المؤلفون: Edmund Kwok-Kwan Tung, Yu-Man Tsui, Karen Man-Fong Sze, Terence Kin Wah Lee, Daniel W.H. Ho, Irene Oi-Lin Ng

المصدر: Oncotarget

مصطلحات موضوعية: 0301 basic medicine, Male, sphere formation, Dishevelled Proteins, Gene Expression, Receptors, G-Protein-Coupled, Mice, 0302 clinical medicine, Protein Phosphatase 1, Tumor Cells, Cultured, Medicine, Phosphorylation, chemistry.chemical_classification, Gene knockdown, Wnt/β-catenin, biology, Protein Stability, Liver Neoplasms, Wnt signaling pathway, Middle Aged, Dishevelled, Ubiquitin ligase, Oncology, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Female, Signal transduction, Research Paper, Protein Binding, Signal Transduction, Adult, Carcinoma, Hepatocellular, Ubiquitin-Protein Ligases, Protein Serine-Threonine Kinases, Models, Biological, 03 medical and health sciences, Cell Line, Tumor, Animals, Humans, Aged, business.industry, Cancer, Protein phosphatase 1, medicine.disease, Repressor Proteins, Disease Models, Animal, 030104 developmental biology, chemistry, post-translational modification, Immunology, biology.protein, Cancer research, tumorigenicity, business, Carrier Proteins

الوصف: Dishevelled-3 (Dvl3) is regarded as a binding hub with many different interacting partners. However, its regulation and mechanism on cancer stemness remain to be explored. In this study, we showed that Dvl3 was significantly overexpressed in human hepatocellular carcinomas (HCCs) and promoted cancer stemness both in vitro and in vivo. We found that the non-phosphorylated (NP)-Dvl3 was more stable than the phosphorylated form, more active in activating β-catenin transcriptional activity, and more potent in enhancing self-renewal ability in HCC cells. Mechanistically, we confirmed that the homeodomain-interacting protein kinase-2 (HIPK2) and E3 ubiquitin ligase ITCH were able to physically bind to Dvl3 protein. Knockdown of HIPK2 and the protein phosphatase regulatory unit C-alpha (PP1Cα) resulted in sustained Dvl3 phosphorylation and hence decrease in the NP form of Dvl3. On the other hand, knockdown of E3 ubiquitin ligase ITCH reduced the phosphorylation-induced degradation and stabilized the phosphorylated Dvl3 protein. Furthermore, the NP-Dvl3 enhanced the LGR5 promoter activity to upregulate LGR5 expression, which was associated with increased cancer stemness in HCC. Our findings established that HIPK2/PP1Cα/ITCH axis sustains the de-phosphorylation of Dvl3. This post-translational modification of Dvl3 in turn maintains LGR5 expression and enhances the cancer stemness properties in HCC.
published_or_final_version

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::90204d510d6b56ec2bbe3a312bf1843bTest
http://europepmc.org/articles/PMC5503623Test

المؤلفون: Chan Young Ock, Woo Ho Kim, Jiwon Koh, Hyung Ho Kim, Yoonjin Kwak, Hye Seung Lee, Sang Hoon Ahn, Sumi Yun, Soo Kyung Nam, Jin Won Kim, Do Joong Park

المصدر: Oncotarget

مصطلحات موضوعية: Male, 0301 basic medicine, Oncology, Pathology, Gene Expression, Cancer Microenvironment, Kaplan-Meier Estimate, CD8-Positive T-Lymphocytes, B7-H1 Antigen, 0302 clinical medicine, Tumor Microenvironment, programmed cell death 1 ligand 1, Aged, 80 and over, Genomics, Middle Aged, Prognosis, tumor-infiltrating lymphocytes, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, Pd l1 expression, Research Paper, Adult, medicine.medical_specialty, Stage ii, Immunomodulation, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Immune system, Stomach Neoplasms, Internal medicine, Biomarkers, Tumor, medicine, Humans, Aged, Neoplasm Staging, Proportional Hazards Models, cancer microenvironment, Tumor-infiltrating lymphocytes, business.industry, Gene Expression Profiling, gastric cancer, Reproducibility of Results, Microsatellite instability, Cancer, medicine.disease, 030104 developmental biology, business, CD8

