scholarly journals Chemoresistance-Associated Silencing of miR-4454 Promotes Colorectal Cancer Aggression through the GNL3L and NF-κB Pathway

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1231 ◽  
Author(s):  
Thetchinamoorthy Kannathasan ◽  
Wei-Wen Kuo ◽  
Ming-Cheng Chen ◽  
Vijaya Padma Viswanadha ◽  
Chia-Yao Shen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Tumor Volume ◽  
Predictive Biomarkers ◽  
Mice Model ◽  
Human Colorectal Cancer ◽  
Guanine Nucleotide Binding Protein ◽  
Cellular Processes ◽  
Nude Mice Model ◽  
Guanine Nucleotide Binding

Guanine nucleotide-binding protein-like-3-like (GNL3L) is a crucial regulator of NF-κB signaling that is aberrantly activated during diverse chemoresistance-associated cellular processes. However, the molecular mechanisms of GNL3L tumor initiation and resistant state are largely unknown. Moreover, the identification of predictive biomarkers is necessary to effectively generate therapeutic strategies for metastatic human colorectal cancer (CRC). This study aims to identify how cells acquire resistance to anticancer drugs and whether the downregulation of miR-4454 is associated with the progression of CRC. Here, we have shown that the overexpression of miR-4454 in resistant tumors is a crucial precursor for the posttranscriptional repression of GNL3L in human chemoresistant CRC progression, and we used doxycycline induced miR-4454 overexpression that significantly reduced tumor volume in a subcutaneous injection nude mice model. Together, these observations highlight that the downregulation of miR-4454 in resistant clones is prominently responsible for maintaining their resistance against anticancer drug therapy. Our study indicates that the development of miR-4454 as a microRNA-based therapeutic approach to silence GNL3L may remarkably reduce oncogenic cell survival that depends on GNL3L/NF-κB signaling, making miR-4454 a candidate for treating metastatic human CRC.

scholarly journals Clinical Importance of Wnt5a in the Pathogenesis of Colorectal Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Mehran Pashirzad ◽  
Thozhukat Sathyapalan ◽  
Amirhossein Sahebkar
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Clinical Importance ◽  
Signaling Cascades ◽  
Cancer Type ◽  
Invasion And Metastasis ◽  
Cellular Processes ◽  
Wnt5a Expression ◽  
Noncanonical Signaling

Wnt5a is one of the potent signaling molecules that initiates responses involved in cancer through activation of both canonical and noncanonical signaling cascades. Wnt5a both directly and indirectly triggers cancer-associated signaling pathways based on the cancer type. In colorectal cancer (CRC), altering Wnt5a expression can influence several cellular processes of tumor cells, including proliferation, differentiation, migration, invasion, and metastasis. This review summarizes the molecular mechanisms and clinical importance of Wnt5a in the pathogenesis of CRC for better understanding the pathogenesis and its potential role as a prognostic marker and as an appropriate therapeutic target in the treatment of this disease in the future.

scholarly journals Intestinal dysbacteriosis activates tumor-associated macrophages to promote epithelial-mesenchymal transition of colorectal cancer

2018 ◽  
Vol 24 (8) ◽  
pp. 480-489 ◽  
Author(s):  
Guangsheng Wan ◽  
Manli Xie ◽  
Hongjie Yu ◽  
Hongyu Chen
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Cell Counting ◽  
Mice Model ◽  
Mesenchymal Transition ◽  
Tnf Α ◽  
Xenograft Mice Model ◽  
Intestinal Dysbacteriosis

In this study we investigated the association between intestinal dysbacteriosis with colorectal cancer progress and the underlying molecular mechanisms. Tumor progression was evaluated using xenograft mice model. The epithelial-mesenchymal transition (EMT) markers were quantified by both real-time PCR and immunoblotting. The serum content of IL-6 and TNF-α were measured with ELISA kits. Cell proliferation was determined by the Cell Counting Kit-8. Intestinal dysbacteriosis was successfully simulated by the administration of a large dose of antibiotics and was demonstrated to promote xenograft tumor growth and induce EMT. Accordingly, the serum concentrations of cytokines IL-6 and TNF-α were significantly increased. Furthermore, the production and secretion of IL-6 and TNF-α were remarkably elevated in macrophages isolated from intestinal dysbiotic mice in comparison with the normal counterparts, and conditioned medium from these was shown to significantly stimulate EMT process in HT29 cells in vitro. Macrophage depletion completely abrogated the pro-tumor effect of intestinal dysbacteriosis. Our results suggest that intestinal dysbacteriosis stimulates macrophage activation and subsequently induces EMT process via secreted pro-inflammatory cytokines IL-6 and TNF-α.

