scholarly journals CSIG-21. BAF60C/SMARCD3 REGULATES TUMOR CELL DISSEMINATION IN MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii32-ii32
Author(s):  
Baoli Hu ◽  
Brad Poore ◽  
Vaibhav Sharma ◽  
Yongchang Guan ◽  
Sameer Agnihotri ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Migration And Invasion ◽  
Orthotopic Mouse Model ◽  
Primary Tumors ◽  
Downstream Signaling ◽  
Tumor Dissemination ◽  
Elevated Expression ◽  
Group 3

Abstract Medulloblastoma, the most common malignant brain tumor in children, is a diverse and heterogeneous disease. Molecular characterization of MB revealed four major subgroups, WNT, SHH, Group 3, and Group 4. Although surgical resection, radiotherapy, and chemotherapy are effective at eliminating some forms, patients with the aggressive tumors cannot be cured with conventional therapies, particularly in Group 3. Group 3 is the most aggressive subtype of this disease, accounting for about 25%-30% of cases, and characterized by frequent metastasis at diagnosis and the worst prognosis among all the subgroups. Metastatic dissemination is a major treatment challenge and strongly associated with poor prognosis in patients with medulloblastoma. However, the molecular mechanisms of tumor cell early dissemination and late metastasis remain largely unknown. Here, we found that Group 3 has elevated expression of BAF60C/SMARCD3, a subcomponent of SWI/SNF complex, which significantly mobilizes nucleosomes and remodels chromatin. Clinically, elevated SMARCD3 mRNA resulted in a poorer prognosis in medulloblastoma patients, which was further validated in 63 patient tumors by immunohistochemical staining for SMARCD3. Interestingly, tumors that had metastasized often had elevated expression of SMARCD3, in all subgroups of medulloblastomas and Group 3 only. An orthotopic mouse model further supported that SMARCD3 is highly expressed in metastatic tumors compared to primary tumors. Importantly, CRISPR-Cas9-mediated SMARCD3 deletion decreased cell migration and invasion in multiple medulloblastoma cell lines. Mechanistically, SMARCD3 deletion led to decreased H3K27me3, suggesting that SMARCD3 may cooperate with PRC2 in regulation of gene expression. Strikingly, SMARCD3 deletion downregulated Reelin signaling pathway, an essential role in neuronal positioning during neurodevelopment, which indicates that tumors with highly expressed SMARCD3 hijack a developmental signaling to promote their dissemination and aggressiveness. Together, our results suggest that inhibition of SMARCD3 controlling downstream signaling may effectively prevent tumor dissemination and improve clinical outcomes in children with medulloblastoma.

scholarly journals MBRS-63. THE ROLE OF THE SWI/SNF COMPLEX SUBUNIT SMARCD3 IN MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii409-iii409
Author(s):  
Brad Poore ◽  
Han Zou ◽  
Vaibhav Sharma ◽  
Ian Pollack ◽  
Baoli Hu
Keyword(s):  
Regulation Of Gene Expression ◽  
Orthotopic Mouse Model ◽  
Primary Tumors ◽  
Group 4 ◽  
Tumor Dissemination ◽  
Elevated Expression ◽  
Group 3 ◽  
Genomic Regions ◽  
Medulloblastoma Cell Lines

Abstract Medulloblastoma is the most common malignant brain tumor in children, with the Group 3 (G3) having the worst prognosis of the subgroups (WNT, SHH, and Group 4). We aimed to determine the underlying differences between G3 and the other subgroups, with an emphasis on genes that control the epigenome for developing effective treatments for patients with this disease. To this end, we found that G3 has elevated expression of the SWI/SNF subcomponent, SMARCD3 (P<0.001), which serves to guide the SWI/SNF complex to different genomic regions through interactions with various transcription factors. However, little is known about function of SMARCD3 in cancer, particularly in medulloblastoma. Clinically, elevated SMARCD3 mRNA resulted in a poorer prognosis in medulloblastoma patients (P<0.0001), which was further validated in 63 patient tumors by immunohistochemical staining for SMARCD3. Interestingly, tumors that had metastasized often had elevated expression of SMARCD3, in all subgroups of medulloblastomas (P<0.0001) and G3 only (P<0.01) based on analyzing multiple published databases. An orthotopic mouse model further supported that SMARCD3 is highly expressed in metastatic tumors compared to primary tumors. Importantly, CRISPR-CAS9-mediated SMARCD3 deletion decreased cell migration in medulloblastoma cell lines. Mechanistically, SMARCD3 deletion led to decreased H3K27me3, suggesting that SMARCD3 may cooperate with PRC2 in regulation of gene expression. Together, our results indicate that SMARCD3 plays a significant role in the development of metastatic dissemination in medulloblastoma, especially in the G3 subgroup. Thus, targeting the SMARCD3-containing SWI/SNF Complex may effectively prevent tumor dissemination and improve clinical outcomes in children with medulloblastoma.