الوصف: // Jiwon Koh 1 , Chan-Young Ock 2 , Jin Won Kim 3 , Soo Kyung Nam 4 , Yoonjin Kwak 4 , Sumi Yun 5 , Sang-Hoon Ahn 6 , Do Joong Park 6 , Hyung-Ho Kim 6 , Woo Ho Kim 1 , Hye Seung Lee 4 1 Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul 03080, Republic of Korea 2 Department of Internal Medicine, Seoul National University Hospital, Jongno-gu, Seoul 03080, Republic of Korea 3 Department of Internal Medicine, Seoul National University Bundang Hospital, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea 4 Department of Pathology, Seoul National University Bundang Hospital, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea 5 Department of Pathology, Soonchunhyang University Seoul Hospital, Yongsan-gu, Seoul 04401, Republic of Korea 6 Department of Surgery, Seoul National University Bundang Hospital, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea Correspondence to: Hye Seung Lee, email: hye2@snu.ac.kr Keywords: gastric cancer, programmed cell death 1 ligand 1, tumor-infiltrating lymphocytes, cancer microenvironment Received: November 22, 2016 Accepted: February 06, 2017 Published: February 17, 2017 ABSTRACT We co-assessed PD-L1 expression and CD8 + tumor-infiltrating lymphocytes in gastric cancer (GC), and categorized into 4 microenvironment immune types. Immunohistochemistry ( PD-L1 , CD8, Foxp3, E-cadherin, and p53), PD-L1 mRNA in situ hybridization (ISH), microsatellite instability (MSI), and EBV ISH were performed in 392 stage II/III GCs treated with curative surgery and fluoropyrimidine-based adjuvant chemotherapy, and two public genome databases were analyzed for validation. PD-L1 + was found in 98/392 GCs (25.0%). The proportions of immune types are as follows: PD-L1 + /CD8 High, 22.7%; PD-L1 − /CD8 Low , 22.7%; PD-L1 + /CD8 Low , 2.3%; PD-L1 − /CD8 High , 52.3%. PD-L1 + /CD8 High type accounted for majority of EBV + and MSI-high (MSI-H) GCs (92.0% and 66.7%, respectively), and genome analysis from public datasets demonstrated similar pattern. PD-L1 − /CD8 High showed the best overall survival (OS) and PD-L1 − /CD8 Low the worst ( P < 0.001). PD-L1 expression alone was not associated with OS, however, PD-L1 − /CD8 High type compared to PD-L1 + /CD8 High was independent favorable prognostic factor of OS by multivariate analysis ( P = 0.042). Adaptation of recent molecular classification based on EBV, MSI, E-cadherin, and p53 showed no significant survival differences. These findings support the close relationship between PD-L1/CD8 status based immune types and EBV + , MSI-H GCs, and their prognostic significance in stage II/III GCs.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d913a898c0fba67386f920ed1ba4c9e1Test
https://doi.org/10.18632Test/oncotarget.15465

المؤلفون: Asaduzzaman Khan, Saber Imani, Chunli Wei, Shangyi Fu, Luquan Yang, Junjiang Fu, Jingliang Cheng, Xiuli Xiao, Mousumi Tania, Xianqin Zhang, Xianning Zhang

المصدر: Oncotarget

مصطلحات موضوعية: 0301 basic medicine, Adult, Pathology, medicine.medical_specialty, Epithelial-Mesenchymal Transition, Blotting, Western, thymoquinone, Antineoplastic Agents, Breast Neoplasms, medicine.disease_cause, Real-Time Polymerase Chain Reaction, Metastasis, 03 medical and health sciences, Twist transcription factor, 0302 clinical medicine, breast cancer, Cell Movement, microRNA-34a, microRNA, medicine, Benzoquinones, metastasis, Humans, Neoplasm Invasiveness, Epithelial–mesenchymal transition, Receptor, Notch1, Aged, Cell growth, business.industry, Twist-Related Protein 1, Nuclear Proteins, Zinc Finger E-box-Binding Homeobox 1, Cell migration, Middle Aged, medicine.disease, Gene Expression Regulation, Neoplastic, MicroRNAs, 030104 developmental biology, Oncology, MicroRNA 34a, 030220 oncology & carcinogenesis, embryonic structures, Cancer research, Female, Carcinogenesis, business, Research Paper, Transcription Factors