Antitumor activities of bevacizumab for KRAS, BRAF, and PIK3CA mutated human colorectal cancer xenograft models.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 362-362 ◽  
Author(s):  
Suguru Harada ◽  
Mieko Yanagisawa ◽  
Toshiki Iwai ◽  
Satoshi Aida ◽  
Mitsue Kurasawa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antitumor Effect ◽  
Tumor Volume ◽  
Colorectal Cancers ◽  
Human Colorectal Cancer ◽  
Colorectal Cancer Cell Lines ◽  
Xenograft Models

362 Background: In colorectal cancer, it has been reported that mutations (mts) in KRAS, BRAF, or PIK3CA can have a negative impact on molecular target therapies. Especially, a KRAS mt represents a predictive biomarker for resistance to anti-EGFR antibodies. Bevacizumab (BV), an anti-VEGF-A antibody, has been demonstrated to have clinical benefits in colorectal cancers; however, the impact of mts in especially BRAF or PIK3CA on the efficacy of BV remains unknown. In this study, we examined the antitumor activity of BV in human colorectal cancer xenograft models harboring these mts. Methods: BALB-nu/nu mice were subcutaneously inoculated with 15 colorectal cancer cell lines. BV was intraperitoneally administered every week for 3 weeks at a dose of 5 mg/kg. Antitumor activity was evaluated by determining tumor volume and tumor growth inhibition (TGI) on day 22. The colorectal cancer cell lines used were screened for KRAS, BRAF, and PIK3CA mts by direct sequencing of hot spots. Statistical analysis was performed using Wilcoxon test for tumor volume and TGI and Fisher's exact test for the correlation of genotype and antitumor effect. Results: Genotypes of KRAS, BRAF, and PIK3CA were all wild-type (wt) in COLO320DM, KM-12 and SW48 and in other cell lines were, respectively, as follows: COLO205, HT-29, WiDr and LS411N: wt, mt, and wt; SW620 and LoVo: mt, wt, and wt; HCT-8, HCT116, DLD-1, T84 and LS174T: mt, wt, and mt; RKO: wt, mt and mt. BV as a non-responder (NR) showed no significant antitumor activity in 3 cell lines (WiDr, LoVo and DLD-1), whereas as a responder (R) significant activity was observed in the other 12 cell lines. There was no significant difference in the antitumor effect of BV between cell lines depending on KRAS, BRAF or PIK3CAmutational status in terms of TGI and R/NR ratio (Table). Conclusions: BV shows antitumor effect regardless of mutational status of KRAS, BRAF, or PIK3CA in colorectal cancers. [Table: see text]

scholarly journals Knockdown of lncRNA CCAT1 Inhibits the Progression of Colorectal Cancer via hsa-miR-4679 Mediating the Downregulation of GNG10

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Ning Wang ◽  
Jun Li ◽  
Ju He ◽  
Yong-Guang Jing ◽  
Wei-dong Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Migration And Invasion ◽  
Proliferating Cells ◽  
Guanine Nucleotide Binding Protein ◽  
Colorectal Cell ◽  
Guanine Nucleotide Binding ◽  
Colorectal Cancer Progression

