pathways activated by receptor tyrosine kinases (RTK) play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we focus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes, CRKL, GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets.
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Affiliation(s)
- Leo Y Luo
- Health Sciences and Technology Program, Harvard Medical School, Boston, MA 02115, USA
| | - William C Hahn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
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Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D'Andrea AD. Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer. Cancer Discov 2015. [PMID: 26463832 DOI: 10.1158/2159-8290.cd-15-0714] [] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
UNLABELLED Approximately 50% of epithelial ovarian cancers (EOC) exhibit defective DNA repair via homologous recombination (HR) due to genetic and epigenetic alterations of HR pathway genes. Defective HR is an important therapeutic target in EOC as exemplified by the efficacy of platinum analogues in this disease, as well as the advent of PARP inhibitors, which exhibit synthetic lethality when applied to HR-deficient cells. Here, we describe the genotypic and phenotypic characteristics of HR-deficient EOCs, discuss current and emerging approaches for targeting these tumors, and present challenges associated with these approaches, focusing on development and overcoming resistance. SIGNIFICANCE Defective DNA repair via HR is a pivotal vulnerability of EOC, particularly of the high-grade serous histologic subtype. Targeting defective HR offers the unique opportunity of exploiting molecular differences between tumor and normal cells, thereby inducing cancer-specific synthetic lethality; the promise and challenges of these approaches in ovarian cancer are discussed in this review.
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Affiliation(s)
- Panagiotis A Konstantinopoulos
- Department of Medical Oncology, Medical Gynecologic Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
| | - Raphael Ceccaldi
- Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Geoffrey I Shapiro
- Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Early Drug Development Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Alan D D'Andrea
- Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D'Andrea AD. Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer. Cancer Discov 2015; 5:1137-54. [PMID: 26463832 DOI: 10.1158/2159-8290.cd-15-0714] [Citation(s) in RCA: 668] [Impact Index Per Article: 66.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
Abstract
UNLABELLED Approximately 50% of epithelial ovarian cancers (EOC) exhibit defective DNA repair via homologous recombination (HR) due to genetic and epigenetic alterations of HR pathway genes. Defective HR is an important therapeutic target in EOC as exemplified by the efficacy of platinum analogues in this disease, as well as the advent of PARP inhibitors, which exhibit synthetic lethality when applied to HR-deficient cells. Here, we describe the genotypic and phenotypic characteristics of HR-deficient EOCs, discuss current and emerging approaches for targeting these tumors, and present challenges associated with these approaches, focusing on development and overcoming resistance. SIGNIFICANCE Defective DNA repair via HR is a pivotal vulnerability of EOC, particularly of the high-grade serous histologic subtype. Targeting defective HR offers the unique opportunity of exploiting molecular differences between tumor and normal cells, thereby inducing cancer-specific synthetic lethality; the promise and challenges of these approaches in ovarian cancer are discussed in this review.
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Affiliation(s)
- Panagiotis A Konstantinopoulos
- Department of Medical Oncology, Medical Gynecologic Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
| | - Raphael Ceccaldi
- Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Geoffrey I Shapiro
- Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Early Drug Development Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Alan D D'Andrea
- Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells. Oncogene 2015; 35:2178-85. [PMID: 26257058 PMCID: PMC5125076 DOI: 10.1038/onc.2015.278] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 05/26/2015] [Accepted: 06/09/2015] [Indexed: 12/14/2022]
Abstract
p21-activated kinases (PAKs) are Cdc42/Rac–activated serine-threonine protein kinases that regulate of several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt, and Wnt/b-catenin signaling pathways. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including human breast, ovary, prostate, and brain cancer, due to amplification of the PAK1 gene in an 11q13 amplicon. Genetic or pharmacological inactivation of Pak1 has been shown to reduce proliferation of different cancer cells in vitro and reduce tumor progression in vivo. In this work, we examined the roles of Pak1 in cellular and animal models of PAK1-amplified ovarian cancer. We found that inhibition of Pak1 leads to decreased proliferation and migration in PAK1 amplified/overexpressed ovarian cancer cells, and has no effect in cell that lack such amplification/overexpression. Further, we observed that loss of Pak1 function causes 11q13 amplified ovarian cancer cells to arrest in the G2/M phase of the cell cycle. This arrest correlates with activation of p53 and p21Cip and decreased expression of cyclin B1. These findings suggest that small molecule inhibitors of Pak1 may play a therapeutic role in the ~25% of ovarian cancers characterized by PAK1 gene amplification.
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PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome. Blood 2015; 126:1118-27. [PMID: 26170031 DOI: 10.1182/blood-2014-12-618801] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 06/26/2015] [Indexed: 12/14/2022] Open
Abstract
Poor clinical outcome of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has been attributed to failure of current chemotherapeutic regimens to target leukemic stem cells. We recently identified p21-activated kinase (PAK1) as a downstream effector molecule of H2.0-like homeobox (HLX), a gene functionally relevant for AML pathogenesis. In this study, we find that inhibition of PAK1 activity by small molecule inhibitors or by RNA interference leads to profound leukemia inhibitory effects both in vitro and in vivo. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of the MYC oncogene and a core network of MYC target genes. Importantly, we find that inhibition of PAK1 inhibits primary human leukemic cells including immature leukemic stem cell-enriched populations. Moreover, we find that PAK1 upregulation occurs during disease progression and is relevant for patient survival in MDS. Our studies highlight PAK1 as a novel target in AML and MDS and support the use of PAK1 inhibitors as a therapeutic strategy in these diseases.