الوصف: MicroRNA-34a (miR-34a) plays an essential role against tumorigenesis and progression of cancer metastasis. Here, we analyzed the expression, targets and functional effects of miR-34a on epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs), such as TWIST1, SLUG and ZEB1/2, and an EMT-inducing protein NOTCH1 in breast cancer (BC) cell migration and invasion and its correlation with tumorigenesis and clinical outcomes. Expression of miR-34a is downregulated in human metastatic breast cancers (MBC) compared to normal breast tissues and is negatively correlated with clinicopathological features of MBC patients. Ectopic expression of miR-34a in MBC cell-line BT-549 significantly inhibits cell migration and invasion, but exhibits no clear effect on BC cell growth. We found that miR-34a is able to inactivate EMT signaling pathway with mediatory of NOTCH1, TWIST1, and ZEB1 upon 3'-UTR activity in MBC cell lines, but has no inhibitory effects on SLUG and ZEB2. Furthermore, we investigated the synergistic effects of Thymoquinone (TQ) and miR-34a together on the expression of EMT-associated proteins. Results showed that co-delivery of miR-34a and TQ is able to inactivate EMT signaling pathway by directly targeting TWIST1 and ZEB1 in BT-549 cell line, indicating that they might be a promising therapeutic combination against breast cancer metastasis. Epigenetic inactivation of the EMT-TFs/miR-34a pathway can potentially alter the equilibrium of these regulations, facilitating EMT and metastasis in BC. Altogether, our findings suggest that miR-34a alone could serve as a potential therapeutic agent for MBC, and together with TQ, their therapeutic potential is synergistically enhanced.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::328b75fe73a3fcfb78149e612d79aae0Test
http://europepmc.org/articles/PMC5400590Test

المؤلفون: Yijun Qi, Zhengguang Wang, Fangyuan Xiong, Xiaoshan Wang, Yong Zhu, Haoyuan Yu, Huaqing Zhu

المصدر: Oncotarget

مصطلحات موضوعية: AMPK, Male, 0301 basic medicine, chemotherapy resistance, Apoptosis, AMP-Activated Protein Kinases, Promoter Regions, Genetic, RORα, Orphan receptor, Reverse Transcriptase Polymerase Chain Reaction, Nuclear Receptor Subfamily 1, Group F, Member 1, Middle Aged, Immunohistochemistry, Gene Expression Regulation, Neoplastic, Oncology, Female, RNA Interference, medicine.symptom, Research Paper, Protein Binding, Adult, medicine.medical_specialty, Cell Survival, Blotting, Western, Inflammation, 03 medical and health sciences, Immune system, Stomach Neoplasms, Cell Line, Tumor, Internal medicine, medicine, Humans, gastric carcinoma, Protein kinase A, Aged, Neoplasm Staging, business.industry, Tumor Suppressor Proteins, Ribonucleotides, Aminoimidazole Carboxamide, digestive system diseases, Enzyme Activation, 030104 developmental biology, Endocrinology, Nuclear receptor, Cancer cell, Cancer research, business