Great concerns have raised crucial roles of long noncoding RNAs (lncRNAs) on colorectal cancer progression due to the increasing number of studies in cancer development. Previous studies reveal that lncRNA CCAT1 plays an important role in the progression of a variety of cancers. However, the role of lncRNA CCAT1 in colorectal cancer is still unclear. In this study, we found that in both colorectal tissues and cell lines the level of lncRNA CCAT1 was increased. Downregulation of lncRNA CCAT1 inhibited the proliferation, migration, and invasion of colorectal cell lines and promoted apoptosis. We then found that hsa-miR-4679 could bind to lncRNA CCAT1 directly, and with further functional analyses, we confirmed that lncRNA CCAT1 sponged hsa-miR-4679 to promote the progression of colorectal cancer. Next, we found that hsa-miR-4679 was directly bound to 3 ′ UTR of GNG10 (guanine nucleotide-binding protein, gamma 10). GNG10 overexpression promoted the progression of colorectal cancer, and this phenotype could be reversed by miR-4679 mimics. At last, we knocked down CCAT1 in vivo and found that sh-CCAT1 reduced the tumor size and the number of proliferating cells. In summary, our findings revealed that lncRNA CCAT1 facilitated colorectal cancer progression via the hsa-miR-4679/GNG10 axis and provided new potential therapeutic targets for colorectal cancer.

scholarly journals Significance of Kynurenine 3-Monooxygenase Expression in Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Chun-Yu Liu ◽  
Tzu-Ting Huang ◽  
Ji-Lin Chen ◽  
Pei-Yi Chu ◽  
Chia-Han Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Survival Rates ◽  
Predictive Biomarkers ◽  
Kynurenine Pathway ◽  
Migration And Invasion ◽  
Stem Cell Markers ◽  
Cancer Stem Cell Markers ◽  
Cellular Processes ◽  
Sphere Formation

Colorectal cancer (CRC) is a leading cause of cancer-related deaths. Because of the lack of reliable prognostic and predictive biomarkers for CRC, most patients are often diagnosed at a late stage. The tryptophan–kynurenine pathway plays a crucial role in promoting cancer progression. Kynurenine is considered an oncometabolite in colon cancer, and its downstream metabolites are also associated with CRC. Kynurenine 3-monooxygenase (KMO), a pivotal enzyme that catalyzes kynurenine metabolism, is essential for several cellular processes. In the current study, we explored the role of KMO in CRC. Immunohistochemical results showed that KMO was upregulated in CRC tissues relative to paired healthy tissue and polyps. Moreover, CRC patients with higher KMO expression were associated with higher metastasis and poorer survival rates. Knockdown of KMO decreased the expression of cancer stem cell markers, as well as the sphere-forming, migration, and invasion abilities of CRC cells. Additionally, blockade of the enzymatic activity of KMO using an inhibitor suppressed sphere formation and cell motility in CRC cells. These findings suggest the clinical relevance of KMO in CRC tumorigenesis and aggressiveness.

Functional analysis of drought and salt tolerance mechanisms of mulberry RACK1 gene

2019 ◽  
Vol 39 (12) ◽  
pp. 2055-2069 ◽  
Author(s):  
Changying Liu ◽  
Panpan Zhu ◽  
Wei Fan ◽  
Yang Feng ◽  
Min Kou ◽  
...  
Keyword(s):  
Abiotic Stress ◽  
G Proteins ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Guanine Nucleotide Binding Protein ◽  
Expression Levels ◽  
Drought And Salt Tolerance ◽  
Drought And Salt Stresses ◽  
Guanine Nucleotide Binding ◽  
Eukaryotic Organisms

Abstract The receptor for activated C kinase 1 (RACK1) protein acts as a central hub for the integration of many physiological processes in eukaryotic organisms. Plant RACK1 is implicated in abiotic stress responses, but the underlying molecular mechanisms of stress adaptation remain largely unknown. Here, the overexpression of the mulberry (Morus alba L.) RACK1 gene in Arabidopsis decreased tolerance to drought and salt stresses and MaRACK1 overexpression changed expression levels of genes in response to stress and stimuli. We developed a simple and efficient transient transformation system in mulberry, and the mulberry seedlings transiently expressing MaRACK1 were hypersensitive to drought and salt stresses. The expression levels of guanine nucleotide-binding protein (G-protein) encoding genes in mulberry and Arabidopsis were not affected by MaRACK1 overexpression. The interactions between RACK1 and G-proteins were confirmed, and the RACK1 proteins from mulberry and Arabidopsis could not interact with their respective G-proteins, which indicated that RACK1 may regulate stress responses independently of G-proteins. Additionally, MaRACK1 may regulate drought and salt stress tolerances by interacting with a fructose 1, 6-bisphosphate aldolase. Our findings provide new insights into the mechanisms underlying RACK1 functions in abiotic stress responses and important information for their further characterization.

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