scholarly journals LncRNA MALAT1 Accelerates Cervical Carcinoma Proliferation by Suppressing miR-124 Expression in Cervical Tumor Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Tian Liang ◽  
Yuchen Wang ◽  
Yu Jiao ◽  
Shanshan Cong ◽  
Xinyan Jiang ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Cervical Carcinoma ◽  
Malignant Tumors ◽  
Critical Role ◽  
Loss Of Function ◽  
Cervical Tumor ◽  
Lncrna Malat1

Emerging studies have clarified the critical role of LncRNA MALAT1 in various pathological progressions. Here, we identified its positive relationship with cervical carcinoma proliferation. Cervical carcinoma has been considered as one of the most malignant tumors among female. Thus, our study was designed to investigate the underlying mechanism of LncRNA MALAT1 on cervical tumor cell proliferation. We observed that miR-124 was the potential target of LncRNA MALAT1 in cervical tumor cell lines (Hela, C-33A, Caski, and SiHa), the expression level of which is negatively correlated with LncRNA MALAT1 in cervical tumor cells, tissues of cervical patients, and mice. Gain- or loss-of-function analyses in cervical tumor cells have further verified the regulatory role of MALAT1 on miR-124. Additionally, the proliferation of cervical carcinoma was inhibited by miR-124 overexpression, whereas it was blocked by LV-MALAT1 transfection. In vivo assays, overexpression of miR-124, or knockdown of MALAT1 exhibited beneficial effects on tumor weight, size, and volume, together with elevating the survival rate, tightly related with the progression of cervical cancer. In conclusion, LncRNA MALAT1 disabled the effects of miR-124 as an inhibitory sponge, accelerating the progression of cervical carcinoma.

scholarly journals DUSP12 regulates the tumorigenesis and prognosis of hepatocellular carcinoma

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11929
Author(s):  
Gaoda Ju ◽  
Tianhao Zhou ◽  
Rui Zhang ◽  
Xiaozao Pan ◽  
Bing Xue ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Immune Cells ◽  
Malignant Tumors ◽  
Critical Role ◽  
Normal Liver ◽  
Functional Enrichment ◽  
Loss Of Function ◽  
Liver Tissues

Background Dual specificity protein phosphatase (DUSP)12 is an atypical member of the protein tyrosine phosphatase family, which are overexpressed in multiple types of malignant tumors. This protein family protect cells from apoptosis and promotes the proliferation and motility of cells. However, the pathological role of DUSP12 in hepatocellular carcinoma (HCC) is incompletely understood. Methods We analyzed mRNA expression of DUSP12 between HCC and normal liver tissues using multiple online databases, and explored the status of DUSP12 mutants using the cBioPortal database. The correlation between DUSP12 expression and tumor-infiltrating immune cells was demonstrated using the Tumor Immune Estimation Resource database and the Tumor and Immune System Interaction Database. Loss of function assay was utilized to evaluate the role of DUSP12 in HCC progression. Results DUSP12 had higher expression along with mRNA amplification in HCC tissues compared with those in normal liver tissues, which suggested that higher DUSP12 expression predicted shorter overall survival. Analyses of functional enrichment of differentially expressed genes suggested that DUSP12 regulated HCC tumorigenesis, and that knockdown of DUSP12 expression by short hairpin (sh)RNA decreased the proliferation and migration of HCC cells. Besides, DUSP12 expression was positively associated with the infiltration of cluster of differentiation (CD)4+ T cells (especially CD4+ regulatory T cells), macrophages, neutrophils and dendritic cells. DUSP12 expression was positively associated with immune-checkpoint moieties, and was downregulated in a C3 immune-subgroup of HCC (which had the longest survival). Conclusion These data suggest that DUSP12 may have a critical role in the tumorigenesis, infiltration of immune cells, and prognosis of HCC.

