scholarly journals Interleukin-11 is a Marker for Both Cancer- and Inflammation-Associated Fibroblasts that Contribute to Colorectal Cancer Progression

2020 ◽  
Author(s):  
Takashi Nishina ◽  
Yutaka Deguchi ◽  
Wakami Takeda ◽  
Masato Ohtsuka ◽  
Daisuke Ohshima ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Human Cancer ◽  
Tumor Development ◽  
Disease Free Survival ◽  
Reporter Mice ◽  
Stat3 Phosphorylation ◽  
Colorectal Cancer Progression ◽  
Cancer And Inflammation

SUMMARYInterleukin (IL)-11 is a member of the IL-6 family of cytokines and involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generated Il11 reporter mice. IL-11+ cells appeared in the colon of three murine tumor models, and a murine acute colitis model. Il11ra1 or Il11 deletion attenuated the development of colitis-associated colorectal cancer. IL-11+ cells expressed fibroblast markers, and genes associated with cell proliferation and tissue repair. IL-11 induced STAT3 phosphorylation in colonic fibroblasts, suggesting the activation of IL-11+ fibroblasts. Analysis using the human cancer database revealed that genes enriched in IL-11+ fibroblasts were elevated in human colorectal cancer, and correlated with reduced disease-free survival. Together, our results suggested that tumor cells induced IL-11+ fibroblasts, and that a feed-forward loop between IL-11 and IL-11+ fibroblasts might contribute to tumor development.

scholarly journals Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Takashi Nishina ◽  
Yutaka Deguchi ◽  
Daisuke Ohshima ◽  
Wakami Takeda ◽  
Masato Ohtsuka ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Human Cancer ◽  
Tumor Development ◽  
Gene Signature ◽  
Free Survival ◽  
Expression Of Genes ◽  
Reporter Mice ◽  
Interleukin 11

AbstractInterleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generate Il11 reporter mice. IL-11+ cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11+ cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11+ fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11+ fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.

scholarly journals Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway

Oncogenesis ◽  
2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Xin Huang ◽  
Yichao Hou ◽  
Xiaoling Weng ◽  
Wenjing Pang ◽  
Lidan Hou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Copper Complex ◽  
Aerobic Glycolysis ◽  
Active Role ◽  
Downstream Effector ◽  
Glycolysis Pathway ◽  
Colorectal Cancer Progression

AbstractExploring novel anticancer drugs to optimize the efficacy may provide a benefit for the treatment of colorectal cancer (CRC). Disulfiram (DSF), as an antialcoholism drug, is metabolized into diethyldithiocarbamate-copper complex (CuET) in vivo, which has been reported to exert the anticancer effects on various tumors in preclinical studies. However, little is known about whether CuET plays an anti-cancer role in CRC. In this study, we found that CuET had a marked effect on suppressing CRC progression both in vitro and in vivo by reducing glucose metabolism. Mechanistically, using RNA-seq analysis, we identified ALDH1A3 as a target gene of CuET, which promoted cell viability and the capacity of clonal formation and inhibited apoptosis in CRC cells. MicroRNA (miR)-16-5p and 15b-5p were shown to synergistically regulate ALDH1A3, which was negatively correlated with both of them and inversely correlated with the survival of CRC patients. Notably, using co-immunoprecipitation followed with mass spectrometry assays, we identified PKM2 as a direct downstream effector of ALDH1A3 that stabilized PKM2 by reducing ubiquitination. Taken together, we disclose that CuET treatment plays an active role in inhibiting CRC progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis–mediated aerobic glycolysis pathway.

scholarly journals LAT1 and ASCT2 Related microRNAs as Potential New Therapeutic Agents against Colorectal Cancer Progression

