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.

scholarly journals The Role of M3 Muscarinic Receptor Ligand-Induced Kinase Signaling in Colon Cancer Progression

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 308 ◽  
Author(s):  
Mazen Tolaymat ◽  
Shannon Larabee ◽  
Shien Hu ◽  
Guofeng Xie ◽  
Jean-Pierre Raufman
Keyword(s):  
Colon Cancer ◽  
Protein Kinase ◽  
Muscarinic Receptor ◽  
Cancer Progression ◽  
The United States ◽  
Mitogen Activated Protein Kinase ◽  
Migration And Invasion ◽  
Colon Cancer Progression ◽  
M3 Muscarinic Receptor ◽  
The Impact

Despite a reduction in incidence over the past decade, colon cancer remains the second most common cause of cancer death in the United States; recent demographics suggest this disease is now afflicting younger persons. M3 muscarinic receptor (M3R) mRNA and protein are over-expressed in colon cancer, and M3R can be activated by both traditional (e.g., acetylcholine) and non-traditional (e.g., bile acids) muscarinic ligands. In this review, we weigh the data supporting a prominent role for key protein kinases downstream of M3R activation in promoting colon cancer progression and dissemination. Specifically, we explore the roles that downstream activation of the mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK), protein kinase C, p38 MAPK, and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathways play in mediating colon cancer cell proliferation, survival, migration and invasion. We assess the impact of M3R-stimulated induction of selected matrix metalloproteinases germane to these hallmarks of colon cancer progression. In this context, we also critically review the reproducibility of findings derived from a variety of in vivo and in vitro colon cancer models, and their fidelity to human disease. Finally, we summarize the therapeutic potential of targeting various steps from ligand-M3R interaction to the activation of key downstream molecules.

NEAT1 promotes colon cancer progression through sponging miR‐495‐3p and activating CDK6 in vitro and in vivo

2019 ◽  
Vol 234 (11) ◽  
pp. 19582-19591 ◽  
Author(s):  
Zhiyun He ◽  
Jie Dang ◽  
Ailin Song ◽  
Xiang Cui ◽  
Zhijun Ma ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Colon Cancer Progression

scholarly journals Secernin-1 Contributes to Colon Cancer Progression through Enhancing Matrix Metalloproteinase-2/9 Exocytosis

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Shengtao Lin ◽  
Tao Jiang ◽  
Yang Yu ◽  
Huamei Tang ◽  
Su Lu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Matrix Metalloproteinase ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Bioinformatics Analysis ◽  
Tumor Development ◽  
Matrix Metalloproteinase 2 ◽  
Cancer Cell Proliferation ◽  
Colon Cancer Progression

Emerging evidence shows that exocytosis plays a key role in tumor development and metastasis. Secernin-1 (SCRN1) is a novel regulator of exocytosis. Our previous work identified SCRN1 as a tumor-associated gene by bioinformatics analysis of transcriptomes. In this study, we demonstrated the aberrant overexpression of SCRN1 at mRNA and protein level in colon cancer. We also revealed that overexpression of SCRN1 was significantly associated with the tumor development and poor prognosis. Experimentsin vitrovalidated that SCRN1 may promote cancer cell proliferation and secretion of matrix metalloproteinase-2/9 (MMP-2/9) proteins to accelerate tumor progression.

scholarly journals SGLT2 inhibition slows tumor growth in mice by reversing hyperinsulinemia

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Ali R. Nasiri ◽  
Marcos R. Rodrigues ◽  
Zongyu Li ◽  
Brooks P. Leitner ◽  
Rachel J. Perry
Keyword(s):  
Colon Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Colon Adenocarcinoma ◽  
Sglt2 Inhibitors ◽  
Multiple Tumor ◽  
Increased Risk ◽  
Colon Cancer Progression