الوصف: // Zhengguang Wang 1 , Fangyuan Xiong 2 , Xiaoshan Wang 1 , Yijun Qi 1 , Haoyuan Yu 1 , Yong Zhu 1 , Huaqing Zhu 2 1 Department of Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, P.R. China 2 Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, P.R. China Correspondence to: Zhengguang Wang, email: wangzhengguang@ahmu.edu.cn Keywords: gastric carcinoma, RORα, AMPK, apoptosis, chemotherapy resistance Received: November 02, 2016 Accepted: December 23, 2016 Published: December 29, 2016 ABSTRACT Retinoid-related orphan receptor α (RORα) is a nuclear receptor, which regulates inflammation and immune responses, lipid metabolism and circadian rhythm. Although RORα suppresses breast tumor invasion, it is unknown whether RORα is dysregulated in gastric cancer leading to cellular survival. Therefore, we hypothesize that RORα is dysfunctional in gastric carcinoma and this causes decreased apoptosis in gastric cancer cells. To test this hypothesis, we employed human gastric cancer tissues with different stages to determine RORα expression, as well as in vitro human gastric cancer cells to determine how RORα is reduced during apoptosis. We found that the expression of RORα was reduced in gastric tissues with cancer, and this correlated with increased TNM stages. The mechanisms underlying RORα reduction is due to the reduced activation of AMP-activated protein kinase (AMPK), as a selective AMPK activator AICAR increased RORα activation and level in human gastric cancer cells. Furthermore, AICAR treatment increased RORα recruitment on the promoters of tumor suppressor genes (i.e., FBXM7, SEMA3F and p21) leading to apoptosis in human gastric cancer cells. Taken together, RORα reduction occurs in gastric cancer leading to the survival of tumor cells, which is attenuated by AMPK. Therefore, both RORα and AMPK are potential targets for the intervention and therapy in gastric carcinoma.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ba20fca37b2357ff49ea45d423ca74deTest
https://doi.org/10.18632Test/oncotarget.14364

المؤلفون: Hyog Young Kwon, Dongjun Jeong, Lan Thi Hanh Phi, Hyungjoo Kim, Ying-Gui Yang, Ita Novita Sari, Moo Jun Baek

المصدر: Oncotarget

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Oncology, Poor prognosis, medicine.medical_specialty, Epithelial-Mesenchymal Transition, Colorectal cancer, Caveolin 1, colorectal cancer, Disease, INTERFERON-INDUCED TRANSMEMBRANE PROTEIN 1, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Cell Line, Tumor, Internal medicine, metastasis, Humans, Medicine, Neoplasm Metastasis, RNA, Small Interfering, Aged, Cell Proliferation, business.industry, Middle Aged, medicine.disease, Antigens, Differentiation, IFITM1, 030104 developmental biology, Biological significance, 030220 oncology & carcinogenesis, Immunology, Cancer cell, Disease Progression, Female, Ectopic expression, prognosis, Colorectal Neoplasms, business, Research Paper

الوصف: // Ita Novita Sari 1, * , Ying-Gui Yang 1, * , Lan Thi Hanh Phi 1 , Hyungjoo Kim 2 , Moo Jun Baek 3 , Dongjun Jeong 2 , Hyog Young Kwon 1 1 Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Republic of Korea 2 Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University, Republic of Korea 3 Department of Surgery, Department of Pathology, College of Medicine, Soonchunhyang University, Republic of Korea * These authors contributed equally to this work Correspondence to: Hyog Young Kwon, email: hykwon@sch.ac.kr Dongjun Jeong, email: juny1024@sch.ac.kr Keywords: IFITM1, colorectal cancer, prognosis, metastasis Received: June 06, 2016 Accepted: November 07, 2016 Published: November 12, 2016 ABSTRACT Interferon-induced transmembrane protein 1 (IFITM1) has been shown to be implicated in multiple cancers, yet little is known about biological significance of IFITM1 in colorectal cancer. Here, we show that IFITM1 is highly expressed in metastatic colorectal cancer cell lines as well as colorectal patient-derived tumor samples, and its expression is associated with a poor prognosis of the disease. Also, IFITM1 depletion resulted in a significant reduction in the mobility of cancer cell lines, whereas ectopic expression of IFITM1 promoted the migration of cancer cells. Epithelial-mesenchymal transition (EMT) signature was dysregulated by both loss and gain of function of IFITM1, which was partially reverted by Caveolin-1 (CAV1). Therefore, these results suggest that IFITM1 may be a prognostic marker and an attractive target to achieve better therapeutic outcomes in colorectal cancer.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0081f0a812143a1aa78eb59f76a2c99aTest
https://doi.org/10.18632Test/oncotarget.13325