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 195
Author(s):  
Francisca Dias ◽  
Cristina Almeida ◽  
Ana Luísa Teixeira ◽  
Mariana Morais ◽  
Rui Medeiros
Keyword(s):  
Colorectal Cancer ◽  
Amino Acid ◽  
Cancer Progression ◽  
Cell Metabolism ◽  
Tumor Development ◽  
Amino Acid Transporters ◽  
Epigenetic Alterations ◽  
Therapeutic Approaches ◽  
Colorectal Cancer Progression ◽  
Made In

The development and progression of colorectal cancer (CRC) have been associated with genetic and epigenetic alterations and more recently with changes in cell metabolism. Amino acid transporters are key players in tumor development, and it is described that tumor cells upregulate some AA transporters in order to support the increased amino acid (AA) intake to sustain the tumor additional needs for tumor growth and proliferation through the activation of several signaling pathways. LAT1 and ASCT2 are two AA transporters involved in the regulation of the mTOR pathway that has been reported as upregulated in CRC. Some attempts have been made in order to develop therapeutic approaches to target these AA transporters, however none have reached the clinical setting so far. MiRNA-based therapies have been gaining increasing attention from pharmaceutical companies and now several miRNA-based drugs are currently in clinical trials with promising results. In this review we combine a bioinformatic approach with a literature review in order to identify a miRNA profile with the potential to target both LAT1 and ASCT2 with potential to be used as a therapeutic approach against CRC.

scholarly journals Long non-coding RNA AGER-1 inhibits colorectal cancer progression through sponging miR-182

2020 ◽  
Vol 35 (1) ◽  
pp. 10-18 ◽  
Author(s):  
Mingzhu Lin ◽  
Yinyan Li ◽  
Jianfeng Xian ◽  
Jinbin Chen ◽  
Yingyi Feng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Vital Role ◽  
Normal Tissues ◽  
Non Coding Rna ◽  
Colorectal Cancer Progression ◽  
And Migration ◽  
Long Non Coding Rna

Objective: Abundant evidence has illustrated that long non-coding RNA (lncRNA) plays a vital role in the regulation of tumor development and progression. Ectopic expression of a novel lncRNA, termed lnc-AGER-1, has been discovered in cancers, and this lncRNA was reported to exert an anti-tumor effect. However, its biological mechanism remains unelucidated in colorectal cancer. Methods: A total of 159 paired colorectal cancer specimens and adjacent tissues was applied to detect the expression of lnc-AGER-1 by the quantitative Real-time PCR (qRT-PCR), and a series of functional assays was executed to uncover the role of this lncRNA on colorectal cancer. Results: We found that the expression of lnc-AGER-1 in the tumor tissues was significantly down-regulated, while compared with adjacent normal tissues (0.0115 ± 0.0718 vs. 0.0347 ± 0.157; P < 0.0001). Also, lnc-AGER-1 was observably associated with clinical T status (r = −0.184, P = 0.024). Patients with advanced T status exerted a significantly lower level of lnc-AGER-1 than those with early T status (20.0% vs. 40.7%, P = 0.021). Over-expression of lnc-AGER-1 inhibited cell proliferation and migration efficiency, and induced cell cycle arrest at the G0/G1 phase, and promoted cell apoptosis. Further research proved that lnc-AGER-1 altered the expression of its neighbor gene, AGER, through acting as a competing endogenous RNA for miR-182 in colorectal cancer. Conclusion: lnc-AGER-1 has a suppressive role in colorectal cancer development via modulating AGER, which may serve as a target for colorectal cancer diagnosis and treatment.

scholarly journals LncRNA DQ786243 contributes to proliferation and metastasis of colorectal cancer both in vitro and in vivo

2016 ◽  
Vol 36 (3) ◽  
Author(s):  
Longci Sun ◽  
Hanbing Xue ◽  
Chunhui Jiang ◽  
Hong Zhou ◽  
Lei Gu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Migration And Invasion ◽  
Cycle Progression ◽  
Proliferation And Metastasis ◽  
Non Coding Rnas ◽  
Colorectal Cancer Progression