scholarly journals FAM83A-AS1 Promotes Tumor Progression Through MET Signaling in Lung Adenocarcinoma

2021 ◽  
Author(s):  
Shengbin Bai ◽  
Huijie Zhao ◽  
Xaofei Zeng ◽  
Baoyue Lin ◽  
Yinghan Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Migration And Invasion ◽  
Functional Studies ◽  
Cycle Arrest ◽  
Elevated Expression ◽  
Lung Cancer Therapy ◽  
Prognosis Marker ◽  
Cancer Tissues

Abstract Background Studies demonstrate that long non-coding RNAs (lncRNAs) play critical roles in the occurrence and development of cancer. However, many of the molecular mechanisms underlying lncRNAs role in this process remains unclear. Methods Here, we analyzed lncRNA expression in lung cancer tissues based on RNA-Seq analysis and found that lncRNA FAM83A-AS1 was one of the top up-regulated lncRNAs in lung adenocarcinoma and elevated expression of FAM83A-AS1 was significantly associated with poor patient survival. We validated these results using RT-PCR and an independent cohort of lung cancer. Results Functional studies indicated that knockdown of FAM83A-AS1 decreased cell proliferation, colony formation, migration and invasion in H1299 and H838 lung cancer cells. Knockdown of FAM83A-AS1 induced the autophagy and cell cycle arrest at G2. Mechanistically, we found that MET, p62 and phosphor S6K proteins were decreased upon FAM83A-AS1 knockdown. Conclusion In conclusion, FAM83A-AS1 may have potential as a diagnosis/prognosis marker and its oncogenic role could lead to potential targeting for lung cancer therapy.

scholarly journals Manganese systemic distribution is modulated in vivo during tumor progression and affects tumor cell migration and invasion in vitro

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mariana Paranhos Stelling ◽  
Mariana Alves Soares ◽  
Simone Coutinho Cardoso ◽  
Juliana Maria Motta ◽  
Joice Côrtes de Abreu ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Tumor Progression ◽  
Common Ground ◽  
Central Element ◽  
Soluble Form ◽  
Migration And Invasion ◽  
Primary Tumors

AbstractMetastatic disease remains the leading cause of death in cancer and understanding the mechanisms involved in tumor progression continues to be challenging. This work investigates the role of manganese in tumor progression in an in vivo model of tumor growth. Our data revealed that manganese accumulates within primary tumors and secondary organs as manganese-rich niches. Consequences of such phenomenon were investigated, and we verified that short-term changes in manganese alter cell surface molecules syndecan-1 and β1-integrin, enhance collective cell migration and invasive behavior. Long-term increased levels of manganese do not affect cell growth and viability but enhance cell migration. We also observed that manganese is secreted from tumor cells in extracellular vesicles, rather than in soluble form. Finally, we describe exogenous glycosaminoglycans that counteract manganese effects on tumor cell behavior. In conclusion, our analyses describe manganese as a central element in tumor progression by accumulating in Mn-rich niches in vivo, as well as in vitro, affecting migration and extracellular vesicle secretion in vitro. Manganese accumulation in specific regions of the organism may not be a common ground for all cancers, nevertheless, it represents a new aspect of tumor progression that deserves special attention.

scholarly journals MBRS-72. MiR-212 FUNCTIONS AS A TUMOR SUPPRESSOR GENE IN GROUP 3 MEDULLOBLASTOMA VIA TARGETING NUCLEAR FACTOR I/B (NFIB)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii411-iii411
Author(s):  
Naveenkumar Perumal ◽  
Ranjana Kanchan ◽  
Pranita Atri ◽  
Ramakanth Venkata ◽  
Ishwor Thapa ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Luciferase Assay ◽  
Multi Drug Resistance ◽  
Migration And Invasion ◽  
Stem Cell Markers ◽  
Tumor Cell Proliferation ◽  
Group 3