Determinating the role of the E3 Ubiquitin Ligase Ariadne 2 in mammalian systemss

2007 ◽  
Vol 30 (4) ◽  
pp. 87
Author(s):  
A. E. Lin ◽  
A. Wakeham ◽  
A. You-Ten ◽  
G. Wood ◽  
T. W. Mak
Keyword(s):  
Function Analysis ◽  
Critical Role ◽  
Ring Finger ◽  
E3 Ligase ◽  
Signalling Pathways ◽  
Loss Of Function ◽  
In Vivo Models

Ubiquitination is a eukaryotic process of selective proteolysis, where a highly conserved ubiquitin protein is selectively added as a chain to the targeted to a protein for degradation. In recent years, the process of ubiquitination has been shown to be a critical mechanism that can affect essential signalling pathways, including apoptosis, cell cycle arrest and induction of the inflammatory response. Thus, alterations in the ubiquitination process can alter signalling pathways pivotal to numerous disease pathologies. This is clearly demonstrated in perturbations of ubiquitination in the NFκB giving rise to cancer and other immunological disease processes. To gain insight into pathways that require regulation by ubiquitination, our lab has directed focus on the highly conserved E3 ligase, Ariadne 2. Ariadne 2 is characterized as a putative RING finger E3 ligase and is part of the family of highly conserved RBR (RING-B-Box-RING) superfamily. The role of Ariadne 2 has been well studied in Drosophila melanogaster, however, little is known of the function of Ariadne 2 in mammalian systems. Therefore, the main objectives of the project are as follows: To determine the biological role of Ariadne 2, the role of Ariadne 2 in development and differentiation, and the consequences of in vivo loss of Ariadne 2 expression. We are currently investigating the role of Ariadne 2 as an E3 ligase and its involvement in the immune response. To date, we have shown that Ariadne 2 is ubiquitously expressed, especially in the brain, heart, spleen and thymus. For in vivo loss of function analysis, mice were generated by homologous recombination to be deficient for Ariadne 2. These deficient mice die prematurely soon after birth, suggesting a critical role for Ariadne 2 in development and survival. We are currently focusing on the role of Ariadne 2 in development and it’s role in immune pathologies, in particular, spontaneous autoimmunity, using both in vitro studies and in vivo models.

p125 focal adhesion kinase promotes malignant astrocytoma cell proliferation in vivo

2000 ◽  
Vol 113 (23) ◽  
pp. 4221-4230 ◽  
Author(s):  
D. Wang ◽  
J.R. Grammer ◽  
C.S. Cobbs ◽  
J.E. Stewart ◽  
Z. Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Focal Adhesion ◽  
Fold Increase ◽  
Astrocytic Tumor ◽  
Malignant Astrocytoma

p125 focal adhesion kinase (p125FAK) is a cytoplasmic tyrosine kinase that is activated upon engagement of integrin cell adhesion receptors, and initiates several signaling events that modulate cell function in vitro. To determine the biologic role of p125FAK in malignant astrocytic tumor cells, U-251MG human malignant astrocytoma cells were stably transfected with p125FAK cDNA using the TET-ON system, and stable clones isolated that exhibited an estimated 5- or 20-fold increase in p125FAK expression on administration of 0.1 or 2.0 microg/ml doxycycline, respectively. In vitro studies demonstrated that induction of p125FAK resulted in a 2- to 3-fold increase in cell migration, increased p130CAS phosphorylation, localization of exogenous p125FAK to focal adhesions, and a 2-fold increase in soft agar growth. To determine the role of p125FAK in vivo, clones were injected stereotactically into the brains of scid mice. A 4.5-fold estimated increase in p125FAK expression was induced by administration of doxycycline in the drinking water. Analysis of xenograft brains demonstrated that, upon induction of p125FAK, there was a 1.6- to 2.8-fold increase in tumor cell number, and an increase in mAb PCNA-labeling of tumor cells in the absence of a change in the apoptotic index. Compared to normal brain, the expression of p125FAK was elevated in malignant astrocytic tumor biopsies from patient samples. These data demonstrate for the first time that p125FAK promotes tumor cell proliferation in vivo, and that the underlying mechanism is not associated with a reduction in apoptosis.