المؤلفون: Wei Liu, Xiaonian Zhu, Fen Tang, Yuan Ren, Xueyan Miao, Shengkui Tan, Linyuan Qin, Chunhua Bei, Guifang Tang, Wei Luo

المصدر: Oncotarget

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Carcinoma, Hepatocellular, Epithelial-Mesenchymal Transition, Biology, medicine.disease_cause, zinc finger E-box binding homeobox 1 (ZEB1), Metastasis, hepatocellular carcinoma (HCC), 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Humans, Neoplasm Invasiveness, Epithelial–mesenchymal transition, neoplasms, Transcription factor, Aged, Cell Proliferation, Zinc Finger E-box Binding Homeobox 2, Zinc finger, Regulation of gene expression, Liver Neoplasms, Zinc Finger E-box-Binding Homeobox 1, zinc finger E-box binding homeobox 2 (ZEB2), Middle Aged, MYC associated zinc finger protein (MAZ), medicine.disease, digestive system diseases, DNA-Binding Proteins, epithelial-mesenchymal transition (EMT), 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Cancer research, Female, Carcinogenesis, Research Paper, Transcription Factors

الوصف: // Wei Luo 1, * , Xiaonian Zhu 1, * , Wei Liu 1 , Yuan Ren 1 , Chunhua Bei 1 , Linyuan Qin 1 , Xueyan Miao 1 , Fen Tang 2 , Guifang Tang 2 , Shengkui Tan 1 1 School of Public Health, Guilin Medical University, Guilin 541004, Guangxi, People’s Republic of China 2 Department of Hepatology, The Affiliated Nanxishan Hospital of Guilin Medical University, Guilin 541004, Guangxi, People’s Republic of China * These authors contributed equally to this work Correspondence to: Shengkui Tan, email: sktan2008@sina.cn Keywords: MYC associated zinc finger protein (MAZ), hepatocellular carcinoma (HCC), zinc finger E-box binding homeobox 1 (ZEB1), zinc finger E-box binding homeobox 2 (ZEB2), epithelial-mesenchymal transition (EMT) Received: July 11, 2016 Accepted: November 09, 2016 Published: November 16, 2016 ABSTRACT MYC associated zinc finger protein (MAZ) plays a key role in regulation of gene expression and tumor development. Studies have shown that deregulated expression of MAZ is closely related to the progression of tumors such as glioblastoma, breast cancer, prostate cancer and liposarcoma. However, the role of MAZ in hepatocellular carcinoma (HCC) has not been fully elucidated. Here, we found that expression of MAZ was increased in HCC and correlated to the distant metastasis of HCC. Moreover, we found that MAZ had a relationship with zinc finger E-box binding homeobox 1 and 2 (ZEB1 and ZEB2), two important mesenchymal markers in epithelial-mesenchymal transition (EMT) that were over-expressed in HCC. After knocking-down MAZ expression in HCC cell lines using RNA interruption, HCC cell proliferation, tumorigenesis, invasion and migration were significantly inhibited. In addition, we found that expression of other EMT markers was also changed besides ZEB1 and ZEB2 by decreasing MAZ expression, both detected in vivo and in vitro assays. Therefore, we conclude that MAZ can promote the invasion and metastasis of HCC by inducing EMT.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4205d123701cd0d57ca5c6989fff1748Test
https://doi.org/10.18632Test/oncotarget.13416

المؤلفون: Duaa Al-Subait, Jamila Chakir, Latifa Koussih, Hesam Movassagh, Lianyu Shan, Naresh Singh Redhu, Abdelilah S. Gounni, Nazanin Tatari, Michael Roth, Mahdi Khattabi, Michael Tamm