Abstract Medulloblastoma (MB), the most frequent malignant pediatric brain tumor is divided into four primary subgroups, i.e. wingless-type (WNT), sonic hedgehog (SHH), group 3, and group 4. Haploinsufficiency of chromosome 17p13.3 and c-myc amplification distinguish high-risk group 3 tumors and are associated with rapid recurrence and early mortality. We sought to identify the role of miR-212, which resides on chromosome 17p13.3, in the pathophysiology of group 3 medulloblastoma. RNA expression analyses revealed dramatically reduced levels of miR-212 in group 3 tumors and cell lines mainly through epigenetic silencing via histone modification (deacetylation). Restoring in vitro expression reduced tumor cell proliferation with decreased p-AKT and p-ERK levels, colony formation, migration and invasion in group 3 MB. Interestingly, a shift in differential c-myc phosphorylation (from serine-62 to threonine-58) was noted, resulting in reduced total c-myc levels, concurrent with elevated cellular apoptosis. In turn, pro-apoptotic binding partners of c-myc, i.e. Bin-1 and P19ARF, were upregulated in these cells. A dual luciferase assay confirmed direct targeting of miR-212 to NFIB, a nuclear transcription factor implicated in metastasis and recurrence. Concurrently, increased expression of NFIB was confirmed in group 3 MB tumors with poor survival in high NFIB-expressing patients. Transient NFIB silencing in vitro reduced tumor cell proliferation, migration and invasion, and medullosphere formation along with a reduction in stem cell markers (Nanog, Oct4, Sox2, CD133) and the multi-drug resistance maker, ABCG2. Taken together, these results substantiate the tumor suppressive role of miR-212 in group 3 medulloblastomas and provide a potential new therapeutic target, NFIB.

scholarly journals BIOL-07. MIR-212 FUNCTIONS AS A TUMOR SUPPRESSOR GENE IN GROUP 3 MEDULLOBLASTOMA VIA TARGETING NUCLEAR FACTOR I/B (NFIB)

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i4-i4
Author(s):  
Naveenkumar Perumal ◽  
Ranjana Kanchan ◽  
David Doss ◽  
Pranita Atri ◽  
Ramakanth Chirravuri Venkata ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wound Healing ◽  
Tumor Cell ◽  
Colony Formation ◽  
Tumor Recurrence ◽  
Migration And Invasion ◽  
Tumor Cell Proliferation ◽  
Group 3

Abstract Medulloblastoma (MB), the most frequent malignant pediatric brain tumor is subdivided into four primary subgroups, i.e. wingless-type (WNT), sonic hedgehog (SHH), group 3, and group 4. Haploinsufficiency of chromosome 17p13.3 and c-myc amplification distinguish high-risk group 3 tumors, which are associated with rapid metastasis, recurrence and early mortality. We sought to identify the role of miR-212, which resides on chromosome 17p13.3, in the pathophysiology of group 3 MB. RNA expression analyses revealed dramatically reduced levels of miR-212 in group 3 tumors and cell lines mainly through epigenetic silencing via histone modifications (deacetylation). Restoring in vitro miR-212 expression reduced tumor cell proliferation, colony formation, wound healing, migration and invasion with decreased p-AKT and p-ERK levels in group 3 MB cell lines. Interestingly, a shift in differential c-myc phosphorylation (from serine-62 to threonine-58) was also discovered with miR-212 expression, resulting in reduced total c-myc levels, concurrent with elevated cellular apoptosis. In turn, pro-apoptotic binding partners of c-myc, i.e. Bin-1 and P19ARF, were upregulated in these cells. These findings were recapitulated in stable inducible miR-212 expressing tumor cells. Using a combination of transcriptomic data and a dual luciferase assay, we isolated an important oncogenic target of miR-212, i.e, NFIB, a nuclear transcription factor implicated in metastasis and recurrence. Increased expression of NFIB was confirmed in group 3 tumors, with poor survival shown in high NFIB-expressing patients. As prior, transient NFIB silencing in vitro reduced not only tumor cell proliferation, colony formation, wound healing, migration and invasion, but also medullosphere formation along with decreased expression of stem cell markers (Nanog, Oct4, Sox2, CD133), confirming its role in tumor recurrence possibly via augmenting tumor stemness. Taken together, these results substantiate the tumor suppressive role of miR-212 in group 3 MB and provide a potential new oncogenic target implicated in tumor recurrence, NFIB.