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Abstract
INTRODUCTION Rho GTPases are master regulators of actomyosin structure and dynamics and play pivotal roles in a variety of cellular processes including cell morphology, gene transcription, cell cycle progression, and cell adhesion. Because aberrant Rho GTPase signaling activities are widely associated with human cancer, key components of Rho GTPase signaling pathways have attracted increasing interest as potential therapeutic targets. Similar to Ras, Rho GTPases themselves were, until recently, deemed "undruggable" because of structure-function considerations. Several approaches to interfere with Rho GTPase signaling have been explored and show promise as new ways for tackling cancer cells. AREAS COVERED This review focuses on the recent progress in targeting the signaling activities of three prototypical Rho GTPases, that is, RhoA, Rac1, and Cdc42. The authors describe the involvement of these Rho GTPases, their key regulators and effectors in cancer. Furthermore, the authors discuss the current approaches for rationally targeting aberrant Rho GTPases along their signaling cascades, upstream and downstream of Rho GTPases, and posttranslational modifications at a molecular level. EXPERT OPINION To date, while no clinically effective drugs targeting Rho GTPase signaling for cancer treatment are available, tool compounds and lead drugs that pharmacologically inhibit Rho GTPase pathways have shown promise. Small-molecule inhibitors targeting Rho GTPase signaling may add new treatment options for future precision cancer therapy, particularly in combination with other anti-cancer agents.
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Affiliation(s)
- Yuan Lin
- Division of Experimental Hematology and Cancer Biology, Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA
| | - Yi Zheng
- Division of Experimental Hematology and Cancer Biology, Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA
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Ding CB, Yu WN, Feng JH, Luo JM. Structure and function of Gab2 and its role in cancer (Review). Mol Med Rep 2015; 12:4007-4014. [PMID: 26095858 PMCID: PMC4526075 DOI: 10.3892/mmr.2015.3951] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 05/19/2015] [Indexed: 12/30/2022] Open
Abstract
The docking proteins of the Grb-associated binder (Gab) family transduce cellular signals between receptors and intracellular downstream effectors, and provide a platform for protein-protein interactions. Gab2, a key member of the Gab family of proteins, is involved in the amplification and integration of signal transduction, evoked by a variety of extracellular stimuli, including growth factors, cytokines and antigen receptors. Gab2 protein lacks intrinsic catalytic activity; however, when phosphorylated by protein-tyrosine kinases (PTKs), Gab2 recruits several Src homology-2 (SH2) domain-containing proteins, including the SH2-containing protein tyrosine phosphatase 2 (SHP2), the p85 subunit of phosphoinositide-3 kinase (PI3K), phospholipase C-γ (PLCγ)1, Crk, and GC-GAP. Through these interactions, the Gab2 protein triggers various downstream signal effectors, including SHP2/rat sarcoma viral oncogene/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase and PI3K/AKT, involved in cell growth, differentiation, migration and apoptosis. It has been previously reported that aberrant Gab2 and/or Gab2 signaling is closely associated with human tumorigenesis, particularly in breast cancer, leukemia and melanoma. The present review aimed to focus on the structure and effector function of Gab2, its role in cancer and its potential for use as an effective therapeutic target.
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Affiliation(s)
- Chen-Bo Ding
- Department of Immunology and Immunology Innovation Base for Postgraduate Education in Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563099, P.R. China
| | - Wei-Na Yu
- Department of Immunology and Immunology Innovation Base for Postgraduate Education in Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563099, P.R. China
| | - Ji-Hong Feng
- Department of Oncology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563099, P.R. China
| | - Jun-Min Luo
- Department of Immunology and Immunology Innovation Base for Postgraduate Education in Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563099, P.R. China
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Davis SJ, Sheppard KE, Anglesio MS, George J, Traficante N, Fereday S, Intermaggio MP, Menon U, Gentry-Maharaj A, Lubinski J, Gronwald J, Pearce CL, Pike MC, Wu A, Kommoss S, Pfisterer J, du Bois A, Hilpert F, Ramus SJ, Bowtell DDL, Huntsman DG, Pearson RB, Simpson KJ, Campbell IG, Gorringe KL. Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition. Mol Cancer Ther 2015; 14:1495-503. [PMID: 25852062 DOI: 10.1158/1535-7163.mct-15-0039] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 03/19/2015] [Indexed: 11/16/2022]
Abstract
Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of amplified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number amplified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling.
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Affiliation(s)
- Sally J Davis
- Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Karen E Sheppard
- Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Michael S Anglesio
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Joshy George
- Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
| | - Nadia Traficante
- Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
| | - Sian Fereday
- Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
| | - Maria P Intermaggio
- Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Usha Menon
- Gynaecological Cancer Research Centre, Women's Cancer, University College London, Institute for Women's Health, London, United Kingdom
| | - Aleksandra Gentry-Maharaj
- Gynaecological Cancer Research Centre, Women's Cancer, University College London, Institute for Women's Health, London, United Kingdom
| | - Jan Lubinski
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Jacek Gronwald
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | | | - Malcolm C Pike
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Anna Wu
- Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Stefan Kommoss
- Department of Gynecology and Obstetrics, Tuebingen University, Tuebingen, Germany
| | - Jacobus Pfisterer
- Department of Gynecology and Obstetrics, Kiel University, Kiel, Germany
| | - Andreas du Bois
- Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Klinik (HSK), Essen, Germany
| | - Felix Hilpert
- University Hospital Schleswig-Holstein, Kiel, Germany
| | - Susan J Ramus
- Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - David D L Bowtell
- Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
| | - David G Huntsman
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Richard B Pearson
- Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Kaylene J Simpson
- Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
| | - Ian G Campbell
- Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Kylie L Gorringe
- Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
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