Abstract Background Obesity confers an increased risk and accelerates the progression of multiple tumor types in rodents and humans, including both breast and colon cancer. Because sustained weight loss is rarely achieved, therapeutic approaches to slow or prevent obesity-associated cancer development have been limited, and mechanistic insights as to the obesity-cancer connection have been lacking. Methods E0771 breast tumors and MC38 colon tumors were treated in vivo in mice and in vitro with two mechanistically different insulin-lowering agents, a controlled-release mitochondrial protonophore (CRMP) and sodium-glucose cotransporter-2 (SGLT2) inhibitors, and tumor growth and glucose metabolism were assessed. Groups were compared by ANOVA with Bonferroni’s multiple comparisons test. Results Dapagliflozin slows tumor growth in two mouse models (E0771 breast cancer and MC38 colon adenocarcinoma) of obesity-associated cancers in vivo, and a mechanistically different insulin-lowering agent, CRMP, also slowed breast tumor growth through its effect to reverse hyperinsulinemia. In both models and with both agents, tumor glucose uptake and oxidation were not constitutively high, but were hormone-responsive. Restoration of hyperinsulinemia by subcutaneous insulin infusion abrogated the effects of both dapagliflozin and CRMP to slow tumor growth. Conclusions Taken together, these data demonstrate that hyperinsulinemia per se promotes both breast and colon cancer progression in obese mice, and highlight SGLT2 inhibitors as a clinically available means of slowing obesity-associated tumor growth due to their glucose- and insulin-lowering effects.

scholarly journals Therapeutic targeting of SLC6A8 creatine transporter inhibits KRAS mutant and wildtype colon cancer and modulates human creatine levels

2021 ◽  
Author(s):  
Isabel Kurth ◽  
Norihiro Yamaguchi ◽  
Celia Andreu-Agullo ◽  
Helen S. Tian ◽  
Subhasree Sridhar ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Phase 1 ◽  
Creatine Transporter ◽  
Tumor Cell Apoptosis ◽  
Creatine Kinase B ◽  
Colon Cancer Progression ◽  
Creatine Metabolism

ABSTRACTColorectal cancer (CRC) is a leading cause of cancer mortality. Creatine metabolism was previously shown to critically regulate colon cancer progression. We report that RGX-202, an oral small-molecule SLC6A8 creatine transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels and induces tumor cell apoptosis in CRC. RGX-202 suppressed tumor growth across KRAS wild-type and KRAS mutant xenograft, syngeneic and patient-derived xenograft colorectal cancers. Anti-tumor efficacy correlated with tumoral expression of creatine kinase B. Combining RGX-202 with 5- fluorouracil or the DHODH inhibitor leflunomide caused regressions of multiple colorectal xenograft and PDX tumors of distinct mutational backgrounds. RGX-202 also perturbed creatine metabolism in metastatic CRC patients enrolled in a Phase-1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of pre-clinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, revealing a critical target for CRC.

scholarly journals MicroRNA miR-29a inhibits colon cancer progression by downregulating B7-H3 expression: potential molecular targets for colon cancer therapy

2020 ◽  
Author(s):  
Jin Wang ◽  
Xiaojuan Chen ◽  
Chen Xie ◽  
Mingbing Sun ◽  
Chenrui Hu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Colon Carcinoma ◽  
Cancer Progression ◽  
Molecular Targets ◽  
Expression Levels ◽  
Invasion And Migration ◽  
Normal Tissues ◽  
Colon Cancer Progression ◽  
And Migration

Abstract BackgroudMiR-29a belongs to one of the subtypes of miRNAs known as non-coding single-stranded RNAs, and is preferentially expressed in normal tissues. B7-H3, a member of the B7/CD28 immunoglobulin superfamily, was shown to be overexpressed in several solid malignant tumors, including colon cancer. In addition, it is associated with tumor progression and poor prognosis.MethodsWe used immunohistochemical and western blotting to assess B7-H3 protein expression levels in colon cancer and adjacent normal tissues, and then compared their relationships with clinicopathological factors. Quantitative real time reverse transcription PCR was used to assess B7-H3 and miRNA-29a mRNA expression levels, and then their relationship and clinical significance were evaluated. In addition, colon cancer Caco-2 cells, which constitutively overexpress B7-H3, were transfected with lentivirus particles for miR-29a upregulation. Invasion and migration assays were carried out in vitro along with the establishment of a subcutaneous xenograft model in vivo to determine the role of miRNA-29a in colon cancer progression.ResultsThe B7-H3 protein showed elevated expression in colon carcinoma, and was relevant to TNM staging, lymph node metastasis and reduced survival. Meanwhile, miR-29a was preferentially expressed in normal colon tissues while B7-H3 transcript levels had no marked differences between tumor and normal tissue specimens. In vitro, miR-29a upregulation resulted in reduced B7-H3 expression. Furthermore, miR-29a upregulation reduced the invasive and migratory abilities of colon carcinoma cells. In animal models, upregulation of miR-29a slowed down the growth of subcutaneous xenotransplanted tumors, and resulted in prolonged survival time.ConclusionMiR-29a downregulates B7-H3 expression and accordingly inhibits colon cancer progression, invasion and migration, indicating miR-29a and B7-H3 might represent novel molecular targets for advanced immunotherapy in colon cancer.