المصدر: Oncotarget

مصطلحات موضوعية: 0301 basic medicine, Male, rac1 GTP-Binding Protein, Platelet-derived growth factor, Time Factors, neuropilin 1, platelet-derived growth factor, chemistry.chemical_compound, airway remodeling, Neuropilin 1, Receptors, Platelet-Derived Growth Factor, semaphorin 3A, Phosphorylation, biology, Hyperplasia, respiratory system, musculoskeletal system, 3. Good health, Cell biology, Oncology, Female, Platelet-derived growth factor receptor, Signal Transduction, Adult, STAT3 Transcription Factor, Myocytes, Smooth Muscle, Bronchi, Cell Line, 03 medical and health sciences, Young Adult, Downregulation and upregulation, Semaphorin, Pathology Section, medicine, Humans, Cell Proliferation, Glycogen Synthase Kinase 3 beta, business.industry, Cell growth, SEMA3A, Muscle, Smooth, Semaphorin-3A, asthma, medicine.disease, Research Paper: Pathology, Neuropilin-1, respiratory tract diseases, 030104 developmental biology, chemistry, Case-Control Studies, Immunology, biology.protein, business

الوصف: Airway smooth muscle (ASM) hyperplasia is a key feature of airway remodeling in development of lung diseases such as asthma. Anomalous proliferation of ASM cells directly contributes to ASM hyperplasia. However, the molecular mechanisms controlling ASM cell proliferation are not completely understood. Semaphorins are versatile regulators of various cellular processes including cell growth and proliferation. The role of semaphorins in ASM cell proliferation has remained to be addressed. Here, we report that semaphorin 3A (Sema3A) receptor, neuropilin 1 (Nrp1), is expressed on human ASM cells (HASMC) isolated from healthy and asthmatic donors and treatment of these cells with exogenous Sema3A inhibits growth factor-induced proliferation. Sema3A inhibitory effect on HASMC proliferation is associated with decreased tyrosine phosphorylation of PDGFR, downregulation of Rac1 activation, STAT3 and GSK-3β phosphorylation. Bronchial sections from severe asthmatics displayed immunoreactivity of Nrp1, suggestive of functional contribution of Sema3A-Nrp1 axis in airway remodeling. Together, our data suggest Sema3A-Nrp1 signaling as a novel regulatory pathway of ASM hyperplasia.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fa586885bf774197ec533c9676528cf5Test
http://europepmc.org/articles/PMC5348316Test

المؤلفون: Anna A. Brożyna, Wojciech Jóźwicki, Cezary Skobowiat, Andrzej Slominski, Anton M. Jetten

المصدر: Oncotarget

مصطلحات موضوعية: 0301 basic medicine, Oncology, Keratinocytes, Male, Pathology, Skin Neoplasms, vitamin D, Disease, 0302 clinical medicine, Medicine, Neoplasm Metastasis, RORα, RORγ, Skin, Aged, 80 and over, Melanoma, Nuclear Receptor Subfamily 1, Group F, Member 1, Middle Aged, Nuclear Receptor Subfamily 1, Group F, Member 3, Tumor Pathology, 3. Good health, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Disease Progression, Melanocytes, Female, Research Paper, Adult, medicine.medical_specialty, Tumor suppressor gene, 03 medical and health sciences, Young Adult, Internal medicine, Cell Line, Tumor, Vitamin D and neurology, melanoma, Humans, melanocytic nevi, neoplasms, Nevus, Aged, Cell Proliferation, Neoplasm Staging, Retrospective Studies, business.industry, Gene Expression Profiling, Cancer, medicine.disease, 030104 developmental biology, Human melanoma, business, Biomedical sciences, Follow-Up Studies