This article aims to find the key long non-coding RNAs (LncRNAs) associated with colorectal cancer (CRC) and to study its biological functions in colorectal cancer progression. Our study has shown that upregulated LncRNA DQ786243 can regulate cell proliferation, cell cycle progression, cell apoptosis, migration, and invasion in CRC cells. Xenograft experiments confirmed that the growth of xenograft tumors formed by CRC cells was suppressed after silencing LncRNA DQ786243 expression. In conclusion, our study suggests that LncRNA DQ786243 is an oncogene that promotes tumor progression and leads us to propose that LncRNAs may serve as key regulatory hubs in CRC progression.

scholarly journals The Long Noncoding RNA HOTAIR Promotes Colorectal Cancer Progression by Sponging miR-197

2018 ◽  
Vol 26 (3) ◽  
pp. 473-481 ◽  
Author(s):  
Xinyang Lu ◽  
Zhiqiang Liu ◽  
Xiaofei Ning ◽  
Lunhua Huang ◽  
Biao Jiang
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Migration And Invasion ◽  
Downstream Target ◽  
Potential Applications ◽  
Colorectal Cancer Progression

The long noncoding RNA HOX transcript antisense RNA (HOTAIR) has been found to be overexpressed in many human malignancies and involved in tumor progression and metastasis. Although the downstream target through which HOTAIR modulates tumor metastasis is not well known, evidence suggests that microRNA-197 (miR-197) might be involved in this event. In the present study, the significance of HOTAIR and miR-197 in the progression of colorectal cancer was detected in vitro and in vivo. We found that HOTAIR expression was significantly increased in colorectal cancer cells and tissues. In contrast, the expression of miR-197 was obviously decreased. We further demonstrated that HOTAIR knockdown promoted apoptosis and inhibited cell proliferation, migration, and invasion in vitro and in vivo. Moreover, HOTAIR modulated the progression of colorectal cancer by competitively binding miR-197. Taken together, our study has identified a novel pathway through which HOTAIR exerts its oncogenic role and provided a molecular basis for potential applications of HOTAIR in the prognosis and treatment of colorectal cancer.

scholarly journals lncRNA GAU1 Induces GALNT8 Overexpression and Potentiates Colorectal Cancer Progression

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Xuemei Tang ◽  
Haoyu Ruan ◽  
Liu Dong ◽  
Sihan Li ◽  
Zhiyuan Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Human Cancer ◽  
Enrichment Analysis ◽  
Cancer Cell Proliferation ◽  
Cancer Transcriptome ◽  
Tcga Dataset ◽  
Colorectal Cancer Progression ◽  
In Vitro Treatment

lncRNA is a key epigenetic regulator in biological processes. In the human cancer transcriptome library MiTranscriptome, we identified GAU1 as the top upregulated lncRNA in colorectal cancer (CRC) by sample set enrichment analysis (overexpression ranking percentile = 99.75 %, P < 10 − 50 ), which is coexpressed with the potential oncogene GALNT8 (Spearman rho = 0.67 , P = 2.44 × 10 − 23 , TCGA dataset n = 184 ). Experimental data revealed that GAU1 regulates the expression of GALNT8. The overexpression of either GAU1 or GALNT8 significantly promotes the cell cycle and proliferation of CRC cell lines and correlates with poor prognosis in patients with CRC ( P = 3.04 × 10 − 2 ), while silencing of GAU1 or GALNT8 suppressed the cancer cell proliferation and induced the CRC cell line resistance to oxaliplatin in vitro treatment. Our results suggested that the previously less studied GAU1 and GALNT8 may play as CRC prognosis markers and potential targets for chemotherapy treatment.

scholarly journals A specific Upregulated lncRNA in Colorectal Cancer Promotes Cancer Progression by Modulating miR-185-5p/CCND2 Axis

