scholarly journals Regeneration linked miRNA modify tumor phenotype and can enforce multi-lineage growth arrest in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Siamak Salehi ◽  
Oliver D. Tavabie ◽  
Augusto Villanueva ◽  
Julie Watson ◽  
David Darling ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Inhibition ◽  
Tumor Aggressiveness ◽  
Novel Treatment ◽  
Tumor Phenotype ◽  
Aggressive Tumor ◽  
In Vivo Growth ◽  
Regulation Of Regeneration

AbstractRegulated cell proliferation is an effector mechanism of regeneration, whilst dysregulated cell proliferation is a feature of cancer. We have previously identified microRNA (miRNA) that regulate successful and failed human liver regeneration. We hypothesized that these regulators may directly modify tumor behavior. Here we show that inhibition of miRNAs -503 and -23a, alone or in combination, enhances tumor proliferation in hepatocyte and non-hepatocyte derived cancers in vitro, driving more aggressive tumor behavior in vivo. Inhibition of miRNA-152 caused induction of DNMT1, site-specific methylation with associated changes in gene expression and in vitro and in vivo growth inhibition. Enforced changes in expression of two miRNA recapitulating changes observed in failed regeneration led to complete growth inhibition of multi-lineage cancers in vivo. Our results indicate that regulation of regeneration and tumor aggressiveness are concordant and that miRNA-based inhibitors of regeneration may constitute a novel treatment strategy for human cancers.

Dimethyladamantylmaleimide-induced in vitro and in vivo growth inhibition of human colon cancer Colo205 cells

2002 ◽  
Vol 13 (5) ◽  
pp. 533-543 ◽  
Author(s):  
Jane-Jen Wang ◽  
Yaw-Terng Chern ◽  
Yuh-Fang Chang ◽  
Tsung-Yun Liu ◽  
Chin-Wen Chi
Keyword(s):  
Colon Cancer ◽  
Growth Inhibition ◽  
Human Colon ◽  
Human Colon Cancer ◽  
In Vivo Growth

scholarly journals In vitro and in vivo growth inhibition of prostate cancer by the small molecule imiquimod

2013 ◽  
Vol 42 (6) ◽  
pp. 2087-2093 ◽  
Author(s):  
JU-HEE HAN ◽  
JUNGLIM LEE ◽  
SOO-JIN JEON ◽  
EUN-SUN CHOI ◽  
SUNG-DAE CHO ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Growth Inhibition ◽  
Small Molecule ◽  
In Vivo Growth

scholarly journals Short-Term Resveratrol Exposure Causes In Vitro and In Vivo Growth Inhibition and Apoptosis of Bladder Cancer Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e89806 ◽  
Author(s):  
Mo-Li Wu ◽  
Hong Li ◽  
Li-Jun Yu ◽  
Xiao-Yan Chen ◽  
Qing-You Kong ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Short Term ◽  
Bladder Cancer Cells ◽  
In Vivo Growth

Targeting GCK pathway: a novel and selective therapeutic strategy against RAS mutated multiple myeloma

Blood ◽  
2020 ◽  
Author(s):  
Shirong Li ◽  
Jing Fu ◽  
Jun Yang ◽  
Huihui Ma ◽  
Divaya Bhutani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Growth Inhibition ◽  
Alternative Therapy ◽  
Braf Mutations ◽  
Ras Mutation ◽  
Ras Mutations ◽  
Cell Proliferation Inhibition

In multiple myeloma (MM), frequent mutations of NRAS, KRAS, or BRAF are found in up to 50% of newly diagnosed patients. The majority of the NRAS, KRAS, and BRAF mutations occur in hotspots causing constitutive activation of the corresponding proteins. Thus targeting RAS mutation in MM will increase therapeutic efficiency and potentially overcome drug-resistance. We identified Germinal Center Kinase (GCK) as a novel therapeutic target in MM with RAS mutation. GCK knockdown in MM cells demonstrated in vitro and in vivo that silencing of GCK induces MM cell growth inhibition, associated with blocked MKK4/7-JNK phosphorylation and impaired degradation of IKZF1/3, BCL-6, and c-MYC. These effects were rescued by overexpression of an shRNA-resistant GCK, thereby excluding the potential off-target effects of GCK knockdown. In contrast, overexpression of shRNA-resistant GCK kinase-dead mutant (K45A) inhibited MM cell proliferation and failed to rescue the effects of GCK knockdown on MM growth inhibition, indicating that GCK kinase activity is critical for regulating MM cell proliferation and survival. Importantly, the higher sensitivity to GCK knockdown in RASMut cells suggests that targeting GCK is effective in multiple myeloma which harbors RAS mutations. In accordance with the effects of GCK knockdown, the GCK inhibitor TL4-12 dose-dependently downregulated IKZF1 and BCL-6 and led to MM cell proliferation inhibition accompanied by induction of apoptosis. Hereby our data identify GCK as a novel target in RASMut MM cells, providing a rationale to treat RAS mutations in MM. Furthermore, GCK inhibitors might represent an alternative therapy to overcome IMiD-resistance in MM.

scholarly journals Effect of Dickkopf-1 (Dkk-1) and SP600125, a JNK Inhibitor, on Wnt Signaling in Canine Prostate Cancer Growth and Bone Metastases

2021 ◽  
Vol 8 (8) ◽  
pp. 153
Author(s):  
Wachiraphan Supsavhad ◽  
Bardes B. Hassan ◽  
Jessica K. Simmons ◽  
Wessel P. Dirksen ◽  
Said M. Elshafae ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Wnt Signaling ◽  
Mrna Expression ◽  
Bone Tumor ◽  
Tumor Phenotype ◽  
Dickkopf 1

Human Dickkopf-1 (Dkk-1) upregulates a noncanonical Wnt/JNK pathway, resulting in osteoclast stimulation, cell proliferation, and epithelial-to-mesenchymal transition (EMT) of cancer cells. Ace-1-Dkk-1, a canine prostate cancer (PCa) cell line overexpressing Dkk-1, was used to investigate Wnt signaling pathways in PCa tumor growth. SP600125, a JNK inhibitor, was used to examine whether it would decrease tumor growth and bone tumor phenotype in canine PCa cells in vitro and in vivo. Ace-1-VectorYFP-Luc and Ace-1-Dkk-1YFP-Luc cells were transplanted subcutaneously, while Ace-1-Dkk-1YFP-Luc was transplanted intratibially into nude mice. The effects of Dkk-1 and SP600125 on cell proliferation, in vivo tumor growth, and bone tumor phenotype were investigated. The mRNA expression levels of Wnt/JNK-related genes were measured using RT-qPCR. Dkk-1 significantly increased the mRNA expression of Wnt/JNK-signaling-related genes. SP600125 significantly upregulated the mRNA expression of osteoblast differentiation genes and downregulated osteoclastic-bone-lysis-related genes in vitro. SP600125 significantly decreased tumor volume and induced spindle-shaped tumor cells in vivo. Mice bearing intratibial tumors had increased radiographic density of the intramedullary new bone, large foci of osteolysis, and increased cortical lysis with abundant periosteal new bone formation. Finally, SP600125 has the potential to serve as an alternative adjuvant therapy in some early-stage PCa patients, especially those with high Dkk-1 expression.

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