scholarly journals Candidate genes for panhypopituitarism identified by gene expression profiling

2011 ◽  
Vol 43 (19) ◽  
pp. 1105-1116 ◽  
Author(s):  
Amanda H. Mortensen ◽  
James W. MacDonald ◽  
Debashis Ghosh ◽  
Sally A. Camper
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Human Pituitary ◽  
Temporal Regulation ◽  
Pituitary Development ◽  
Expression Of Genes ◽  
Elevated Expression

Mutations in the transcription factors PROP1 and PIT1 (POU1F1) lead to pituitary hormone deficiency and hypopituitarism in mice and humans. The dysmorphology of developing Prop1 mutant pituitaries readily distinguishes them from those of Pit1 mutants and normal mice. This and other features suggest that Prop1 controls the expression of genes besides Pit1 that are important for pituitary cell migration, survival, and differentiation. To identify genes involved in these processes we used microarray analysis of gene expression to compare pituitary RNA from newborn Prop1 and Pit1 mutants and wild-type littermates. Significant differences in gene expression were noted between each mutant and their normal littermates, as well as between Prop1 and Pit1 mutants. Otx2, a gene critical for normal eye and pituitary development in humans and mice, exhibited elevated expression specifically in Prop1 mutant pituitaries. We report the spatial and temporal regulation of Otx2 in normal mice and Prop1 mutants, and the results suggest Otx2 could influence pituitary development by affecting signaling from the ventral diencephalon and regulation of gene expression in Rathke's pouch. The discovery that Otx2 expression is affected by Prop1 deficiency provides support for our hypothesis that identifying molecular differences in mutants will contribute to understanding the molecular mechanisms that control pituitary organogenesis and lead to human pituitary disease.

scholarly journals Could Extracellular Vesicles Contribute to Generation or Awakening of “Sleepy” Metastatic Niches?

2021 ◽  
Vol 9 ◽  
Author(s):  
Alberto Hernández-Barranco ◽  
Laura Nogués ◽  
Héctor Peinado
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Residual Disease ◽  
Tumor Development ◽  
Extracellular Vesicle ◽  
Primary Tumors ◽  
Favorable Conditions ◽  
Cell Dormancy

Pre-metastatic niches provide favorable conditions for tumor cells to disseminate, home to and grow in otherwise unfamiliar and distal microenvironments. Tumor-derived extracellular vesicles are now recognized as carriers of key messengers secreted by primary tumors, signals that induce the formation of pre-metastatic niches. Recent evidence suggests that tumor cells can disseminate from the very earliest stages of primary tumor development. However, once they reach distal sites, tumor cells can persist in a dormant state for long periods of time until their growth is reactivated and they produce metastatic lesions. In this new scenario, the question arises as to whether extracellular vesicles could influence the formation of these metastatic niches with dormant tumor cells? (here defined as “sleepy niches”). If so, what are the molecular mechanisms involved? In this perspective-review article, we discuss the possible influence of extracellular vesicles in early metastatic dissemination and whether they might play a role in tumor cell dormancy. In addition, we comment whether extracellular vesicle-mediated signals may be involved in tumor cell awakening, considering the possibility that extracellular vesicles might serve as biomarkers to detect early metastasis and/or minimal residual disease (MRD) monitoring.

scholarly journals Integrated genomic and transcriptomic analysis reveals unique characteristics of hepatic metastases and pro-metastatic role of complement C1q in pancreatic ductal adenocarcinoma

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jianyu Yang ◽  
Ping Lin ◽  
Minwei Yang ◽  
Wei Liu ◽  
Xueliang Fu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Hepatic Metastases ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
M2 Macrophage ◽  
Gene Expressions ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Molecular Features