الوصف: // Anna A. Brozyna 1, 2 , Wojciech Joźwicki 1, 2 , Cezary Skobowiat 3 , Anton Jetten 4 , Andrzej T. Slominski 5,6, 7 1 Department of Tumor Pathology and Pathomorphology, Oncology Centre - Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland 2 Department of Tumor Pathology and Pathomorphology, Faculty of Health Sciences, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland 3 Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland 4 Cell Biology Section, Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA 5 Department of Dermatology, Cancer Chemoprevention Program, University of Alabama at Birmingham, AL, USA 6 Comprehensive Cancer Center, Cancer Chemoprevention Program, University of Alabama at Birmingham, AL, USA 7 Pathology and Laboratory Medicine Service, VA Medical Center, Birmingham, AL, USA Correspondence to: Anna A. Brozyna, email: anna.brozyna@cm.umk.pl Andrzej T. Slominski, email: aslominski@uabmc.edu Keywords: melanoma, RORα, RORγ, melanocytic nevi, vitamin D Received: February 19, 2016 Accepted: July 18, 2016 Published: August 11, 2016 ABSTRACT The retinoic acid-related orphan receptors (RORs) regulate several physiological and pathological processes, including immune functions, development and cancer. To study the potential role of RORs in melanoma progression, we analysed RORα and RORγ expression in nevi and primary melanomas and non-lesional skin and metastases in relation to melanoma clinico-pathomorphological features. The expression of RORα and RORγ was lower in melanomas than in nevi and decreased during melanoma progression, with lowest levels found in primary melanomas at stages III and IV and in melanoma metastases. Their expression correlated with pathomorphological pTNM parameters being low in aggressive tumors and being high in tumors showing histological markers of good prognosis. Higher nuclear levels of RORα and RORγ and of cytoplasmic RORγ correlated with significantly longer overall and disease free survival time. Highly pigmented melanomas showed significantly lower level of nuclear RORs. This study shows that human melanoma development and aggressiveness is associated with decreased expression of RORα and RORγ, suggesting that RORs could be important in melanoma progression and host responses against the tumor. Furthermore, it suggests that RORα and RORγ might constitute a novel druggable target in anti-melanoma management using tumor suppressor gene therapy restoring their normal functions.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::933ad3c78fc52973fd2c2caf813dd945Test
http://europepmc.org/articles/PMC5325362Test

المؤلفون: Yang Yang, Lingyu Zhao, Lumin Wang, Chen Huang, Jun Yang, Ni Hou, Kang He, Dongdong Tong, Hongfei Sun, Tusheng Song, Xiaofei Wang

المصدر: Oncotarget

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, MAPK/ERK pathway, Cell, cell progression, medicine.disease_cause, Bioinformatics, Mice, 03 medical and health sciences, 0302 clinical medicine, Animals, Humans, Medicine, Genes, Tumor Suppressor, Protein kinase B, Aged, Early Growth Response Protein 1, Homeodomain Proteins, Cyclin-dependent kinase 1, business.industry, Computational Biology, Cancer, hepatocellular carcinoma, Middle Aged, Cell cycle, medicine.disease, ErbB Receptors, MicroRNAs, miR-203a, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Disease Progression, Cancer research, EGR1, Female, business, Carcinogenesis, HOXD3, Signal Transduction, Transcription Factors, Research Paper

الوصف: // Lumin Wang 1 , Hongfei Sun 1 , Xiaofei Wang 1 , Ni Hou 1 , Lingyu Zhao 1 , Dongdong Tong 1 , Kang He 1 , Yang Yang 1 , Tusheng Song 1 , Jun Yang 3 , Chen Huang 1, 2, 4 1 Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, P.R. China 2 Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, P.R. China 3 Department of Pathology, Second Affiliated Hospital of Xi’an Jiaotong University College of Medicine, Xi’an, Shaanxi, P.R. China 4 Cardiovascular Research Center, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, P.R. China Correspondence to: Chen Huang, email: hchen@mail.xjtu.edu.cn Jun Yang, email: yangjundr@163.com Keywords: EGR1, miR-203a, HOXD3, hepatocellular carcinoma, cell progression Received: February 23, 2016 Accepted: April 26, 2016 Published: May 26, 2016 ABSTRACT EGR1 plays a critical role in cancer progression. However, its precise role in hepatocellular carcinoma has not been elucidated. In this study, we found that the overexpression of EGR1 suppresses hepatocellular carcinoma cell proliferation and increases cell apoptosis by binding to the miR-203a promoter sequence. In addition, we investigated the function of miR-203a on progression of HCC cells. We verified that the effect of overexpression of miR-203a is consistent with that of EGR1 in regulation of cell progression. Through bioinformatic analysis and luciferase assays, we confirmed that miR-203a targets HOXD3. Silencing HOXD3 could block transition of the G2/M phase, increase cell apoptosis, decrease the expression of cell cycle and apoptosis-related proteins, EGFR, p-AKT, p-ERK, CCNB1, CDK1 and Bcl2 by targeting EGFR through EGFR/AKT and ERK cell signaling pathways. Likewise, restoration of HOXD3 counteracted the effects of miR-203a expression. In conclusion, our findings are the first to demonstrate that EGR1 is a key player in the transcriptional control of miR-203a, and that miR-203a acts as an anti-oncogene to suppress HCC tumorigenesis by targeting HOXD3 through EGFR-related cell signaling pathways.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8bb2089b1be4e0b111bd9c230a0df0f3Test
https://doi.org/10.18632Test/oncotarget.9605