scholarly journals Interplay between chromatin-modifying enzymes controls colon cancer progression through Wnt signaling

2013 ◽  
Vol 23 (8) ◽  
pp. 2120-2131 ◽  
Author(s):  
Martine Chevillard-Briet ◽  
Muriel Quaranta ◽  
Aude Grézy ◽  
Lise Mattera ◽  
Céline Courilleau ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Wnt Signaling ◽  
Cancer Progression ◽  
Colon Cancer Progression

scholarly journals Erk dimers inhibition is a therapeutic target in thyroid cancer

2016 ◽  
Vol 62 (5) ◽  
pp. 52-53
Author(s):  
Adrián Acuña-Ruiz ◽  
Miguel Zaballos-Sánchez ◽  
Garcilaso Riesco-Eizaguirre ◽  
Pilar Santisteban ◽  
P. Crespo
Keyword(s):  
Thyroid Cancer ◽  
Signaling Pathway ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Migration And Invasion ◽  
In Vivo Model ◽  
Erk Pathway ◽  
Melanoma Tumor ◽  
Orthotopic Mouse Model

Thyroid carcinoma is the most common endocrine malignancy, and its incidence is rapidly rising in the world. Its initiation and progression involves multiple genetic and epigenetic alterations whereby BRAF and RAS mutations lead to the activation of the ERK signaling pathway. Recently, significant advances have been accomplished by developing pharmacological agents directed against the kinases of the RAS-ERK pathway. However, most of the molecules tested have undesired side effects and promote drug resistance. Consequently, it is imperative to find alternative RAS-ERK pathway inhibitors. It has been shown that by inhibiting ERKs dimerization it is possible to suppress tumor progression. DEL22379, a small molecule inhibitor for ERK dimerization, has been identified to impede the growth of melanoma tumor cells driven by RAS-ERK pathway oncogenes, without affecting ERK phosphorylation (Cancer Cell 28:17082 2015). The aim of this work is to study the role played by ERK dimerization and its inhibition using DEL22379 in thyroid cancer progression. We have used an in vitro model of thyroid tumor cells harboring oncogenic drivers (RAS or BRAF) to complete viability, migration and invasion assays as well as an orthotopic mouse model with anaplastic cells as an in vivo model. We observed that in BRAF mutated cells, ERK dimer formation is sustained for longer compared to the RAS mutated or control cells, resulting in the altered activation of the effected signaling pathway. RAS mutated cells are resistant to DEL22379 in vitro, while BRAF mutated cells are not able to form ERK dimers upon inhibitor addition. Consequently, these cells lose their invasive and migratory potential as well as displaying low viability. Preliminary results suggest DEL22379 treatment inhibits tumor growth in orthotopic mice. These results describe a new molecule that could be effectively used as a therapy in thyroid cancers harboring BRAF or RAS mutated genes. We have observed it is able to partially revert the tumorigenic phenotype, which may result in an improved prognosis in thyroid cancer patients.

scholarly journals Lnc HAGLR Promotes Colon Cancer Progression Through Sponging miR‐185‐5p and Activating CDK4 and CDK6 in vitro and in vivo

2020 ◽  
Vol Volume 13 ◽  
pp. 5913-5925 ◽  
Author(s):  
Weixuan Sun ◽  
Wenting Nie ◽  
Zhaoyi Wang ◽  
Haolong Zhang ◽  
Yezhou Li ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Colon Cancer Progression
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