2021 ◽  
Author(s):  
Junshu Li ◽  
Yanhong Ji ◽  
Na Chen ◽  
Huiling Wang ◽  
Chao Fang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Network Analysis ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Gene Mutations ◽  
Disease Free Survival ◽  
Luciferase Reporter ◽  
Colorectal Cancer Patients

Abstract BackgroundAdenomatous polyposis coli (APC) gene mutations were found in most colorectal cancer patients and functioned as an important inducer of tumorigenesis. Long non-coding RNA (lncRNA) plays a crucial role in the pathogenesis of various diseases, including colorectal cancer (CRC). Here we investigated the role of SURC which is specific upregulated in CRC progression. MethodsBased on the previous microarray results, weighted correlation network analysis (WGCNA) and lncRNA-mRNA co-expression network analysis were used to identify a lncRNA (SURC) and found it was specific up-regulated in CRC patients by qPCR and FISH staining. Chromatin immunoprecipitation (ChIP) assay was used to demonstrate the regulatory effect and mechanism of APC mutation on SURC expression. The effects of SURC on proliferation and cell cycle were determined by in vitro and in vivo experiments. Chromatin Isolation by RNA Purification (CHIRP) and luciferase reporter assay were carried out to illustrate the interaction between SURC, miR-185-5p and CCND2.ResultsWe found that SURC was specific up-regulated in CRC, but not in other solid tumor, when compared with normal adjacent tissues. High expression of SURC correlates with poorer disease-free survival and overall survival of CRC patients. Mutated APC protein resulted in stabilization of β-catenin in CRC, which promotes the transcription of SURC via binding to its promoter. Knockdown of SURC impaired CRC cell proliferation, colony formation and CRC tumor growth. Mechanistically, after transcription, SURC was transferred to cytoplasm and inhibits miR-185-5p expression via binding to miR-185-5p and inhibiting the synthesis of miR-185-5p from pri-miR-185-5p, which results in CCND2 expression.ConclusionCollectively, these results indicated that SURC promoted CRC tumor growth via interacting with miR-185-5p and regulating the activity of miR-185-5p/CCND2 axis which would be a novel diagnosis and prognosis prediction target for CRC.

scholarly journals Targeting OLFML3 in Colorectal Cancer Suppresses Tumor Growth and Angiogenesis, and Increases the Efficacy of Anti-PD1 Based Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4625
Author(s):  
Jimmy Stalin ◽  
Beat A. Imhof ◽  
Oriana Coquoz ◽  
Rachel Jeitziner ◽  
Philippe Hammel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Molecular Subtype ◽  
Human Cancer ◽  
Tumor Development ◽  
Tumor Grade ◽  
Tissue Expression ◽  
In Vivo Studies

The role of the proangiogenic factor olfactomedin-like 3 (OLFML3) in cancer is unclear. To characterize OLFML3 expression in human cancer and its role during tumor development, we undertook tissue expression studies, gene expression analyses of patient tumor samples, in vivo studies in mouse cancer models, and in vitro coculture experiments. OLFML3 was expressed at high levels, mainly in blood vessels, in multiple human cancers. We focused on colorectal cancer (CRC), as elevated expression of OLFML3 mRNA correlated with shorter relapse-free survival, higher tumor grade, and angiogenic microsatellite stable consensus molecular subtype 4 (CMS4). Treatment of multiple in vivo tumor models with OLFML3-blocking antibodies and deletion of the Olfml3 gene from mice decreased lymphangiogenesis, pericyte coverage, and tumor growth. Antibody-mediated blockade of OLFML3 and deletion of host Olfml3 decreased the recruitment of tumor-promoting tumor-associated macrophages and increased infiltration of the tumor microenvironment by NKT cells. Importantly, targeting OLFML3 increased the antitumor efficacy of anti-PD-1 checkpoint inhibitor therapy. Taken together, the results demonstrate that OLFML3 is a promising candidate therapeutic target for CRC.

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