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers due to its high metastasis rate in the liver. However, little is known about the molecular features of hepatic metastases due to difficulty in obtaining fresh tissues and low tumor cellularity. Results We conduct exome sequencing and RNA sequencing for synchronous surgically resected primary tumors and the paired hepatic metastases from 17 hepatic oligometastatic pancreatic ductal adenocarcinoma and validate our findings in specimens from 35 of such cases. The comprehensive analysis of somatic mutations, copy number alterations, and gene expressions show high similarity between primary tumors and hepatic metastases. However, hepatic metastases also show unique characteristics, such as a higher degree of 3p21.1 loss, stronger abilities of proliferation, downregulation of epithelial to mesenchymal transition activity, and metabolic rewiring. More interesting, altered tumor microenvironments are observed in hepatic metastases, especially a higher proportion of tumor infiltrating M2 macrophage and upregulation of complement cascade. Further experiments demonstrate that expression of C1q increases in primary tumors and hepatic metastases, C1q is mainly produced by M2 macrophage, and C1q promotes migration and invasion of PDAC cells. Conclusion Taken together, we find potential factors that contribute to different stages of PDAC metastasis. Our study broadens the understanding of molecular mechanisms driving PDAC metastasis.

scholarly journals Prion Protein at the Leading Edge: Its Role in Cell Motility

2020 ◽  
Vol 21 (18) ◽  
pp. 6677
Author(s):  
Mariana Brandão Prado ◽  
Maria Isabel Melo Escobar ◽  
Rodrigo Nunes Alves ◽  
Bárbara Paranhos Coelho ◽  
Camila Felix de Lima Fernandes ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Motility ◽  
Prion Protein ◽  
Molecular Mechanisms ◽  
Cell Movement ◽  
Cellular Prion Protein ◽  
Matrix Proteins ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Tumor Dissemination

Cell motility is a central process involved in fundamental biological phenomena during embryonic development, wound healing, immune surveillance, and cancer spreading. Cell movement is complex and dynamic and requires the coordinated activity of cytoskeletal, membrane, adhesion and extracellular proteins. Cellular prion protein (PrPC) has been implicated in distinct aspects of cell motility, including axonal growth, transendothelial migration, epithelial–mesenchymal transition, formation of lamellipodia, and tumor migration and invasion. The preferential location of PrPC on cell membrane favors its function as a pivotal molecule in cell motile phenotype, being able to serve as a scaffold protein for extracellular matrix proteins, cell surface receptors, and cytoskeletal multiprotein complexes to modulate their activities in cellular movement. Evidence points to PrPC mediating interactions of multiple key elements of cell motility at the intra- and extracellular levels, such as integrins and matrix proteins, also regulating cell adhesion molecule stability and cell adhesion cytoskeleton dynamics. Understanding the molecular mechanisms that govern cell motility is critical for tissue homeostasis, since uncontrolled cell movement results in pathological conditions such as developmental diseases and tumor dissemination. In this review, we discuss the relevant contribution of PrPC in several aspects of cell motility, unveiling new insights into both PrPC function and mechanism in a multifaceted manner either in physiological or pathological contexts.

scholarly journals Disrupting ß-catenin dependent Wnt signaling activates an invasive gene program predictive of colon cancer progression

2019 ◽  
Author(s):  
George T. Chen ◽  
Delia F. Tifrea ◽  
Rabi Murad ◽  
Yung Lyou ◽  
Ali Mortazavi ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Wnt Signaling ◽  
Cancer Progression ◽  
Drug Targets ◽  
Migration And Invasion ◽  
Orthotopic Mouse Model ◽  
Colon Cancer Progression ◽  
Elevated Expression ◽  
Recent Classification

AbstractThe recent classification of colon cancer into molecular subtypes revealed that patients with the poorest prognosis harbor tumors with the lowest levels of Wnt signaling. This is contrary to the long-standing understanding that overactive Wnt signaling promotes tumor progression from early initiation stages through to the later stages including invasion and metastasis. Here, we lower the levels of Wnt signaling in colon cancer via interference with two different steps in the pathway that lie upstream or downstream of the effector protein ß-catenin. We find that these Wnt-reduced cancer cells exhibit a more aggressive disease phenotype, including increased mobility in vitro and localized invasion in an orthotopic mouse model. RNA sequencing reveals that interference with Wnt signaling leads to an upregulation of gene programs that favor cell migration and invasion. We identify a set of upregulated genes common among the Wnt perturbations and find that elevated expression of these genes is strongly predictive of poor patient outcomes in early-invasive colon cancer. These genes may have clinical applications as patient biomarkers or new drug targets to be used in concert with existing therapies.One Sentence SummaryLow Wnt Signaling Leads to Invasive Tumor Phenotypes in Colorectal Cancer.

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