scholarly journals The critical role of ASD-related gene CNTNAP3 in regulating synaptic development and social behavior in mice

2018 ◽  
Author(s):  
Da-li Tong ◽  
Rui-guo Chen ◽  
Yu-lan Lu ◽  
Wei-ke Li ◽  
Yue-fang Zhang ◽  
...  
Keyword(s):  
Critical Role ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Inhibitory Synapses ◽  
Scaffolding Proteins ◽  
Loss Of Function ◽  
Chinese Han

AbstractAccumulated genetic evidences indicate that the contactin associated protein-like (CNTNAP) family is implicated in autism spectrum disorders (ASD). In this study, we identified genetic mutations in the CNTNAP3 gene from Chinese Han ASD cohorts and Simons Simplex Collections. We found that CNTNAP3 interacted with synaptic adhesion proteins Neuroligin1 and Neuroligin2, as well as scaffolding proteins PSD95 and Gephyrin. Significantly, we found that CNTNAP3 played an opposite role in controlling the development of excitatory and inhibitory synapses in vitro and in vivo, in which ASD mutants exhibited loss-of-function effects. In this study, we showed that Cntnap3-null mice exhibited deficits in social interaction, spatial learning and prominent repetitive behaviors. These evidences elucidate the pivotal role of CNTNAP3 in synapse development and social behaviors, providing the mechanistic insights for ASD.

scholarly journals 157 A critical role of CD40 and CD70 signaling in cDC1s in expansion and antitumor efficacy of adoptively transferred tumor-specific T cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A171-A171
Author(s):  
Takaaki Oba ◽  
Toshifumi Hoki ◽  
Takayoshi Yamauchi ◽  
Tibor Keler ◽  
Henry Marsh ◽  
...  
Keyword(s):  
T Cells ◽  
Adoptive Cell Therapy ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Antitumor Efficacy ◽  
Tumor Control ◽  
Type I ◽  
Loss Of Function

BackgroundAdoptive cell therapy (ACT) with antigen-specific CD8+ T cells is a promising approach for treating patients with various solid malignancies including melanoma. In vivo expansion of adoptively transferred T cells is one of the major determinants of successful ACT. On the other hand, a frequently overlooked consideration is that the host antigen-presenting cells affect the antitumor efficacy of ACT. Accumulating evidence suggests that tumor-residing Batf3-dependent conventional type I dendritic cells (cDC1s) play an important role in trafficking of adoptively transferred T cells into the tumor by producing chemokines such as CXCL10, and improve antitumor efficacy of ACT. However, a role of cDC1s in expansion of adoptively transferred T cells remains unclear.MethodsWe utilized Pmel-1 T cell receptor transgenic T cells in the B16 melanoma model to investigate the role of cDC1s in expansion of adoptively transferred tumor-specific T cells.ResultsWhile adoptive transfer of in vitro-activated Pmel-1 T cells with vaccination of cognate antigen, hgp100, agonistic anti-CD40 monoclonal antibody (mAb), and Toll-like receptor 7 (TLR7) agonist delayed the tumor growth and survival in wild type C57BL/6 mice (WT), antitumor efficacy of ACT was completely abrogated in Batf3-/- mice. Flow cytometric analysis of peripheral blood showed expansion of adoptively transferred Pmel-1 T cells was significantly compromised in WT mice but not in in Batf3-/- mice. Mechanistically, loss-of-function studies using mixed bone marrow chimera reconstituted with Batf3-/- and CD40-/- (Batf3-/-/CD40-/-), Batf3-/- and CD70-/- (Batf3-/-/CD70-/-), or Batf3-/- and CD80/86-/- (Batf3-/-/CD80/86-/-) revealed CD40-CD70 axis but not CD80/86 signaling in host cDC1s plays an important role in expansion of adoptively transferred T cells. Accordingly, overall survival of Batf3-/-/CD70-/- mixed chimeric was significantly shorter than that of Batf3-/-/WT mice, while survival of Batf3-/-/CD80/86-/- mice was similar to that of Batf3-/-/WT mice. Furthermore, induction of cDC1s by administration of Fms-like tyrosine kinase 3 receptor ligand (gain-of-function) demonstrated significantly enhanced in vivo expansion of adoptively transferred Pmel-1 T cells associated with improved tumor control and survival.ConclusionsThese findings elucidate a role of host cDC1s in expansion of adoptively transferred in vivo restimulated tumor-specific T cells, and identify CD40 and CD70 as key molecules.