المؤلفون: Jianpo Lian, Yu Zhu, Guang Ning, Lieyu Xu, Yicheng Qi, Weiqing Wang, Xiaojing Wang, Yunze Xu

المصدر: Oncotarget

مصطلحات موضوعية: 0301 basic medicine, MAPK/ERK pathway, Adult, Male, Pathology, medicine.medical_specialty, Cell Survival, EGFR, Mice, Nude, crosstalk, Receptor, IGF Type 1, 03 medical and health sciences, Erlotinib Hydrochloride, 0302 clinical medicine, IGF1R, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, medicine, Adrenocortical Carcinoma, Adrenocortical carcinoma, Animals, Humans, Pyrroles, Protein kinase B, PI3K/AKT/mTOR pathway, Insulin-like growth factor 1 receptor, EGFR inhibitors, Aged, business.industry, Drug Synergism, Middle Aged, medicine.disease, Xenograft Model Antitumor Assays, Adrenal Cortex Neoplasms, body regions, ErbB Receptors, 030104 developmental biology, Pyrimidines, Oncology, coinhibition therapy, 030220 oncology & carcinogenesis, Cancer research, Female, Erlotinib, business, medicine.drug, Research Paper

الوصف: // Lieyu Xu 1, * , Yicheng Qi 2, * , Yunze Xu 1, 3, * , Jianpo Lian 1 , Xiaojing Wang 1 , Guang Ning 2 , Weiqing Wang 2 , Yu Zhu 1 1 Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China 2 Department of Endocrinology, Clinical Center of Shanghai Endocrine and Metabolic Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China 3 Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China * These authors contributed equally and shared the first authorship Correspondence to: Yu Zhu, email: zyyyhyq@126.com Keywords: adrenocortical carcinoma, EGFR, IGF1R, coinhibition therapy, crosstalk Received: November 22, 2015 Accepted: March 29, 2016 Published: April 18, 2016 ABSTRACT Purpose: Adrenocortical carcinoma (ACC) is a rare tumor with very poor prognosis and no effective treatment. The aim of this study was to explore a novel therapy co-targeting EGFR and IGF1R in vitro and vivo . Methods : The expression of EGFR and IGF1R were evaluated in a series of adrenocortical tumors by immunohistochemistry. Cell viability of ACC cell lines H295R and SW13 were determined by MTT assay after treatment with the combination of EGFR inhibitor Erlotinib and IGF1R inhibitor NVP-AEW541. Apoptosis was assessed by flow cytometry. The mechanism within intracellular signaling pathways was analyzed by Western blot. Mice bearing human ACC xenografts were treated with Erlotinib and NVP-AEW541, and the effects on tumour growth were assessed. Results: Our results show a significant over-expression of EGFR (66.67%) and IGF1R (80.0%) in ACC. Besides, the co-overexpression of EGFR and IGF1R was seen in 8/15 ACCs, as compared with ACAs ( P

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::256e80b61e6a3e74c442411b66bc69c2Test
http://europepmc.org/articles/PMC5094996Test