scholarly journals Cancer-Associated Fibroblasts in Conversation with Tumor Cells in Endometrial Cancers: A Partner in Crime

2021 ◽  
Vol 22 (17) ◽  
pp. 9121
Author(s):  
De Pradip ◽  
Aske Jennifer ◽  
Dey Nandini
Keyword(s):  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cross Talk ◽  
Critical Role ◽  
Immune Surveillance ◽  
Endometrial Cancers

A tumor cell carrying characteristic genomic alteration(s) exists within its host’s microenvironment. The tumor microenvironment (TME) renders holistic support to the tumor via cross-talk between tumor cells and three components of TME, immune components, vascular components, and fibroblast components. The tempero-spatial interaction of tumor cells with its microenvironment is the deterministic factor for tumor growth, progression, resistance to therapy, and its outcome in clinics. TME (1) facilitates proliferation, and the ensuing metastasis-associated phenotypes, (2) perturbs immune surveillance and supports tumor cells in their effort to evade immune recognition, and (3) actively participates in developing drug-induced resistance in cancer cells. Cancer-Associated Fibroblast (CAF) is a unique component of TME. CAF is the host mesenchyme immediately surrounding the tumor cells in solid tumors. It facilitates tumor growth and progression and participates in developing drug resistance in tumor cells by playing a critical role in all the ways mentioned above. The clinical outcome of a disease is thus critically contributed to by the CAF component of TME. Although CAFs have been identified historically, the functional relevance of CAF-tumor cell cross-talk and their influence on angiogenic and immune-components of TME are yet to be characterized in solid tumors, especially in endometrial cancers. Currently, the standard of care for the treatment of endometrial cancers is primarily guided by therapies directed towards the disease’s tumor compartment and immune compartments. Unfortunately, in the current state of therapies, a complete response (CR) to the therapy is still limited despite a more commonly achieved partial response (PR) and stable disease (SD) in patients. Acknowledging the limitations of the current sets of therapies based on only the tumor and immune compartments of the disease, we sought to put forward this review based on the importance of the cross-talk between CAF of the tumor microenvironment and tumor cells. The premise of the review is to recognize the critical role of CAF in disease progression. This manuscript presents a systemic review of the role of CAF in endometrial cancers. We critically interrogated the active involvement of CAF in the tumor compartment of endometrial cancers. Here we present the functional characteristics of CAF in the context of endometrial cancers. We review (1) the characteristics of CAF, (2) their evolution from being anti-tumor to pro-tumor, (3) their involvement in regulating growth and several metastasis-associated phenotypes of tumor cells, (4) their participation in perturbing immune defense and evading immune surveillance, and (5) their role in mediating drug resistance via tumor-CAF cross-talk with particular reference to endometrial cancers. We interrogate the functional characteristics of CAF in the light of its dialogue with tumor cells and other components of TME towards developing a CAF-based strategy for precision therapy to supplement tumor-based therapy. The purpose of the review is to present a new vision and initiate a thought process which recognizes the importance of CAF in a tumor, thereby resulting in a novel approach to the design and management of the disease in endometrial cancers.

scholarly journals Depleting RhoA/Stress Fiber-Organized Fibronectin Matrices on Tumor Cells Non-Autonomously Aggravates Fibroblast-Driven Tumor Cell Growth

2020 ◽  
Vol 21 (21) ◽  
pp. 8272
Author(s):  
Li-Tzu Huang ◽  
Chen-Lung Tsai ◽  
Shin-Huei Huang ◽  
Ming-Min Chang ◽  
Wen-Tsan Chang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Stress Fiber ◽  
Tumor Cell Growth ◽  
Primary Tumor Growth

Fibronectin (FN) expressed by tumor cells has been known to be tumor suppressive but the pericellular FN (periFN) assembled on circulating tumor cells appears to evidently promote distant metastasis. Whereas the regulation of periFN assembly in suspended cells has currently been under investigation, how it is regulated in adherent tumor cells and the role of periFN in primary tumor growth remain elusive. Techniques of RNAi, plasmid transfections, immunoblotting, fluorescence/immunohistochemistry staining, cell proliferation assays, and primary tumor growth in C57BL6 mice and Fischer 344 rats were employed in this study. We found that endogenously synthesized FN in adherent tumor cells was required for periFN assembly which was aligned by RhoA-organized actin stress fiber (SF). Depleting periFN on adherent tumor cells congruently promoted in vivo tumor growth but surprisingly did not autonomously impact on in vitro tumor cell proliferation and apoptosis, suggestive of a non-autonomous role of periFN in in vivo tumor growth. We showed that the proliferative ability of shFN-expressing tumor cells was higher than shScramble cells did in the presence of fibroblasts. Altogether, these results suggested that depriving RhoA/SF-regulated periFN matrices non-autonomously promotes fibroblast-mediated tumor cell growth.

A Molecular Approach to Immunoscintigraphy: A Study of the T-Antigen Conformation on the Surface of Tumors

1987 ◽  
Vol 26 (01) ◽  
pp. 1-6 ◽  
Author(s):  
S. Selvaraj ◽  
M. R. Suresh ◽  
G. McLean ◽  
D. Willans ◽  
C. Turner ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Tumor Cell ◽  
T Antigen ◽  
Human Carcinomas ◽  
Animal Tumor ◽  
Synthetic Antigens

The role of glycoconjugates in tumor cell differentiation has been well documented. We have examined the expression of the two anomers of the Thomsen-Friedenreich antigen on the surface of human, canine and murine tumor cell membranes both in vitro and in vivo. This has been accomplished through the synthesis of the disaccharide terminal residues in both a and ß configuration. Both entities were used to generate murine monoclonal antibodies which recognized the carbohydrate determinants. The determination of fine specificities of these antibodies was effected by means of cellular uptake, immunohistopathology and immunoscintigraphy. Examination of pathological specimens of human and canine tumor tissue indicated that the expressed antigen was in the β configuration. More than 89% of all human carcinomas tested expressed the antigen in the above anomeric form. The combination of synthetic antigens and monoclonal antibodies raised specifically against them provide us with invaluable tools for the study of tumor marker expression in humans and their respective animal tumor models.

scholarly journals NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2999
Author(s):  
Deborah Reynaud ◽  
Roland Abi Nahed ◽  
Nicolas Lemaitre ◽  
Pierre-Adrien Bolze ◽  
Wael Traboulsi ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Cells ◽  
Major Gene ◽  
Critical Role ◽  
Orthotopic Model ◽  
Independent Manner ◽  
Maternal Immune Response ◽  
The Impact

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

scholarly journals The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Brianna J. Klein ◽  
Anagha Deshpande ◽  
Khan L. Cox ◽  
Fan Xuan ◽  
Mohamad Zandian ◽  
...  
Keyword(s):  
Critical Role ◽  
Cellular Transformation ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Nucleosome Core ◽  
Stem And Progenitor Cells ◽  
Transforming Activity

AbstractChromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10PZP-dependent CALM-AF10-mediated leukemogenesis.

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